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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. 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

  4. 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.

  5. 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.

  6. 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.

  7. Upgrades to the LLNL flash x-ray induction linear accelerator (FXR)

    SciTech Connect

    Scarpetti, R. D., LLNL

    1997-06-30

    The FXR is an induction linear accelerator used for flash radiography at the Lawrence Livermore National Laboratory's Site 300 Test Facility. The FXR was originally completed in 1982 and has been in continuous use as a radiographic tool. At that time the FXR produced a 17MeV, 2.2 kA burst of electrons for a duration of 65 ns. An upgrade of the FXR was recently completed. The purpose of this upgrade was to improve the performance of the FXR by increasing the energy of the electron injector from 1.2 MeV to 2.5 MeV and the beam current from 2.2 kA to 3 kA, improving the magnetic transport system by redesigning the solenoidal transport focus coils, reducing the rf coupling of the electron beam to the accelerator cells, and by adding additional beam diagnostics. We will describe the injector upgrades and performance as well as our efforts to tune the accelerator by minimizing beam corkscrew motion and the impact of Beam Breakup Instability on beam centroid motion throughout the beam line as the current is increased to 3 kA.

  8. Optimization of a novel class of benzimidazole-based farnesoid X receptor (FXR) agonists to improve physicochemical and ADME properties.

    PubMed

    Richter, Hans G F; Benson, G M; Bleicher, K H; Blum, D; Chaput, E; Clemann, N; Feng, S; Gardes, C; Grether, U; Hartman, P; Kuhn, B; Martin, R E; Plancher, J-M; Rudolph, M G; Schuler, F; Taylor, S

    2011-02-15

    Structure-guided lead optimization of recently described benzimidazolyl acetamides addressed the key liabilities of the previous lead compound 1. These efforts culminated in the discovery of 4-{(S)-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetylamino}-3-fluoro-benzoic acid 7g, a highly potent and selective FXR agonist with excellent physicochemical and ADME properties and potent lipid lowering activity after oral administration to LDL receptor deficient mice.

  9. 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

  10. 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.

  11. SAR studies on FXR modulators led to the discovery of the first combined FXR antagonistic/TGR5 agonistic compound.

    PubMed

    Lamers, Christina; Merk, Daniel; Gabler, Matthias; Flesch, Daniel; Kaiser, Astrid; Schubert-Zsilavecz, Manfred

    2016-01-01

    Bile acids can serve as signaling molecules by activating the nuclear receptor FXR and the G-protein-coupled receptor TGR5 and both bile acid receptors are prominent experimental drug targets. Results/methodology: In this study we optimized the fatty acid mimetic compound pirinixic acid to a new scaffold with the aim to develop novel FXR modulatory compounds. After a multistep structure-activity optimization process, we discovered FXR agonistic compounds and the first dual FXR antagonistic and TGR5 agonistic compound 79a. With this novel dual activity profile on both bile acid receptors 79a might be a valuable pharmalogical tool to further study the bile acid signaling network.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. Discrete Variables Function Optimization Using Accelerated Biogeography-Based Optimization

    NASA Astrophysics Data System (ADS)

    Lohokare, M. R.; Pattnaik, S. S.; Devi, S.; Panigrahi, B. K.; Das, S.; Jadhav, D. G.

    Biogeography-Based Optimization (BBO) is a bio-inspired and population based optimization algorithm. This is mainly formulated to optimize functions of discrete variables. But the convergence of BBO to the optimum value is slow as it lacks in exploration ability. The proposed Accelerated Biogeography-Based Optimization (ABBO) technique is an improved version of BBO. In this paper, authors accelerated the original BBO to enhance the exploitation and exploration ability by modified mutation operator and clear duplicate operator. This significantly improves the convergence characteristics of the original algorithm. To validate the performance of ABBO, experiments have been conducted on unimodal and multimodal benchmark functions of discrete variables. The results shows excellent performance when compared with other modified BBOs and other optimization techniques like stud genetic algorithm (SGA) and ant colony optimization (ACO). The results are also analyzed by using two paired t- test.

  18. 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.

  19. Evolutionary optimization methods for accelerator design

    NASA Astrophysics Data System (ADS)

    Poklonskiy, Alexey A.

    Many problems from the fields of accelerator physics and beam theory can be formulated as optimization problems and, as such, solved using optimization methods. Despite growing efficiency of the optimization methods, the adoption of modern optimization techniques in these fields is rather limited. Evolutionary Algorithms (EAs) form a relatively new and actively developed optimization methods family. They possess many attractive features such as: ease of the implementation, modest requirements on the objective function, a good tolerance to noise, robustness, and the ability to perform a global search efficiently. In this work we study the application of EAs to problems from accelerator physics and beam theory. We review the most commonly used methods of unconstrained optimization and describe the GATool, evolutionary algorithm and the software package, used in this work, in detail. Then we use a set of test problems to assess its performance in terms of computational resources, quality of the obtained result, and the tradeoff between them. We justify the choice of GATool as a heuristic method to generate cutoff values for the COSY-GO rigorous global optimization package for the COSY Infinity scientific computing package. We design the model of their mutual interaction and demonstrate that the quality of the result obtained by GATool increases as the information about the search domain is refined, which supports the usefulness of this model. We Giscuss GATool's performance on the problems suffering from static and dynamic noise and study useful strategies of GATool parameter tuning for these and other difficult problems. We review the challenges of constrained optimization with EAs and methods commonly used to overcome them. We describe REPA, a new constrained optimization method based on repairing, in exquisite detail, including the properties of its two repairing techniques: REFIND and REPROPT. We assess REPROPT's performance on the standard constrained

  20. An algorithm for online optimization of accelerators

    SciTech Connect

    Huang, Xiaobiao; Corbett, Jeff; Safranek, James; Wu, Juhao

    2013-10-01

    We developed a general algorithm for online optimization of accelerator performance, i.e., online tuning, using the performance measure as the objective function. This method, named robust conjugate direction search (RCDS), combines the conjugate direction set approach of Powell's method with a robust line optimizer which considers the random noise in bracketing the minimum and uses parabolic fit of data points that uniformly sample the bracketed zone. Moreover, it is much more robust against noise than traditional algorithms and is therefore suitable for online application. Simulation and experimental studies have been carried out to demonstrate the strength of the new algorithm.

  1. 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.

  2. SUMOylation of the Farnesoid X Receptor (FXR) Regulates the Expression of FXR Target Genes*

    PubMed Central

    Balasubramaniyan, Natarajan; Luo, Yuhuan; Sun, An-Qiang; Suchy, Frederick J.

    2013-01-01

    The farnesoid X receptor (FXR) belongs to a family of ligand-activated transcription factors that regulate many aspects of metabolism including bile acid homeostasis. Here we show that FXR is covalently modified by the small ubiquitin-like modifier (Sumo1), an important regulator of cell signaling and transcription. Well conserved consensus sites at lysine 122 and 275 in the AF-1 and ligand binding domains, respectively, of FXR were subject to SUMOylation in vitro and in vivo. Chromatin immunoprecipitation (ChIP) analysis showed that Sumo1 was recruited to the bile salt export pump (BSEP), the small heterodimer partner (SHP), and the OSTα-OSTβ organic solute transporter loci in a ligand-dependent fashion. Sequential chromatin immunoprecipitation (ChIP-ReChIP) verified the concurrent binding of FXR and Sumo1 to the BSEP and SHP promoters. Overexpression of Sumo1 markedly decreased binding and/or recruitment of FXR to the BSEP and SHP promoters on ChIP-ReChIP. SUMOylation did not have an apparent effect on nuclear localization of FXR. Expression of Sumo1 markedly inhibited the ligand-dependent, transactivation of BSEP and SHP promoters by FXR/retinoid X receptor α (RXRα) in HepG2 cells. In contrast, mutations that abolished SUMOylation of FXR or siRNA knockdown of Sumo1 expression augmented the transactivation of BSEP and SHP promoters by FXR. Pathways for SUMOylation were significantly altered during obstructive cholestasis with differential Sumo1 recruitment to the promoters of FXR target genes. In conclusion, FXR is subject to SUMOylation that regulates its capacity to transactivate its target genes in normal liver and during obstructive cholestasis. PMID:23546875

  3. 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

  4. Estimating The Reliability of the Lawrence Livermore National Laboratory (LLNL) Flash X-ray (FXR) Machine

    SciTech Connect

    Ong, M M; Kihara, R; Zentler, J M; Kreitzer, B R; DeHope, W J

    2007-06-27

    At Lawrence Livermore National Laboratory (LLNL), our flash X-ray accelerator (FXR) is used on multi-million dollar hydrodynamic experiments. Because of the importance of the radiographs, FXR must be ultra-reliable. Flash linear accelerators that can generate a 3 kA beam at 18 MeV are very complex. They have thousands, if not millions, of critical components that could prevent the machine from performing correctly. For the last five years, we have quantified and are tracking component failures. From this data, we have determined that the reliability of the high-voltage gas-switches that initiate the pulses, which drive the accelerator cells, dominates the statistics. The failure mode is a single-switch pre-fire that reduces the energy of the beam and degrades the X-ray spot-size. The unfortunate result is a lower resolution radiograph. FXR is a production machine that allows only a modest number of pulses for testing. Therefore, reliability switch testing that requires thousands of shots is performed on our test stand. Study of representative switches has produced pre-fire statistical information and probability distribution curves. This information is applied to FXR to develop test procedures and determine individual switch reliability using a minimal number of accelerator pulses.

  5. "Real-Life" Pulse Flattening on the LLNL Flash X-ray (FXR) Machine

    SciTech Connect

    DeHope, W J; Jacob, J S; Kihara, R; Ong, M; Zentler, J M

    2007-06-25

    High-resolution radiography using high-current electron accelerators based on the linear induction accelerator principle requires the linac's final spot on the X-ray target to be millimeter-sized. The requisite final focusing solenoid is adjusted for a specific beam energy at its entrance, hence, temporal variation of entrance beam energy results in a less than optimal time-averaged spot size. The FXR (Flash X-Ray) induction linac facility at Lawrence Livermore National Laboratory will be briefly described with an emphasis on its pulsed power system. In principle, the pulsed Blumleins at the heart of the system output a square pulse when discharged at the peak of their charging waveform so that, with correct cell timing synchronization, the effective beam output into the final focusing solenoid should be optimally flat. We have found that real-life consideration of transmission line and pulse power details in both the injector and accelerator sections of the machine results in significant energy variations in the final beam. We have implemented methods of measurement and analysis that permits this situation to be quantified and improved upon. The improvement will be linked to final beam spot size and enhancement in expected radiographic resolution.

  6. Discovery of novel and orally active FXR agonists for the potential treatment of dyslipidemia & diabetes.

    PubMed

    Richter, Hans G F; Benson, Gregory M; Blum, Denise; Chaput, Evelyne; Feng, Song; Gardes, Christophe; Grether, Uwe; Hartman, Peter; Kuhn, Bernd; Martin, Rainer E; Plancher, Jean-Marc; Rudolph, Markus G; Schuler, Franz; Taylor, Sven; Bleicher, Konrad H

    2011-01-01

    Herein we describe the synthesis and structure activity relationship of a new class of FXR agonists identified from a high-throughput screening campaign. Further optimization of the original hits led to molecules that were highly active in an LDL-receptor KO model for dyslipidemia. The most promising candidate is discussed in more detail. Copyright © 2010 Elsevier Ltd. All rights reserved.

  7. FXR and its ligands inhibit the function of platelets

    PubMed Central

    Vaiyapuri, Sakthivel; Ali, Marfoua S.; Sasikumar, Parvathy; Sage, Tanya; Flora, Gagan D; Bye, Alex P; Kriek, Neline; Dorchies, Emilie; Molendi-Coste, Olivier; Dombrowicz, David; Staels, Bart; Bishop-Bailey, David

    2016-01-01

    Objective While initially seemingly paradoxical due to the lack of nucleus, platelets possess a number of transcription factors that regulate their function through DNA-independent mechanisms. These include the Farnesoid X Receptor (FXR), a member of the superfamily of ligand-activated transcription factors that has been identified as a bile acid receptor. In this study, we show that FXR is present in human platelets and FXR ligands, GW4064 and 6-ECDCA, modulate platelet activation nongenomically. Approach and Results FXR ligands inhibited the activation of platelets in response to stimulation of collagen or thrombin receptors, resulting in diminished intracellular calcium mobilization and secretion, fibrinogen binding and aggregation. Exposure to FXR ligands also reduced integrin αIIbβ3 outside-in signaling and thereby reduced the ability of platelets to spread and to stimulate clot retraction. FXR function in platelets was found to be associated with the modulation of cGMP levels in platelets and associated downstream inhibitory signaling. Platelets from FXR-deficient mice were refractory to the actions of FXR agonists on platelet function and cyclic nucleotide signaling, firmly linking the non-genomic actions of these ligands to the FXR receptor. Conclusion This study provides support for the ability of FXR ligands to modulate platelet activation. The athero-protective effects of GW4064, with its novel antiplatelet effects, indicate FXR as a potential target for prevention of athero-thrombotic disease. PMID:27758768

  8. A variational perspective on accelerated methods in optimization.

    PubMed

    Wibisono, Andre; Wilson, Ashia C; Jordan, Michael I

    2016-11-22

    Accelerated gradient methods play a central role in optimization, achieving optimal rates in many settings. Although many generalizations and extensions of Nesterov's original acceleration method have been proposed, it is not yet clear what is the natural scope of the acceleration concept. In this paper, we study accelerated methods from a continuous-time perspective. We show that there is a Lagrangian functional that we call the Bregman Lagrangian, which generates a large class of accelerated methods in continuous time, including (but not limited to) accelerated gradient descent, its non-Euclidean extension, and accelerated higher-order gradient methods. We show that the continuous-time limit of all of these methods corresponds to traveling the same curve in spacetime at different speeds. From this perspective, Nesterov's technique and many of its generalizations can be viewed as a systematic way to go from the continuous-time curves generated by the Bregman Lagrangian to a family of discrete-time accelerated algorithms.

  9. Time optimal paths and acceleration lines of robotic manipulators

    NASA Technical Reports Server (NTRS)

    Shiller, Zvi; Dubowsky, Steven

    1987-01-01

    The concept of acceleration lines and their correlation with time-optimal paths of robotic manipulators is presented. The acceleration lines represent the directions of maximum tip acceleration from a point in the manipulator work-space, starting at a zero velocity. These lines can suggest the number and shapes of time-optimal paths for a class of manipulators. It is shown that nonsingular time-optimal paths are tangent to one of the acceleration lines near the end-points. A procedure for obtaining near-optimal paths, utilizing the acceleration lines, is developed. These paths are obtained by connecting the end-points with B splines tangent to the acceleration lines. The near-minimum paths are shown to yield better traveling times than the straight-line path between the same end-points. The near-minimum paths can be used as initial conditions in existing optimization methods to speed-up convergence and computation time. This method can be used for online robot path planning and for interactive designs of robotic-cell layouts. Examples of time-optimal paths of a two-link manipulator, obtained by other optimization procedures and their acceleration lines, are shown.

  10. 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.

  11. Direct methylation of FXR by Set7/9, a lysine methyltransferase, regulates the expression of FXR target genes

    PubMed Central

    Balasubramaniyan, Natarajan; Ananthanarayanan, Meena

    2012-01-01

    The farnesoid X receptor (FXR) is a ligand (bile acid)-dependent nuclear receptor that regulates target genes involved in every aspect of bile acid homeostasis. Upon binding of ligand, FXR recruits an array of coactivators and associated proteins, some of which have intrinsic enzymatic activity that modify histones or even components of the transcriptional complex. In this study, we show chromatin occupancy by the Set7/9 methyltransferase at the FXR response element (FXRE) and direct methylation of FXR in vivo and in vitro at lysine 206. siRNA depletion of Set7/9 in the Huh-7 liver cell line decreased endogenous mRNAs of the FXR target genes, the short heterodimer partner (SHP) and bile salt export pump (BSEP). Mutation of the methylation site at K206 of FXR to an arginine prevented methylation by Set7/9. A pan-methyllysine antibody recognized the wild-type FXR but not the K206R mutant form. An electromobility shift assay showed that methylation by Set7/9 enhanced binding of FXR/retinoic X receptor-α to the FXRE. Interaction between hinge domain of FXR (containing K206) and Set7/9 was confirmed by coimmunoprecipitation, GST pull down, and mammalian two-hybrid experiments. Set7/9 overexpression in Huh-7 cells significantly enhanced transactivation of the SHP and BSEP promoters in a ligand-dependent fashion by wild-type FXR but not the K206R mutant FXR. A Set7/9 mutant deficient in methyltransferase activity was also not effective in increasing transactivation of the BSEP promoter. These studies demonstrate that posttranslational methylation of FXR by Set7/9 contributes to the transcriptional activation of FXR-target genes. PMID:22345554

  12. 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.

  13. Tissue-specific actions of FXR in metabolism and cancer.

    PubMed

    Gadaleta, Raffaella Maria; Cariello, Marica; Sabbà, Carlo; Moschetta, Antonio

    2015-01-01

    The nuclear Farnesoid X Receptor (FXR) is a transcription factor critically involved in metabolic homeostasis in the gut-liver axis. FXR activity is mediated by hormonal and dietary signals and driven by bile acids (BAs), which are the natural FXR ligands. Given the great physiological importance in BA homeostasis, as well as in the regulation of glucose and lipid metabolism, FXR plays a pivotal role in the pathogenesis of a wide range of disease of the liver, biliary tract and intestine, including hepatic and colorectal cancer. In the last years several studies have shown the relative FXR tissue-specific importance, highlighting synergism and additive effects in the liver and intestine. Gain- and loss-of-FXR-function mouse models have been generated in order to identify the biological processes and the molecular FXR targets. Taking advantage of the knowledge on the structure-activity relationship of BAs for FXR, semi-synthetic and synthetic molecules have been generated to obtain more selective and powerful FXR activators than BAs. This article is part of a Special Issue entitled: Linking transcription to physiology in lipodomics. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. 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.

  15. Optimization of the factors that accelerate leaching

    SciTech Connect

    Fuhrmann, M.; Pietrzak, R.F.; Franz, E.M.; Heiser, J.H. III; Colombo, P.

    1989-03-01

    The prediction of long-term leachability of low-level radioactive waste forms is an essential element of disposal-site performance assessment. This report describes experiments and modeling techniques used to develop an accelerated leach test that meets this need. The acceleration in leaching rates caused by the combinations of two or more factors were experimentally determined. These factors were identified earlier as being able to individually accelerate leaching. They are: elevated temperature, the size of the waste form, the ratio of the volume of leachant to the surface area of the waste form, and the frequency of replacement of the leachant. The solidification agents employed were ones that are currently used to treat low-level radioactive wastes, namely portland type I cement, bitumen, and vinyl ester-styrene. The simulated wastes, sodium sulfate, sodium tetraborate, and incinerator ash, are simplified representatives of typical low-level waste streams. Experiments determined the leaching behavior of the radionuclides of cesium (Cs-137), strontium (Sr-85), and cobalt (Co-60 or Co-57) from several different formulations of solidification agents and waste types. Leaching results were based upon radiochemical and elemental analyses of aliquots of the leachate, and on its total alkalinity and pH at various times during the experiment (up to 120 days). Solid phase analyses were carried out by Scanning/Electron Microscopy and Energy Dispersive Spectroscopy on the waste forms before and after some leaching experiments. 43 refs., 96 figs., 16 tabs.

  16. A variational perspective on accelerated methods in optimization

    PubMed Central

    Wibisono, Andre; Wilson, Ashia C.; Jordan, Michael I.

    2016-01-01

    Accelerated gradient methods play a central role in optimization, achieving optimal rates in many settings. Although many generalizations and extensions of Nesterov’s original acceleration method have been proposed, it is not yet clear what is the natural scope of the acceleration concept. In this paper, we study accelerated methods from a continuous-time perspective. We show that there is a Lagrangian functional that we call the Bregman Lagrangian, which generates a large class of accelerated methods in continuous time, including (but not limited to) accelerated gradient descent, its non-Euclidean extension, and accelerated higher-order gradient methods. We show that the continuous-time limit of all of these methods corresponds to traveling the same curve in spacetime at different speeds. From this perspective, Nesterov’s technique and many of its generalizations can be viewed as a systematic way to go from the continuous-time curves generated by the Bregman Lagrangian to a family of discrete-time accelerated algorithms. PMID:27834219

  17. Impact of Global Fxr Deficiency on Experimental Acute Pancreatitis and Genetic Variation in the FXR Locus in Human Acute Pancreatitis

    PubMed Central

    Nijmeijer, Rian M.; Schaap, Frank G.; Smits, Alexander J. J.; Kremer, Andreas E.; Akkermans, Louis M. A.; Kroese, Alfons B. A.; Rijkers, Ger. T.; Schipper, Marguerite E. I.; Verheem, André; Wijmenga, Cisca; Gooszen, Hein G.; van Erpecum, Karel J.

    2014-01-01

    Background Infectious complications often occur in acute pancreatitis, related to impaired intestinal barrier function, with prolonged disease course and even mortality as a result. The bile salt nuclear receptor farnesoid X receptor (FXR), which is expressed in the ileum, liver and other organs including the pancreas, exhibits anti-inflammatory effects by inhibiting NF-κB activation and is implicated in maintaining intestinal barrier integrity and preventing bacterial overgrowth and translocation. Here we explore, with the aid of complementary animal and human experiments, the potential role of FXR in acute pancreatitis. Methods Experimental acute pancreatitis was induced using the CCK-analogue cerulein in wild-type and Fxr-/- mice. Severity of acute pancreatitis was assessed using histology and a semi-quantitative scoring system. Ileal permeability was analyzed in vitro by Ussing chambers and an in vivo permeability assay. Gene expression of Fxr and Fxr target genes was studied by quantitative RT-PCR. Serum FGF19 levels were determined by ELISA in acute pancreatitis patients and healthy volunteers. A genetic association study in 387 acute pancreatitis patients and 853 controls was performed using 9 tagging single nucleotide polymorphisms (SNPs) covering the complete FXR gene and two additional functional SNPs. Results In wild-type mice with acute pancreatitis, ileal transepithelial resistance was reduced and ileal mRNA expression of Fxr target genes Fgf15, SHP, and IBABP was decreased. Nevertheless, Fxr-/- mice did not exhibit a more severe acute pancreatitis than wild-type mice. In patients with acute pancreatitis, FGF19 levels were lower than in controls. However, there were no associations of FXR SNPs or haplotypes with susceptibility to acute pancreatitis, or its course, outcome or etiology. Conclusion We found no evidence for a major role of FXR in acute human or murine pancreatitis. The observed altered Fxr activity during the course of disease may be a

  18. The bile acid sensor FXR regulates insulin transcription and secretion.

    PubMed

    Renga, Barbara; Mencarelli, Andrea; Vavassori, Piero; Brancaleone, Vincenzo; Fiorucci, Stefano

    2010-03-01

    Farnesoid X Receptor plays an important role in maintaining bile acid, cholesterol homeostasis and glucose metabolism. Here we investigated whether FXR is expressed by pancreatic beta-cells and regulates insulin signaling in pancreatic beta-cell line and human islets. We found that FXR activation induces positive regulatory effects on glucose-induced insulin transcription and secretion by genomic and non-genomic activities. Genomic effects of FXR activation relay on the induction of the glucose regulated transcription factor KLF11. Indeed, results from silencing experiments of KLF11 demonstrate that this transcription factor is essential for FXR activity on glucose-induced insulin gene transcription. In addition FXR regulates insulin secretion by non-genomic effects. Thus, activation of FXR in betaTC6 cells increases Akt phosphorylation and translocation of the glucose transporter GLUT2 at plasma membrane, increasing the glucose uptake by these cells. In vivo experiments on Non Obese Diabetic (NOD) mice demonstrated that FXR activation delays development of signs of diabetes, hyperglycemia and glycosuria, by enhancing insulin secretion and by stimulating glucose uptake by the liver. These data established that an FXR-KLF11 regulated pathway has an essential role in the regulation of insulin transcription and secretion induced by glucose.

  19. Optimization of accelerated charged particle beam for ADS energy production

    NASA Astrophysics Data System (ADS)

    Baldin, A. A.; Berlev, A. I.; Paraipan, M.; Tyutyunnikov, S. I.

    2017-01-01

    A comparative analysis and optimization of energy efficiency for proton and ion beams in ADS systems is performed via simulation using a GEANT4 code with account for energy consumption for different accelerator types. It is demonstrated that for light nuclei, beginning from 7Li, with energies above 1 GeV/nucleon, ion beams are considerably (several times) more efficient than the 1-3 GeV proton beam. The possibility of achieving energy deposition equivalent to 1 GeV protons in a quasi-infinite uranium target with higher efficiency (and twice as small accelerator size) in the case of acceleration of light ions is substantiated.

  20. FXR1 regulates transcription and is required for growth of human cancer cells with TP53/FXR2 homozygous deletion

    PubMed Central

    Fan, Yichao; Yue, Jiao; Xiao, Mengtao; Han-Zhang, Han; Wang, Yao Vickie; Ma, Chun; Deng, Zhilin; Li, Yingxiang; Yu, Yanyan; Wang, Xinghao; Niu, Shen; Hua, Youjia; Weng, Zhiping; Atadja, Peter

    2017-01-01

    Tumor suppressor p53 prevents cell transformation by inducing apoptosis and other responses. Homozygous TP53 deletion occurs in various types of human cancers for which no therapeutic strategies have yet been reported. TCGA database analysis shows that the TP53 homozygous deletion locus mostly exhibits co-deletion of the neighboring gene FXR2, which belongs to the Fragile X gene family. Here, we demonstrate that inhibition of the remaining family member FXR1 selectively blocks cell proliferation in human cancer cells containing homozygous deletion of both TP53 and FXR2 in a collateral lethality manner. Mechanistically, in addition to its RNA-binding function, FXR1 recruits transcription factor STAT1 or STAT3 to gene promoters at the chromatin interface and regulates transcription thus, at least partially, mediating cell proliferation. Our study anticipates that inhibition of FXR1 is a potential therapeutic approach to targeting human cancers harboring TP53 homozygous deletion. PMID:28767039

  1. 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.

  2. Transcriptional regulation of autophagy by an FXR/CREB axis

    PubMed Central

    Seok, Sunmi; Fu, Ting; Choi, Sung-E; Li, Yang; Zhu, Rong; Kumar, Subodh; Sun, Xiaoxiao; Yoon, Gyesoon; Kang, Yup; Zhong, Wenxuan; Ma, Jian; Kemper, Byron; Kemper, Jongsook Kim

    2014-01-01

    Lysosomal degradation of cytoplasmic components by autophagy is essential for cellular survival and homeostasis under nutrient-deprived conditions1–4. Acute regulation of autophagy by nutrient-sensing kinases is well defined3, 5–7, but longer-term transcriptional regulation is relatively unknown. Here we show that the fed-state sensing nuclear receptor FXR8, 9 and the fasting transcriptional activator CREB10, 11 coordinately regulate the hepatic autophagy gene network. Pharmacological activation of FXR repressed many autophagy genes and inhibited autophagy even in fasted mice and feeding-mediated inhibition of macroautophagy was attenuated in FXR-knockout mice. From mouse liver ChIP-seq data12–15, FXR and CREB binding peaks were detected at 178 and 112, respectively, of 230 autophagy-related genes, and 78 genes showed shared binding, mostly in their promoter regions. CREB promoted lipophagy, autophagic degradation of lipids16, under nutrient-deprived conditions, and FXR inhibited this response. Mechanistically, CREB upregulated autophagy genes, including Atg7, Ulk1, and Tfeb, by recruiting the coactivator CRTC2. After feeding or pharmacological activation, FXR trans-repressed these genes by disrupting the functional CREB/CRTC2 complex. This study identifies the novel FXR/CREB axis as a key physiological switch regulating autophagy, resulting in sustained nutrient regulation of autophagy during feeding/fasting cycles. PMID:25383523

  3. 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.

  4. Acceleration of quantum optimal control theory algorithms with mixing strategies.

    PubMed

    Castro, Alberto; Gross, E K U

    2009-05-01

    We propose the use of mixing strategies to accelerate the convergence of the common iterative algorithms utilized in quantum optimal control theory (QOCT). We show how the nonlinear equations of QOCT can be viewed as a "fixed-point" nonlinear problem. The iterative algorithms for this class of problems may benefit from mixing strategies, as it happens, e.g., in the quest for the ground-state density in Kohn-Sham density-functional theory. We demonstrate, with some numerical examples, how the same mixing schemes utilized in this latter nonlinear problem may significantly accelerate the QOCT iterative procedures.

  5. FXR agonist activity of conformationally constrained analogs of GW 4064

    SciTech Connect

    Akwabi-Ameyaw, Adwoa; 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.; Navas, III, Frank; Parks, Derek J.; Spearing, Paul K.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce

    2010-09-27

    Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.

  6. 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.

  7. Differential modulation of FXR activity by chlorophacinone and ivermectin analogs.

    PubMed

    Hsu, Chia-Wen; Hsieh, Jui-Hua; Huang, Ruili; Pijnenburg, Dirk; Khuc, Thai; Hamm, Jon; Zhao, Jinghua; Lynch, Caitlin; van Beuningen, Rinie; Chang, Xiaoqing; Houtman, René; Xia, Menghang

    2016-12-15

    Chemicals that alter normal function of farnesoid X receptor (FXR) have been shown to affect the homeostasis of bile acids, glucose, and lipids. Several structural classes of environmental chemicals and drugs that modulated FXR transactivation were previously identified by quantitative high-throughput screening (qHTS) of the Tox21 10K chemical collection. In the present study, we validated the FXR antagonist activity of selected structural classes, including avermectin anthelmintics, dihydropyridine calcium channel blockers, 1,3-indandione rodenticides, and pyrethroid pesticides, using in vitro assay and quantitative structural-activity relationship (QSAR) analysis approaches. (Z)-Guggulsterone, chlorophacinone, ivermectin, and their analogs were profiled for their ability to alter CDCA-mediated FXR binding using a panel of 154 coregulator motifs and to induce or inhibit transactivation and coactivator recruitment activities of constitutive androstane receptor (CAR), liver X receptor alpha (LXRα), or pregnane X receptor (PXR). Our results showed that chlorophacinone and ivermectin had distinct modes of action (MOA) in modulating FXR-coregulator interactions and compound selectivity against the four aforementioned functionally-relevant nuclear receptors. These findings collectively provide mechanistic insights regarding compound activities against FXR and possible explanations for in vivo toxicological observations of chlorophacinone, ivermectin, and their analogs. Published by Elsevier Inc.

  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 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

  10. 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.

  11. Optimization of positrons generation based on laser wakefield electron acceleration

    NASA Astrophysics Data System (ADS)

    Wu, Yuchi; Han, Dan; Zhang, Tiankui; Dong, Kegong; Zhu, Bin; Yan, Yonghong; Gu, Yuqiu

    2016-08-01

    Laser based positron represents a new particle source with short pulse duration and high charge density. Positron production based on laser wakefield electron acceleration (LWFA) has been investigated theoretically in this paper. Analytical expressions for positron spectra and yield have been obtained through a combination of LWFA and cascade shower theories. The maximum positron yield and corresponding converter thickness have been optimized as a function of driven laser power. Under the optimal condition, high energy (>100 MeV ) positron yield up to 5 ×1011 can be produced by high power femtosecond lasers at ELI-NP. The percentage of positrons shows that a quasineutral electron-positron jet can be generated by setting the converter thickness greater than 5 radiation lengths.

  12. 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.

  13. FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states.

    PubMed

    Kemper, Jongsook Kim; Xiao, Zhen; Ponugoti, Bhaskar; Miao, Ji; Fang, Sungsoon; Kanamaluru, Deepthi; Tsang, Stephanie; Wu, Shwu-Yuan; Chiang, Cheng-Ming; Veenstra, Timothy D

    2009-11-01

    The nuclear bile acid receptor FXR is critical for regulation of lipid and glucose metabolism. Here, we report that FXR is a target of SIRT1, a deacetylase that mediates nutritional and hormonal modulation of hepatic metabolism. Lysine 217 of FXR is the major acetylation site targeted by p300 and SIRT1. Acetylation of FXR increases its stability but inhibits heterodimerization with RXRalpha, DNA binding, and transactivation activity. Downregulation of hepatic SIRT1 increased FXR acetylation with deleterious metabolic outcomes. Surprisingly, in mouse models of metabolic disease, FXR interaction with SIRT1 and p300 was dramatically altered, FXR acetylation levels were elevated, and overexpression of SIRT1 or resveratrol treatment reduced acetylated FXR levels. Our data demonstrate that FXR acetylation is normally dynamically regulated by p300 and SIRT1 but is constitutively elevated in metabolic disease states. Small molecules that inhibit FXR acetylation by targeting SIRT1 or p300 may be promising therapeutic agents for metabolic disorders.

  14. 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

  15. 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.

  16. Upregulation of Decorin by FXR in Vascular Smooth Muscle Cells

    PubMed Central

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

    2008-01-01

    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. PMID:18514055

  17. Accelerated monotonic convergence of optimal control over quantum dynamics.

    PubMed

    Ho, Tak-San; Rabitz, Herschel

    2010-08-01

    The control of quantum dynamics is often concerned with finding time-dependent optimal control fields that can take a system from an initial state to a final state to attain the desired value of an observable. This paper presents a general method for formulating monotonically convergent algorithms to iteratively improve control fields. The formulation is based on a two-point boundary-value quantum control paradigm (TBQCP) expressed as a nonlinear integral equation of the first kind arising from dynamical invariant tracking control. TBQCP is shown to be related to various existing techniques, including local control theory, the Krotov method, and optimal control theory. Several accelerated monotonic convergence schemes for iteratively computing control fields are derived based on TBQCP. Numerical simulations are compared with the Krotov method showing that the new TBQCP schemes are efficient and remain monotonically convergent over a wide range of the iteration step parameters and the control pulse lengths, which is attributable to the trap-free character of the transition probability quantum dynamics control landscape.

  18. Regulation of FXR Transcriptional Activity in Health and Disease: Emerging Roles of FXR Cofactors and Post-Translational Modifications

    PubMed Central

    Kemper, Jongsook Kim

    2010-01-01

    Abnormally elevated lipid and glucose levels due to the disruption of metabolic homeostasis play causative roles in the development of metabolic diseases. A cluster of metabolic conditions, including dyslipidemia, abdominal obesity, and insulin resistance, is referred to as metabolic syndrome which has been increasing globally at an alarming rate. The primary nuclear bile acid receptor, Farnesoid X Receptor (FXR, NR1H4), plays important roles in controlling lipid and glucose levels by regulating expression of target genes in response to bile acid signaling in enterohepatic tissues. In this review, I discuss how signal-dependent FXR transcriptional activity is dynamically regulated under normal physiological conditions and how it is dysregulated in metabolic disease states. I focus on the emerging roles of post-translational modifications (PTMs) and transcriptional cofactors in modulating FXR transcriptional activity and pathways. Dysregulation of nuclear receptor transcriptional signaling due to aberrant PTMs and cofactor interactions are key determinants in the development of metabolic diseases. Therefore, targeting such abnormal PTMs and transcriptional cofactors of FXR in disease states may provide a new molecular strategy for development of pharmacological agents to treat metabolic syndrome. PMID:21130162

  19. Regulation of FXR transcriptional activity in health and disease: Emerging roles of FXR cofactors and post-translational modifications.

    PubMed

    Kemper, Jongsook Kim

    2011-08-01

    Abnormally elevated lipid and glucose levels due to the disruption of metabolic homeostasis play causative roles in the development of metabolic diseases. A cluster of metabolic conditions, including dyslipidemia, abdominal obesity, and insulin resistance, is referred to as metabolic syndrome, which has been increasing globally at an alarming rate. The primary nuclear bile acid receptor, Farnesoid X Receptor (FXR, NR1H4), plays important roles in controlling lipid and glucose levels by regulating expression of target genes in response to bile acid signaling in enterohepatic tissues. In this review, I discuss how signal-dependent FXR transcriptional activity is dynamically regulated under normal physiological conditions and how it is dysregulated in metabolic disease states. I focus on the emerging roles of post-translational modifications (PTMs) and transcriptional cofactors in modulating FXR transcriptional activity and pathways. Dysregulation of nuclear receptor transcriptional signaling due to aberrant PTMs and cofactor interactions are key determinants in the development of metabolic diseases. Therefore, targeting such abnormal PTMs and transcriptional cofactors of FXR in disease states may provide a new molecular strategy for development of pharmacological agents to treat metabolic syndrome. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.

  20. 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

  1. Activation of FXR protects against renal fibrosis via suppressing Smad3 expression

    PubMed Central

    Zhao, Kai; He, Jialin; Zhang, Yan; Xu, Zhizhen; Xiong, Haojun; Gong, Rujun; Li, Song; Chen, Shan; He, Fengtian

    2016-01-01

    Renal fibrosis is the common pathway of most chronic kidney disease progression to end-stage renal failure. The nuclear receptor FXR (farnesoid X receptor), a multiple functional transcription factor, plays an important role in protecting against fibrosis. The TGFβ-Smad signaling has a central role in kidney fibrosis. However, it remains unclear whether FXR plays direct anti-fibrotic effect in renal fibrosis via regulating TGFβ-Smad pathway. In this study, we found that the level of FXR was negatively correlated with that of Smad3 and fibronectin (a marker of fibrosis) in human fibrotic kidneys. Activation of FXR suppressed kidney fibrosis and downregulated Smad3 expression, which was markedly attenuated by FXR antagonist. Moreover, the FXR-mediated repression of fibrosis was significantly alleviated by ectopic expression of Smad3. Luciferase reporter assay revealed that FXR activation inhibited the transcriptional activity of Smad3 gene promoter. The in vivo experiments showed that FXR agonist protected against renal fibrosis and downregulated Smad3 expression in UUO mice. These results suggested that FXR may serve as an important negative regulator for manipulating Smad3 expression, and the FXR/Smad3 pathway may be a novel target for the treatment of renal fibrosis. PMID:27853248

  2. Accelerating next generation sequencing data analysis with system level optimizations.

    PubMed

    Kathiresan, Nagarajan; Temanni, Ramzi; Almabrazi, Hakeem; Syed, Najeeb; Jithesh, Puthen V; Al-Ali, Rashid

    2017-08-22

    Next generation sequencing (NGS) data analysis is highly compute intensive. In-memory computing, vectorization, bulk data transfer, CPU frequency scaling are some of the hardware features in the modern computing architectures. To get the best execution time and utilize these hardware features, it is necessary to tune the system level parameters before running the application. We studied the GATK-HaplotypeCaller which is part of common NGS workflows, that consume more than 43% of the total execution time. Multiple GATK 3.x versions were benchmarked and the execution time of HaplotypeCaller was optimized by various system level parameters which included: (i) tuning the parallel garbage collection and kernel shared memory to simulate in-memory computing, (ii) architecture-specific tuning in the PairHMM library for vectorization, (iii) including Java 1.8 features through GATK source code compilation and building a runtime environment for parallel sorting and bulk data transfer (iv) the default 'on-demand' mode of CPU frequency is over-clocked by using 'performance-mode' to accelerate the Java multi-threads. As a result, the HaplotypeCaller execution time was reduced by 82.66% in GATK 3.3 and 42.61% in GATK 3.7. Overall, the execution time of NGS pipeline was reduced to 70.60% and 34.14% for GATK 3.3 and GATK 3.7 respectively.

  3. FXR Controls the Tumor Suppressor NDRG2 and FXR Agonists Reduce Liver Tumor Growth and Metastasis in an Orthotopic Mouse Xenograft Model

    PubMed Central

    Deuschle, Ulrich; Schüler, Julia; Schulz, Andreas; Schlüter, Thomas; Kinzel, Olaf; Abel, Ulrich; Kremoser, Claus

    2012-01-01

    The farnesoid X receptor (FXR) is expressed predominantly in tissues exposed to high levels of bile acids and controls bile acid and lipid homeostasis. FXR−/− mice develop hepatocellular carcinoma (HCC) and show an increased prevalence for intestinal malignancies, suggesting a role of FXR as a tumor suppressor in enterohepatic tissues. The N-myc downstream-regulated gene 2 (NDRG2) has been recognized as a tumor suppressor gene, which is downregulated in human hepatocellular carcinoma, colorectal carcinoma and many other malignancies. We show reduced NDRG2 mRNA in livers of FXR−/− mice compared to wild type mice and both, FXR and NDRG2 mRNAs, are reduced in human HCC compared to normal liver. Gene reporter assays and Chromatin Immunoprecipitation data support that FXR directly controls NDRG2 transcription via IR1-type element(s) identified in the first introns of the human, mouse and rat NDRG2 genes. NDRG2 mRNA was induced by non-steroidal FXR agonists in livers of mice and the magnitude of induction of NDRG2 mRNA in three different human hepatoma cell lines was increased when ectopically expressing human FXR. Growth and metastasis of SK-Hep-1 cells was strongly reduced by non-steroidal FXR agonists in an orthotopic liver xenograft tumor model. Ectopic expression of FXR in SK-Hep1 cells reduced tumor growth and metastasis potential of corresponding cells and increased the anti-tumor efficacy of FXR agonists, which may be partly mediated via increased NDRG2 expression. FXR agonists may show a potential in the prevention and/or treatment of human hepatocellular carcinoma, a devastating malignancy with increasing prevalence and limited therapeutic options. PMID:23056173

  4. 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.

  5. FXR silencing in human colon cancer by DNA methylation and KRAS signaling.

    PubMed

    Bailey, Ann M; Zhan, Le; Maru, Dipen; Shureiqi, Imad; Pickering, Curtis R; Kiriakova, Galina; Izzo, Julie; He, Nan; Wei, Caimiao; Baladandayuthapani, Veerabhadran; Liang, Han; Kopetz, Scott; Powis, Garth; Guo, Grace L

    2014-01-01

    Farnesoid X receptor (FXR) is a bile acid nuclear receptor described through mouse knockout studies as a tumor suppressor for the development of colon adenocarcinomas. This study investigates the regulation of FXR in the development of human colon cancer. We used immunohistochemistry of FXR in normal tissue (n = 238), polyps (n = 32), and adenocarcinomas, staged I-IV (n = 43, 39, 68, and 9), of the colon; RT-quantitative PCR, reverse-phase protein array, and Western blot analysis in 15 colon cancer cell lines; NR1H4 promoter methylation and mRNA expression in colon cancer samples from The Cancer Genome Atlas; DNA methyltransferase inhibition; methyl-DNA immunoprecipitation (MeDIP); bisulfite sequencing; and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) knockdown assessment to investigate FXR regulation in colon cancer development. Immunohistochemistry and quantitative RT-PCR revealed that expression and function of FXR was reduced in precancerous lesions and silenced in a majority of stage I-IV tumors. FXR expression negatively correlated with phosphatidylinositol-4, 5-bisphosphate 3 kinase signaling and the epithelial-to-mesenchymal transition. The NR1H4 promoter is methylated in ~12% colon cancer The Cancer Genome Atlas samples, and methylation patterns segregate with tumor subtypes. Inhibition of DNA methylation and KRAS silencing both increased FXR expression. FXR expression is decreased early in human colon cancer progression, and both DNA methylation and KRAS signaling may be contributing factors to FXR silencing. FXR potentially suppresses epithelial-to-mesenchymal transition and other oncogenic signaling cascades, and restoration of FXR activity, by blocking silencing mechanisms or increasing residual FXR activity, represents promising therapeutic options for the treatment of colon cancer.

  6. 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

  7. Farnesoid-X Receptor (FXR) as a Promising Pharmaceutical Target in Atherosclerosis.

    PubMed

    Moris, Demetrios; Giaginis, Constantinos; Tsourouflis, Gerasimos; Theocharis, Stamatios

    2017-05-31

    Atherosclerosis (AS) is a major cause of death and morbidity in Western world and is strongly connected with atherogenic lipoproteins and inflammation. Bile acids (BA) act as activating signals of endogenous ligands such as Farnesoid-X receptor (FXR). Primary data indicate a potential role of FXR in AS. The therapeutic value of FXR ligands in AS is unknown. With the present review, we analyzed the efficacy of FXR agonists as a therapeutic modalities against AS. In this aspect, we performed an electronic search through Pub- Med/MEDLINE database by using the key terms: FXR*, Farnesoid X receptor*, atherosclerosis*, bile acids* and agonism*. According to our analysis, the FXR seems to be a promising therapeutic target in the atherosclerosis natural history. FXR agonism could exert protective effects in the development and evolution of AS. However, concomitant side effects such as the reduction of plasma HDL have been reported. Finally, results from undergoing clinical trials with synthetic FXR agonists will shed more light to the precise role of FXR agonism in AS treatment. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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

    PubMed

    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.

  9. 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

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

    PubMed

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

    2016-07-20

    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.

  11. 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.

  12. Development of cable fed flash X-ray (FXR) system

    NASA Astrophysics Data System (ADS)

    Menon, Rakhee; Mitra, S.; Patel, A. S.; Kumar, R.; Singh, G.; Senthil, K.; Kumar, Ranjeet; Kolge, T. S.; Roy, Amitava; Acharya, S.; Biswas, D.; Sharma, Archana

    2017-08-01

    Flash X-ray sources driven by pulsed power find applications in industrial radiography, and a portable X-ray source is ideal where the radiography needs to be taken at the test site. A compact and portable flash X-ray (FXR) system based on a Marx generator has been developed with the high voltage fed to the FXR tube via a cable feed-through arrangement. Hard bremsstrahlung X-rays of few tens of nanosecond duration are generated by impinging intense electron beams on an anode target of high Z material. An industrial X-ray source is developed with source size as low as 1 mm. The system can be operated from 150 kV to 450 kV peak voltages and a dose of 10 mR has been measured at 1 m distance from the source window. The modeling of the FXR source has been carried out using particle-in-cell and Monte Carlo simulations for the electron beam dynamics and X-ray generation, respectively. The angular dose profile of X-ray has been measured and compared with the simulation.

  13. Development of cable fed flash X-ray (FXR) system.

    PubMed

    Menon, Rakhee; Mitra, S; Patel, A S; Kumar, R; Singh, G; Senthil, K; Kumar, Ranjeet; Kolge, T S; Roy, Amitava; Acharya, S; Biswas, D; Sharma, Archana

    2017-08-01

    Flash X-ray sources driven by pulsed power find applications in industrial radiography, and a portable X-ray source is ideal where the radiography needs to be taken at the test site. A compact and portable flash X-ray (FXR) system based on a Marx generator has been developed with the high voltage fed to the FXR tube via a cable feed-through arrangement. Hard bremsstrahlung X-rays of few tens of nanosecond duration are generated by impinging intense electron beams on an anode target of high Z material. An industrial X-ray source is developed with source size as low as 1 mm. The system can be operated from 150 kV to 450 kV peak voltages and a dose of 10 mR has been measured at 1 m distance from the source window. The modeling of the FXR source has been carried out using particle-in-cell and Monte Carlo simulations for the electron beam dynamics and X-ray generation, respectively. The angular dose profile of X-ray has been measured and compared with the simulation.

  14. Optimization of vehicle accelerator-brake pedal foot travel time.

    PubMed

    Glass, S W; Suggs, C W

    1977-12-01

    This study was directed towards reducing the lag time between stimulus and incidence of braking. The effect of the relative vertical heights of the brake and accelerator pedals on foot travel time was the subject of the first part of the investigation. In the second part, two new pedal designs in which the accelerator was mounted directly on the brake pedal were evaluated. A significant reduction in foot travel time of approximately 12.5% was realised by locating the accelerator pedal 25-50 mm (1-2 in) higher than the brake pedal. Mounting of the accelerator pedal adjacent to or directly on the brake pedal allowed reductions in braking lag time of 46% to 74%.

  15. 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.

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

    PubMed Central

    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

    2015-01-01

    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

  17. 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. © 2014 The Authors.

  18. Strategies for Optimal Control Design of Normal Acceleration Command Following on the F-16

    DTIC Science & Technology

    1992-12-01

    AU-A258 975 AFITi LiAZ/ -l’r iL i ,.A,-J8 DTIC SELECTE STRATEGIES FOR OPTIMAL CONTROL DESIGN OF NORMAL ACCELERATION COMMAND FOLLOWING ON THE F-16...FOR OPTIMAL CONTROL DESIGN OF NORMAL ACCELERATION COMMAND FOLLOWING ON THE F-16 THESIS Presented to the Faculty of the School of Engineering of the Air...designers seeking to develop optimal controllers, and if this work brings the eventual use of one of these optimal methods on an actual aircraft one step

  19. Development of time resolved fluorescence resonance energy transfer-based assay for FXR antagonist discovery.

    PubMed

    Yu, Donna D; Lin, Wenwei; Chen, Taosheng; Forman, Barry M

    2013-07-15

    FXR (farnesoid X receptor, NRIH4), a nuclear receptor, plays a major role in the control of cholesterol metabolism. FXR ligands have been investigated in preclinical studies for targeted therapy against metabolic diseases, but have shown limitations. Therefore, there is a need for new agonist or antagonist ligands of FXR, both for potential clinical applications, as well as to further elucidate its biological functions. Here we describe the use of the X-ray crystal structure of FXR complexed with the potent small molecule agonist GW4064 to design and synthesize a novel fluorescent, high-affinity probe (DY246) for time resolved fluorescence resonance energy transfer (TR-FRET) assays. We then used the TR-FRET assay for high throughput screening of a library of over 5000 bioactive compounds. From this library, we identified 13 compounds that act as putative FXR transcriptional antagonists.

  20. 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

  1. Development of Time Resolved Fluorescence Resonance Energy Transfer-based Assay for FXR Antagonist Discovery

    PubMed Central

    Yu, Donna D.; Lin, Wenwei; Chen, Taosheng; Forman, Barry M.

    2013-01-01

    FXR (farnesoid X receptor, NRIH4), a nuclear receptor, plays a major role in the control of cholesterol metabolism. FXR ligands have been investigated in preclinical studies for targeted therapy against metabolic diseases, but have shown limitations. Therefore, there is a need for new agonist or antagonist ligands of FXR, both for potential clinical applications, as well as to further elucidate its biological functions. Here we describe the use of the X-ray crystal structure of FXR complexed with the potent small molecule agonist GW4064 to design and synthesize a novel fluorescent, high-affinity probe (DY246) for time resolved fluorescence resonance energy transfer (TR-FRET) assays. We then used the TR-FRET assay for high throughput screening of a library of over 5,000 bioactive compounds. From this library, we identified 13 compounds that act as putative FXR transcriptional antagonists. PMID:23688559

  2. 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.

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

    PubMed Central

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

    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

  4. 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.

  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. Acceleration techniques in the univariate Lipschitz global optimization

    NASA Astrophysics Data System (ADS)

    Sergeyev, Yaroslav D.; Kvasov, Dmitri E.; Mukhametzhanov, Marat S.; De Franco, Angela

    2016-10-01

    Univariate box-constrained Lipschitz global optimization problems are considered in this contribution. Geometric and information statistical approaches are presented. The novel powerful local tuning and local improvement techniques are described in the contribution as well as the traditional ways to estimate the Lipschitz constant. The advantages of the presented local tuning and local improvement techniques are demonstrated using the operational characteristics approach for comparing deterministic global optimization algorithms on the class of 100 widely used test functions.

  8. A note on the adaptive optimal control of ion accelerator facilities

    SciTech Connect

    Huang, T. )

    1990-06-01

    The application of optimal control theory to the computer control system of an ion accelerator facility is presented. The process is shown to consist of mathematical modeling of the underlying process, parameter identification, as well as some design methods of the optimal computer control and the techniques of realizing adaptive control.

  9. 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.

  10. 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.

  11. N-Myristoylation regulates the axonal distribution of the fragile X-related protein FXR2P

    PubMed Central

    Stackpole, Emily E.; Akins, Michael R.; Fallon, Justin R.

    2014-01-01

    Fragile X Syndrome, the leading cause of inherited intellectual disability and autism, is caused by loss of function of Fragile X mental retardation protein (FMRP). FMRP is an RNA binding protein that regulates local protein synthesis in the somatodendritic compartment. However, emerging evidence also indicates important roles for FMRP in axonal and presynaptic function. In particular, FMRP and its homolog FXR2P localize axonally and presynaptically to discrete endogenous structures in the brain termed Fragile X granules (FXGs). FXR2P is a component of all FXGs and is necessary for the axonal and presynaptic localization of FMRP to these structures. We therefore sought to identify and characterize structural features of FXR2P that regulate its axonal localization. Sequence analysis reveals that FXR2P harbors a consensus N-terminal myristoylation sequence (MGXXXS) that is absent in FMRP. Using click chemistry with wild type and an unmyristoylatable G2A mutant we demonstrate that FXR2P is N-myristoylated on glycine 2, establishing it as a lipid-modified RNA binding protein. To investigate the role of FXR2P N-myristoylation in neurons we generated fluorescently tagged wild type and unmyristoylatable FXR2P (WT and G2A, respectively) and expressed them in primary cortical cultures. Both FXR2PWT and FXR2PG2A are expressed at equivalent overall levels and are capable of forming FMRP-containing axonal granules. However, FXR2PWT granules are largely restricted to proximal axonal segments while granules formed with unmyristoylatable FXR2PG2A are localized throughout the axonal arbor, including in growth cones. These studies indicate that N-terminal myristoylation of the RNA binding protein FXR2P regulates its localization within the axonal arbor. Moreover, since FMRP localization within axonal domains requires its association with FXR2P, these findings suggest that FXR2P lipid modification is a control point for the axonal and presynaptic distribution of FMRP. PMID:25109237

  12. Urinary metabolomics in Fxr-null mice reveals activated adaptive metabolic pathways upon bile acid challenge.

    PubMed

    Cho, Joo-Youn; Matsubara, Tsutomu; Kang, Dong Wook; Ahn, Sung-Hoon; Krausz, Kristopher W; Idle, Jeffrey R; Luecke, Hans; Gonzalez, Frank J

    2010-05-01

    Farnesoid X receptor (FXR) is a nuclear receptor that regulates genes involved in synthesis, metabolism, and transport of bile acids and thus plays a major role in maintaining bile acid homeostasis. In this study, metabolomic responses were investigated in urine of wild-type and Fxr-null mice fed cholic acid, an FXR ligand, using ultra-performance liquid chromatography (UPLC) coupled with electrospray time-of-flight mass spectrometry (TOFMS). Multivariate data analysis between wild-type and Fxr-null mice on a cholic acid diet revealed that the most increased ions were metabolites of p-cresol (4-methylphenol), corticosterone, and cholic acid in Fxr-null mice. The structural identities of the above metabolites were confirmed by chemical synthesis and by comparing retention time (RT) and/or tandem mass fragmentation patterns of the urinary metabolites with the authentic standards. Tauro-3alpha,6,7alpha,12alpha-tetrol (3alpha,6,7alpha,12alpha-tetrahydroxy-5beta-cholestan-26-oyltaurine), one of the most increased metabolites in Fxr-null mice on a CA diet, is a marker for efficient hydroxylation of toxic bile acids possibly through induction of Cyp3a11. A cholestatic model induced by lithocholic acid revealed that enhanced expression of Cyp3a11 is the major defense mechanism to detoxify cholestatic bile acids in Fxr-null mice. These results will be useful for identification of biomarkers for cholestasis and for determination of adaptive molecular mechanisms in cholestasis.

  13. Ageing Fxr deficient mice develop increased energy expenditure, improved glucose control and liver damage resembling NASH.

    PubMed

    Bjursell, Mikael; Wedin, Marianne; Admyre, Therése; Hermansson, Majlis; Böttcher, Gerhard; Göransson, Melker; Lindén, Daniel; Bamberg, Krister; Oscarsson, Jan; Bohlooly-Y, Mohammad

    2013-01-01

    Nuclear receptor subfamily 1, group H, member 4 (Nr1h4, FXR) is a bile acid activated nuclear receptor mainly expressed in the liver, intestine, kidney and adrenal glands. Upon activation, the primary function is to suppress cholesterol 7 alpha-hydroxylase (Cyp7a1), the rate-limiting enzyme in the classic or neutral bile acid synthesis pathway. In the present study, a novel Fxr deficient mouse line was created and studied with respect to metabolism and liver function in ageing mice fed chow diet. The Fxr deficient mice were similar to wild type mice in terms of body weight, body composition, energy intake and expenditure as well as behaviours at a young age. However, from 15 weeks of age and onwards, the Fxr deficient mice had almost no body weight increase up to 39 weeks of age mainly because of lower body fat mass. The lower body weight gain was associated with increased energy expenditure that was not compensated by increased food intake. Fasting levels of glucose and insulin were lower and glucose tolerance was improved in old and lean Fxr deficient mice. However, the Fxr deficient mice displayed significantly increased liver weight, steatosis, hepatocyte ballooning degeneration and lobular inflammation together with elevated plasma levels of ALT, bilirubin and bile acids, findings compatible with non-alcoholic steatohepatitis (NASH) and cholestasis. In conclusion, ageing Fxr deficient mice display late onset leanness associated with elevated energy expenditure and improved glucose control but develop severe NASH-like liver pathology.

  14. 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.

  15. Differential effects of FXR or TGR5 activation in cholangiocarcinoma progression.

    PubMed

    Erice, O; Labiano, I; Arbelaiz, A; Santos-Laso, A; Munoz-Garrido, P; Jimenez-Agüero, R; Olaizola, P; Caro-Maldonado, A; Martín-Martín, N; Carracedo, A; Lozano, E; Marin, J J; O'Rourke, C J; Andersen, J B; Llop, J; Gómez-Vallejo, V; Padro, D; Martin, A; Marzioni, M; Adorini, L; Trauner, M; Bujanda, L; Perugorria, M J; Banales, J M

    2017-09-13

    Cholangiocarcinoma (CCA) is an aggressive tumor type affecting cholangiocytes. CCAs frequently arise under certain cholestatic liver conditions. Intrahepatic accumulation of bile acids may facilitate cocarcinogenic effects by triggering an inflammatory response and cholangiocyte proliferation. Here, the role of bile acid receptors FXR and TGR5 in CCA progression was evaluated. FXR and TGR5 expression was determined in human CCA tissues and cell lines. An orthotopic model of CCA was established in immunodeficient mice and tumor volume was monitored by magnetic resonance imaging under chronic administration of the specific FXR or TGR5 agonists, obeticholic acid (OCA) or INT-777 (0,03% in chow; Intercept Pharmaceuticals), respectively. Functional effects of FXR or TGR5 activation were evaluated on CCA cells in vitro. FXR was downregulated whereas TGR5 was upregulated in human CCA tissues compared to surrounding normal liver tissue. FXR expression correlated with tumor differentiation and TGR5 correlated with perineural invasion. TGR5 expression was higher in perihilar than in intrahepatic CCAs. In vitro, FXR was downregulated and TGR5 was upregulated in human CCA cells compared to normal human cholangiocytes. OCA halted CCA growth in vivo, whereas INT-777 showed no effect. In vitro, OCA inhibited CCA cell proliferation and migration which was associated with decreased mitochondrial energy metabolism. INT-777, by contrast, stimulated CCA cell proliferation and migration, linked to increased mitochondrial energy metabolism. Activation of FXR inhibits, whereas TGR5 activation may promote, CCA progression by regulating proliferation, migration and mitochondrial energy metabolism. Modulation of FXR or TGR5 activities may represent potential therapeutic strategies for CCA. Copyright © 2017 Elsevier B.V. All rights reserved.

  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. 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.

  18. 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.

  19. Identification of an N-oxide pyridine GW4064 analog as a potent FXR agonist.

    PubMed

    Feng, Song; Yang, Minmin; Zhang, Zhenshan; Wang, Zhanguo; Hong, Di; Richter, Hans; Benson, Gregory Martin; Bleicher, Konrad; Grether, Uwe; Martin, Rainer E; Plancher, Jean-Marc; Kuhn, Bernd; Rudolph, Markus Georg; Chen, Li

    2009-05-01

    According to the docking studies and the analysis of a co-crystal structure of GW4064 with FXR, a series of 3-aryl heterocyclic isoxazole analogs were designed and synthesized. N-Oxide pyridine analog (7b) was identified as a promising FXR agonist with potent binding affinity and good efficacy, supporting our hypothesis that through an additional hydrogen bond interaction between the pyridine substituent of isoxazole analogs and Tyr373 and Ser336 of FXR, binding affinity and functional activity could be improved.

  20. Synthesis and biological evaluations of chalcones, flavones and chromenes as farnesoid x receptor (FXR) antagonists.

    PubMed

    Zhang, Guoning; Liu, Shuainan; Tan, Wenjuan; Verma, Ruchi; Chen, Yuan; Sun, Deyang; Huan, Yi; Jiang, Qian; Wang, Xing; Wang, Na; Xu, Yang; Wong, Chiwai; Shen, Zhufang; Deng, Ruitang; Liu, Jinsong; Zhang, Yanqiao; Fang, Weishuo

    2017-03-31

    Farnesoid X receptor (FXR), a nuclear receptor mainly distributed in liver and intestine, has been regarded as a potential target for the treatment of various metabolic diseases, cancer and infectious diseases related to liver. Starting from two previously identified chalcone-based FXR antagonists, we tried to increase the activity through the design and synthesis of a library containing chalcones, flavones and chromenes, based on substitution manipulation and conformation (ring closure) restriction strategy. Many chalcones and four chromenes were identified as microM potent FXR antagonists, among which chromene 11c significantly decreased the plasma and hepatic triglyceride level in KKay mice.

  1. 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.

  2. 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

  3. 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

    2015-07-08

    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.

  4. 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.

  5. Design of an X-band accelerating structure using a newly developed structural optimization procedure

    NASA Astrophysics Data System (ADS)

    Huang, Xiaoxia; Fang, Wencheng; Gu, Qiang; Zhao, Zhentang

    2017-05-01

    An X-band high gradient accelerating structure is a challenging technology for implementation in advanced electron linear accelerator facilities. The present work discusses the design of an X-band accelerating structure for dedicated application to a compact hard X-ray free electron laser facility at the Shanghai Institute of Applied Physics, and numerous design optimizations are conducted with consideration for radio frequency (RF) breakdown, RF efficiency, short-range wakefields, and dipole/quadrupole field modes, to ensure good beam quality and a high accelerating gradient. The designed X-band accelerating structure is a constant gradient structure with a 4π/5 operating mode and input and output dual-feed couplers in a racetrack shape. The design process employs a newly developed effective optimization procedure for optimization of the X-band accelerating structure. In addition, the specific design of couplers providing high beam quality by eliminating dipole field components and reducing quadrupole field components is discussed in detail.

  6. FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states

    PubMed Central

    Kemper, Jongsook Kim; Xiao, Zhen; Ponugoti, Bhaskar; Miao, Ji; Fang, Sungsoon; Kanamaluru, Deepthi; Tsang, Stephanie; Wu, Shwu-Yuan; Chiang, Cheng-Ming; Veenstra, Timothy D.

    2009-01-01

    Summary The nuclear bile acid receptor FXR is critical for regulation of lipid and glucose metabolism. Here we report that FXR is a target of SIRT1, a deacetylase that mediates nutritional and hormonal modulation of hepatic metabolism. Lysine 217 of FXR is the major acetylation site targeted by p300 and SIRT1. Acetylation of FXR increases its stability but inhibits heterodimerization with RXRα, DNA binding, and transactivation activity. Down-regulation of hepatic SIRT1 increased FXR acetylation with deleterious metabolic outcomes. Surprisingly, in mouse models of metabolic disease, FXR interaction with SIRT1 and p300 was dramatically altered, FXR acetylation levels were elevated, and overexpression of SIRT1 or resveratrol treatment reduced acetylated FXR levels. Our data demonstrate that FXR acetylation is normally dynamically regulated by p300 and SIRT1 but is constitutively elevated in metabolic disease states. Small molecules that inhibit FXR acetylation by targeting SIRT1 or p300 may be promising therapeutic agents for metabolic disorders. PMID:19883617

  7. Long-term Administration of Nuclear Bile Acid Receptor FXR Agonist Prevents Spontaneous Hepatocarcinogenesis in Abcb4(-/-) Mice.

    PubMed

    Cariello, Marica; Peres, Claudia; Zerlotin, Roberta; Porru, Emanuele; Sabbà, Carlo; Roda, Aldo; Moschetta, Antonio

    2017-09-11

    Altered bile acid (BA) signaling is associated with hepatotoxicity. The farnesoid X receptor (FXR) is a nuclear receptor that transcriptionally regulates BA homeostasis. Mice with FXR ablation present hepatocarcinoma (HCC) due to high toxic BA levels. Mice with Abcb4 ablation accumulate toxic BA within the bile ducts and present HCC. We have previously shown that intestinal specific activation of FXR by transgenic VP16-FXR chimera is able to reduce BA pool size and prevent HCC. Here we tested chemical FXR activation by administering for 15 months the dual FXR/ membrane G protein-coupled receptor (TGR5) agonist INT-767 (6α-ethyl-3α,7α,23-trihydroxy-24-nor-5β-cholan-23-sulphate) to Fxr(-/-) and Abcb4(-/-) mice. HCC number and size were significantly reduced by INT-767 administration. In contrast, no changes in HCC tumor number and size were observed in Fxr(-/-) mice fed with or without INT-767. Notably, INT-767 preserved the hepatic parenchyma, improved hepatic function and down-regulated pro-inflammatory cytokines. Moreover, in Abcb4(-/-) mice INT-767 prevented fibrosis by reducing collagen expression and deposition. Thus, long term activation of FXR is able to reduce BA pool, reprogram BA metabolism and prevent HCC. These data provide the impetus to address the bona fide therapeutic potential of FXR activation in disease with BA-associated development of HCC.

  8. 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

  9. Hardware acceleration vs. algorithmic acceleration: can GPU-based processing beat complexity optimization for CT?

    NASA Astrophysics Data System (ADS)

    Neophytou, Neophytos; Xu, Fang; Mueller, Klaus

    2007-03-01

    Three-dimensional computed tomography (CT) is a compute-intensive process, due to the large amounts of source and destination data, and this limits the speed at which a reconstruction can be obtained. There are two main approaches to cope with this problem: (i) lowering the overall computational complexity via algorithmic means, and/or (ii) running CT on specialized high-performance hardware. Since the latter requires considerable capital investment into rather inflexible hardware, the former option is all one has typically available in a traditional CPU-based computing environment. However, the emergence of programmable commodity graphics hardware (GPUs) has changed this situation in a decisive way. In this paper, we show that GPUs represent a commodity high-performance parallel architecture that resonates very well with the computational structure and operations inherent to CT. Using formal arguments as well as experiments we demonstrate that GPU-based 'brute-force' CT (i.e., CT at regular complexity) can be significantly faster than CPU-based as well as GPU-based CT with optimal complexity, at least for practical data sizes. Therefore, the answer to the title question: "Can GPU-based processing beat complexity optimization for CT?" is "Absolutely!"

  10. FXR activation improves myocardial fatty acid metabolism in a rodent model of obesity-driven cardiotoxicity.

    PubMed

    Mencarelli, A; Cipriani, S; Renga, B; D'Amore, C; Palladino, G; Distrutti, E; Baldelli, F; Fiorucci, S

    2013-02-01

    Obesity-driven lipotoxicity is a risk factors for cardiovascular disease. The Farnesoid X Receptor (FXR) is a bile acids sensor and member of the nuclear receptor superfamily. Activation of FXR lowers plasma triacylglycerols and glucose levels through a mechanism that involves both the repression of key regulatory genes in the liver and the modulation of insulin sensitivity in peripheral tissues. In the present study we have investigated whether administering obese (fa/fa) Zucker rats, a genetic model of obesity associated with dyslipidemia and insulin resistance, with an FXR ligand protects against lipid-induced cardiomyopathy. FXR is expressed in neonatal cardiomyocytes and the treatment with FXR agonists, chenodeoxycholic acid (CDCA), and GW4064, increased the mRNA expression of FXR and its canonical target gene, the small heterodimer partner (SHP), as well as proliferator-activated receptor alpha PPARα, acyl-CoA oxidase (AOX) and pyruvate dehydrogenase kinase (PDK-4). Feeding obese fa/fa rats with CDCA, 12 weeks, reduced hyperinsulinemia and hyperlipidaemia. The histological-pathological analysis of hearts demonstrated that treatment with the FXR ligand reduced lipid heart content decreased the rate of apoptosis, fibrosis scores and restored heart insulin signalling. Chronic CDCA administration, in the heart, induced PPARα and PPARα-regulated genes involved in β-oxidation. FXR agonism exerts beneficial effects in a genetic model of lipid-induced cardiomyopathy. The striking benefit of this therapy on cardiac function in this model warrants an effort to determine whether a counterpart of this activity translates in human settings. Copyright © 2011 Elsevier B.V. All rights reserved.

  11. 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

  12. Nutrient-sensing nuclear receptors PPARα and FXR control liver energy balance.

    PubMed

    Preidis, Geoffrey A; Kim, Kang Ho; Moore, David D

    2017-04-03

    The nuclear receptors PPARα (encoded by NR1C1) and farnesoid X receptor (FXR, encoded by NR1H4) are activated in the liver in the fasted and fed state, respectively. PPARα activation induces fatty acid oxidation, while FXR controls bile acid homeostasis, but both nuclear receptors also regulate numerous other metabolic pathways relevant to liver energy balance. Here we review evidence that they function coordinately to control key nutrient pathways, including fatty acid oxidation and gluconeogenesis in the fasted state and lipogenesis and glycolysis in the fed state. We have also recently reported that these receptors have mutually antagonistic impacts on autophagy, which is induced by PPARα but suppressed by FXR. Secretion of multiple blood proteins is a major drain on liver energy and nutrient resources, and we present preliminary evidence that the liver secretome may be directly suppressed by PPARα, but induced by FXR. Finally, previous studies demonstrated a striking deficiency in bile acid levels in malnourished mice that is consistent with results in malnourished children. We present evidence that hepatic targets of PPARα and FXR are dysregulated in chronic undernutrition. We conclude that PPARα and FXR function coordinately to integrate liver energy balance.

  13. Optimization of Aero Engine Acceleration Control in Combat State Based on Genetic Algorithms

    NASA Astrophysics Data System (ADS)

    Li, Jie; Fan, Ding; Sreeram, Victor

    2012-03-01

    In order to drastically exploit the potential of the aero engine and improve acceleration performance in the combat state, an on-line optimized controller based on genetic algorithms is designed for an aero engine. For testing the validity of the presented control method, detailed joint simulation tests of the designed controller and the aero engine model are performed in the whole flight envelope. Simulation test results show that the presented control algorithm has characteristics of rapid convergence speed, high efficiency and can fully exploit the acceleration performance potential of the aero engine. Compared with the former controller, the designed on-line optimized controller (DOOC) can improve the security of the acceleration process and greatly enhance the aero engine thrust in the whole range of the flight envelope, the thrust increases an average of 8.1% in the randomly selected working states. The plane which adopts DOOC can acquire better fighting advantage in the combat state.

  14. 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.

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

    SciTech Connect

    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. -- Highlights: •FXR inhibits the proliferation of liver cancer cells by prolonging G0/G1 phase. •Microarray results indicate that mTOR-S6k signaling is involved in cellular processes in which FXR plays an important role. •FXR blocks the growth of liver cancer cells via the inhibition of the mTOR/S6K signaling pathway in vitro and in vivo.

  16. 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.

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

    SciTech Connect

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

    2016-01-15

    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 10{sup 22} W cm{sup −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.

  18. 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

  19. 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.

  20. Design of Linear Accelerator (LINAC) tanks for proton therapy via Particle Swarm Optimization (PSO) and Genetic Algorithm (GA) approaches

    SciTech Connect

    Castellano, T.; De Palma, L.; Laneve, D.; Strippoli, V.; Cuccovilllo, A.; Prudenzano, F.; Dimiccoli, V.; Losito, O.; Prisco, R.

    2015-07-01

    A homemade computer code for designing a Side- Coupled Linear Accelerator (SCL) is written. It integrates a simplified model of SCL tanks with the Particle Swarm Optimization (PSO) algorithm. The computer code main aim is to obtain useful guidelines for the design of Linear Accelerator (LINAC) resonant cavities. The design procedure, assisted via the aforesaid approach seems very promising, allowing future improvements towards the optimization of actual accelerating geometries. (authors)

  1. Optimization and control of electron beams from laser wakefield accelerations using asymmetric laser pulses

    NASA Astrophysics Data System (ADS)

    Gopal, K.; Gupta, D. N.

    2017-10-01

    Optimization and control of electron beam quality in laser wakefield acceleration are explored by using a temporally asymmetric laser pulse of the sharp rising front portion. The temporally asymmetric laser pulse imparts stronger ponderomotive force on the ambient plasma electrons. The stronger ponderomotive force associated with the asymmetric pulse significantly affects the injection of electrons into the wakefield and consequently the quality of the injected bunch in terms of injected charge, mean energy, and emittance. Based on particle-in-cell simulations, we report to generate a monoenergetic electron beam with reduced emittance and enhanced charge in laser wakefield acceleration using an asymmetric pulse of duration 30 fs.

  2. FXR inhibits gankyrin in mouse livers and prevents development of liver cancer

    PubMed Central

    Jiang, Yanjun; Iakova, Polina; Jin, Jingling; Sullivan, Emily; Sharin, Vladislav; Hong, Il-Hwa; Anakk, Sayee; Mayor, Angela; Darlington, Gretchen; Finegold, Milton; Moore, David; Timchenko, Nikolai A.

    2013-01-01

    One of the early events in development of liver cancer is a neutralization of tumor suppressor proteins Rb, p53, HNF4α and C/EBPα. The elimination of these proteins is mediated by a small subunit of proteasome, gankyrin, which is activated by cancer. The aim of this study was to determine mechanisms which repress gankyrin in quiescent livers and mechanisms of activation of gankyrin in liver cancer. We found that farnesoid X receptor, FXR, inhibits expression of gankyrin in quiescent livers by silencing the gankyrin promoter through HDAC1-C/EBPβ complexes. C/EBPβ is a key transcription factor which delivers HDAC1 to gankyrin promoter and causes epigenetic silencing of the promoter. We show that down-regulation of C/EBPβ in mouse hepatoma cells and in mouse livers reduces C/EBPβ-HDAC1 complexes and activates the gankyrin promoter. Deletion of FXR signaling in mice leads to de-repression of the gankyrin promoter and to spontaneous development of liver cancer at 12 months of age. DEN-mediated liver cancer in WT mice also involves the reduction of FXR and activation of gankyrin. Examination of liver cancer in old mice and liver cancer in human patients revealed that FXR is reduced; while gankyrin is elevated during spontaneous development of liver cancer. Searching for animal models with altered levels of FXR, we found that long-lived Little mice have high levels of FXR and do not develop liver cancer with age and after DEN injections due to failure to activate gankyrin and eliminate Rb, p53, HNF4α and C/EBPα proteins. CONCLUSION FXR prevents liver cancer by inhibiting the gankyrin promoter via C/EBPβ-HDAC1 complexes leading to subsequent protection of tumor suppressor proteins from degradation. PMID:23172628

  3. 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

  4. Involvement of multiple elements in FXR-mediated transcriptional activation of FGF19.

    PubMed

    Miyata, Masaaki; Hata, Tatsuya; Yamakawa, Hiroki; Kagawa, Tatehiro; Yoshinari, Kouichi; Yamazoe, Yasushi

    2012-10-01

    The intestinal endocrine hormone human fibroblast growth factor 19 (FGF19) is involved in the regulation of not only hepatic bile acid metabolism but also carbohydrate and lipid metabolism. In the present study, bile acid/farnesoid X receptor (FXR) responsiveness in the FGF19 promoter region was investigated by a reporter assay using the human colon carcinoma cell line LS174T. The assay revealed the presence of bile acid/FXR-responsive elements in the 5'-flanking region up to 8.8 kb of FGF19. Deletion analysis indicated that regions from -1866 to -1833, from -1427 to -1353, and from -75 to +262 were involved in FXR responsiveness. Four, four, and two consecutive half-sites of nuclear receptors were observed in the three regions, respectively. An electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay revealed FXR/retinoid X receptor α (RXRα) heterodimer binding in these three regions. EMSA and reporter assays using mutated constructs indicated that the nuclear receptor IR1, ER2, and DR8 motifs in the 5'-flanking region were involved in FXR responsiveness of FGF19. Lithocholic acid (LCA) (10 μM), chenodeoxycholic acid (CDCA) (10 μM), or GW4064 (0.1 μM) treatment increased reporter activity in a construct including the three motifs under FXR-expressing conditions whereas LCA and not CDCA or GW4064 treatment increased the reporter activity under pregnane X receptor (PXR)-expressing conditions. These results suggest that FGF19 is transcriptionally activated through multiple FXR-responsive elements in the promoter region.

  5. Identification of a potent synthetic FXR agonist with an unexpected mode of binding and activation

    SciTech Connect

    Soisson, Stephen M.; Parthasarathy, Gopalakrishnan; Adams, Alan D.; Sahoo, Soumya; Sitlani, Ayesha; Sparrow, Carl; Cui, Jisong; Becker, Joseph W.

    2008-07-08

    The farnesoid X receptor (FXR), a member of the nuclear hormone receptor family, plays important roles in the regulation of bile acid and cholesterol homeostasis, glucose metabolism, and insulin sensitivity. There is intense interest in understanding the mechanisms of FXR regulation and in developing pharmaceutically suitable synthetic FXR ligands that might be used to treat metabolic syndrome. We report here the identification of a potent FXR agonist (MFA-1) and the elucidation of the structure of this ligand in ternary complex with the human receptor and a coactivator peptide fragment using x-ray crystallography at 1.9-{angstrom} resolution. The steroid ring system of MFA-1 binds with its D ring-facing helix 12 (AF-2) in a manner reminiscent of hormone binding to classical steroid hormone receptors and the reverse of the pose adopted by naturally occurring bile acids when bound to FXR. This binding mode appears to be driven by the presence of a carboxylate on MFA-1 that is situated to make a salt-bridge interaction with an arginine residue in the FXR-binding pocket that is normally used to neutralize bound bile acids. Receptor activation by MFA-1 differs from that by bile acids in that it relies on direct interactions between the ligand and residues in helices 11 and 12 and only indirectly involves a protonated histidine that is part of the activation trigger. The structure of the FXR:MFA-1 complex differs significantly from that of the complex with a structurally distinct agonist, fexaramine, highlighting the inherent plasticity of the receptor.

  6. Multilevel Optimization Framework for Hierarchical Stiffened Shells Accelerated by Adaptive Equivalent Strategy

    NASA Astrophysics Data System (ADS)

    Wang, Bo; Tian, Kuo; Zhao, Haixin; Hao, Peng; Zhu, Tianyu; Zhang, Ke; Ma, Yunlong

    2016-09-01

    In order to improve the post-buckling optimization efficiency of hierarchical stiffened shells, a multilevel optimization framework accelerated by adaptive equivalent strategy is presented in this paper. Firstly, the Numerical-based Smeared Stiffener Method (NSSM) for hierarchical stiffened shells is derived by means of the numerical implementation of asymptotic homogenization (NIAH) method. Based on the NSSM, a reasonable adaptive equivalent strategy for hierarchical stiffened shells is developed from the concept of hierarchy reduction. Its core idea is to self-adaptively decide which hierarchy of the structure should be equivalent according to the critical buckling mode rapidly predicted by NSSM. Compared with the detailed model, the high prediction accuracy and efficiency of the proposed model is highlighted. On the basis of this adaptive equivalent model, a multilevel optimization framework is then established by decomposing the complex entire optimization process into major-stiffener-level and minor-stiffener-level sub-optimizations, during which Fixed Point Iteration (FPI) is employed to accelerate convergence. Finally, the illustrative examples of the multilevel framework is carried out to demonstrate its efficiency and effectiveness to search for the global optimum result by contrast with the single-level optimization method. Remarkably, the high efficiency and flexibility of the adaptive equivalent strategy is indicated by compared with the single equivalent strategy.

  7. Multilevel Optimization Framework for Hierarchical Stiffened Shells Accelerated by Adaptive Equivalent Strategy

    NASA Astrophysics Data System (ADS)

    Wang, Bo; Tian, Kuo; Zhao, Haixin; Hao, Peng; Zhu, Tianyu; Zhang, Ke; Ma, Yunlong

    2017-06-01

    In order to improve the post-buckling optimization efficiency of hierarchical stiffened shells, a multilevel optimization framework accelerated by adaptive equivalent strategy is presented in this paper. Firstly, the Numerical-based Smeared Stiffener Method (NSSM) for hierarchical stiffened shells is derived by means of the numerical implementation of asymptotic homogenization (NIAH) method. Based on the NSSM, a reasonable adaptive equivalent strategy for hierarchical stiffened shells is developed from the concept of hierarchy reduction. Its core idea is to self-adaptively decide which hierarchy of the structure should be equivalent according to the critical buckling mode rapidly predicted by NSSM. Compared with the detailed model, the high prediction accuracy and efficiency of the proposed model is highlighted. On the basis of this adaptive equivalent model, a multilevel optimization framework is then established by decomposing the complex entire optimization process into major-stiffener-level and minor-stiffener-level sub-optimizations, during which Fixed Point Iteration (FPI) is employed to accelerate convergence. Finally, the illustrative examples of the multilevel framework is carried out to demonstrate its efficiency and effectiveness to search for the global optimum result by contrast with the single-level optimization method. Remarkably, the high efficiency and flexibility of the adaptive equivalent strategy is indicated by compared with the single equivalent strategy.

  8. 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.

  9. Cholesterol Feeding Prevents Hepatic Accumulation of Bile Acids in Cholic Acid-Fed Farnesoid X Receptor (FXR)-Null Mice: FXR-Independent Suppression of Intestinal Bile Acid Absorption

    PubMed Central

    Miyata, Masaaki; Matsuda, Yoshiki; Nomoto, Masahiro; Takamatsu, Yuki; Sato, Nozomi; Hamatsu, Mayumi; Dawson, Paul A.; Gonzalez, Frank J.; Yamazoe, Yasushi

    2009-01-01

    Cholic acid (CA) feeding of farnesoid X receptor (Fxr)-null mice results in markedly elevated hepatic bile acid levels and liver injury. In contrast, Fxr-null mice fed cholesterol plus CA (CA+Chol) do not exhibit liver injury, and hepatic bile acid levels and bile acid pool size are reduced 51 and 40%, respectively, compared with CA-treated Fxr-null mice. These decreases were not observed in wild-type mice. Despite a reduced bile acid pool size, hepatic Cyp7a1 mRNA expression was increased in Fxr-null mice fed the CA+Chol diet, and biliary bile acid output was not changed. Analysis of other potential protective mechanisms revealed significant decreases in portal blood bile acid concentrations and a reduced ileal bile acid absorption capacity, as estimated using an in situ loop method. Fecal bile acid excretion was also increased in Fxr-null mice fed the CA+Chol versus CA diet. The decreased ileal bile acid absorption correlated with decreased ileal apical sodium-dependent bile salt transporter (ASBT) protein expression in brush-border membranes. These results suggest a critical role for ileal bile acid absorption in regulation of hepatic bile acid levels in Fxr-null mice fed CA+Chol. Furthermore, experiments with Fxr-null mice suggest that cholesterol feeding can down-regulate ASBT expression through a pathway independent of FXR. PMID:18988759

  10. 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

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

    PubMed

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

    2012-02-14

    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.

  12. Active vibration control with optimized modified acceleration feedback equipped with adaptive line enhancer

    NASA Astrophysics Data System (ADS)

    Mahmoodi, S. Nima; Craft, Michael J.; Ahmadian, Mehdi

    2010-04-01

    Modified acceleration feedback (MAF) control, an active vibration control method that uses collocated piezoelectric actuator actuators and sensors is improved using an optimal controller. The controller consists of two main parts: 1) Frequency adaptation that uses Adaptive Line Enhancer (ALE), and 2) an optimal controller. Frequency adaptation tracks the frequency of vibrations using ALE. The obtained frequency is then fed to MPPF compensators and the optimal controller. This provides a unique feature for MAF, by extending its domain of capabilities from controlling tonal vibrations to broad band disturbances. The optimal controller consists of a set of optimal gains for wide range of frequencies that is provided, related to the characteristics of the system. Based on the tracked frequency, the optimal control system decides to use which set of gains for the MAF controller. The gains are optimal for the frequencies close to the tracked frequency. The numerical results show that the frequency tracking method that is derived has worked quite well. In addition, the frequency tracking is fast enough to be used in real-time controller. The results also indicate that the MAF can provide significant vibration reduction using the optimal controller.

  13. Active vibration control using optimized modified acceleration feedback with Adaptive Line Enhancer for frequency tracking

    NASA Astrophysics Data System (ADS)

    Nima Mahmoodi, S.; Craft, Michael J.; Southward, Steve C.; Ahmadian, Mehdi

    2011-03-01

    Modified acceleration feedback (MAF) control, an active vibration control method that uses collocated piezoelectric actuators and accelerometer is developed and its gains optimized using an optimal controller. The control system consists of two main parts: (1) frequency adaptation that uses Adaptive Line Enhancer (ALE) and (2) an optimized controller. Frequency adaptation method tracks the frequency of vibrations using ALE. The obtained frequency is then fed to MAF compensators. This provides a unique feature for MAF, by extending its domain of capabilities from controlling a certain mode of vibrations to any excited mode. The optimized MAF controller can provide optimal sets of gains for a wide range of frequencies, based on the characteristics of the system. The experimental results show that the frequency tracking method works quite well and fast enough to be used in a real-time controller. ALE parameters are numerically and experimentally investigated and tuned for optimized frequency tracking. The results also indicate that the MAF can provide significant vibration reduction using the optimized controller. The control power varies for vibration suppression at different resonance frequencies; however, it is always optimized.

  14. 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

  15. Diabetic Nephropathy Is Accelerated by Farnesoid X Receptor Deficiency and Inhibited by Farnesoid X Receptor Activation in a Type 1 Diabetes Model

    PubMed Central

    Wang, Xiaoxin X.; Jiang, Tao; Shen, Yan; Caldas, Yupanqui; Miyazaki-Anzai, Shinobu; Santamaria, Hannah; Urbanek, Cydney; Solis, Nathaniel; Scherzer, Pnina; Lewis, Linda; Gonzalez, Frank J.; Adorini, Luciano; Pruzanski, Mark; Kopp, Jeffrey B.; Verlander, Jill W.; Levi, Moshe

    2010-01-01

    OBJECTIVE The pathogenesis of diabetic nephropathy is complex and involves activation of multiple pathways leading to kidney damage. An important role for altered lipid metabolism via sterol regulatory element binding proteins (SREBPs) has been recently recognized in diabetic kidney disease. Our previous studies have shown that the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor, modulates renal SREBP-1 expression. The purpose of the present study was then to determine if FXR deficiency accelerates type 1 diabetic nephropathy in part by further stimulation of SREBPs and related pathways, and conversely, if a selective FXR agonist can prevent the development of type 1 diabetic nephropathy. RESEARCH DESIGN AND METHODS Insulin deficiency and hyperglycemia were induced with streptozotocin (STZ) in C57BL/6 FXR KO mice. Progress of renal injury was compared with nephropathy-resistant wild-type C57BL/6 mice given STZ. DBA/2J mice with STZ-induced hyperglycemia were treated with the selective FXR agonist INT-747 for 12 weeks. To accelerate disease progression, all mice were placed on the Western diet after hyperglycemia development. RESULTS The present study demonstrates accelerated renal injury in diabetic FXR KO mice. In contrast, treatment with the FXR agonist INT-747 improves renal injury by decreasing proteinuria, glomerulosclerosis, and tubulointerstitial fibrosis, and modulating renal lipid metabolism, macrophage infiltration, and renal expression of SREBPs, profibrotic growth factors, and oxidative stress enzymes in the diabetic DBA/2J strain. CONCLUSIONS Our findings indicate a critical role for FXR in the development of diabetic nephropathy and show that FXR activation prevents nephropathy in type 1 diabetes. PMID:20699418

  16. 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.

  17. 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.

  18. Fragile X mental retardation protein has a unique, evolutionarily conserved neuronal function not shared with FXR1P or FXR2P.

    PubMed

    Coffee, R Lane; Tessier, Charles R; Woodruff, Elvin A; Broadie, Kendal

    2010-01-01

    Fragile X syndrome (FXS), resulting solely from the loss of function of the human fragile X mental retardation 1 (hFMR1) gene, is the most common heritable cause of mental retardation and autism disorders, with syndromic defects also in non-neuronal tissues. In addition, the human genome encodes two closely related hFMR1 paralogs: hFXR1 and hFXR2. The Drosophila genome, by contrast, encodes a single dFMR1 gene with close sequence homology to all three human genes. Drosophila that lack the dFMR1 gene (dfmr1 null mutants) recapitulate FXS-associated molecular, cellular and behavioral phenotypes, suggesting that FMR1 function has been conserved, albeit with specific functions possibly sub-served by the expanded human gene family. To test evolutionary conservation, we used tissue-targeted transgenic expression of all three human genes in the Drosophila disease model to investigate function at (1) molecular, (2) neuronal and (3) non-neuronal levels. In neurons, dfmr1 null mutants exhibit elevated protein levels that alter the central brain and neuromuscular junction (NMJ) synaptic architecture, including an increase in synapse area, branching and bouton numbers. Importantly, hFMR1 can, comparably to dFMR1, fully rescue both the molecular and cellular defects in neurons, whereas hFXR1 and hFXR2 provide absolutely no rescue. For non-neuronal requirements, we assayed male fecundity and testes function. dfmr1 null mutants are effectively sterile owing to disruption of the 9+2 microtubule organization in the sperm tail. Importantly, all three human genes fully and equally rescue mutant fecundity and spermatogenesis defects. These results indicate that FMR1 gene function is evolutionarily conserved in neural mechanisms and cannot be compensated by either FXR1 or FXR2, but that all three proteins can substitute for each other in non-neuronal requirements. We conclude that FMR1 has a neural-specific function that is distinct from its paralogs, and that the unique FMR1 function

  19. MicroRNA-144 Regulates Hepatic ABCA1 and Plasma HDL Following Activation of the Nuclear Receptor FXR

    PubMed Central

    de Aguiar Vallim, Thomas Q.; Tarling, Elizabeth J.; Kim, Tammy; Civelek, Mete; Baldán, Ángel; Esau, Christine; Edwards, Peter A.

    2014-01-01

    Rationale The bile acid receptor Farnesoid-X-Receptor (FXR) regulates many aspects of lipid metabolism by various complex and not fully understood molecular mechanisms. We set out to investigate the molecular mechanisms for FXR-dependent regulation of lipid and lipoprotein metabolism. Objective To identify FXR-regulated microRNAs that were subsequently involved in regulating lipid metabolism. Methods and Results ATP binding cassette transporter A1 (ABCA1) is a major determinant of plasma High Density Lipoprotein (HDL)-cholesterol levels. Here we show that activation of the nuclear receptor FXR in vivo increases hepatic levels of miR-144, which in turn lower hepatic ABCA1 and plasma HDL levels. We identified two complementary sequences to miR-144 in the 3′ untranslated region (UTR) of ABCA1 mRNA that are necessary for miR-144-dependent regulation. Overexpression of miR-144 in vitro decreased both cellular ABCA1 protein and cholesterol efflux to lipid-poor apolipoprotein A-I (ApoA-I) protein, whilst overexpression in vivo reduced hepatic ABCA1 protein and plasma HDL-cholesterol. Conversely, silencing miR-144 in mice increased hepatic ABCA1 protein and HDL-cholesterol. In addition, we utilized tissue-specific FXR deficient mice to show that induction of miR-144 and FXR-dependent hypolipidemia requires hepatic, but not intestinal FXR. Finally, we identified functional FXR response elements (FXREs) upstream of the miR-144 locus, consistent with direct FXR regulation. Conclusion We have identified a novel pathway involving FXR, miR-144 and ABCA1 that together regulate plasma HDL cholesterol. PMID:23519696

  20. 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.

  1. 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).

  2. SU-E-T-270: Optimized Shielding Calculations for Medical Linear Accelerators (LINACs).

    PubMed

    Muhammad, W; Lee, S; Hussain, A

    2012-06-01

    The purpose of radiation shielding is to reduce the effective equivalent dose from a medical linear accelerator (LINAC) to a point outside the room to a level determined by individual state/international regulations. The study was performed to design LINAC's room for newly planned radiotherapy centers. Optimized shielding calculations were performed for LINACs having maximum photon energy of 20 MV based on NCRP 151. The maximum permissible dose limits were kept 0.04 mSv/week and 0.002 mSv/week for controlled and uncontrolled areas respectively by following ALARA principle. The planned LINAC's room was compared to the already constructed (non-optimized) LINAC's room to evaluate the shielding costs and the other facilities those are directly related to the room design. In the evaluation process it was noted that the non-optimized room size (i.e., 610 × 610 cm(2) or 20 feet × 20 feet) is not suitable for total body irradiation (TBI) although the machine installed inside was having not only the facility of TBI but the license was acquired. By keeping this point in view, the optimized INAC's room size was kept 762 × 762 cm 2. Although, the area of the optimized rooms was greater than the non-planned room (i.e., 762 × 762 cm 2 instead of 610 × 610 cm 2), the shielding cost for the optimized LINAC's rooms was reduced by 15%. When optimized shielding calculations were re-performed for non-optimized shielding room (i.e., keeping room size, occupancy factors, workload etc. same), it was found that the shielding cost may be lower to 41 %. In conclusion, non- optimized LINAC's room can not only put extra financial burden on the hospital but also can cause of some serious issues related to providing health care facilities for patients. © 2012 American Association of Physicists in Medicine.

  3. 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.

  4. 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.

  5. Label-Assisted Mass Spectrometry for the Acceleration of Reaction Discovery and Optimization

    PubMed Central

    Cabrera-Pardo, Jaime R.; Chai, David I.; Liu, Song; Mrksich, Milan; Kozmin, Sergey A.

    2014-01-01

    Identification of new reactions expands our knowledge of chemical reactivity and enables new synthetic applications. Accelerating the pace of this discovery process remains challenging. We describe a highly effective and simple platform for screening a large number of potential chemical reactions in order to discover and optimize previously unknown catalytic transformations thereby revealing new chemical reactivity. Our strategy is based on labeling one of the reactants with a polyaromatic chemical tag, which selectively undergoes photoionization-desorption process upon laser irradiation without the assistance of an external matrix and enables rapid mass spectrometric detection of any products originating from such labeled reactants in complex reaction mixtures without any chromatographic separation. This method was successfully employed for high-throughput discovery and subsequent optimization of two previously unknown benzannulation reactions. PMID:23609094

  6. Hierarchical incremental path planning and situation-dependent optimized dynamic motion planning considering accelerations.

    PubMed

    Lai, Xue-Cheng; Ge, Shuzhi Sam; Al Mamun, Abdullah

    2007-12-01

    This paper studies a hierarchical approach for incrementally driving a nonholonomic mobile robot to its destination in unknown environments. The A* algorithm is modified to handle a map containing unknown information. Based on it, optimal (discrete) paths are incrementally generated with a periodically updated map. Next, accelerations in varying velocities are taken into account in predicting the robot pose and the robot trajectory resulting from a motion command. Obstacle constraints are transformed to suitable velocity limits so that the robot can move as fast as possible while avoiding collisions when needed. Then, to trace the discrete path, the system searches for a waypoint-directed optimized motion in a reduced 1-D translation or rotation velocity space. Various situations of navigation are dealt with by using different strategies rather than a single objective function. Extensive simulations and experiments verified the efficacy of the proposed approach.

  7. A Model to optimize a microwave PBG accelerator based on generic unit cell

    NASA Astrophysics Data System (ADS)

    Diana, R.; Giorgio, A.; Marani, R.; Passaro, V.; Perri, A. G.

    2007-01-01

    In this paper a numerical method, based on the well known Floquet-Bloch theory, useful to analyze the physical properties of a PBG based accelerator, is presented. The proposed model has been developed to analyze a 2D lattice characterized by a generic inclination angle between the two primitive translation vectors, thus resulting very useful when a periodic structure without an equilateral triangular or square cell has to be investigated. The numerical method has been optimized in order to account several number of space harmonics with a low CPU time and memory consumption. Comparisons with more complex numerical methods demonstrate the accuracy of our model. Several simulations have been performed to find all the geometrical parameters including the inclination angle of the unit cell, filling factor and index contrast. The proposed method, through an optimization procedure of the photonic band structure, allows to obtain a large spectral purity, high order mode suppression and high Q-values.

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

    PubMed Central

    Dossa, Avafia Y.; Escobar, Oswaldo; Golden, Jamie; Frey, Mark R.; Ford, Henri R.

    2015-01-01

    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

  9. Evolution of the bile salt nuclear receptor FXR in vertebrates*s⃞

    PubMed Central

    Reschly, Erica J.; Ai, Ni; Ekins, Sean; Welsh, William J.; Hagey, Lee R.; Hofmann, Alan F.; Krasowski, Matthew D.

    2008-01-01

    Bile salts, the major end metabolites of cholesterol, vary significantly in structure across vertebrate species, suggesting that nuclear receptors binding these molecules may show adaptive evolutionary changes. We compared across species the bile salt specificity of the major transcriptional regulator of bile salt synthesis, the farnesoid X receptor (FXR). We found that FXRs have changed specificity for primary bile salts across species by altering the shape and size of the ligand binding pocket. In particular, the ligand binding pockets of sea lamprey (Petromyzon marinus) and zebrafish (Danio rerio) FXRs, as predicted by homology models, are flat and ideal for binding planar, evolutionarily early bile alcohols. In contrast, human FXR has a curved binding pocket best suited for the bent steroid ring configuration typical of evolutionarily more recent bile acids. We also found that the putative FXR from the sea squirt Ciona intestinalis, a chordate invertebrate, was completely insensitive to activation by bile salts but was activated by sulfated pregnane steroids, suggesting that the endogenous ligands of this receptor may be steroidal in nature. Our observations present an integrated picture of the coevolution of bile salt structure and of the binding pocket of their target nuclear receptor FXR. PMID:18362391

  10. 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.

  11. 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.

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

    NASA Astrophysics Data System (ADS)

    Snopok, Pavel

    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 50x50 GeV storage ring using higher order correctors; (b) 750x750 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 in

  13. SREBP-2 negatively regulates FXR-dependent transcription of FGF19 in human intestinal cells.

    PubMed

    Miyata, Masaaki; Hata, Tatsuya; Yamazoe, Yasushi; Yoshinari, Kouichi

    2014-01-10

    Sterol regulatory element-binding protein-2 (SREBP-2) is a basic helix-loop-helix-leucine zipper transcription factor that positively regulates transcription of target genes involved in cholesterol metabolism. In the present study, we have investigated a possible involvement of SREBP-2 in human intestinal expression of fibroblast growth factor (FGF)19, which is an endocrine hormone involved in the regulation of lipid and glucose metabolism. Overexpression of constitutively active SREBP-2 decreased FGF19 mRNA levels in human colon-derived LS174T cells. In reporter assays, active SREBP-2 overexpression suppressed GW4064/FXR-mediated increase in reporter activities in regions containing the IR-1 motif (+848 to +5200) in the FGF19 gene. The suppressive effect disappeared in reporter activities in the region containing the IR-1 motif when the mutation was introduced into the IR-1 motif. In electrophoretic mobility shift assays, binding of the FXR/retinoid X receptor α heterodimer to the IR-1 motif was attenuated by adding active SREBP-2, but SREBP-2 binding to the IR-1 motif was not observed. In chromatin immunoprecipitation assays, specific binding of FXR to the IR-1-containing region of the FGF19 gene (+3214 to +3404) was increased in LS174T cells by treatment with cholesterol and 25-hydroxycholesterol. Specific binding of SREBP-2 to FXR was observed in glutathione-S-transferase (GST) pull-down assays. These results suggest that SREBP-2 negatively regulates the FXR-mediated transcriptional activation of the FGF19 gene in human intestinal cells.

  14. Next-generation acceleration and code optimization for light transport in turbid media using GPUs.

    PubMed

    Alerstam, Erik; Lo, William Chun Yip; Han, Tianyi David; Rose, Jonathan; Andersson-Engels, Stefan; Lilge, Lothar

    2010-09-01

    A highly optimized Monte Carlo (MC) code package for simulating light transport is developed on the latest graphics processing unit (GPU) built for general-purpose computing from NVIDIA - the Fermi GPU. In biomedical optics, the MC method is the gold standard approach for simulating light transport in biological tissue, both due to its accuracy and its flexibility in modelling realistic, heterogeneous tissue geometry in 3-D. However, the widespread use of MC simulations in inverse problems, such as treatment planning for PDT, is limited by their long computation time. Despite its parallel nature, optimizing MC code on the GPU has been shown to be a challenge, particularly when the sharing of simulation result matrices among many parallel threads demands the frequent use of atomic instructions to access the slow GPU global memory. This paper proposes an optimization scheme that utilizes the fast shared memory to resolve the performance bottleneck caused by atomic access, and discusses numerous other optimization techniques needed to harness the full potential of the GPU. Using these techniques, a widely accepted MC code package in biophotonics, called MCML, was successfully accelerated on a Fermi GPU by approximately 600x compared to a state-of-the-art Intel Core i7 CPU. A skin model consisting of 7 layers was used as the standard simulation geometry. To demonstrate the possibility of GPU cluster computing, the same GPU code was executed on four GPUs, showing a linear improvement in performance with an increasing number of GPUs. The GPU-based MCML code package, named GPU-MCML, is compatible with a wide range of graphics cards and is released as an open-source software in two versions: an optimized version tuned for high performance and a simplified version for beginners (http://code.google.com/p/gpumcml).

  15. Next-generation acceleration and code optimization for light transport in turbid media using GPUs

    PubMed Central

    Alerstam, Erik; Lo, William Chun Yip; Han, Tianyi David; Rose, Jonathan; Andersson-Engels, Stefan; Lilge, Lothar

    2010-01-01

    A highly optimized Monte Carlo (MC) code package for simulating light transport is developed on the latest graphics processing unit (GPU) built for general-purpose computing from NVIDIA - the Fermi GPU. In biomedical optics, the MC method is the gold standard approach for simulating light transport in biological tissue, both due to its accuracy and its flexibility in modelling realistic, heterogeneous tissue geometry in 3-D. However, the widespread use of MC simulations in inverse problems, such as treatment planning for PDT, is limited by their long computation time. Despite its parallel nature, optimizing MC code on the GPU has been shown to be a challenge, particularly when the sharing of simulation result matrices among many parallel threads demands the frequent use of atomic instructions to access the slow GPU global memory. This paper proposes an optimization scheme that utilizes the fast shared memory to resolve the performance bottleneck caused by atomic access, and discusses numerous other optimization techniques needed to harness the full potential of the GPU. Using these techniques, a widely accepted MC code package in biophotonics, called MCML, was successfully accelerated on a Fermi GPU by approximately 600x compared to a state-of-the-art Intel Core i7 CPU. A skin model consisting of 7 layers was used as the standard simulation geometry. To demonstrate the possibility of GPU cluster computing, the same GPU code was executed on four GPUs, showing a linear improvement in performance with an increasing number of GPUs. The GPU-based MCML code package, named GPU-MCML, is compatible with a wide range of graphics cards and is released as an open-source software in two versions: an optimized version tuned for high performance and a simplified version for beginners (http://code.google.com/p/gpumcml). PMID:21258498

  16. QuickVina: accelerating AutoDock Vina using gradient-based heuristics for global optimization.

    PubMed

    Handoko, Stephanus Daniel; Ouyang, Xuchang; Su, Chinh Tran To; Kwoh, Chee Keong; Ong, Yew Soon

    2012-01-01

    Predicting binding between macromolecule and small molecule is a crucial phase in the field of rational drug design. AutoDock Vina, one of the most widely used docking software released in 2009, uses an empirical scoring function to evaluate the binding affinity between the molecules and employs the iterated local search global optimizer for global optimization, achieving a significantly improved speed and better accuracy of the binding mode prediction compared its predecessor, AutoDock 4. In this paper, we propose further improvement in the local search algorithm of Vina by heuristically preventing some intermediate points from undergoing local search. Our improved version of Vina-dubbed QVina-achieved a maximum acceleration of about 25 times with the average speed-up of 8.34 times compared to the original Vina when tested on a set of 231 protein-ligand complexes while maintaining the optimal scores mostly identical. Using our heuristics, larger number of different ligands can be quickly screened against a given receptor within the same time frame.

  17. FXR mediates a chromatin looping in the GR promoter thus promoting the resolution of colitis in rodents.

    PubMed

    Renga, Barbara; D'Amore, Claudio; Cipriani, Sabrina; Mencarelli, Andrea; Carino, Adriana; Sepe, Valentina; Zampella, Angela; Distrutti, Eleonora; Fiorucci, Stefano

    2013-11-01

    Glucocorticoids (GCs) are important endocrine regulators of a wide range of physiological processes ranging from immune function to glucose and lipid metabolism. For decades, synthetic glucocorticoids such as dexamethasone have been the cornerstone for the clinical treatment of inflammatory bowel diseases (IBD). A previous study has shown that farnesoid X receptor (FXR) enhances the transcription of NR3C1 gene, which encodes for human GR, by binding to a conserved FXR response element (FXRE) in the distal promoter of this gene. In the present study we demonstrate that FXR promotes the resolution of colitis in rodents by enhancing Gr gene transcription. We used the chromatin conformation capture (3C) assay to demonstrate that this FXRE is functional in mediating a head-to-tail chromatin looping, thus increasing Gr transcription efficiency. These findings underscore the importance of FXR/GR axis in the control of intestinal inflammation.

  18. Optimizing density down-ramp injection for beam-driven plasma wakefield accelerators

    NASA Astrophysics Data System (ADS)

    Martinez de la Ossa, A.; Hu, Z.; Streeter, M. J. V.; Mehrling, T. J.; Kononenko, O.; Sheeran, B.; Osterhoff, J.

    2017-09-01

    Density down-ramp (DDR) injection is a promising concept in beam-driven plasma wakefield accelerators for the generation of high-quality witness beams. We review and complement the theoretical principles of the method and employ particle-in-cell (PIC) simulations in order to determine constrains on the geometry of the density ramp and the current of the drive beam, regarding the applicability of DDR injection. Furthermore, PIC simulations are utilized to find optimized conditions for the production of high-quality beams. We find and explain the intriguing result that the injection of an increased charge by means of a steepened ramp favors the generation of beams with lower emittance. Exploiting this fact enables the production of beams with high charge (˜140 pC ), low normalized emittance (˜200 nm ) and low uncorrelated energy spread (0.3%) in sufficiently steep ramps even for drive beams with moderate peak current (˜2.5 kA ).

  19. 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.

  20. Orally Administered Berberine Modulates Hepatic Lipid Metabolism by Altering Microbial Bile Acid Metabolism and the Intestinal FXR Signaling Pathway.

    PubMed

    Sun, Runbin; Yang, Na; Kong, Bo; Cao, Bei; Feng, Dong; Yu, Xiaoyi; Ge, Chun; Huang, Jingqiu; Shen, Jianliang; Wang, Pei; Feng, Siqi; Fei, Fei; Guo, Jiahua; He, Jun; Aa, Nan; Chen, Qiang; Pan, Yang; Schumacher, Justin D; Yang, Chung S; Guo, Grace L; Aa, Jiye; Wang, Guangji

    2017-02-01

    Previous studies suggest that the lipid-lowering effect of berberine (BBR) involves actions on the low-density lipoprotein receptor and the AMP-activated protein kinase signaling pathways. However, the implication of these mechanisms is unclear because of the low bioavailability of BBR. Because the main action site of BBR is the gut and intestinal farnesoid X receptor (FXR) plays a pivotal role in the regulation of lipid metabolism, we hypothesized that the effects of BBR on intestinal FXR signaling pathway might account for its pharmacological effectiveness. Using wild type (WT) and intestine-specific FXR knockout (FXR(int-/-)) mice, we found that BBR prevented the development of high-fat-diet-induced obesity and ameliorated triglyceride accumulation in livers of WT, but not FXR(int-/-) mice. BBR increased conjugated bile acids in serum and their excretion in feces. Furthermore, BBR inhibited bile salt hydrolase (BSH) activity in gut microbiota, and significantly increased the levels of tauro-conjugated bile acids, especially tauro-cholic acid(TCA), in the intestine. Both BBR and TCA treatment activated the intestinal FXR pathway and reduced the expression of fatty-acid translocase Cd36 in the liver. These results indicate that BBR may exert its lipid-lowering effect primarily in the gut by modulating the turnover of bile acids and subsequently the ileal FXR signaling pathway. In summary, we provide the first evidence to suggest a new mechanism of BBR action in the intestine that involves, sequentially, inhibiting BSH, elevating TCA, and activating FXR, which lead to the suppression of hepatic expression of Cd36 that results in reduced uptake of long-chain fatty acids in the liver.

  1. 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.

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

    SciTech Connect

    Snopok, Pavel

    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

  3. 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

  4. 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.

  5. 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

  6. Tuberatolides, potent FXR antagonists from the Korean marine tunicate Botryllus tuberatus.

    PubMed

    Choi, Hyukjae; Hwang, Hoosang; Chin, Jungwook; Kim, Euno; Lee, Jaehwan; Nam, Sang-Jip; Lee, Byoung Chan; Rho, Boon Jo; Kang, Heonjoong

    2011-01-28

    One isoprenoid, tuberatolide A (1), meroterpenoids tuberatolide B (2) and 2'-epi-tuberatolide B (3), and the known meroterpenoids yezoquinolide (4), (R)-sargachromenol (5), and (S)-sargachromenol (6) were isolated from the Korean marine tunicate Botryllus tuberatus. The structures of these compounds were elucidated by NMR, MS, and CD spectroscopic analyses. These terpenoids antagonized the chenodeoxycholic acid (CDCA)-activated human farnesoid X receptor (hFXR) in a cell-based co-transfection assay with IC(50) values as low as 1.5 μM without significant effect on steroid receptors. Furthermore, they released the co-activator peptide from the CDCA-bound hFXR ligand binding domain in cell-free surface plasmon resonance experiments.

  7. Photoinjector optimization using a derivative-free, model-based trust-region algorithm for the Argonne Wakefield Accelerator

    NASA Astrophysics Data System (ADS)

    Neveu, N.; Larson, J.; Power, J. G.; Spentzouris, L.

    2017-07-01

    Model-based, derivative-free, trust-region algorithms are increasingly popular for optimizing computationally expensive numerical simulations. A strength of such methods is their efficient use of function evaluations. In this paper, we use one such algorithm to optimize the beam dynamics in two cases of interest at the Argonne Wakefield Accelerator (AWA) facility. First, we minimize the emittance of a 1 nC electron bunch produced by the AWA rf photocathode gun by adjusting three parameters: rf gun phase, solenoid strength, and laser radius. The algorithm converges to a set of parameters that yield an emittance of 1.08 μm. Second, we expand the number of optimization parameters to model the complete AWA rf photoinjector (the gun and six accelerating cavities) at 40 nC. The optimization algorithm is used in a Pareto study that compares the trade-off between emittance and bunch length for the AWA 70MeV photoinjector.

  8. Optimal Serum Cholesterol Concentrations are Associated with Accelerated Bone Loss in African Ancestry Men

    PubMed Central

    Kuipers, Allison L.; Miljkovic, Iva; Evans, Rhobert; Bunker, Clareann H.; Patrick, Alan L.; Zmuda, Joseph M.

    2016-01-01

    Purpose Studies of lipid and lipoprotein cholesterol associations with bone mineral density (BMD) and bone loss have been inconclusive, and longitudinal data are sparse. Therefore, the aim of this study was to test if fasting serum lipid and lipoprotein cholesterol levels are associated with areal and volumetric BMD and BMD change, Methods We determined the association of serum triglycerides, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol concentrations with cross-sectional and longitudinal (mean follow-up: 6.1 years) measures of BMD in a cohort of 1289 in African ancestry men (mean age: 56.4 years). Fasting serum triglycerides, HDL and LDL were measured at baseline concurrent with BMD assessments. Dual-energy X-ray absorptiometry was used to quantify integral hip BMD and peripheral quantitative computed tomography at the radius and tibia was used to quantify volumetric BMD. Men were categorized as optimal, borderline or high-risk for triglyceride, HDL and LDL concentrations based on adult treatment panel III guidelines. Results Lower serum triglyceride or LDL and higher HDL concentrations were associated with lower trabecular BMD at baseline (all p<0.05). Similarly, men classified as having optimal levels of LDL, HDL or triglycerides at baseline experienced the greatest integral BMD loss at the hip and trabecular BMD loss at the tibia (all p<0.05), independent of potential confounding factors. Conclusions We found that clinically optimal serum lipid and lipoprotein cholesterol concentrations were associated with accelerated bone loss among Afro-Caribbean men. Further studies are needed to better understand the mechanisms involved and potential clinical significance of these findings. PMID:26602914

  9. Cross-talk between farnesoid-X-receptor (FXR) and peroxisome proliferator-activated receptor gamma contributes to the antifibrotic activity of FXR ligands in rodent models of liver cirrhosis.

    PubMed

    Fiorucci, Stefano; Rizzo, Giovanni; Antonelli, Elisabetta; Renga, Barbara; Mencarelli, Andrea; Riccardi, Luisa; Morelli, Antonio; Pruzanski, Mark; Pellicciari, Roberto

    2005-10-01

    The nuclear receptors farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR)gamma exert counter-regulatory effects on hepatic stellate cells (HSCs) and protect against liver fibrosis development in rodents. Here, we investigated whether FXR ligands regulate PPARgamma expression in HSCs and models of liver fibrosis induced in rats by porcine serum and carbon tetrachloride administration and bile duct ligation. Our results demonstrate that HSCs trans-differentiation associated with suppression of PPARgamma mRNA expression, whereas FXR mRNA was unchanged. Exposure of cells to natural and synthetic ligands of FXR, including 6-ethyl chenodeoxycholic acid (6-ECDCA), a synthetic derivative of chenodeoxycholic acid, reversed this effect and increased PPARgamma mRNA by approximately 40-fold. Submaximally effective concentrations of FXR and PPARgamma ligands were additive in inhibiting alpha1(I) collagen mRNA accumulation induced by transforming growth factor (TGF)beta1. Administration of 6-ECDCA in rats rendered cirrhotic by porcine serum and carbon tetrachloride administration or bile duct ligation reverted down-regulation of PPARgamma mRNA expression in HSCs. Cotreatment with 6-ECDCA potentiates the antifibrotic activity of rosiglitazone, a PPARgamma ligand, in the porcine serum model as measured by morphometric analysis of liver collagen content, hydroxyproline, and liver expression of alpha1(I) collagen mRNA, alpha-smooth muscle actin, fibronectin, TGFbeta1, and tissue inhibitor of metalloprotease 1 and 2, whereas it enhanced the expression of PPARgamma and uncoupling protein 2, a PPARgamma-regulated gene, by 2-fold. In conclusion, by using an in vitro and in vivo approach, we demonstrated that FXR ligands up-regulate PPARgamma mRNA in HSCs and in rodent models of liver fibrosis. A FXR-PPARgamma cascade exerts counter-regulatory effects in HSCs activation.

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

    PubMed

    Niu, Tianye; Zhu, Lei

    2012-07-01

    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. 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. ABOCS directly estimates the data fidelity tolerance from the raw projection data. Therefore, as demonstrated in both digital Shepp

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

    PubMed

    Niu, Tianye; Zhu, Lei

    2012-07-01

    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. 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. ABOCS directly estimates the data fidelity tolerance from the raw projection data. Therefore, as demonstrated in both digital Shepp

  12. 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

  13. 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

  14. 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.

  15. Optimal serum cholesterol concentrations are associated with accelerated bone loss in African ancestry men.

    PubMed

    Kuipers, A L; Miljkovic, I; Evans, R; Bunker, C H; Patrick, A L; Zmuda, J M

    2016-04-01

    We tested if serum lipid and lipoprotein cholesterol levels are associated with longitudinal measures of bone mineral density (BMD) in 1289 African ancestry men. After 6 years of mean follow-up, men with clinically optimal levels of low-density lipoprotein (LDL), high-density lipoprotein (HDL), or triglycerides at baseline experienced the greatest BMD loss, independent of potential confounding factors (all p < 0.05). Studies of lipid and lipoprotein cholesterol associations with bone mineral density (BMD) and bone loss have been inconclusive, and longitudinal data are sparse. Therefore, the aim of this study was to test if fasting serum lipid and lipoprotein cholesterol levels are associated with areal and volumetric BMD and BMD change. We determined the association of serum triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol concentrations with cross-sectional and longitudinal (mean follow-up, 6.1 years) measures of BMD in a cohort of 1289 in African ancestry men (mean age, 56.4 years). Fasting serum triglycerides, HDL, and LDL were measured at baseline concurrent with BMD assessments. Dual-energy X-ray absorptiometry was used to quantify integral hip BMD, and peripheral quantitative computed tomography at the radius and tibia was used to quantify volumetric BMD. Men were categorized as optimal, borderline, or high risk for triglyceride, HDL, and LDL concentrations based on Adult Treatment Panel III guidelines. Lower serum triglyceride or LDL and higher HDL concentrations were associated with lower trabecular BMD at baseline (all p < 0.05). Similarly, men classified as having optimal levels of LDL, HDL, or triglycerides at baseline experienced the greatest integral BMD loss at the hip and trabecular BMD loss at the tibia (all p < 0.05), independent of potential confounding factors. We found that clinically optimal serum lipid and lipoprotein cholesterol concentrations were associated with accelerated bone

  16. Accelerated parameter identification in a 3D marine biogeochemical model using surrogate-based optimization

    NASA Astrophysics Data System (ADS)

    Prieß, M.; Piwonski, J.; Koziel, S.; Oschlies, A.; Slawig, T.

    2013-08-01

    We present the application of the Surrogate-based Optimization (SBO) method on a parameter identification problem for a 3-D biogeochemical model. SBO is a method for acceleration of optimization processes when the underlying model itself is of very high computational complexity. In these cases, coupled simulation runs require large amounts of computer time, where optimization runs may become unfeasible even with high-performance hardware. As a consequence, the key idea of SBO is to replace the original and computationally expensive (high-fidelity) model by a so-called surrogate, which is created from a less accurate but computationally cheaper (low-fidelity) model and a suitable correction approach to increase its accuracy. To date, the SBO approach has been widely and successfully used in engineering applications and also for parameter identification in a 1-D marine ecosystem model of NPZD type. In this paper, we apply the approach onto a two-component biogeochemical model. The model is spun-up into a steady seasonal cycle via the Transport Matrix Approach. The low-fidelity model we use consists of a reduced number of spin-up iterations (several decades instead of millennia used for the original model). A multiplicative correction operator is further exploited to extrapolate the rather inaccurate low-fidelity model onto the original one. This corrected model builds our surrogate. We validate this SBO method by twin-experiments that use synthetic observations generated by the original model. We motivate our choice of the low-fidelity model and the multiplicative correction and discuss the computational advantage of SBO in comparison to an expensive parameter optimization in the context of the high-fidelity model. The proposed SBO technique is shown to yield a solution close to the target at a significant gain of computational efficiency. Without further regularization techniques, the method is able to identify most model parameters. The method is simple to

  17. Accelerated barrier optimization compressed sensing (ABOCS) for CT reconstruction with improved convergence

    NASA Astrophysics Data System (ADS)

    Niu, Tianye; Ye, Xiaojing; Fruhauf, Quentin; Petrongolo, Michael; Zhu, Lei

    2014-04-01

    Recently, we proposed a new algorithm of accelerated barrier optimization compressed sensing (ABOCS) for iterative CT reconstruction. The previous implementation of ABOCS uses gradient projection (GP) with a Barzilai-Borwein (BB) step-size selection scheme (GP-BB) to search for the optimal solution. The algorithm does not converge stably due to its non-monotonic behavior. In this paper, we further improve the convergence of ABOCS using the unknown-parameter Nesterov (UPN) method and investigate the ABOCS reconstruction performance on clinical patient data. Comparison studies are carried out on reconstructions of computer simulation, a physical phantom and a head-and-neck patient. In all of these studies, the ABOCS results using UPN show more stable and faster convergence than those of the GP-BB method and a state-of-the-art Bregman-type method. As shown in the simulation study of the Shepp-Logan phantom, UPN achieves the same image quality as those of GP-BB and the Bregman-type methods, but reduces the iteration numbers by up to 50% and 90%, respectively. In the Catphan©600 phantom study, a high-quality image with relative reconstruction error (RRE) less than 3% compared to the full-view result is obtained using UPN with 17% projections (60 views). In the conventional filtered-backprojection reconstruction, the corresponding RRE is more than 15% on the same projection data. The superior performance of ABOCS with the UPN implementation is further demonstrated on the head-and-neck patient. Using 25% projections (91 views), the proposed method reduces the RRE from 21% as in the filtered backprojection (FBP) results to 7.3%. In conclusion, we propose UPN for ABOCS implementation. As compared to GP-BB and the Bregman-type methods, the new method significantly improves the convergence with higher stability and fewer iterations.

  18. Accelerated MRI of the fetal heart using compressed sensing and metric optimized gating.

    PubMed

    Roy, Christopher W; Seed, Mike; Macgowan, Christopher K

    2017-06-01

    To develop and validate a method for accelerated time-resolved imaging of the fetal heart using a combination of compressed sensing (CS) and metric optimized gating (MOG). Joint optimization of CS and MOG reconstructions was used to suppress competing artifact from random undersampling and ungated cardiac motion. Retrospectively and prospectively undersampled adult and fetal data were used to validate the proposed reconstruction algorithm qualitatively based on visual assessment, and quantitatively based on reconstruction error, blur, and MOG timing error. Excellent agreement was observed between the fully sampled and retrospectively undersampled reconstructions, up to an undersampling factor of four. Visually, differences between ECG and MOG reconstructions of adult data were negligible. This was consistent with quantitative comparisons of reconstruction error (RMSEECG  = 0.07-0.13; RMSEMOG  = 0.08-0.13), and image blur (BECG  = 1.03-1.20; BMOG  = 1.03-1.20). The calculated MOG timing error (2-42 ms) was comparable to the acquired temporal resolution (∼60 ms). Quantitative evaluation of retrospectively undersampled (R = 2-8) fetal data (RMSEMOG  = 0.06-0.12; BMOG  = 1.04-1.27) was comparable to the adult volunteer results. CS-MOG for dynamic imaging of the fetal heart was developed and validated. Using CS-MOG, images were obtained up to four times faster than conventional acquisitions. Magn Reson Med 77:2125-2135, 2017. © 2016 International Society for Magnetic Resonance in Medicine. © 2016 International Society for Magnetic Resonance in Medicine.

  19. Accelerated barrier optimization compressed sensing (ABOCS) for CT reconstruction with improved convergence

    PubMed Central

    Niu, Tianye; Ye, Xiaojing; Fruhauf, Quentin; Petrongolo, Michael; Zhu, Lei

    2014-01-01

    Recently, we proposed a new algorithm of accelerated barrier optimization compressed sensing (ABOCS) for iterative CT reconstruction. The previous implementation of ABOCS uses gradient projection (GP) with a Barzilai-Borwein (BB) step-size selection scheme (GP-BB) to search for the optimal solution. The algorithm does not converge stably due to its non-monotonic behavior. In this paper, we further improve the convergence of ABOCS using the unknown-parameter Nesterov (UPN) method and investigate the ABOCS reconstruction performance on clinical patient data. Comparison studies are carried out on reconstructions of computer simulation, a physical phantom and a head-and-neck patient. In all of these studies, the ABOCS results using UPN show more stable and faster convergence than those of the GPBB method and a state-of-the-art Bregman-type method. As shown in the simulation study of the Shepp-Logan phantom, UPN achieves the same image quality as those of GPBB and the Bregman-type method, but reduces the iteration numbers by up to 50% and 90%, respectively. In the Catphan©600 phantom study, a high-quality image with relative reconstruction error (RRE) less than 3% compared to the full-view result is obtained using UPN with 17% projections (60 views). In the conventional filtered-backprojection (FBP) reconstruction, the corresponding RRE is more than 15% on the same projection data. The superior performance of ABOCS with the UPN implementation is further demonstrated on the head-and-neck patient. Using 25% projections (91 views), the proposed method reduces the RRE from 21% as in the FBP results to 7.3%. In conclusion, we propose UPN for ABOCS implementation. As compared to GPBB and the Bregman-type methods, the new method significantly improves the convergence with higher stability and less iterations. PMID:24625411

  20. Optimization of the photoneutron target geometry for e-accelerator based BNCT

    PubMed Central

    Chegeni, Nahid; Pur, Saleh Boveiry; Razmjoo, Sasan; Hoseini, Seydeh Khadijed

    2017-01-01

    Background and aim Today, electron accelerators are taken into consideration as photoneutron sources. Therefore, for maximum production of epithermal neutron flux, designing a photoneutron target is of significant importance. In this paper, the effect of thickness and geometric shape of a photoneutron target on neutron output were investigated. Methods In this study, a pencil photon source with 13, 15, 18, 20 and 25 MeV energies and a diameter of 2 mm was investigated using Monte Carlo simulation method using MCNP code. To optimize the design of the photoneutron target, the tungsten target with various geometries and thicknesses was investigated. Results The maximum neutron flux produced for all target geometries and thicknesses occurred at neutron energy peak of around 0.46 MeV. As the thickness increased to 2 cm, neutron flux increased and then a decreasing trend was observed. For various geometrical shapes, the determining factor in photoneutron output was the effective target thickness in the photon interaction path that increased by the increase in the area of interaction. Another factor was the angle of the photon’s incidence with the target surface that resulted in a significant decrease in photoneutron output in cone-shaped targets Conclusion Three factors including the total neutron flux, neutrons energy spectrum, and convergence of neutrons plays an important role in the selection of geometry and shape of the target that should be investigated considering beam shaping assembly (BSA) shape. PMID:28848635

  1. 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.

  2. Optimization of the photoneutron target geometry for e-accelerator based BNCT.

    PubMed

    Chegeni, Nahid; Pur, Saleh Boveiry; Razmjoo, Sasan; Hoseini, Seydeh Khadijed

    2017-06-01

    Today, electron accelerators are taken into consideration as photoneutron sources. Therefore, for maximum production of epithermal neutron flux, designing a photoneutron target is of significant importance. In this paper, the effect of thickness and geometric shape of a photoneutron target on neutron output were investigated. In this study, a pencil photon source with 13, 15, 18, 20 and 25 MeV energies and a diameter of 2 mm was investigated using Monte Carlo simulation method using MCNP code. To optimize the design of the photoneutron target, the tungsten target with various geometries and thicknesses was investigated. The maximum neutron flux produced for all target geometries and thicknesses occurred at neutron energy peak of around 0.46 MeV. As the thickness increased to 2 cm, neutron flux increased and then a decreasing trend was observed. For various geometrical shapes, the determining factor in photoneutron output was the effective target thickness in the photon interaction path that increased by the increase in the area of interaction. Another factor was the angle of the photon's incidence with the target surface that resulted in a significant decrease in photoneutron output in cone-shaped targets. Three factors including the total neutron flux, neutrons energy spectrum, and convergence of neutrons plays an important role in the selection of geometry and shape of the target that should be investigated considering beam shaping assembly (BSA) shape.

  3. Pulmonary acceleration time to optimize the timing of lung transplant in cystic fibrosis.

    PubMed

    Damy, Thibaud; Burgel, Pierre-Régis; Pepin, Jean-Louis; Boelle, Pierre-Yves; Cracowski, Claire; Murris-Espin, Marlène; Nove-Josserand, Raphaele; Stremler, Nathalie; Simon, Tabassome; Adnot, Serge; Fauroux, Brigitte

    2012-01-01

    Pulmonary hypertension (PH) may affect survival in cystic fibrosis (CF) and can be assessed on echocardiographic measurement of the pulmonary acceleration time (PAT). The study aimed at evaluating PAT as a tool to optimize timing of lung transplant in CF patients. Prospective multicenter longitudinal study of patients with forced expiratory volume in 1 second (FEV1) ≤60% predicted. Echocardiography, spirometry and nocturnal oximetry were obtained as part of the routine evaluation. We included 67 patients (mean FEV1 42±12% predicted), among whom 8 underwent lung transplantation during the mean follow-up of 19±6 months. No patients died. PAT was determined in all patients and correlated negatively with systolic pulmonary artery pressure (sPAP, r=-0.36, P=0.01). Patients in the lowest PAT tertile (<101 ms) had lower FEV1 and worse nocturnal oxygen saturation, and they were more often on the lung transplant waiting list compared to patients in the other tertiles. Kaplan-Meier curves showed a shorter time to lung transplantation in the lowest PAT tertile (P<0.001) but not in patients with sPAP>35 mmHg. By multivariate analysis, FEV(1)and nocturnal desaturation were the main determinants of reduced PAT. A PAT<101 ms reduction is a promising tool for timing of lung transplantation in CF.

  4. An optimized neutron-beam shaping assembly for accelerator-based BNCT.

    PubMed

    Burlon, A A; Kreiner, A J; Valda, A A; Minsky, D M

    2004-11-01

    Different materials and proton beam energies have been studied in order to search for an optimized neutron production target and beam shaping assembly for accelerator-based BNCT. The solution proposed in this work consists of successive stacks of Al, polytetrafluoroethylene, commercially known as Teflon, and LiF as moderator and neutron absorber, and Pb as reflector. This assembly is easy to build and its cost is relatively low. An exhaustive Monte Carlo simulation study has been performed evaluating the doses delivered to a Snyder model head phantom by a neutron production Li-metal target based on the (7)Li(p,n)(7)Be reaction for proton bombarding energies of 1.92, 2.0, 2.3 and 2.5 MeV. Three moderator thicknesses have been studied and the figures of merit show the advantage of irradiating with near-resonance-energy protons (2.3 MeV) because of the relatively high neutron yield at this energy, which at the same time keeps the fast neutron healthy tissue dose limited and leads to the lowest treatment times. A moderator of 34 cm length has shown the best performance among the studied cases.

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

    PubMed

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

    2007-12-07

    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.

  6. 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.

  7. Pulmonary acceleration time to optimize the timing of lung transplant in cystic fibrosis

    PubMed Central

    Damy, Thibaud; Burgel, Pierre-Régis; Pepin, Jean-Louis; Boelle, Pierre-Yves; Cracowski, Claire; Murris-Espin, Marlène; Nove-Josserand, Raphaele; Stremler, Nathalie; Simon, Tabassome; Adnot, Serge; Fauroux, Brigitte

    2012-01-01

    Pulmonary hypertension (PH) may affect survival in cystic fibrosis (CF) and can be assessed on echocardiographic measurement of the pulmonary acceleration time (PAT). The study aimed at evaluating PAT as a tool to optimize timing of lung transplant in CF patients. Prospective multicenter longitudinal study of patients with forced expiratory volume in 1 second (FEV1) ≤60% predicted. Echocardiography, spirometry and nocturnal oximetry were obtained as part of the routine evaluation. We included 67 patients (mean FEV1 42±12% predicted), among whom 8 underwent lung transplantation during the mean follow-up of 19±6 months. No patients died. PAT was determined in all patients and correlated negatively with systolic pulmonary artery pressure (sPAP, r=–0.36, P=0.01). Patients in the lowest PAT tertile (<101 ms) had lower FEV1 and worse nocturnal oxygen saturation, and they were more often on the lung transplant waiting list compared to patients in the other tertiles. Kaplan–Meier curves showed a shorter time to lung transplantation in the lowest PAT tertile (P<0.001) but not in patients with sPAP>35 mmHg. By multivariate analysis, FEV1and nocturnal desaturation were the main determinants of reduced PAT. A PAT<101 ms reduction is a promising tool for timing of lung transplantation in CF. PMID:22558523

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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

  13. Dissociation of Intestinal and Hepatic Activities of FXR and LXRα Supports Metabolic Effects of Terminal Ileum Interposition in Rodents

    PubMed Central

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

    2013-01-01

    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

  14. The region of CQQQKPQRRP of PGC-1{alpha} interacts with the DNA-binding complex of FXR/RXR{alpha}

    SciTech Connect

    Kanaya, Eiko; Jingami, Hisato . E-mail: jingami@mfour.med.kyoto-u.ac.jp

    2006-04-14

    PGC-1{alpha} co-activates transcription by several nuclear receptors. To study the interaction among PGC-1{alpha}, RXR{alpha}/FXR, and DNA, we performed electrophoresis mobility shift assays. The RXR{alpha}/FXR proteins specifically bound to DNA containing the IR-1 sequence in the absence of ligand. When the fusion protein of GST-PGC-1{alpha} was added to the mixture of RXR{alpha}/FXR/DNA, the ligand-influenced retardation of the mobility was observed. The ligand for RXR{alpha} (9-cis-retinoic acid) was necessary for this retardation, whereas, the ligand for FXR, chenodeoxycholic acid, barely had an effect. The results obtained using truncated PGC-1{alpha} proteins suggested that two regions are necessary for PGC-1{alpha} to interact with the DNA-binding complex of RXR{alpha}/FXR. One is the region of the second leucine-rich motif, and the other is that of the amino acid sequence CQQQKPQRRP, present between the second and third leucine-rich motifs. The results obtained with the SPQSS mutation for KPQRR suggested that the basic amino acids are important for the interaction.

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

    PubMed

    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

    2011-11-15

    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.

  16. 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. Copyright © 2016 American Association of Medical Dosimetrists. All rights reserved.

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

    PubMed Central

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

    2016-01-01

    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

  18. Use of marginal distributions constrained optimization (MADCO) for accelerated 2D MRI relaxometry and diffusometry

    NASA Astrophysics Data System (ADS)

    Benjamini, Dan; Basser, Peter J.

    2016-10-01

    Measuring multidimensional (e.g., 2D) relaxation spectra in NMR and MRI clinical applications is a holy grail of the porous media and biomedical MR communities. The main bottleneck is the inversion of Fredholm integrals of the first kind, an ill-conditioned problem requiring large amounts of data to stabilize a solution. We suggest a novel experimental design and processing framework to accelerate and improve the reconstruction of such 2D spectra that uses a priori information from the 1D projections of spectra, or marginal distributions. These 1D marginal distributions provide powerful constraints when 2D spectra are reconstructed, and their estimation requires an order of magnitude less data than a conventional 2D approach. This marginal distributions constrained optimization (MADCO) methodology is demonstrated here with a polyvinylpyrrolidone-water phantom that has 3 distinct peaks in the 2D D-T1 space. The stability, sensitivity to experimental parameters, and accuracy of this new approach are compared with conventional methods by serially subsampling the full data set. While the conventional, unconstrained approach performed poorly, the new method had proven to be highly accurate and robust, only requiring a fraction of the data. Additionally, synthetic T1 -T2 data are presented to explore the effects of noise on the estimations, and the performance of the proposed method with a smooth and realistic 2D spectrum. The proposed framework is quite general and can also be used with a variety of 2D MRI experiments (D-T2,T1 -T2, D -D, etc.), making these potentially feasible for preclinical and even clinical applications for the first time.

  19. Optimization of Moderator Size of Thermal and Epithermal Neutron Source Based on a Compact Accelerator for Neutron Imaging

    NASA Astrophysics Data System (ADS)

    Hasemi, Hiroyuki; Kamiyama, Takashi; Sato, Hirotaka; Kino, Koichi; Kiyanagi, Yoshiaki; Nakajima, Ken

    A compact accelerator-driven neutron source has some advantages over a large accelerator facility in terms of accessibility and usability. Recently, the project to develop a non-destructive testing system for nuclear fuels by neutron imaging using a compact accelerator-driven neutron source has launched in Japan. In this project, the traditional neutron radiography and temperature imaging by neutron resonance absorption spectroscopy (N-RAS) have been studied. From the viewpoint of L/D, a high-brightness moderator is desirable for the neutron imaging. In this study, we investigated the dependence of moderator size on the source brightness and the pulse characteristics of the neutron by simulation calculations to design the moderator for imaging using thermal and epithermal neutrons. As a result, the optimal size of the moderator for the neutron imaging was 6∼7 cm in the energy region from 5 meV to 100 eV.

  20. 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.

  1. 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.

  2. 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.

  3. WE-G-BRCD-08: Virtual Couch Shift (VCS) by Online Plan Re-Optimization for the MRI Linear Accelerator.

    PubMed

    Bol, G; Hissoiny, S; Lagendijk, J; Raaymakers, B

    2012-06-01

    With the MRI accelerator it will be possible to get continuous patient anatomy updates, ranging from organ deformation to patient translation. To compensate for translations, one can re-optimize the treatment plan based on the online MRI images. Consequently, the IMRT optimization system should be fast and robust enough to generate daily a clinically acceptable plan to perform this 'virtual couch shift (VCS)'. The system uses a GPU based Monte-Carlo dose engine (GPUMCD) for online beamlet generation in a 1.5 T magnetic field and a fast inverse dose optimization algorithm (FIDO). For four phantom and two clinical cases (cervix and kidney), we generated clinically acceptable plans. The given plans are regenerated after a series of x, y, and z translations (up to 34 mm) of the patient anatomy, without adapting the optimization constraints as used during the initial optimization. The differences between the original plan and the regenerated plans are evaluated by using the gamma criterion and the relative D99 target coverage. The system accurately reproduced the initial dose distribution after translating the phantom and patient anatomies. The gamma criterion of 2%/2 mm is satisfied for 99.2% all target voxels and for 97.2% for all OAR voxels. The relative D99 differences are almost 0.0 with a small standard deviation. With current hardware, a 7 beam cervix beamlet generation and IMRT optimization takes 141 seconds, the kidney case takes only 14 seconds. We developed a system which is fast and accurate enough to perform a VCS by online re-optimization for the MRI accelerator. Currently we are adding sequencing to the system. We expect that this method can also be used for compensating patient rotations and tissue deformation and with this go towards realtime adaptive treatment planning and delivery. © 2012 American Association of Physicists in Medicine.

  4. FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis

    PubMed Central

    Verbeke, Len; Mannaerts, Inge; Schierwagen, Robert; Govaere, Olivier; Klein, Sabine; Vander Elst, Ingrid; Windmolders, Petra; Farre, Ricard; Wenes, Mathias; Mazzone, Massimiliano; Nevens, Frederik; van Grunsven, Leo A.; Trebicka, Jonel; Laleman, Wim

    2016-01-01

    Hepatic inflammation drives hepatic stellate cells (HSC), resulting in liver fibrosis. The Farnesoid-X receptor (FXR) antagonizes inflammation through NF-κB inhibition. We investigated preventive and therapeutic effects of FXR agonist obeticholic acid (OCA) on hepatic inflammation and fibrosis in toxic cirrhotic rats. Cirrhosis was induced by thioacetamide (TAA) intoxication. OCA was given during or after intoxication with vehicle-treated rats as controls. At sacrifice, fibrosis, hemodynamic and biochemical parameters were assessed. HSC activation, cell turn-over, hepatic NF-κB activation, pro-inflammatory and pro-fibrotic cytokines were determined. The effect of OCA was further evaluated in isolated HSC, Kupffer cells, hepatocytes and liver sinusoidal endothelial cells (LSEC). OCA decreased hepatic inflammation and fibrogenesis during TAA-administration and reversed fibrosis in established cirrhosis. Portal pressure decreased through reduced intrahepatic vascular resistance. This was paralleled by decreased expression of pro-fibrotic cytokines (transforming growth-factor β, connective tissue growth factor, platelet-derived growth factor β-receptor) as well as markers of hepatic cell turn-over, by blunting effects of pro-inflammatory cytokines (e.g. monocyte chemo-attractant protein-1). In vitro, OCA inhibited both LSEC and Kupffer cell activation; while HSC remained unaffected. This related to NF-κB inhibition via up-regulated IκBα. In conclusion, OCA inhibits hepatic inflammation in toxic cirrhotic rats resulting in decreased HSC activation and fibrosis. PMID:27634375

  5. 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.

  6. Pharmacophore modeling, 3D-QSAR and molecular docking studies of benzimidazole derivatives as potential FXR agonists.

    PubMed

    Sindhu, Thangaraj; Srinivasan, Pappu

    2014-08-01

    Farnesoid X receptor (FXR) is a potential therapeutic target for the treatment of diabetes mellitus. Atom-based three-dimensional quantitative structure activity relationship (3D-QSAR) models were developed for a series of 48 benzimidazole-based agonists of FXR. A total of five pharmacophore hypotheses were generated based on the survival score to build QSAR models. HHHRR was considered as a best model that consisted of three hydrophobic features (H) and two aromatic rings (R). The best hypothesis, HHHRR yielded a 3D-QSAR model with good statistical value (R(2)) of 0.8974 for a training set of 39 compounds and also showed good predictive power with correlation coefficient (Q(2)) of 0.7559 for a test set of nine compounds. Furthermore, molecular docking simulation was performed to understand the binding affinity of 48 benzimidazole-based compounds against the active site of human FXR protein. Docking results revealed that both the most active and least active compounds showed similar binding mode to the experimentally observed binding mode of co-crystallized ligand. The generated 3D contour maps revealed the structure activity relationship of the compounds. Substitution effects at different positions of benzimidazole derivatives would lead to the discovery of new agonists against human FXR protein.

  7. Effects of alfalfa saponin extract on mRNA expression of Ldlr, LXRα, and FXR in BRL cells*

    PubMed Central

    Liang, Xin-ping; Zhang, Dong-qiang; Chen, Yan-yan; Guo, Rui; Wang, Jie; Wang, Cheng-zhang; Shi, Ying-hua

    2015-01-01

    We studied the effects of alfalfa saponin extract (ASE) on low density lipoprotein receptor (Ldlr), liver X receptor α (LXRα), and farnesoid X receptor (FXR) in normal and hyperlipidemic Buffalo rat liver (BRL) cells. Normal and hyperlipidemic BRL cells were divided into eight groups: normal, or normal cells treated with 50, 100, and 150 mg/L ASE, hyperlipidemic, or hyperlipidemic cells treated with 50, 100, and 150 mg/L ASE. After treatment for 24 h, Ldlr, LXRα, and FXR mRNA expression levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Data showed that mRNA expression of Ldlr in normal BRL cells was significantly up-regulated by ASE treatment and mRNA expressions of LXRα and FXR were significantly down-regulated both in normal and hyperlipidemic BRL cells after ASE treatment. Thus, ASE might ameliorate hepatic steatosis by regulating genes involved in cholesterol metabolism, including up-regulation of Ldlr as well as down-regulation of LXRα and FXR. PMID:26055909

  8. 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

  9. 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

  10. 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.

  11. OPTIMIZATION AND SINGLE-SHOT CHARACTERIZATION OF ULTRASHORT THz PULSES FROM A LASER WAKEFIELD ACCELERATOR

    SciTech Connect

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

    2009-05-04

    We present spatiotemporal characterization of J-class ultrashort THz pulses generated from a laser wakefield accelerator (LWFA). Accelerated electrons, resulting from the interaction of a high-intensity laser pulse with a plasma, emit high-intensity THz pulses as coherent transition radiation. Such high peak-power THz pulses, suitable for high-field (MV/cm) pump-probe experiments, also provide a non-invasive bunch-length diagnostic and thus feedback for the accelerator. The characterization of the THz pulses includes energy measurement using a Golay cell, 2D sign-resolved electro-optic measurement and single-shot spatiotemporal electric-field distribution retrieval using a new technique, coined temporal electric-field cross-Correlation (TEX). All three techniques corroborate THz pulses of 5 muJ, with peak fields of 100's of kV/cm and ~;;0:4 ps rms duration.

  12. Optimization of laser parameters to obtain high-energy, high-quality electron beams through laser-plasma acceleration

    SciTech Connect

    Samant, Sushil Arun; Sarkar, Deepangkar; Krishnagopal, Srinivas; Upadhyay, Ajay K.; Jha, Pallavi

    2010-10-15

    The propagation of an intense (a{sub 0}=3), short-pulse (L{approx}{lambda}{sub p}) laser through a homogeneous plasma has been investigated. Using two-dimensional simulations for a{sub 0}=3, the pulse-length and spot-size at three different plasma densities were optimized in order to get a better quality beam in laser wakefield accelerator. The study reveals that with increasing pulse-length the acceleration increases, but after a certain pulse-length (L>0.23{lambda}{sub p}) the emittance blows-up unacceptably. For spot-sizes less than that given by k{sub p0}r{sub s}=2{radical}(a{sub 0}), trapping is poor or nonexistent, and the optimal spot-size is larger. The deviation of the optimal spot-size from this formula increases as the density decreases. The efficacy of these two-dimensional simulations has been validated by running three-dimensional simulations at the highest density. It has been shown that good quality GeV-class beams can be obtained at plasma densities of {approx}10{sup 18} cm{sup -3}. The quality of the beam can be substantially improved by selecting only the high-energy peak; in this fashion an energy-spread of better than 1% and a current in tens of kA can be achieved, which are important for applications such as free-electron lasers.

  13. Waltonitone inhibits proliferation of hepatoma cells and tumorigenesis via FXR-miR-22-CCNA2 signaling pathway

    PubMed Central

    Yang, Fan; Gong, Junting; Wang, Guangyun; Chen, Peng; Yang, Li; Wang, Zhengtao

    2016-01-01

    Waltonitone (WA), an ursane-type pentacyclic triterpene extracted from Gentiana waltonii Burkill, was recently appeared to exert anti-tumor effect. However, the biological underpinnings underlying the role of WA in hepatocellular carcinoma (HCC) cells have not been completely elucidated. Our previous report indicated that the FXR-regulated miR-22-CCNA2 pathway contributed to the progression and development of HCC. Besides, a wide spectrum of microRNAs (miRNAs) could be up- or down-regulated upon WA treatment, including miR-22. Hence, we aimed to determine whether WA inhibited HCC cell proliferation via the FXR-miR-22-CCNA2 axis. In this study, we observed a significant downregulation of FXR and miR-22, along with upregulation of CCNA2 in 80 paired tumors relative to adjacent normal tissues of HCC subjects, which were obtained from the available GEO database in NCBI (GSE22058). Furthermore, we validated the expression patterns of these three targets in another set of HCC samples and found the highly correlation within each other. Additionally, our data demonstrated that WA induced miR-22 and repressed CCNA2 in HCC cells, which contributed to the cell proliferation arrest. In addition, evidence suggested that either miR-22 silencing or FXR knockdown reversed the diminished CCNA2 expression as well as cell proliferation inhibition caused by WA treatment and WA inhibited tumor masses in vivo in a subcutaneous xenograft mouse model of HCC. Overall, our data indicated that WA inhibited HCC cell proliferation and tumorigenesis through miR-22-regulated CCNA2 repression, which was at least partially through FXR modulation. PMID:27738335

  14. Waltonitone inhibits proliferation of hepatoma cells and tumorigenesis via FXR-miR-22-CCNA2 signaling pathway.

    PubMed

    Yang, Fan; Gong, Junting; Wang, Guangyun; Chen, Peng; Yang, Li; Wang, Zhengtao

    2016-11-15

    Waltonitone (WA), an ursane-type pentacyclic triterpene extracted from Gentiana waltonii Burkill, was recently appeared to exert anti-tumor effect. However, the biological underpinnings underlying the role of WA in hepatocellular carcinoma (HCC) cells have not been completely elucidated. Our previous report indicated that the FXR-regulated miR-22-CCNA2 pathway contributed to the progression and development of HCC. Besides, a wide spectrum of microRNAs (miRNAs) could be up- or down-regulated upon WA treatment, including miR-22. Hence, we aimed to determine whether WA inhibited HCC cell proliferation via the FXR-miR-22-CCNA2 axis. In this study, we observed a significant downregulation of FXR and miR-22, along with upregulation of CCNA2 in 80 paired tumors relative to adjacent normal tissues of HCC subjects, which were obtained from the available GEO database in NCBI (GSE22058). Furthermore, we validated the expression patterns of these three targets in another set of HCC samples and found the highly correlation within each other. Additionally, our data demonstrated that WA induced miR-22 and repressed CCNA2 in HCC cells, which contributed to the cell proliferation arrest. In addition, evidence suggested that either miR-22 silencing or FXR knockdown reversed the diminished CCNA2 expression as well as cell proliferation inhibition caused by WA treatment and WA inhibited tumor masses in vivo in a subcutaneous xenograft mouse model of HCC. Overall, our data indicated that WA inhibited HCC cell proliferation and tumorigenesis through miR-22-regulated CCNA2 repression, which was at least partially through FXR modulation.

  15. 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.

  16. Target optimization for desired X-ray spectra produced by laser plasma accelerated electrons

    NASA Astrophysics Data System (ADS)

    Lobok, Maxim; Brantov, Andrey; Bychenkov, Valery

    2016-10-01

    Different regimes of electron acceleration from low-density targets are investigated using three-dimensional numerical simulations. Multiple spatial target density profiles were examined, including laser pre-pulse modified targets. The size of the plasma corona is shown to be one of the main parameters characterizing the temperature and number of hot electrons, which determine the yield of X-ray radiation and its hardness. The generation of X-ray radiation by laser accelerated electrons, which impact the converter target located behind the laser target, was studied. The X-ray spectra were computed using Monte-Carlo simulations. This work was partially supported by the Russian Foundation for Basic Research 16-02-00088-a.

  17. Optimization of radiation acceleration regime and the target structure in laser plasma interaction

    NASA Astrophysics Data System (ADS)

    Dudnikova, Galina; Lui, Chuan; Papadopoulos, Dennis; Sagdeev, Roald; Zigler, Ari

    2009-11-01

    Recent work [1,2] indicates that under proper conditions the interaction of ultra-short, high power lasers with thin foils can generate ion beams in the 100-200 MeV energy range with relatively low velocity dispersion. This technology can have major implications to medical ion proton cancer therapy since it can provide a relatively inexpensive table-top alternative to the current used traditional cyclotrons. This paper presents a simulation trade-off study of laser driven generation of quasi-monochromatic ion beams in the thin-foil Radiation Pressure Acceleration (RPA) regime. The radiation pressure accelerates the electron cloud, which in its turn transfers accelerates the ions due to the induced longitudinal charge separation fields. A series of two and three-dimensional PIC simulations are presented with emphasis on stabilizing the target plasma against Raleigh-Taylor and modulational instabilities. Such instabilities are known as the main obstacles in achieving monochromatic beams. [4pt] [1] B. Eliasson, C. Lui, et al. New Jour. Phys., 11, 2009.[0pt] [2] F. Pegoraro, S.V. Bulanov. Laser Phys., v19, N 2, 2009.

  18. 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.

  19. A dual agonist of farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5, INT-767, reverses age-related kidney disease in mice.

    PubMed

    Wang, Xiaoxin X; Luo, Yuhuan; Wang, Dong; Adorini, Luciano; Pruzanski, Mark; Dobrinskikh, Evgenia; Levi, Moshe

    2017-07-21

    Even in healthy individuals, renal function gradually declines during aging. However, an observed variation in the rate of this decline has raised the possibility of slowing or delaying age-related kidney disease. One of the most successful interventional measures that slows down and delays age-related kidney disease is caloric restriction. We undertook the present studies to search for potential factors that are regulated by caloric restriction and act as caloric restriction mimetics. Based on our prior studies with the bile acid-activated nuclear hormone receptor farnesoid X receptor (FXR) and G protein-coupled membrane receptor TGR5 that demonstrated beneficial effects of FXR and TGR5 activation in the kidney, we reasoned that FXR and TGR5 could be excellent candidates. We therefore determined the effects of aging and caloric restriction on the expression of FXR and TGR5 in the kidney. We found that FXR and TGR5 expression levels are decreased in the aging kidney and that caloric restriction prevents these age-related decreases. Interestingly, in long-lived Ames dwarf mice, renal FXR and TGR5 expression levels were also increased. A 2-month treatment of 22-month-old C57BL/6J mice with the FXR-TGR5 dual agonist INT-767 induced caloric restriction-like effects and reversed age-related increases in proteinuria, podocyte injury, fibronectin accumulation, TGF-β expression, and, most notably, age-related impairments in mitochondrial biogenesis and mitochondrial function. Furthermore, in podocytes cultured in serum obtained from old mice, INT-767 prevented the increases in the proinflammatory markers TNF-α, toll-like receptor 2 (TLR2), and TLR4. In summary, our results indicate that FXR and TGR5 may play an important role in modulation of age-related kidney disease. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  20. FXR-mediated down-regulation of CYP7A1 dominates LXRalpha in long-term cholesterol-fed NZW rabbits.

    PubMed

    Xu, Guorong; Li, Hai; Pan, Lu-Xing; Shang, Quan; Honda, Akira; Ananthanarayanan, M; Erickson, Sandra K; Shneider, Benjamin L; Shefer, Sarah; Bollineni, Jaya; Forman, Barry M; Matsuzaki, Yasushi; Suchy, Frederick J; Tint, G Stephen; Salen, Gerald

    2003-10-01

    We investigated how cholesterol feeding regulates cholesterol 7alpha-hydroxylase (CYP7A1) via the nuclear receptors farnesoid X receptor (FXR) and liver X receptor alpha (LXRalpha) in New Zealand white rabbits. After 1 day of 2% cholesterol feeding, when the bile acid pool size had not expanded, mRNA levels of the FXR target genes short-heterodimer partner (SHP) and sterol 12alpha-hydroxylase (CYP8B) were unchanged, indicating that FXR activation remained constant. In contrast, the mRNA levels of the LXRalpha target genes ATP binding cassette transporter A1 (ABCA1) and cholesteryl ester transfer protein (CETP) increased 5-fold and 2.3-fold, respectively, associated with significant increases in hepatic concentrations of oxysterols. Activity and mRNA levels of CYP7A1 increased 2.4 times and 2.2 times, respectively. After 10 days of cholesterol feeding, the bile acid pool size increased nearly 2-fold. SHP mRNA levels increased 4.1-fold while CYP8B declined 64%. ABCA1 mRNA rose 8-fold and CETP mRNA remained elevated. Activity and mRNA of CYP7A1 decreased 60% and 90%, respectively. Feeding cholesterol for 1 day did not enlarge the ligand pool size or change FXR activation, while LXRalpha was activated highly secondary to increased hepatic oxysterols. As a result, CYP7A1 was up-regulated. After 10 days of cholesterol feeding, the bile acid (FXR ligand) pool size increased, which activated FXR and inhibited CYP7A1 despite continued activation of LXRalpha. Thus, in rabbits, when FXR and LXRalpha are activated simultaneously, the inhibitory effect of FXR overrides the stimulatory effect of LXRalpha to suppress CYP7A1 mRNA expression.

  1. Fragile X Proteins FMRP and FXR2P Control Synaptic GluA1 Expression and Neuronal Maturation via Distinct Mechanisms.

    PubMed

    Guo, Weixiang; Polich, Eric D; Su, Juan; Gao, Yu; Christopher, Devin M; Allan, Andrea M; Wang, Min; Wang, Feifei; Wang, Guangfu; Zhao, Xinyu

    2015-06-16

    Fragile X mental retardation protein (FMRP) and its autosomal paralog FXR2P are selective neuronal RNA-binding proteins, and mice that lack either protein exhibit cognitive deficits. Although double-mutant mice display more severe learning deficits than single mutants, the molecular mechanism behind this remains unknown. In the present study, we discovered that FXR2P (also known as FXR2) is important for neuronal dendritic development. FMRP and FXR2P additively promote the maturation of new neurons by regulating a common target, the AMPA receptor GluA1, but they do so via distinct mechanisms: FXR2P binds and stabilizes GluA1 mRNA and enhances subsequent protein expression, whereas FMRP promotes GluA1 membrane delivery. Our findings unveil important roles for FXR2P and GluA1 in neuronal development, uncover a regulatory mechanism of GluA1, and reveal a functional convergence between fragile X proteins in neuronal development. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

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

    PubMed

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

    2012-02-01

    A 2.45 GHz microwave ion source coupled with a magnesium charge exchange canal (C × 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(2) samples from various preparation sources are injected into the source through a glass capillary at 370 μl∕min. Routine system parameters are about 120-140 μA of negative (12)C current after the C × C, leading to about 400 (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.

  3. 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.

  4. Acceleration of Experiment-Based Evolutionary Multi-Objective Optimization Using Fitness Estimation

    NASA Astrophysics Data System (ADS)

    Kaji, Hirotaka; Kita, Hajime

    Evolutionary Multi-objective Optimization (EMO) is expected to be a powerful optimization framework for real world problems such as engineering design. Recent progress in automatic control and instrumentation provides us with a smart environment called Hardware In the Loop Simulation (HILS) for experiment-based optimization. However, since conventional technique of Multi-Objective Evolutionary Algorithms (MOEAs) requires a large number of evaluations, it is difficult to apply it to real world problems of costly evaluation. To make Experiment-Based EMO (EBEMO) using the HILS environment feasible, the most important pre-requisite is reduction of the number of necessary fitness evaluations. In the EBEMO, the performance of the evaluation reduction under uncertainty such as observation noise is highly important, although the previous works often assume noise-free environments. In this paper, we propose an evaluation reduction to overcome the above-mentioned problem by selecting the solution candidates by means of the estimated fitness before applying them to the real experiment in MOEAs. This technique is called ‘Pre-selection’. For the estimation of fitness, we adopt locally weighted regression. The effectiveness of the proposed method was examined by some numerical experiments and also two-objective four-variable optimization problem of a real internal-combustion engine using HILS.

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

    PubMed

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

    2014-12-01

    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. 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. For relatively large and complex three-field head and neck cases, i.e., >100,000 spots with a target volume of ∼ 1000 cm(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. 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 45,000 dollars. The fast calculation and

  6. 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

  7. Optimization of the LBNL Laser Wakefield Accelerator as a Compact, Powerful Terahertz Source

    NASA Astrophysics Data System (ADS)

    Plateau, Guillaume; Matlis, Nicholas; van Tilborg, Jeroen; Nakamura, Kei; Geddes, Cameron; Toth, Csaba; Schroeder, Carl; Esarey, Eric; Leemans, Wim

    2007-11-01

    At LBNL, laser wakefield accelerators (LWFA) routinely produce ultrashort electron bunches with energies up to 1 GeV [1]. As femtosecond electron bunches exit the plasma they radiate a strong burst in the terahertz range [2,3] via coherent transition radiation (CTR). Measuring the CTR properties allows non-invasive bunch-length diagnostics [4], a key to continuing rapid advance in LWFA technology. We present measurements demonstrating both the shot-to-shot stability of bunch parameters, and femtosecond synchronization between the bunch, the THz pulse, and the laser beam. In addition we present a technique for enhancing CTR generation from LWFA-produced electron beams, increasing its suitability for applications. [1] W.P. Leemans et al., Nature Physics 2, 696 (2006); [2] W.P. Leemans et al., PRL 91, 074802 (2003); [3] C.B. Schroeder et al., PRE 69, 016501 (2004); [4] J. van Tilborg et al., PRL 96, 014801 (2006)

  8. Optimizing scan parameters for antibody microarray experiments: accelerating robust systems diagnostics for life sciences.

    PubMed

    Gu, Qiang; Sivanandam, Thamil Mani

    2014-06-01

    Microarray experiments are a centerpiece of postgenomics life sciences and the current efforts to develop systems diagnostics for personalized medicine. The majority of antibody microarray experiments are fluorescence-based, which utilizes a scanner to convert target signals into image files for subsequent quantification. Certain scan parameters such as the laser power and photomultiplier tube gain (PMT) can influence the readout of fluorescent intensities and thus may affect data quantitation. To date, however, there is no consensus of how to determine the optimal settings of microarray scanners. Here we show that different settings of the laser power and PMT not only affect the signal intensities but also the accuracy of antibody microarray experiments. More importantly, we demonstrate an experimental approach using two fluorescent dyes to determine optimal settings of scan parameters for microarray experiments. These measures provide added quality control of microarray experiments, and thus help to improve the accuracy of quantitative outcome in microarray experiments in the above contexts.

  9. 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.

  10. 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. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. 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

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

    PubMed

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

    2012-10-01

    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. A mobile light intraoperative accelerator (LIAC(®), 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(TM) EBT and EBT2) in PMMA and in a Solid Water(®) 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. 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(®) 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 reduced, both R(50) and R(max) move towards the phantom surface. Comparing the

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

    PubMed Central

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

    2010-01-01

    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

  14. Optimized undulator to generate low energy photons from medium to high energy accelerators

    NASA Astrophysics Data System (ADS)

    Chung, Ting-Yi; Chiu, Mau-Sen; Luo, Hao-Wen; Yang, Chin-Kang; Huang, Jui-Che; Jan, Jyh-Chyuan; Hwang, Ching-Shiang

    2017-07-01

    While emitting low energy photons from a medium or high energy storage ring, the on-axis heat load on the beam line optics can become a critical issue. In addition, the heat load in the bending magnet chamber, especially in the vertical and circular polarization mode of operation may cause some concern. In this work, we compare the heat loads for the APPLE-II and the Knot-APPLE, both optimized to emit 10 eV photons from the 3 GeV TPS. Under this constraint the heat load analysis, synchrotron radiation performance and features in various polarization modes are presented. Additional consideration is given to beam dynamics effect.

  15. A version of the Trasco Intense Proton Source optimized for accelerator driven system purposes

    NASA Astrophysics Data System (ADS)

    Ciavola, G.; Celona, L.; Gammino, S.; Presti, M.; Andò, L.; Passarello, S.; Zhang, XZh.; Consoli, F.; Chines, F.; Percolla, C.; Calzona, V.; Winkler, M.

    2004-05-01

    A full set of measurements of the magnetic field has been carried out to define a different design of the TRASCO Intense Proton Source (TRIPS) magnetic system, based on permanent magnets, in order to increase the reliability of the source. The two coils of the source generate a maximum field of 150 mT and the optimum field was determined around 95 mT. The OPERA-3D package was used to simulate the magnetic field and a new magnetic system was designed as a combination of three rings of NdFeB magnets and soft iron. The high voltage insulation has been completely modified, in order to avoid any electronics at 80 kV voltage. The description of the magnetic measurements and the comparison with the simulations are presented, along with the mechanical design of the new version permanent magnet TRIPS (PM-TRIPS) and the new design of the extraction system. Finally the modification of the low energy beam transfer line (LEBT), which now includes a 30° bending magnet, will be outlined, with special regard to the accelerator availability improvement which can be obtained with the installation of two PM-TRIPS sources or more on the LEBT.

  16. MicroRNA-194 inhibition improves dietary-induced non-alcoholic fatty liver disease in mice through targeting on FXR.

    PubMed

    Nie, Hezhongrong; Song, Chunli; Wang, Daming; Cui, Shengjin; Ren, Tingyu; Cao, Zhaopeng; Liu, Qing; Chen, Zeyan; Chen, Xiaoyong; Zhou, Yiwen

    2017-09-22

    Non-alcoholic fatty liver disease (NAFLD) affects obesity-associated metabolic syndrome, which exhibits hepatic steatosis, insulin insensitivity and glucose intolerance. Previous studies indicated that hepatic microRNAs (miRs) play critical roles in the development of NAFLD. In this study, we aim to explore the pathophysiological role of miR-194 in obesity-mediated metabolic dysfunction. Our findings show that the high fat diet or palmitic acid treatment significantly increase hepatic miR-194 levels in vivo and in vitro. Silence of miR-194 protects palmitic acid-induced inflammatory response in cultured hepatocytes, and attenuates structural disorders, lipid deposits and inflammatory response in fatty liver. MiR-194 inhibitor also improves glucose and insulin intolerance in obese mice. Through dual luciferase assay, we demonstrate that miR-194 directly binds to FXR/Nr1h4 3'-UTR, and inhibits gene expression of FXR/Nr1h4. Furthermore, overexpression of miR-194 downregulates FXR/Nr1h4 in cultured hepatocytes, but miR-194 inhibitor reversely increases FXR/Nr1h4 expression in obese mouse liver tissues. On the contrast, silence of FXR/Nr1h4 abolishes the hepatic benefits in obese mice treated with miR-194 inhibitor. Present study provides a novel finding that suppression of miR-194 attenuates dietary-induced NAFLD via upregulation of FXR/Nr1h4. The findings suggest miR-194/FXR are potential diagnostic markers and therapeutic targets for NAFLD. Copyright © 2017. Published by Elsevier B.V.

  17. Design and optimization of Compact Linear Collider main linac accelerating structure

    NASA Astrophysics Data System (ADS)

    Zha, Hao; Grudiev, Alexej

    2016-11-01

    The Compact Linear Collider (CLIC) main linac uses waveguide damped structure as its baseline design. The current baseline structure design written in the CLIC Conceptual Design Report is named "CLIC-G." Recent activities on the CLIC-G design including high power tests on structure prototypes and the study of machining cost assessment had raised the need of reoptimizing the structure design to minimize the machining cost and the pulse surface temperature rise. This work presents optimization of the structure geometry, high-order-mode (HOM) damping loads and the design of a HOM-free power splitter for the input coupler. Compared to the current baseline design CLIC-G, the new structure design reduced the pulse surface temperature rise, input power and manufacturing cost and achieves better suppression to the long range transverse wakefield. Cell disks and damping loads for the new structure design are also more compact than those of the CLIC-G design.

  18. 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.

  19. Cyclosporin A induced toxicity in mouse liver slices is only slightly aggravated by Fxr-deficiency and co-occurs with upregulation of pro-inflammatory genes and downregulation of genes involved in mitochondrial functions.

    PubMed

    Szalowska, Ewa; Pronk, Tessa E; Peijnenburg, Ad Acm

    2015-10-20

    The transcription factor farnesoid X receptor (FXR) governs bile acid and energy homeostasis, is involved in inflammation, and has protective functions in the liver. In the present study we investigated the effect of Fxr deficiency in mouse precision cut liver slices (PCLS) exposed to a model hepatotoxicant cyclosporin A (CsA). It was anticipated that Fxr deficiency could aggravate toxicity of CsA in PCLS and pinpoint to novel genes/processes regulated by FXR. To test this hypothesis, PCLS obtained from livers of wild type mice (WT-PCLS) and Fxr-knockout mice (FXRKO-PCLS) were treated with 40 μM CsA for 24 h and 48 h. ATP and histological assays were applied to assess the viability of PCLS. DNA microarrays combined with bioinformatics analysis were used to identify genes and processes that were affected by CsA in WT-PCLS and/or FXRKO-PCLS. In addition, WT-PCLS and FXRKO-PCLS were exposed to the endogenous FXR ligand chenodeoxycholic acid (CDCA) and subjected to q-PCR to determine whether subsets of known FXR-targets and the identified genes were regulated upon FXR activation in an FXR-dependent manner. No difference in viability was observed between WT-PCLS and FXRKO-PCLS upon CsA treatment. Transcriptomics data analysis revealed that CsA significantly upregulated stress-response and inflammation and significantly downregulated processes involved in lipid and glucose metabolism in WT-PCLS and FXRKO-PCLS. However, only in FXRKO-PCLS, CsA upregulated additional pro-inflammatory genes and downregulated genes related to mitochondrial functions. Furthermore, only in WT-PCLS, CDCA upregulated a subset of known FXR-target genes as well as the regulator of inflammation and mitochondrial functions peroxisome proliferator- activated receptor delta (Ppar delta). Although FXR governs energy metabolism, no major differences in response to CsA could be observed between WT-PCLS and FXRKO-PCLS in regulation of processes involved in lipid and glucose metabolism. This finding

  20. New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond.

    PubMed

    Beuers, Ulrich; Trauner, Michael; Jansen, Peter; Poupon, Raoul

    2015-04-01

    Cholestasis is an impairment of bile formation/flow at the level of the hepatocyte and/or cholangiocyte. The first, and for the moment, most established medical treatment is the natural bile acid (BA) ursodeoxycholic acid (UDCA). This secretagogue improves, e.g. in intrahepatic cholestasis of pregnancy or early stage primary biliary cirrhosis, impaired hepatocellular and cholangiocellular bile formation mainly by complex post-transcriptional mechanisms. The limited efficacy of UDCA in various cholestatic conditions urges for development of novel therapeutic approaches. These include nuclear and membrane receptor agonists and BA derivatives. The nuclear receptors farnesoid X receptor (FXR), retinoid X receptor (RXR), peroxisome proliferator-activated receptor α (PPARα), and pregnane X receptor (PXR) are transcriptional modifiers of bile formation and at present are under investigation as promising targets for therapeutic interventions in cholestatic disorders. The membrane receptors fibroblast growth factor receptor 4 (FGFR4) and apical sodium BA transporter (ASBT) deserve attention as additional therapeutic targets, as does the potential therapeutic agent norUDCA, a 23-C homologue of UDCA. Here, we provide an overview on established and future promising therapeutic agents and their potential molecular mechanisms and sites of action in cholestatic diseases.

  1. Beam tests on the 4-kA, 1. 5-MeV injector for FXR

    SciTech Connect

    Kulke, B.; Kihara, R.; Ravenscroft, D.; Scarpetti, R.; Vogtlin, G.

    1981-01-01

    The new flash x-ray machine (FXR) at Lawrence Livermore National Laboratory is scheduled for completion in late 1981. This is a 54 module, linear induction accelertor, designed to deliver 500 Roentgen at 1 m as bremsstrahlung from a 20 MeV, 4 kA, 60 ns pulsed electron beam. The 9 cm diameter, cold-cathode electron source generates a 15 kA emitted beam at 1.5 MeV, and collimation is being used to reduce the transmitted current to 3.5 kA, with an emittance of 70 mr-cm. The collimated beam diameter is 4 cm. Six ferrite-loaded cavities are used in tandem to energize the injector. The high voltage performance of the injector cavities and other pulsed-power conditioning elements was tested earlier in a series of 10/sup 5/ shots at 400 kV per cavity. An overview of the injector design and of the beam test results is given.

  2. The Path to High Q-Factors in Superconducting Accelerating Cavities: Flux Expulsion and Surface Resistance Optimization

    SciTech Connect

    Martinello, Martina

    2016-12-01

    Accelerating cavities are devices resonating in the radio-frequency (RF) range used to accelerate charged particles in accelerators. Superconducting accelerating cavities are made out of niobium and operate at the liquid helium temperature. Even if superconducting, these resonating structures have some RF driven surface resistance that causes power dissipation. In order to decrease as much as possible the power losses, the cavity quality factor must be increased by decreasing the surface resistance. In this dissertation, the RF surface resistance is analyzed for a large variety of cavities made with different state-of-the-art surface treatments, with the goal of finding the surface treatment capable to return the highest Q-factor values in a cryomodule-like environment. This study analyzes not only the superconducting properties described by the BCS surface resistance, which is the contribution that takes into account dissipation due to quasi-particle excitations, but also the increasing of the surface resistance due to trapped flux. When cavities are cooled down below their critical temperature inside a cryomodule, there is always some remnant magnetic field that may be trapped increasing the global RF surface resistance. This thesis also analyzes how the fraction of external magnetic field, which is actually trapped in the cavity during the cooldown, can be minimized. This study is performed on an elliptical single-cell horizontally cooled cavity, resembling the geometry of cavities cooled in accelerator cryomodules. The horizontal cooldown study reveals that, as in case of the vertical cooldown, when the cooling is performed fast, large thermal gradients are created along the cavity helping magnetic flux expulsion. However, for this geometry the complete magnetic flux expulsion from the cavity equator is more difficult to achieve. This becomes even more challenging in presence of orthogonal magnetic field, that is easily trapped on top of the cavity equator

  3. The path to high Q-factors in superconducting accelerating cavities: Flux expulsion and surface resistance optimization

    NASA Astrophysics Data System (ADS)

    Martinello, Martina

    Accelerating cavities are devices resonating in the radio-frequency (RF) range used to accelerate charged particles in accelerators. Superconducting accelerating cavities are made out of niobium and operate at the liquid helium temperature. Even if superconducting, these resonating structures have some RF driven surface resistance that causes power dissipation. In order to decrease as much as possible the power losses, the cavity quality factor must be increased by decreasing the surface resistance. In this dissertation, the RF surface resistance is analyzed for a large variety of cavities made with different state-of-the-art surface treatments, with the goal of finding the surface treatment capable to return the highest Q-factor values in a cryomodule-like environment. This study analyzes not only the superconducting properties described by the BCS surface resistance, which is the contribution that takes into account dissipation due to quasi-particle excitations, but also the increasing of the surface resistance due to trapped flux. When cavities are cooled down below their critical temperature inside a cryomodule, there is always some remnant magnetic field that may be trapped increasing the global RF surface resistance. This thesis also analyzes how the fraction of external magnetic field, which is actually trapped in the cavity during the cooldown, can be minimized. This study is performed on an elliptical single-cell horizontally cooled cavity, resembling the geometry of cavities cooled in accelerator cryomodules. The horizontal cooldown study reveals that, as in case of the vertical cooldown, when the cooling is performed fast, large thermal gradients are created along the cavity helping magnetic flux expulsion. However, for this geometry the complete magnetic flux expulsion from the cavity equator is more difficult to achieve. This becomes even more challenging in presence of orthogonal magnetic field, that is easily trapped on top of the cavity equator

  4. Retinoic acid represses CYP7A1 expression in human hepatocytes and HepG2 cells by FXR/RXR-dependent and independent mechanisms.

    PubMed

    Cai, Shi-Ying; He, Hongwei; Nguyen, Trong; Mennone, Albert; Boyer, James L

    2010-08-01

    Cholesterol 7alpha-hydroxylase (CYP7A1) plays a key role in maintaining lipid and bile salt homeostasis as it is the rate-limiting enzyme converting cholesterol to bile acids. Deficiency of CYP7A1 leads to hyperlipidemia in man and mouse. Hyperlipidemia is often seen in patients when treated with high-dose retinoic acid (RA), but the molecular mechanisms remain elusive. Our present study revealed that CYP7A1 mRNA expression is greatly repressed by RA in both human hepatocytes and HepG2 cells where increased fibroblast growth factor 19 (FGF19) and small heterodimer partner (SHP) expressions were also observed, suggesting farnesoid X receptor (FXR) and retinoid X receptor (RXR) were activated. Promoter reporter assays demonstrate that all-trans RA (atRA) specifically activated FXR/RXR. However, detailed molecular analyses indicate that this activation is through RXR, whose ligand is 9-cis RA. Knocking down of FXR or RXRalpha by small interference RNA (siRNA) in human hepatocytes increased CYP7A1 basal expression, but the repressive effect of atRA persisted, suggesting there are also FXR/RXR-independent mechanisms mediating atRA repression of CYP7A1 expression. Chromatin immunoprecipitation (ChIP) assay and cell transfection results indicate that PGC-1alpha plays a role in the FXR/RXR-independent mechanism. Our findings may provide a potential explanation for hyperlipidemic side effects observed in some patients treated with high-dose RA.

  5. 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

  6. 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.

  7. 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.

  8. 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

    2016-09-12

    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.

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

    PubMed Central

    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

  10. Inactivation of Adenomatous Polyposis Coli Reduces Bile Acid/Farnesoid X Receptor Expression through Fxr gene CpG Methylation in Mouse Colon Tumors and Human Colon Cancer Cells.

    PubMed

    Selmin, Ornella I; Fang, Changming; Lyon, Adam M; Doetschman, Tom C; Thompson, Patricia A; Martinez, Jesse D; Smith, Jeffrey W; Lance, Peter M; Romagnolo, Donato F

    2016-02-01

    The farnesoid X receptor (FXR) regulates bile acid (BA) metabolism and possesses tumor suppressor functions. FXR expression is reduced in colorectal tumors of subjects carrying inactivated adenomatous polyposis coli (APC). Identifying the mechanisms responsible for this reduction may offer new molecular targets for colon cancer prevention. We investigated how APC inactivation influences the regulation of FXR expression in colonic mucosal cells. We hypothesized that APC inactivation would epigenetically repress nuclear receptor subfamily 1, group H, member 4 (FXR gene name) expression through increased CpG methylation. Normal proximal colonic mucosa and normal-appearing adjacent colonic mucosa and colon tumors were collected from wild-type C57BL/6J and Apc-deficient (Apc(Min) (/+)) male mice, respectively. The expression of Fxr, ileal bile acid-binding protein (Ibabp), small heterodimer partner (Shp), and cyclooxygenase-2 (Cox-2) were determined by real-time polymerase chain reaction. In both normal and adjacent colonic mucosa and colon tumors, we measured CpG methylation of Fxr in bisulfonated genomic DNA. In vitro, we measured the impact of APC inactivation and deoxycholic acid (DCA) treatment on FXR expression in human colon cancer HCT-116 cells transfected with silencing RNA for APC and HT-29 cells carrying inactivated APC. In Apc(Min) (/+) mice, constitutive CpG methylation of the Fxrα3/4 promoter was linked to reduced (60-90%) baseline Fxr, Ibabp, and Shp and increased Cox-2 expression in apparently normal adjacent mucosa and colon tumors. Apc knockdown in HCT-116 cells increased cellular myelocytomatosis (c-MYC) and lowered (∼50%) FXR expression, which was further reduced (∼80%) by DCA. In human HCT-116 but not HT-29 colon cancer cells, DCA induced FXR expression and lowered CpG methylation of FXR. We conclude that the loss of APC function favors the silencing of FXR expression through CpG hypermethylation in mouse colonic mucosa and human colon cells

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

    PubMed

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

    2012-03-07

    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 (D(p)). Heart and ipsilateral lung receiving 5% D(p) and 15% D(p), respectively, was 3.2-3.6 times lower for CARMEN plans. Ipsilateral breast receiving 50% D(p) and 100% D(p) 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.

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

    PubMed Central

    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

  13. 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

    2016-03-03

    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.

  14. FXR agonists enhance the sensitivity of biliary tract cancer cells to cisplatin via SHP dependent inhibition of Bcl-xL expression

    PubMed Central

    Wang, Wei; Zhan, Ming; Li, Qi; Chen, Wei; Chu, Huiling; Huang, Qihong; Hou, Zhaoyuan; Man, Mohan; Wang, Jian

    2016-01-01

    Chemoresistance is common in patients with biliary tract cancer (BTC) including gallbladder cancer (GBC) and cholangiocarcinoma (CC). Therefore, it is necessary to identify effective chemotherapeutic agents for BTC. In the present study, we for the first time tested the effect of farnesoid X receptor (FXR) agonists GW4064 and CDCA (chenodeoxycholic acid) in combination with cisplatin (CDDP) on increasing the chemosensitivity in BTC. Our results show that co-treatment of CDDP with FXR agonists remarkably enhance chemosensitivity of BTC cells. Mechanistically, we found that activation of FXR induced expression of small heterodimer partner (SHP), which in turn inhibited signal transducer and activator of transcription 3 (STAT3) phosphorylation and resulted in down-regulation of Bcl-xL expression in BTC cells, leading to increased susceptibility to CDDP. Moreover, the experiments on tumor-bearing mice showed that GW4064/CDDP co-treatment inhibited the tumor growth in vivo by up-regulating SHP expression and down-regulating STAT3 phosphorylation. These results suggest CDDP in combination with FXR agonists could be a potential new therapeutic strategy for BTC. PMID:27127878

  15. 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.

  16. The EMG activity-acceleration relationship to quantify the optimal vibration load when applying synchronous whole-body vibration.

    PubMed

    Di Giminiani, Riccardo; Masedu, Francesco; Padulo, Johnny; Tihanyi, Jozsef; Valenti, Marco

    2015-12-01

    To date are lacking methodological approaches to individualizing whole-body vibration (WBV) intensity. The aim of this study was: (1) to determine the surface-electromyography-root-mean-square (sEMG(RMS))-acceleration load relationship in the vastus lateralis (VL), vastus medialis (VM), rectus femoris (RF), lateral gastrocnemius (LG) muscles during synchronous WBV, and (2) to assess the reliability of the acceleration corresponding to the maximal sEMG(RMS). Twenty-five sportsman voluntarily took part in this study with a single-group, repeated-measures design. All subjects postured themselves in an isometric half-squat during nine trials in the following conditions: no vibrations and random vibrations of different acceleration loads (from 0.12 to 5.72 g). The sEMG(RMS) were dependent on the acceleration loads in the VL (p = 0.0001), LG (p = 0.0001) and VM (p = 0.011) muscles; while RF was not affected by the acceleration loads (p = 0.508). The comparisons among the sEMG(RMS)-accelerations relationships revealed a significant difference between the LG and the others muscles (p = 0.001). No significant difference was found between the different thigh muscles (p > 0.05). The intra-class correlation coefficient ranged from 0.87 to 0.99 for the measurements performed on the LG, VL and VM. The sEMG(RMS)-acceleration relationship in the VL, VM and LG is a reliable test to individualize the WBV intervention. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. 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.

  18. Gut microbiota-associated bile acid deconjugation accelerates hepatic steatosis in ob/ob mice.

    PubMed

    Park, M-Y; Kim, S J; Ko, E K; Ahn, S-H; Seo, H; Sung, M-K

    2016-09-01

    Nonalcoholic hepatic fat accumulation has been hypothesized to be associated with alterations in gut microbiota composition, although mechanistic explanations for this link are largely insufficient. The aim of this study was to elucidate the microbiota-driven mechanisms involved in the development of nonalcoholic hepatic steatosis. Ob/ob mice and their wild-type lean control mice were fed an AIN-93G diet for 12 weeks. Faecal microbiota composition, faecal bile acid (BA) profile and intestinal and hepatic markers of BA metabolism were analysed. Ob/ob mice had significantly less faecal taurine-conjugated BAs compared to their lean controls. The proportions of butyrate-producing bacteria were lower in ob/ob mice compared to those in lean mice. Intestinal expression of farnesoid X receptor (FXR) mRNA was significantly higher, whereas hepatic expression of cholesterol-7α-hydroxylase 1 (CYP7A1) and small heterodimer partner (SHP) were significantly lower in ob/ob mice compared to those in control mice. Microbiota-associated BAs deconjugation may induce nonalcoholic fatty liver disease (NAFLD) by activating intestinal FXR signalling and blocking hepatic FXR-SHP pathway, thereby accelerating fat synthesis. We provided evidences that changes in the gut microbiota and their metabolites can alter the profile of BAs, thereby providing a mechanism by which an altered microbiota profile contributes to the development of NAFLD. © 2016 The Society for Applied Microbiology.

  19. Processing of radioactive waste by the use of low energy ({le} 100 MeV) charged particle accelerators. Optimization problems

    SciTech Connect

    Mushnikov, V.N.; Ozhigov, L.S.; Khizhnyak, N.A.

    1993-12-31

    The radiation processing of long-lived radiotoxic elements is based on transmutation reactions under the action of various particles and energies. Among the different particle sources the most promising is the proton accelerator. The present work studied the process of radiation deactivation in the stationary proton flux as functions of their flux density and energy. The Bateman-Robinson differential equations were solved.

  20. 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.

  1. Consolidated Tactical Network Analysis for Optimizing Bandwidth: Marine Corps Support Wide Area Network (SWAN) and TCP Accelerators

    DTIC Science & Technology

    2009-09-01

    Engineering Command and the SWAN lab on Camp Pendleton to evaluate components being considered for upgrade. This thesis explores these testing approaches...consulting agencies, the U.S. Army Information Systems Engineering Command and the SWAN lab on Camp Pendleton to evaluate components being considered for...The accelerators will be tested at the Marine Corps Tactical System Support Activity’s (MCTSSA) SWAN lab on Camp Pendleton. This testbed is a

  2. Conceptual design of a pulsed-power accelerator optimized for megajoule-class 1-TPa dynamic-material-physics experiments

    DOE PAGES

    Stygar, William A.; Reisman, David B.; Stoltzfus, Brian S.; ...

    2016-07-07

    In this study, we have developed a conceptual design of a next-generation pulsed-power accelerator that is optmized for driving megajoule-class dynamic-material-physics experiments at pressures as high as 1 TPa. The design is based on an accelerator architecture that is founded on three concepts: single-stage electrical-pulse compression, impedance matching, and transit-time-isolated drive circuits. Since much of the accelerator is water insulated, we refer to this machine as Neptune. The prime power source of Neptune consists of 600 independent impedance-matched Marx generators. As much as 0.8 MJ and 20 MA can be delivered in a 300-ns pulse to a 16-mΩ physics load;more » hence Neptune is a megajoule-class 20-MA arbitrary waveform generator. Neptune will allow the international scientific community to conduct dynamic equation-of-state, phase-transition, mechanical-property, and other material-physics experiments with a wide variety of well-defined drive-pressure time histories. Because Neptune can deliver on the order of a megajoule to a load, such experiments can be conducted on centimeter-scale samples at terapascal pressures with time histories as long as 1 μs.« less

  3. 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

  4. Laser-assisted skin closure (LASC) using a 815-nm diode laser system: determination of an optimal dose to accelerate wound healing

    NASA Astrophysics Data System (ADS)

    Capon, Alexandre; Mitchell, Valerie A.; Sumian, Chryslain C.; Gauthier, Beatrice; Mordon, Serge R.

    1999-01-01

    This study aimed to evaluate a 815 nm diode-laser system to assist wound closure. It was proposed to determine an optimal fluence being able to accelerate and improve heating process without thermal damage after laser irradiation. Male hairless rats with dorsal skin incisions were used for the study. Different fluences were screened (76 to 346 J/cm2) in a first phase with clinical examination at 3, 7, 15 and 21 days after surgery. Best results were obtained for a fluence of 145 J/cm2 and 3 sec time of exposure. A second phase was conducted to valid these parameters with histological study and determination of tensile strength at 3, 7, 15 and 21 days after surgery. LASC was 4 times faster to process than conventional suture. In the laser group with an optimal fluence of 145 J/cm2, healing was accelerated. The resulting scar was more indiscernible than in the control groups. Histological aspect was better with continuous epidermis and dermis at 3 days in most cases. Tensile strength was 30 to 58% greater than in control groups (1141 g/cm2 at 7 days in the laser group versus 856 g/cm2 and 724 g/cm2 in the control groups, p < 0.001).

  5. An atherogenic diet decreases liver FXR gene expression and causes severe hepatic steatosis and hepatic cholesterol accumulation: effect of endurance training.

    PubMed

    Côté, Isabelle; Ngo Sock, Emilienne Tudor; Lévy, Émile; Lavoie, Jean-Marc

    2013-08-01

    The aim of this study was to determine the effects of an atherogenic diet (AD; 40 % lipid, 1.25 % cholesterol, kcal) on triglyceride (TAG) and cholesterol accumulation in liver and on gene expression of liver X receptor (LXR) and farnesoid X receptor (FXR) and their target genes and to observe if these responses are affected by endurance training. Sprague-Dawley rats (n = 32) were divided into two groups and randomly assigned to an AD or a standard diet (SD) for 7 weeks. Half of the rats in each group were assigned to an exercise training program for 5 days/week. The AD resulted in a large (P < 0.01) accumulation in liver TAG (4×) along with elevated liver and plasma cholesterol without any gain in peripheral fat mass. The liver TAG and cholesterol accumulations were associated with an important reduction (P < 0.01; 60 %) in FXR, but no change in LXR transcripts. Accompanying the reduction in FXR gene expression, we found an increase (P < 0.001) in SREBP-1c and a decrease (P < 0.01) in MTP mRNAs suggesting an increased lipogenesis and a reduced VLDL production, respectively. The AD was also associated with lower HMG-CoA-r, squalene synthase, and ABCG8 transcripts (P < 0.001). In the intestine, exercise training resulted in higher NPC1L1, ABCG5, and ABCG8 in SD-fed animals, while all these increases were suppressed under the AD feeding. It is concluded that dietary cholesterol favors liver TAG and cholesterol accumulations associated with an important reduction in FXR transcripts.

  6. The statin class of HMG-CoA reductase inhibitors demonstrate differential activation of the nuclear receptors PXR, CAR and FXR, as well as their downstream target genes.

    PubMed

    Howe, Katharine; Sanat, Faizah; Thumser, Alfred E; Coleman, Tanya; Plant, Nick

    2011-07-01

    The therapeutic class of HMG-CoA reductase inhibitors, the statins are central agents in the treatment of hypercholesterolaemia and the associated conditions of cardiovascular disease, obesity and metabolic syndrome. Although statin therapy is generally considered safe, a number of known adverse effects do occur, most commonly treatment-associated muscular pain. In vitro evidence also supports the potential for drug-drug interactions involving this class of agents, and to examine this a ligand-binding assay was used to determine the ability of six clinically used statins for their ability to directly activate the nuclear receptors pregnane X-receptor (PXR), farnesoid X-receptor (FXR) and constitutive androstane receptor (CAR), demonstrating a relative activation of PXR>FXR>CAR. Using reporter gene constructs, we demonstrated that this order of activation is mirrored at the transcriptional activation level, with PXR-mediated gene activation being pre-eminent. Finally, we described a novel regulatory loop, whereby activation of FXR by statins increases PXR reporter gene expression, potentially enhancing PXR-mediated responses. Delineating the molecular interactions of statins with nuclear receptors is an important step in understanding the full biological consequences of statin exposure. This demonstration of their ability to directly activate nuclear receptors, leading to nuclear receptor cross-talk, has important potential implications for their use within a polypharmacy paradigm.

  7. Accelerating ordered subsets image reconstruction for X-ray CT using spatially non-uniform optimization transfer

    PubMed Central

    Kim, Donghwan; Pal, Debashish; Thibault, Jean-Baptiste; Fessler, Jeffrey A.

    2013-01-01

    Statistical image reconstruction algorithms in X-ray CT provide improved image quality for reduced dose levels but require substantial computation time. Iterative algorithms that converge in few iterations and that are amenable to massive parallelization are favorable in multiprocessor implementations. The separable quadratic surrogate (SQS) algorithm is desirable as it is simple and updates all voxels simultaneously. However, the standard SQS algorithm requires many iterations to converge. This paper proposes an extension of the SQS algorithm that leads to spatially non-uniform updates. The non-uniform (NU) SQS encourages larger step sizes for the voxels that are expected to change more between the current and the final image, accelerating convergence, while the derivation of NU-SQS guarantees monotonic descent. Ordered subsets (OS) algorithms can also accelerate SQS, provided suitable “subset balance” conditions hold. These conditions can fail in 3D helical cone-beam CT due to incomplete sampling outside the axial region-of-interest (ROI). This paper proposes a modified OS algorithm that is more stable outside the ROI in helical CT. We use CT scans to demonstrate that the proposed NU-OS-SQS algorithm handles the helical geometry better than the conventional OS methods and “converges” in less than half the time of ordinary OS-SQS. PMID:23751959

  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

    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

  9. Acceleration of the Particle Swarm Optimization for Peierls–Nabarro modeling of dislocations in conventional and high-entropy alloys

    DOE PAGES

    Pei, Zongrui; Max-Planck-Inst. fur Eisenforschung, Duseldorf; Eisenbach, Markus

    2017-02-06

    Dislocations are among the most important defects in determining the mechanical properties of both conventional alloys and high-entropy alloys. The Peierls-Nabarro model supplies an efficient pathway to their geometries and mobility. The difficulty in solving the integro-differential Peierls-Nabarro equation is how to effectively avoid the local minima in the energy landscape of a dislocation core. Among the other methods to optimize the dislocation core structures, we choose the algorithm of Particle Swarm Optimization, an algorithm that simulates the social behaviors of organisms. By employing more particles (bigger swarm) and more iterative steps (allowing them to explore for longer time), themore » local minima can be effectively avoided. But this would require more computational cost. The advantage of this algorithm is that it is readily parallelized in modern high computing architecture. We demonstrate the performance of our parallelized algorithm scales linearly with the number of employed cores.« less

  10. Acceleration of the Particle Swarm Optimization for Peierls-Nabarro modeling of dislocations in conventional and high-entropy alloys

    NASA Astrophysics Data System (ADS)

    Pei, Zongrui; Eisenbach, Markus

    2017-06-01

    Dislocations are among the most important defects in determining the mechanical properties of both conventional alloys and high-entropy alloys. The Peierls-Nabarro model supplies an efficient pathway to their geometries and mobility. The difficulty in solving the integro-differential Peierls-Nabarro equation is how to effectively avoid the local minima in the energy landscape of a dislocation core. Among the other methods to optimize the dislocation core structures, we choose the algorithm of Particle Swarm Optimization, an algorithm that simulates the social behaviors of organisms. By employing more particles (bigger swarm) and more iterative steps (allowing them to explore for longer time), the local minima can be effectively avoided. But this would require more computational cost. The advantage of this algorithm is that it is readily parallelized in modern high computing architecture. We demonstrate the performance of our parallelized algorithm scales linearly with the number of employed cores.

  11. Optimization-driven identification of genetic perturbations accelerates the convergence of model parameters in ensemble modeling of metabolic networks.

    PubMed

    Zomorrodi, Ali R; Lafontaine Rivera, Jimmy G; Liao, James C; Maranas, Costas D

    2013-09-01

    The ensemble modeling (EM) approach has shown promise in capturing kinetic and regulatory effects in the modeling of metabolic networks. Efficacy of the EM procedure relies on the identification of model parameterizations that adequately describe all observed metabolic phenotypes upon perturbation. In this study, we propose an optimization-based algorithm for the systematic identification of genetic/enzyme perturbations to maximally reduce the number of models retained in the ensemble after each round of model screening. The key premise here is to design perturbations that will maximally scatter the predicted steady-state fluxes over the ensemble parameterizations. We demonstrate the applicability of this procedure for an Escherichia coli metabolic model of central metabolism by successively identifying single, double, and triple enzyme perturbations that cause the maximum degree of flux separation between models in the ensemble. Results revealed that optimal perturbations are not always located close to reaction(s) whose fluxes are measured, especially when multiple perturbations are considered. In addition, there appears to be a maximum number of simultaneous perturbations beyond which no appreciable increase in the divergence of flux predictions is achieved. Overall, this study provides a systematic way of optimally designing genetic perturbations for populating the ensemble of models with relevant model parameterizations.

  12. 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.

  13. 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.

  14. Optimized therapeutic neutron beam for accelerator-based BNCT by analyzing the neutron angular distribution from (7)Li(p,n)(7)Be reaction.

    PubMed

    Kim, Kyung-O; Kim, Jong Kyung; Kim, Soon Young

    2009-01-01

    Perpendicular neutrons (i.e., solid angle bin of 50-150 degrees ) among ones generated from (7)Li(p,n)(7)Be reaction were used to produce an optimized therapeutic neutron beam for accelerator-based BNCT. A new beam port assembly was also designed to shape the fast neutrons into epithermal ones and to reduce unnecessary radiation including gammas. As a result of a simulation, it is found that a tumor at a depth of 60mm from the head skin could be treated within 5 minutes, if a typical tumor is assumed to be taken about 20RBEGy for therapeutic treatment. It is, thus, expected that the neutrons emitted into the solid angle bin of 50-150 degrees from (7)Li(p,n)(7)Be reaction are very effective in producing epithermal neutron beams for BNCT.

  15. Optimism

    PubMed Central

    Carver, Charles S.; Scheier, Michael F.; Segerstrom, Suzanne C.

    2010-01-01

    Optimism is an individual difference variable that reflects the extent to which people hold generalized favorable expectancies for their future. Higher levels of optimism have been related prospectively to better subjective well-being in times of adversity or difficulty (i.e., controlling for previous well-being). Consistent with such findings, optimism has been linked to higher levels of engagement coping and lower levels of avoidance, or disengagement, coping. There is evidence that optimism is associated with taking proactive steps to protect one's health, whereas pessimism is associated with health-damaging behaviors. Consistent with such findings, optimism is also related to indicators of better physical health. The energetic, task-focused approach that optimists take to goals also relates to benefits in the socioeconomic world. Some evidence suggests that optimism relates to more persistence in educational efforts and to higher later income. Optimists also appear to fare better than pessimists in relationships. Although there are instances in which optimism fails to convey an advantage, and instances in which it may convey a disadvantage, those instances are relatively rare. In sum, the behavioral patterns of optimists appear to provide models of living for others to learn from. PMID:20170998

  16. 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.

  17. Can Accelerators Accelerate Learning?

    SciTech Connect

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

    2009-03-10

    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.

  18. 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.

  19. 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.

  20. 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.

  1. Blinded evaluation of farnesoid X receptor (FXR) ligands binding using molecular docking and free energy calculations

    NASA Astrophysics Data System (ADS)

    Selwa, Edithe; Elisée, Eddy; Zavala, Agustin; Iorga, Bogdan I.

    2017-09-01

    Our participation to the D3R Grand Challenge 2 involved a protocol in two steps, with an initial analysis of the available structural data from the PDB allowing the selection of the most appropriate combination of docking software and scoring function. Subsequent docking calculations showed that the pose prediction can be carried out with a certain precision, but this is dependent on the specific nature of the ligands. The correct ranking of docking poses is still a problem and cannot be successful in the absence of good pose predictions. Our free energy calculations on two different subsets provided contrasted results, which might have the origin in non-optimal force field parameters associated with the sulfonamide chemical moiety.

  2. 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.

  3. An overlapping binding site in the CYP7A1 promoter allows activation of FXR to override the stimulation by LXRalpha.

    PubMed

    Shang, Quan; Pan, Luxing; Saumoy, Monica; Chiang, John Y L; Tint, G Stephen; Salen, Gerald; Xu, Guorong

    2007-10-01

    The aim of this study was to explore why in rabbits activation of farnesoid X receptor (FXR) is dominant over activated liver X receptor-alpha (LXRalpha) in the regulation of CYP7A1. We cloned the rabbit CYP7A1 promoter and found a fetoprotein transcription factor (FTF) binding element embedded within the LXRalpha binding site (LXRE). Gel shift assays demonstrated that FTF competes with LXRalpha for binding to LXRE. Short heterodimer partner (SHP) enhances the competitive ability of FTF. Studies in HepG2 cells showed that SHP combined with FTF had more powerful effect to offset the stimulation of CYP7A1 by LXRalpha. Gel shift and chromatin immunoprecipitation assays demonstrated that SHP with FTF diminished LXRalpha binding to the CYP7A1 promoter. In vivo studies in rabbits fed cholesterol for 10 days showed that hepatic expression of SHP but not FTF rose and LXRalpha-bound LXRE decreased. We propose that the SHP/FTF heterodimer occupies LXRE via the embedded FTF binding element and blocks LXRalpha from recruiting to LXRE. Therefore, activation of FXR, which upregulates SHP expression, will eliminate the stimulatory effect of LXRalpha on the CYP7A1 promoter because increased levels of SHP combined with FTF diminish the recruitment of LXRalpha to CYP7A1 promoter.

  4. BAR502, a dual FXR and GPBAR1 agonist, promotes browning of white adipose tissue and reverses liver steatosis and fibrosis

    PubMed Central

    Carino, Adriana; Cipriani, Sabrina; Marchianò, Silvia; Biagioli, Michele; Santorelli, Chiara; Donini, Annibale; Zampella, Angela; Monti, Maria Chiara; Fiorucci, Stefano

    2017-01-01

    Non-alcoholic steatohepatitis (NASH) is a highly prevalent chronic liver disease. Here, we have investigated whether BAR502, a non-bile acid, steroidal dual ligand for FXR and GPBAR1, reverses steato-hepatitis in mice fed a high fat diet (HFD) and fructose. After 9 week, mice on HFD gained ≈30% of b.w (P < 0.01 versus naïve) and were insulin resistant. These overweighting and insulin resistant mice were randomized to receive HFD or HFD in combination with BAR502. After 18 weeks, HFD mice developed NASH like features with severe steato-hepatitis and fibrosis, increased hepatic content of triacylglycerol and cholesterol and expression of SREPB1c, FAS, ApoC2, PPARα and γ, α-SMA, α1 collagen and MCP1 mRNAs. Treatment with BAR502 caused a ≈10% reduction of b.w., increased insulin sensitivity and circulating levels of HDL, while reduced steatosis, inflammatory and fibrosis scores and liver expression of SREPB1c, FAS, PPARγ, CD36 and CYP7A1 mRNA. BAR502 increased the expression of SHP and ABCG5 in the liver and SHP, FGF15 and GLP1 in intestine. BAR502 promoted the browning of epWAT and reduced liver fibrosis induced by CCl4. In summary, BAR502, a dual FXR and GPBAR1 agonist, protects against liver damage caused by HFD by promoting the browning of adipose tissue. PMID:28202906

  5. CEBAF Accelerator Achievements

    NASA Astrophysics Data System (ADS)

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

    2011-05-01

    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.

  6. Breakthrough: Fermilab Accelerator Technology

    ScienceCinema

    None

    2016-07-12

    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.

  7. Future accelerators (?)

    SciTech Connect

    John Womersley

    2003-08-21

    I describe the future accelerator facilities that are currently foreseen for electroweak scale physics, neutrino physics, and nuclear structure. I will explore the physics justification for these machines, and suggest how the case for future accelerators can be made.

  8. SU-F-BRA-14: Optimization of Dosimetric Guidelines for Accelerated Partial Breast Irradiation (APBI) Using the Strut-Adjusted Volume Implant (SAVI)

    SciTech Connect

    Mooney, K; Altman, M; Garcia-Ramirez, J; Thomas, M; Zoberi, I; Mullen, D; DeWees, T; Esthappan, J

    2015-06-15

    Purpose: Treatment planning guidelines for accelerated partial breast irradiation (ABPI) using the strut-adjusted volume implant (SAVI) are inconsistent between the manufacturer and NSABP B-39/RTOG 0413 protocol. Furthermore neither set of guidelines accounts for different applicator sizes. The purpose of this work is to establish guidelines specific to the SAVI that are based on clinically achievable dose distributions. Methods: Sixty-two consecutive patients were implanted with a SAVI and prescribed to receive 34 Gy in 10 fractions twice daily using high dose-rate (HDR) Ir-192 brachytherapy. The target (PTV-EVAL) was defined per NSABP. The treatments were planned and evaluated using a combination of dosimetric planning goals provided by the NSABP, the manufacturer, and our prior clinical experience. Parameters evaluated included maximum doses to skin and ribs, and volumes of PTV-EVAL receiving 90%, 95%, 100%, 150%, and 200% of the prescription (V90, etc). All target parameters were evaluated for correlation with device size using the Pearson correlation coefficient. Revised dosimetric guidelines for target coverage and heterogeneity were determined from this population. Results: Revised guidelines for minimum target coverage (ideal in parentheses): V90≥95%(97%), V95≥90%(95%), V100≥88%(91%). The only dosimetric parameters that were significantly correlated (p<0.05) with device size were V150 and V200. Heterogeneity criteria were revised for the 6–1 Mini/6-1 applicators to V150≤30cc and V200≤15cc, and unchanged for the other sizes. Re-evaluation of patient plans showed 90% (56/62) met the revised minimum guidelines and 76% (47/62) met the ideal guidelines. All and 56/62 patients met our institutional guidelines for maximum skin and rib dose, respectively. Conclusions: We have optimized dosimetric guidelines for the SAVI applicators, and found that implementation of these revised guidelines for SAVI treatment planning yielded target coverage exceeding

  9. New World and Old World Alphaviruses Have Evolved to Exploit Different Components of Stress Granules, FXR and G3BP Proteins, for Assembly of Viral Replication Complexes

    PubMed Central

    Kim, Dal Young; Reynaud, Josephine M.; Rasalouskaya, Aliaksandra; Akhrymuk, Ivan; Mobley, James A.; Frolov, Ilya; Frolova, Elena I.

    2016-01-01

    The positive-strand RNA viruses initiate their amplification in the cell from a single genome delivered by virion. This single RNA molecule needs to become involved in replication process before it is recognized and degraded by cellular machinery. In this study, we show that distantly related New World and Old World alphaviruses have independently evolved to utilize different cellular stress granule-related proteins for assembly of complexes, which recruit viral genomic RNA and facilitate formation of viral replication complexes (vRCs). Venezuelan equine encephalitis virus (VEEV) utilizes all members of the Fragile X syndrome (FXR) family, while chikungunya and Sindbis viruses exploit both members of the G3BP family. Despite being in different families, these proteins share common characteristics, which determine their role in alphavirus replication, namely, the abilities for RNA-binding and for self-assembly into large structures. Both FXR and G3BP proteins interact with virus-specific, repeating amino acid sequences located in the C-termini of hypervariable, intrinsically disordered domains (HVDs) of viral nonstructural protein nsP3. We demonstrate that these host factors orchestrate assembly of vRCs and play key roles in RNA and virus replication. Only knockout of all of the homologs results in either pronounced or complete inhibition of replication of different alphaviruses. The use of multiple homologous proteins with redundant functions mediates highly efficient recruitment of viral RNA into the replication process. This independently evolved acquisition of different families of cellular proteins by the disordered protein fragment to support alphavirus replication suggests that other RNA viruses may utilize a similar mechanism of host factor recruitment for vRC assembly. The use of different host factors by alphavirus species may be one of the important determinants of their pathogenesis. PMID:27509095

  10. Atorvastatin induces bile acid-synthetic enzyme Cyp7a1 by suppressing FXR signaling in both liver and intestine in mice.

    PubMed

    Fu, Zidong Donna; Cui, Julia Yue; Klaassen, Curtis D

    2014-12-01

    Statins are effective cholesterol-lowering drugs to treat CVDs. Bile acids (BAs), the end products of cholesterol metabolism in the liver, are important nutrient and energy regulators. The present study aims to investigate how statins affect BA homeostasis in the enterohepatic circulation. Male C57BL/6 mice were treated with atorvastatin (100 mg/kg/day po) for 1 week, followed by BA profiling by ultra-performance LC-MS/MS. Atorvastatin decreased BA pool size, mainly due to less BA in the intestine. Surprisingly, atorvastatin did not alter total BAs in the serum or liver. Atorvastatin increased the ratio of 12α-OH/non12α-OH BAs. Atorvastatin increased the mRNAs of the BA-synthetic enzymes cholesterol 7α-hydroxylase (Cyp7a1) (over 10-fold) and cytochrome P450 27a1, the BA uptake transporters Na⁺/taurocholate cotransporting polypeptide and organic anion transporting polypeptide 1b2, and the efflux transporter multidrug resistance-associated protein 2 in the liver. Noticeably, atorvastatin suppressed the expression of BA nuclear receptor farnesoid X receptor (FXR) target genes, namely small heterodimer partner (liver) and fibroblast growth factor 15 (ileum). Furthermore, atorvastatin increased the mRNAs of the organic cation uptake transporter 1 and cholesterol efflux transporters Abcg5 and Abcg8 in the liver. The increased expression of BA-synthetic enzymes and BA transporters appear to be a compensatory response to maintain BA homeostasis after atorvastatin treatment. The Cyp7a1 induction by atorvastatin appears to be due to suppressed FXR signaling in both the liver and intestine.

  11. Advanced Accelerators for Medical Applications

    NASA Astrophysics Data System (ADS)

    Uesaka, Mitsuru; Koyama, Kazuyoshi

    We review advanced accelerators for medical applications with respect to the following key technologies: (i) higher RF electron linear accelerator (hereafter "linac"); (ii) optimization of alignment for the proton linac, cyclotron and synchrotron; (iii) superconducting magnet; (iv) laser technology. Advanced accelerators for medical applications are categorized into two groups. The first group consists of compact medical linacs with high RF, cyclotrons and synchrotrons downsized by optimization of alignment and superconducting magnets. The second group comprises laserbased acceleration systems aimed of medical applications in the future. Laser plasma electron/ion accelerating systems for cancer therapy and laser dielectric accelerating systems for radiation biology are mentioned. Since the second group has important potential for a compact system, the current status of the established energy and intensity and of the required stability are given.

  12. Advanced Accelerators for Medical Applications

    NASA Astrophysics Data System (ADS)

    Uesaka, Mitsuru; Koyama, Kazuyoshi

    We review advanced accelerators for medical applications with respect to the following key technologies: (i) higher RF electron linear accelerator (hereafter “linac”); (ii) optimization of alignment for the proton linac, cyclotron and synchrotron; (iii) superconducting magnet; (iv) laser technology. Advanced accelerators for medical applications are categorized into two groups. The first group consists of compact medical linacs with high RF, cyclotrons and synchrotrons downsized by optimization of alignment and superconducting magnets. The second group comprises laser-based acceleration systems aimed of medical applications in the future. Laser plasma electron/ion accelerating systems for cancer therapy and laser dielectric accelerating systems for radiation biology are mentioned. Since the second group has important potential for a compact system, the current status of the established energy and intensity and of the required stability are given.

  13. Radical Acceleration

    ERIC Educational Resources Information Center

    Gross, Miraca U. M.; Van Vliet, Helen E.

    2005-01-01

    Research has found that teachers' objections to accelerating gifted students are mainly based on a fear that acceleration will lead to social or emotional damage. Ironically, it is the academic and emotional maturity which characterizes intellectually gifted students, coupled with their high levels of academic achievement, which makes them such…

  14. RECIRCULATING ACCELERATION

    SciTech Connect

    BERG,J.S.; GARREN,A.A.; JOHNSTONE,C.

    2000-04-07

    This paper compares various types of recirculating accelerators, outlining the advantages and disadvantages of various approaches. The accelerators are characterized according to the types of arcs they use: whether there is a single arc for the entire recirculator or there are multiple arcs, and whether the arc(s) are isochronous or non-isochronous.

  15. Optimizing the acceleration and resolution of three-dimensional fat image navigators for high-resolution motion correction at 7T.

    PubMed

    Gallichan, Daniel; Marques, José P

    2017-02-01

    To investigate the effect of spatial resolution and parallel imaging acceleration factor on the quality of the motion estimates derived from image navigators with a three-dimensional (3D) gradient-recalled echo (GRE) acquisition with fat excitation (3D FatNavs) for neuroimaging at 7T. Six healthy subjects were scanned for 10 min, during which time repeated GRE volumes were acquired during small movements-alternating between fat and water excitations (WaterNavs)-allowing retrospective decimation of the data to simulate a variety of combinations of image resolution and acceleration factor. Bias and error in the motion estimates were then compared across navigator parameters. The 2-mm, 4 × 4 accelerated data (TRvolume  = 1.2 s) provided motion estimates that were almost indistinguishable from those from the full original acquisition (2 mm, 2 × 2, TRvolume  = 5.2 s). For faster navigators, it was found that good accuracy and precision were achievable with TRvolume  = 144 ms, using a lower spatial resolution (4 mm, 6 × 6 acceleration) to avoid the bias observed at exceptionally high acceleration factors (8 × 8 or higher). Parameter estimates from WaterNavs and FatNavs showed close agreement with FatNavs, with better performance at exceptionally high acceleration factors. Our data help to guide the parameter choice for 3D FatNavs when a compromise must be reached between the quality of the motion estimates and the available scan time. Magn Reson Med 77:547-558, 2017. © 2016 International Society for Magnetic Resonance in Medicine. © 2016 International Society for Magnetic Resonance in Medicine.

  16. 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. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. "Light sail" acceleration reexamined.

    PubMed

    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.

  18. '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.

  19. LINEAR ACCELERATOR

    DOEpatents

    Colgate, S.A.

    1958-05-27

    An improvement is presented in linear accelerators for charged particles with respect to the stable focusing of the particle beam. The improvement consists of providing a radial electric field transverse to the accelerating electric fields and angularly introducing the beam of particles in the field. The results of the foregoing is to achieve a beam which spirals about the axis of the acceleration path. The combination of the electric fields and angular motion of the particles cooperate to provide a stable and focused particle beam.

  20. Wakefield accelerators

    SciTech Connect

    Simpson, J.D.

    1990-01-01

    The search for new methods to accelerate particle beams to high energy using high gradients has resulted in a number of candidate schemes. One of these, wakefield acceleration, has been the subject of considerable R D in recent years. This effort has resulted in successful proof of principle experiments and in increased understanding of many of the practical aspects of the technique. Some wakefield basics plus the status of existing and proposed experimental work is discussed, along with speculations on the future of wake field acceleration. 10 refs., 6 figs.

  1. Muon Acceleration - RLA and FFAG

    SciTech Connect

    Bogacz, Alex

    2011-10-01

    Various acceleration schemes for muons are presented. The overall goal of the acceleration systems: large acceptance acceleration to 25 GeV and 'beam shaping' can be accomplished by various fixed field accelerators at different stages. They involve three superconducting linacs: a single pass linear Pre-accelerator followed by a pair of multi-pass Recirculating Linear Accelerators (RLA) and finally a non-scaling FFAG ring. The present baseline acceleration scenario has been optimized to take maximum advantage of appropriate acceleration scheme at a given stage. The solenoid based Pre-accelerator offers very large acceptance and facilitates correction of energy gain across the bunch and significant longitudinal compression trough induced synchrotron motion. However, far off-crest acceleration reduces the effective acceleration gradient and adds complexity through the requirement of individual RF phase control for each cavity. The RLAs offer very efficient usage of high gradient superconducting RF and ability to adjust path-length after each linac pass through individual return arcs with uniformly periodic FODO optics suitable for chromatic compensation of emittance dilution with sextupoles. However, they require spreaders/recombiners switchyards at both linac ends and significant total length of the arcs. The non-scaling Fixed Field Alternating Gradient (FFAG) ring combines compactness with very large chromatic acceptance (twice the injection energy) and it allows for large number of passes through the RF (at least eight, possibly as high as 15).

  2. ION ACCELERATOR

    DOEpatents

    Bell, J.S.

    1959-09-15

    An arrangement for the drift tubes in a linear accelerator is described whereby each drift tube acts to shield the particles from the influence of the accelerating field and focuses the particles passing through the tube. In one embodiment the drift tube is splii longitudinally into quadrants supported along the axis of the accelerator by webs from a yoke, the quadrants. webs, and yoke being of magnetic material. A magnetic focusing action is produced by energizing a winding on each web to set up a magnetic field between adjacent quadrants. In the other embodiment the quadrants are electrically insulated from each other and have opposite polarity voltages on adjacent quadrants to provide an electric focusing fleld for the particles, with the quadrants spaced sufficienily close enough to shield the particles within the tube from the accelerating electric field.

  3. Acceleration switch

    DOEpatents

    Abbin, J.P. Jr.; Devaney, H.F.; Hake, L.W.

    1979-08-29

    The disclosure relates to an improved integrating acceleration switch of the type having a mass suspended within a fluid filled chamber, with the motion of the mass initially opposed by a spring and subsequently not so opposed.

  4. Acceleration switch

    DOEpatents

    Abbin, Jr., Joseph P.; Devaney, Howard F.; Hake, Lewis W.

    1982-08-17

    The disclosure relates to an improved integrating acceleration switch of the type having a mass suspended within a fluid filled chamber, with the motion of the mass initially opposed by a spring and subsequently not so opposed.

  5. LINEAR ACCELERATOR

    DOEpatents

    Christofilos, N.C.; Polk, I.J.

    1959-02-17

    Improvements in linear particle accelerators are described. A drift tube system for a linear ion accelerator reduces gap capacity between adjacent drift tube ends. This is accomplished by reducing the ratio of the diameter of the drift tube to the diameter of the resonant cavity. Concentration of magnetic field intensity at the longitudinal midpoint of the external sunface of each drift tube is reduced by increasing the external drift tube diameter at the longitudinal center region.

  6. Treatment with the natural FXR agonist chenodeoxycholic acid reduces clearance of plasma LDL whilst decreasing circulating PCSK9, lipoprotein(a) and apolipoprotein C-III.

    PubMed

    Ghosh Laskar, M; Eriksson, M; Rudling, M; Angelin, B

    2017-06-01

    The natural farnesoid X receptor (FXR) agonist chenodeoxycholic acid (CDCA) suppresses hepatic cholesterol and bile acid synthesis and reduces biliary cholesterol secretion and triglyceride production. Animal studies have shown that bile acids downregulate hepatic LDL receptors (LDLRs); however, information on LDL metabolism in humans is limited. Kinetics of autologous (125) I-LDL were determined in 12 male subjects at baseline and during treatment with CDCA (15 mg kg(-1) day(-1) ). In seven patients with gallstones treated with CDCA for 3 weeks before cholecystectomy, liver biopsies were collected and analysed for enzyme activities and for specific LDLR binding. Serum samples obtained before treatment and at surgery were analysed for markers of lipid metabolism, lipoproteins and the LDLR modulator proprotein convertase subtilisin/kexin type 9 (PCSK9). Chenodeoxycholic acid treatment increased plasma LDL cholesterol by ~10% as a result of reduced clearance of plasma LDL-apolipoprotein (apo)B; LDL production was somewhat reduced. The reduction in LDL clearance occurred within 1 day after initiation of treatment. In CDCA-treated patients with gallstones, hepatic microsomal cholesterol 7α-hydroxylase and HMG-CoA reductase activities were reduced by 83% and 54%, respectively, and specific LDLR binding was reduced by 20%. During treatment, serum levels of fibroblast growth factor 19 and total and LDL cholesterol increased, whereas levels of 7α-hydroxy-4-cholesten-3-one, lathosterol, PCSK9, apoA-I, apoC-III, lipoprotein(a), triglycerides and insulin were reduced. Chenodeoxycholic acid has a broad influence on lipid metabolism, including reducing plasma clearance of LDL. The reduction in circulating PCSK9 may dampen its effect on hepatic LDLRs and plasma LDL cholesterol. Further studies of the effects of other FXR agonists on cholesterol metabolism in humans seem warranted, considering the renewed interest for such therapy in liver disease and diabetes. © 2017 The

  7. 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. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Advanced accelerator theory development

    SciTech Connect

    Sampayan, S.E.; Houck, T.L.; Poole, B.; Tishchenko, N.; Vitello, P.A.; Wang, I.

    1998-02-09

    A new accelerator technology, the dielectric wall accelerator (DWA), is potentially an ultra compact accelerator/pulsed power driver. This new accelerator relies on three new components: the ultra-high gradient insulator, the asymmetric Blumlein and low jitter switches. In this report, we focused our attention on the first two components of the DWA system the insulators and the asymmetric Blumlein. First, we sought to develop the necessary design tools to model and scale the behavior of the high gradient insulator. To perform this task we concentrated on modeling the discharge processes (i.e., initiation and creation of the surface discharge). In addition, because these high gradient structures exhibit favorable microwave properties in certain accelerator configurations, we performed experiments and calculations to determine the relevant electromagnetic properties. Second, we performed circuit modeling to understand energy coupling to dynamic loads by the asymmetric Blumlein. Further, we have experimentally observed a non-linear coupling effect in certain asymmetric Blumlein configurations. That is, as these structures are stacked into a complete module, the output voltage does not sum linearly and a lower than expected output voltage results. Although we solved this effect experimentally, we performed calculations to understand this effect more fully to allow better optimization of this DWA pulse-forming line system.

  9. CAIPIRINHA accelerated SPACE enables 10-min isotropic 3D TSE MRI of the ankle for optimized visualization of curved and oblique ligaments and tendons.

    PubMed

    Kalia, Vivek; Fritz, Benjamin; Johnson, Rory; Gilson, Wesley D; Raithel, Esther; Fritz, Jan

    2017-09-01

    To test the hypothesis that a fourfold CAIPIRINHA accelerated, 10-min, high-resolution, isotropic 3D TSE MRI prototype protocol of the ankle derives equal or better quality than a 20-min 2D TSE standard protocol. Following internal review board approval and informed consent, 3-Tesla MRI of the ankle was obtained in 24 asymptomatic subjects including 10-min 3D CAIPIRINHA SPACE TSE prototype and 20-min 2D TSE standard protocols. Outcome variables included image quality and visibility of anatomical structures using 5-point Likert scales. Non-parametric statistical testing was used. P values ≤0.001 were considered significant. Edge sharpness, contrast resolution, uniformity, noise, fat suppression and magic angle effects were without statistical difference on 2D and 3D TSE images (p > 0.035). Fluid was mildly brighter on intermediate-weighted 2D images (p < 0.001), whereas 3D images had substantially less partial volume, chemical shift and no pulsatile-flow artifacts (p < 0.001). Oblique and curved planar 3D images resulted in mildly-to-substantially improved visualization of joints, spring, bifurcate, syndesmotic, collateral and sinus tarsi ligaments, and tendons (p < 0.001, respectively). 3D TSE MRI with CAIPIRINHA acceleration enables high-spatial resolution oblique and curved planar MRI of the ankle and visualization of ligaments, tendons and joints equally well or better than a more time-consuming anisotropic 2D TSE MRI. • High-resolution 3D TSE MRI improves visualization of ankle structures. • Limitations of current 3D TSE MRI include long scan times. • 3D CAIPIRINHA SPACE allows now a fourfold-accelerated data acquisition. • 3D CAIPIRINHA SPACE enables high-spatial-resolution ankle MRI within 10 min. • 10-min 3D CAIPIRINHA SPACE produces equal-or-better quality than 20-min 2D TSE.

  10. Acceleration Studies

    NASA Technical Reports Server (NTRS)

    Rogers, Melissa J. B.

    1993-01-01

    Work to support the NASA MSFC Acceleration Characterization and Analysis Project (ACAP) was performed. Four tasks (analysis development, analysis research, analysis documentation, and acceleration analysis) were addressed by parallel projects. Work concentrated on preparation for and implementation of near real-time SAMS data analysis during the USMP-1 mission. User support documents and case specific software documentation and tutorials were developed. Information and results were presented to microgravity users. ACAP computer facilities need to be fully implemented and networked, data resources must be cataloged and accessible, future microgravity missions must be coordinated, and continued Orbiter characterization is necessary.

  11. Genetic algorithms and their applications in accelerator physics

    SciTech Connect

    Hofler, Alicia S.

    2013-12-01

    Multi-objective optimization techniques are widely used in an extremely broad range of fields. Genetic optimization for multi-objective optimization was introduced in the accelerator community in relatively recent times and quickly spread becoming a fundamental tool in multi-dimensional optimization problems. This discussion introduces the basics of the technique and reviews applications in accelerator problems.

  12. Accelerated Achievement

    ERIC Educational Resources Information Center

    Ford, William J.

    2010-01-01

    This article focuses on the accelerated associate degree program at Ivy Tech Community College (Indiana) in which low-income students will receive an associate degree in one year. The three-year pilot program is funded by a $2.3 million grant from the Lumina Foundation for Education in Indianapolis and a $270,000 grant from the Indiana Commission…

  13. Particle acceleration

    NASA Technical Reports Server (NTRS)

    Vlahos, L.; Machado, M. E.; Ramaty, R.; Murphy, R. J.; Alissandrakis, C.; Bai, T.; Batchelor, D.; Benz, A. O.; Chupp, E.; Ellison, D.

    1986-01-01

    Data is compiled from Solar Maximum Mission and Hinothori satellites, particle detectors in several satellites, ground based instruments, and balloon flights in order to answer fundamental questions relating to: (1) the requirements for the coronal magnetic field structure in the vicinity of the energization source; (2) the height (above the photosphere) of the energization source; (3) the time of energization; (4) transistion between coronal heating and flares; (5) evidence for purely thermal, purely nonthermal and hybrid type flares; (6) the time characteristics of the energization source; (7) whether every flare accelerates protons; (8) the location of the interaction site of the ions and relativistic electrons; (9) the energy spectra for ions and relativistic electrons; (10) the relationship between particles at the Sun and interplanetary space; (11) evidence for more than one acceleration mechanism; (12) whether there is single mechanism that will accelerate particles to all energies and also heat the plasma; and (13) how fast the existing mechanisms accelerate electrons up to several MeV and ions to 1 GeV.

  14. ACCELERATION INTEGRATOR

    DOEpatents

    Pope, K.E.

    1958-01-01

    This patent relates to an improved acceleration integrator and more particularly to apparatus of this nature which is gyrostabilized. The device may be used to sense the attainment by an airborne vehicle of a predetermined velocitv or distance along a given vector path. In its broad aspects, the acceleration integrator utilizes a magnetized element rotatable driven by a synchronous motor and having a cylin drical flux gap and a restrained eddy- current drag cap deposed to move into the gap. The angular velocity imparted to the rotatable cap shaft is transmitted in a positive manner to the magnetized element through a servo feedback loop. The resultant angular velocity of tae cap is proportional to the acceleration of the housing in this manner and means may be used to measure the velocity and operate switches at a pre-set magnitude. To make the above-described dcvice sensitive to acceleration in only one direction the magnetized element forms the spinning inertia element of a free gyroscope, and the outer housing functions as a gimbal of a gyroscope.

  15. Plasma accelerator

    DOEpatents

    Wang, Zhehui; Barnes, Cris W.

    2002-01-01

    There has been invented an apparatus for acceleration of a plasma having coaxially positioned, constant diameter, cylindrical electrodes which are modified to converge (for a positive polarity inner electrode and a negatively charged outer electrode) at the plasma output end of the annulus between the electrodes to achieve improved particle flux per unit of power.

  16. Accelerated Achievement

    ERIC Educational Resources Information Center

    Ford, William J.

    2010-01-01

    This article focuses on the accelerated associate degree program at Ivy Tech Community College (Indiana) in which low-income students will receive an associate degree in one year. The three-year pilot program is funded by a $2.3 million grant from the Lumina Foundation for Education in Indianapolis and a $270,000 grant from the Indiana Commission…

  17. Suppressing Thermal Energy Drift In The LLNL Flash X-Ray Accelerator Using Linear Disk Resistor Stacks

    SciTech Connect

    Kreitzer, B R; Houck, T L; Luchterhand, O C

    2011-07-19

    This paper addresses thermal drift in sodium thiosulfate liquid resistors and their replacement with linear disk resistors from HVR Advanced Power Components. Sodium thiosulfate resistors in the FXR induction linear accelerator application have a temperature coefficient of {approx}1.8%/C. The FXR Marx banks send an 8kJ pulse through eight 524 cm{sup 3} liquid resistors at a repetition rate of up to 1 every 45 seconds. Every pulse increases the temperature of the solution by {approx}0.4 C which produces a 0.7% change in resistance. The typical cooling rate is {approx}0.4 C per minute which results in {approx}0.1% energy drop per pulse during continuous pulsed operations. A radiographic accelerator is extraordinarily sensitive to energy variations. Changes in beam energy produce movement in beam transport, changes in spot size, and large dose variations. If self-heating were the only problem, we could predict the increase in input voltage required to compensate for the energy loss. However, there are other variables that influence the temperature of the resistors such as focus magnet heating, changes in room temperature, changes in cooling water, where the cell is located, etc. Additionally not all of the resistors have equivalent cooling rates and as many as 32 resistors are driven from a single power source. The FXR accelerator group elected to replace the sodium thiosulfate resistors with HVR Linear Disk Resistors in a stack type configuration. With data limited for these resistors when used in oil and at low resistance values, a full characterization needed to be performed. High currents (up to 15kA), high voltages (up to 400kV), and Fast Rise times (<10ns) made a resistor choice difficult. Other solid resistors have been tried and had problems at the connection points and with the fact that the resistivity changed as they absorbed oil. The selected HVR resistors have the advantage of being manufactured with the oil impregnated in to them so this characteristic

  18. Particle Accelerators in China

    NASA Astrophysics Data System (ADS)

    Zhang, Chuang; Fang, Shouxian

    As the special machines that can accelerate charged particle beams to high energy by using electromagnetic fields, particle accelerators have been widely applied in scientific research and various areas of society. The development of particle accelerators in China started in the early 1950s. After a brief review of the history of accelerators, this article describes in the following sections: particle colliders, heavy-ion accelerators, high-intensity proton accelerators, accelerator-based light sources, pulsed power accelerators, small scale accelerators, accelerators for applications, accelerator technology development and advanced accelerator concepts. The prospects of particle accelerators in China are also presented.

  19. Accelerated Profile HMM Searches.

    PubMed

    Eddy, Sean R

    2011-10-01

    Profile hidden Markov models (profile HMMs) and probabilistic inference methods have made important contributions to the theory of sequence database homology search. However, practical use of profile HMM methods has been hindered by the computational expense of existing software implementations. Here I describe an acceleration heuristic for profile HMMs, the "multiple segment Viterbi" (MSV) algorithm. The MSV algorithm computes an optimal sum of multiple ungapped local alignment segments using a striped vector-parallel approach previously described for fast Smith/Waterman alignment. MSV scores follow the same statistical distribution as gapped optimal local alignment scores, allowing rapid evaluation of significance of an MSV score and thus facilitating its use as a heuristic filter. I also describe a 20-fold acceleration of the standard profile HMM Forward/Backward algorithms using a method I call "sparse rescaling". These methods are assembled in a pipeline in which high-scoring MSV hits are passed on for reanalysis with the full HMM Forward/Backward algorithm. This accelerated pipeline is implemented in the freely available HMMER3 software package. Performance benchmarks show that the use of the heuristic MSV filter sacrifices negligible sensitivity compared to unaccelerated profile HMM searches. HMMER3 is substantially more sensitive and 100- to 1000-fold faster than HMMER2. HMMER3 is now about as fast as BLAST for protein searches.

  20. Compact accelerator

    DOEpatents

    Caporaso, George J.; Sampayan, Stephen E.; Kirbie, Hugh C.

    2007-02-06

    A compact linear accelerator having at least one strip-shaped Blumlein module which guides a propagating wavefront between first and second ends and controls the output pulse at the second end. Each Blumlein module has first, second, and third planar conductor strips, with a first dielectric strip between the first and second conductor strips, and a second dielectric strip between the second and third conductor strips. Additionally, the compact linear accelerator includes a high voltage power supply connected to charge the second conductor strip to a high potential, and a switch for switching the high potential in the second conductor strip to at least one of the first and third conductor strips so as to initiate a propagating reverse polarity wavefront(s) in the corresponding dielectric strip(s).

  1. MUON ACCELERATION

    SciTech Connect

    BERG,S.J.

    2003-11-18

    One of the major motivations driving recent interest in FFAGs is their use for the cost-effective acceleration of muons. This paper summarizes the progress in this area that was achieved leading up to and at the FFAG workshop at KEK from July 7-12, 2003. Much of the relevant background and references are also given here, to give a context to the progress we have made.

  2. BICEP's acceleration

    SciTech Connect

    Contaldi, Carlo R.

    2014-10-01

    The recent Bicep2 [1] detection of, what is claimed to be primordial B-modes, opens up the possibility of constraining not only the energy scale of inflation but also the detailed acceleration history that occurred during inflation. In turn this can be used to determine the shape of the inflaton potential V(φ) for the first time — if a single, scalar inflaton is assumed to be driving the acceleration. We carry out a Monte Carlo exploration of inflationary trajectories given the current data. Using this method we obtain a posterior distribution of possible acceleration profiles ε(N) as a function of e-fold N and derived posterior distributions of the primordial power spectrum P(k) and potential V(φ). We find that the Bicep2 result, in combination with Planck measurements of total intensity Cosmic Microwave Background (CMB) anisotropies, induces a significant feature in the scalar primordial spectrum at scales k∼ 10{sup -3} Mpc {sup -1}. This is in agreement with a previous detection of a suppression in the scalar power [2].

  3. Laser acceleration

    NASA Astrophysics Data System (ADS)

    Tajima, T.; Nakajima, K.; Mourou, G.

    2017-02-01

    The fundamental idea of Laser Wakefield Acceleration (LWFA) is reviewed. An ultrafast intense laser pulse drives coherent wakefield with a relativistic amplitude robustly supported by the plasma. While the large amplitude of wakefields involves collective resonant oscillations of the eigenmode of the entire plasma electrons, the wake phase velocity ˜ c and ultrafastness of the laser pulse introduce the wake stability and rigidity. A large number of worldwide experiments show a rapid progress of this concept realization toward both the high-energy accelerator prospect and broad applications. The strong interest in this has been spurring and stimulating novel laser technologies, including the Chirped Pulse Amplification, the Thin Film Compression, the Coherent Amplification Network, and the Relativistic Mirror Compression. These in turn have created a conglomerate of novel science and technology with LWFA to form a new genre of high field science with many parameters of merit in this field increasing exponentially lately. This science has triggered a number of worldwide research centers and initiatives. Associated physics of ion acceleration, X-ray generation, and astrophysical processes of ultrahigh energy cosmic rays are reviewed. Applications such as X-ray free electron laser, cancer therapy, and radioisotope production etc. are considered. A new avenue of LWFA using nanomaterials is also emerging.

  4. Intestine-specific Deletion of Sirt1 in Mice Impairs DCoH2–HNF1α–FXR Signaling and Alters Systemic Bile Acid Homeostasis

    PubMed Central

    Kazgan, Nevzat; Metukuri, Mallikarjuna R.; Purushotham, Aparna; Lu, Jing; Rao, Anuradha; Lee, Sangkyu; Pratt-Hyatt, Matthew; Lickteig, Andrew; Csanaky, Ivan; Zhao, Yingming; Dawson, Paul A.; Li, Xiaoling

    2014-01-01

    Background & Aims Sirtuin 1 (SIRT1), the most conserved mammalian NAD+-dependent protein deacetylase, is an important metabolic sensor in many tissues. However, little is known about its role in the small intestine, which absorbs and senses nutrients. We investigated the functions of intestinal Sirt1 in systemic bile acid and cholesterol metabolism in mice. Methods Sirt1 was specifically deleted from intestines of mice using the Flox-villin-Cre system (Sirt1 iKO mice). Intestinal and heptic tissues were collected, and bile acid absorption was analyzed using the everted gut sac experiment. Systemic bile acid metabolism was studied in Sirt1 iKO and Flox control mice placed on standard diets, diets containing 0.5% cholic acid or 1.25% cholesterol, or lithogenic diets. Results Sirt1 iKO mice had reduced intestinal Fxr signaling via Hnf1a compared with controls, which reduced expression of the bile acid transporter genes Asbt and Mcf2l (encodes Ost) and absorption of ileal bile acids. Sirt1 regulated Hnf1α–Fxr signaling partially through Dcoh2, which increases dimerization of Hnf1α. Sirt1 was found to deacetylate DCoH2, promoting its interaction with Hnf1α and inducing DNA binding by Hnf1α. Intestine-specific deletion of Sirt1 increased hepatic bile acid biosynthesis, reduced hepatic accumulation of bile acids, and protected animals from liver damage from high-bile acid diets. Conclusions Intestinal Sirt1, a key nutrient sensor, is required for ileal bile acid absorption and systemic bile acid homeostasis in mice. We delineated the mechanism of metabolic regulation of Hnf1α–Fxr signaling. Reagents designed to inhibit intestinal SIRT1 might be developed to treat bile acid-related diseases such as cholestasis. PMID:24389307

  5. Hardware accelerated ray cast of volume data and volume gradient for an optimized splines-based multi-resolution 2D-3D registration

    NASA Astrophysics Data System (ADS)

    Zhang, Xuan; Zheng, Guoyan

    2007-03-01

    This paper describes a method for DRR generation as well as for volume gradients projection using hardware accelerated 2D texture mapping and accumulation buffering and demonstrates its application in 2D-3D registration of X-ray fluoroscopy to CT images. The robustness of the present registration scheme are guaranteed by taking advantage of a coarse-to-fine processing of the volume/image pyramids based on cubic B-splines. A human cadaveric spine specimen together with its ground truth was used to compare the present scheme with a purely software-based scheme in three aspects: accuracy, speed, and capture ranges. Our experiments revealed an equivalent accuracy and capture ranges but with much shorter registration time with the present scheme. More specifically, the results showed 0.8 mm average target registration error, 55 second average execution time per registration, and 10 mm and 10° capture ranges for the present scheme when tested on a 3.0 GHz Pentium 4 computer.

  6. Poster - Thurs Eve-08: Passive shimming optimization of a permanent magnet structure for a prototype coupled MRI-medical linear accelerator.

    PubMed

    Tadic, T; Fallone, B G

    2008-07-01

    The ultimate goal of radiation therapy is to increase tumor control while reducing normal tissue complications. This is accomplished by conforming the radiation dose delivered to a patient to the tumor geometry, permitting the delivery of higher doses to the target volume while decreasing the dose in surrounding normal tissues. In order to best achieve this goal, our group is pursuing the design of a 0.2T biplanar magnetic resonance imager (MRI) coupled with a medical linear accelerator, which will be capable of performing real-time image guided radiotherapy. In a simplified design of the permanent magnet structure for this system, large paramagnetic plates which affect the characteristics of the magnetic field in the imaging volume are used to hold the magnetic material in place. Since the sole purpose of the MRI module of this unit is to provide geometrical information regarding the shape and position of the target volume during irradiation, obtaining distortion-free images is critical. In the present work, we seek a particular surface topology on the pole plates of the permanent magnet structure which minimizes the overall size of the pole plates while maximizing the homogeneity of the magnetic field in the imaging volume. A rose ring design is investigated with the aid of finite element analysis and the results indicate that a significant improvement in field uniformity is obtained as compared to the simplest design possible. © 2008 American Association of Physicists in Medicine.

  7. Ameliorative effect of naringin in acetaminophen-induced hepatic and renal toxicity in laboratory rats: role of FXR and KIM-1.

    PubMed

    Adil, Mohammad; Kandhare, Amit D; Ghosh, Pinaki; Venkata, Shivakumar; Raygude, Kiran S; Bodhankar, Subhash L

    2016-07-01

    Acetaminophen (APAP) is an analgesic and antipyretic agent commonly known agent to cause hepatic and renal toxicity at a higher dose. Naringin, a bioflavonoid possesses multiple pharmacological properties such as antioxidant, anti-inflammatory, analgesic and anti-hyperlipidemic activity. To evaluate the effect of naringin against the APAP-induced hepatic and renal toxicity. Male Wistar albino rats (180-220 g) were divided into various groups, and toxicity was induced by APAP (700 mg/kg, p.o., 14 days). Naringin (20, 40 and 80 mg/kg, p.o.) or Silymarin (25 mg/kg) was administered to rats 2 h before APAP oral administration. Various biochemical, molecular and histopathological parameter were accessed in hepatic and renal tissue. Naringin pretreatment significantly decreased (p < 0.05) serum creatinine, blood urea nitrogen, bilirubin, aspartate transaminase, alanine transaminase, lactate dehydrogenase, low-density lipoprotein, very low-density lipoprotein, cholesterol and triglycerides as compared with APAP control rats. Decreased level of serum albumin, uric acid, and high-density lipoprotein were also significantly restored (p < 0.05) by naringin pretreatment. It also significantly restores (p < 0.05) the altered level of superoxide dismutase, reduced glutathione, malondialdehyde and nitric oxide in hepatic and renal tissue. Moreover, altered mRNA expression of hepatic farnesoid X receptor and renal injury molecule-1 (KIM-1) were significantly restored (p < 0.05) by naringin treatment. Naringin treatment also reduced histological alteration induced by APAP in the liver and kidney. Naringin exerts its hepato- and nephroprotective effect via modulation of oxido-nitrosative stress, FXR and KIM-1 mRNA expression.

  8. Advanced concepts for acceleration

    SciTech Connect

    Keefe, D.

    1986-07-01

    Selected examples of advanced accelerator concepts are reviewed. Such plasma accelerators as plasma beat wave accelerator, plasma wake field accelerator, and plasma grating accelerator are discussed particularly as examples of concepts for accelerating relativistic electrons or positrons. Also covered are the pulsed electron-beam, pulsed laser accelerator, inverse Cherenkov accelerator, inverse free-electron laser, switched radial-line accelerators, and two-beam accelerator. Advanced concepts for ion acceleration discussed include the electron ring accelerator, excitation of waves on intense electron beams, and two-wave combinations. (LEW)

  9. Laser produced streams of Ge ions accelerated and optimized in the electric fields for implantation into SiO2 substrates.

    PubMed

    Rosinski, M; Giuffrida, L; Parys, P; Gasior, P; Fazio, E; Mezzasalma, A M; Torrisi, L; Ando, L; Wolowski, J

    2012-02-01

    Ge crystals were prepared by means of laser-induced ion implantation technique. A Nd:YAG pulsed laser (repetition rate: 10 Hz; pulse duration: 3.5 ns; pulse energy: ∼0.5 J) was used both as an ion source and to carry out the ablation processes. The optimization of the laser-generated ion beam parameters in a broad energy and current density range has been obtained controlling the electrostatic field parameters. Numerical simulations of the focusing system, performed adopting an OPERA 3D code, and an investigation of the ion characteristics, using the ion time-of-flight method, have allowed to optimize the preparation parameters. The structural properties of the samples were investigated by means of x-ray photoelectron, micro-Raman spectroscopies, and scanning electron microscopy techniques. Experimental results show that, by appropriately varying the ion implantation parameters and by a post-preparation annealing treatment, it is possible to achieve the development of a micrometer-sized crystalline Ge phase and∕or an amorphous one.

  10. Laser produced streams of Ge ions accelerated and optimized in the electric fields for implantation into SiO2 substratesa)

    NASA Astrophysics Data System (ADS)

    Rosinski, M.; Giuffrida, L.; Parys, P.; Gasior, P.; Fazio, E.; Mezzasalma, A. M.; Torrisi, L.; Ando, L.; Wolowski, J.

    2012-02-01

    Ge crystals were prepared by means of laser-induced ion implantation technique. A Nd:YAG pulsed laser (repetition rate: 10 Hz; pulse duration: 3.5 ns; pulse energy: ˜0.5 J) was used both as an ion source and to carry out the ablation processes. The optimization of the laser-generated ion beam parameters in a broad energy and current density range has been obtained controlling the electrostatic field parameters. Numerical simulations of the focusing system, performed adopting an OPERA 3D code, and an investigation of the ion characteristics, using the ion time-of-flight method, have allowed to optimize the preparation parameters. The structural properties of the samples were investigated by means of x-ray photoelectron, micro-Raman spectroscopies, and scanning electron microscopy techniques. Experimental results show that, by appropriately varying the ion implantation parameters and by a post-preparation annealing treatment, it is possible to achieve the development of a micrometer-sized crystalline Ge phase and/or an amorphous one.

  11. Laser produced streams of Ge ions accelerated and optimized in the electric fields for implantation into SiO{sub 2} substrates

    SciTech Connect

    Rosinski, M.; Parys, P.; Gasior, P.; Wolowski, J.; Giuffrida, L.; Torrisi, L.; Fazio, E.; Mezzasalma, A. M.; Ando, L.

    2012-02-15

    Ge crystals were prepared by means of laser-induced ion implantation technique. A Nd:YAG pulsed laser (repetition rate: 10 Hz; pulse duration: 3.5 ns; pulse energy: {approx}0.5 J) was used both as an ion source and to carry out the ablation processes. The optimization of the laser-generated ion beam parameters in a broad energy and current density range has been obtained controlling the electrostatic field parameters. Numerical simulations of the focusing system, performed adopting an OPERA 3D code, and an investigation of the ion characteristics, using the ion time-of-flight method, have allowed to optimize the preparation parameters. The structural properties of the samples were investigated by means of x-ray photoelectron, micro-Raman spectroscopies, and scanning electron microscopy techniques. Experimental results show that, by appropriately varying the ion implantation parameters and by a post-preparation annealing treatment, it is possible to achieve the development of a micrometer-sized crystalline Ge phase and/or an amorphous one.

  12. Accelerators and the Accelerator Community

    SciTech Connect

    Malamud, Ernest; Sessler, Andrew

    2008-06-01

    In this paper, standing back--looking from afar--and adopting a historical perspective, the field of accelerator science is examined. How it grew, what are the forces that made it what it is, where it is now, and what it is likely to be in the future are the subjects explored. Clearly, a great deal of personal opinion is invoked in this process.

  13. Community Petascale Project for Accelerator Science and Simulation: Advancing Computational Science for Future Accelerators and Accelerator Technologies

    SciTech Connect

    Spentzouris, P.; Cary, J.; McInnes, L.C.; Mori, W.; Ng, C.; Ng, E.; Ryne, R.; /LBL, Berkeley

    2011-11-14

    The design and performance optimization of particle accelerators are essential for the success of the DOE scientific program in the next decade. Particle accelerators are very complex systems whose accurate description involves a large number of degrees of freedom and requires the inclusion of many physics processes. Building on the success of the SciDAC-1 Accelerator Science and Technology project, the SciDAC-2 Community Petascale Project for Accelerator Science and Simulation (ComPASS) is developing a comprehensive set of interoperable components for beam dynamics, electromagnetics, electron cooling, and laser/plasma acceleration modelling. ComPASS is providing accelerator scientists the tools required to enable the necessary accelerator simulation paradigm shift from high-fidelity single physics process modeling (covered under SciDAC1) to high-fidelity multiphysics modeling. Our computational frameworks have been used to model the behavior of a large number of accelerators and accelerator R&D experiments, assisting both their design and performance optimization. As parallel computational applications, the ComPASS codes have been shown to make effective use of thousands of processors. ComPASS is in the first year of executing its plan to develop the next-generation HPC accelerator modeling tools. ComPASS aims to develop an integrated simulation environment that will utilize existing and new accelerator physics modules with petascale capabilities, by employing modern computing and solver technologies. The ComPASS vision is to deliver to accelerator scientists a virtual accelerator and virtual prototyping modeling environment, with the necessary multiphysics, multiscale capabilities. The plan for this development includes delivering accelerator modeling applications appropriate for each stage of the ComPASS software evolution. Such applications are already being used to address challenging problems in accelerator design and optimization. The ComPASS organization

  14. Impact accelerations

    NASA Technical Reports Server (NTRS)

    Vongierke, H. E.; Brinkley, J. W.

    1975-01-01

    The degree to which impact acceleration is an important factor in space flight environments depends primarily upon the technology of capsule landing deceleration and the weight permissible for the associated hardware: parachutes or deceleration rockets, inflatable air bags, or other impact attenuation systems. The problem most specific to space medicine is the potential change of impact tolerance due to reduced bone mass and muscle strength caused by prolonged weightlessness and physical inactivity. Impact hazards, tolerance limits, and human impact tolerance related to space missions are described.

  15. Direct amidation of carboxylic acids catalyzed by ortho-iodo arylboronic acids: catalyst optimization, scope, and preliminary mechanistic study supporting a peculiar halogen acceleration effect.

    PubMed

    Gernigon, Nicolas; Al-Zoubi, Raed M; Hall, Dennis G

    2012-10-05

    The importance of amides as a component of biomolecules and synthetic products motivates the development of catalytic, direct amidation methods employing free carboxylic acids and amines that circumvent the need for stoichiometric activation or coupling reagents. ortho-Iodophenylboronic acid 4a has recently been shown to catalyze direct amidation reactions at room temperature in the presence of 4A molecular sieves as dehydrating agent. Herein, the arene core of ortho-iodoarylboronic acid catalysts has been optimized with regards to the electronic effects of ring substitution. Contrary to the expectation, it was found that electron-donating substituents are preferable, in particular, an alkoxy substituent positioned para to the iodide. The optimal new catalyst, 5-methoxy-2-iodophenylboronic acid (MIBA, 4f), was demonstrated to be kinetically more active than the parent des-methoxy catalyst 4a, providing higher yields of amide products in shorter reaction times under mild conditions at ambient temperature. Catalyst 4f is recyclable and promotes the formation of amides from aliphatic carboxylic acids and amines, and from heteroaromatic carboxylic acids and other functionalized substrates containing moieties like a free phenol, indole and pyridine. Mechanistic studies demonstrated the essential role of molecular sieves in this complex amidation process. The effect of substrate stoichiometry, concentration, and measurement of the catalyst order led to a possible catalytic cycle based on the presumed formation of an acylborate intermediate. The need for an electronically enriched ortho-iodo substituent in catalyst 4f supports a recent theoretical study (Marcelli, T. Angew. Chem. Int. Ed.2010, 49, 6840-6843) with a purported role for the iodide as a hydrogen-bond acceptor in the orthoaminal transition state.

  16. Accelerating Commercial Remote Sensing

    NASA Technical Reports Server (NTRS)

    1995-01-01

    Through the Visiting Investigator Program (VIP) at Stennis Space Center, Community Coffee was able to use satellites to forecast coffee crops in Guatemala. Using satellite imagery, the company can produce detailed maps that separate coffee cropland from wild vegetation and show information on the health of specific crops. The data can control coffee prices and eventually may be used to optimize application of fertilizers, pesticides and irrigation. This would result in maximal crop yields, minimal pollution and lower production costs. VIP is a mechanism involving NASA funding designed to accelerate the growth of commercial remote sensing by promoting general awareness and basic training in the technology.

  17. Measurements of electron-induced neutrons as a tool for determination of electron temperature of fast electrons in the task of optimization laser-produced plasma ions acceleration.

    PubMed

    Sakaki, H; Nishiuchi, M; Maeda, S; Sagisaka, A; Pirozhkov, A S; Pikuz, T; Faenov, A; Ogura, K; Fukami, T; Matsukawa, K; Kanasaki, M; Fukuda, Y; Yogo, A; Esirkepov, T; Kiriyama, H; Shimomura, T; Nakai, Y; Tanoue, M; Torimoto, K; Okamoto, M; Sato, T; Niita, K; Tamura, J; Nishio, K; Sako, H; Yamauchi, T; Watanabe, Y; Bulanov, S; Kondo, K

    2014-02-01

    High intensity laser-plasma interaction has attracted considerable interest for a number of years. The laser-plasma interaction is accompanied by generation of various charged particle beams, such as high-energy proton and ions with high charge to mass ratio (Q/M; same as multi-charged ions). Results of simultaneous novel measurements of electron-induced photonuclear neutrons (photoneutron), which are a diagnostic of the laser-plasma interaction, are proposed to use for optimization of the laser-plasma ion generation. The proposed method is demonstrated by the laser irradiation with the intensity of 1 × 10(21) W/cm(2) on the metal foil target. The photoneutrons are measured by using NE213 liquid scintillation detectors. Heavy-ion signal is registered with the CR-39 track detector simultaneously. The measured signals of the electron-induced photoneutrons are well reproduced by using the Particle and Heavy Ion Transport code System. The results obtained provide useful approach for analyzing the various laser based ion beams.

  18. DOGBONE GEOMETRY FOR RECIRCULATING ACCELERATORS.

    SciTech Connect

    BERG,J.S.; JOHNSTONE,C.; SUMMERS,D.

    2001-06-18

    Most scenarios for accelerating muons require recirculating acceleration. A racetrack shape for the accelerator requires particles with lower energy in early passes to traverse almost the same length of arc as particles with the highest energy. This extra arc length may lead to excess decays and excess cost. Changing the geometry to a dogbone shape, where there is a single linac and the beam turns completely around at the end of the linac, returning to the same end of the linac from which it exited, addresses this problem. In this design, the arc lengths can be proportional to the particle's momentum. This paper proposes an approximate cost model for a recirculating accelerator, attempts to make cost-optimized designs for both racetrack and dogbone geometries, and demonstrates that the dogbone geometry does appear to be more cost effective.

  19. Accelerator system and method of accelerating particles

    NASA Technical Reports Server (NTRS)

    Wirz, Richard E. (Inventor)

    2010-01-01

    An accelerator system and method that utilize dust as the primary mass flux for generating thrust are provided. The accelerator system can include an accelerator capable of operating in a self-neutralizing mode and having a discharge chamber and at least one ionizer capable of charging dust particles. The system can also include a dust particle feeder that is capable of introducing the dust particles into the accelerator. By applying a pulsed positive and negative charge voltage to the accelerator, the charged dust particles can be accelerated thereby generating thrust and neutralizing the accelerator system.

  20. Modeling lateral acceleration effects on pilot performance

    NASA Technical Reports Server (NTRS)

    Korn, J.; Kleinan, D. L.

    1982-01-01

    Attendant to the direct side force maneuver of a Vectored Force Fighter is the transverse acceleration imposed on the pilot. This lateral acceleration (Gy), when combind with a positive Gz stress, is a potential source of pilot tracking performance impairment. A research effort to investigate these performance decrements includes experimental as well as anaytical pilot performance modeling using the Optimal Control Model.

  1. Preliminary tests of the electrostatic plasma accelerator

    NASA Technical Reports Server (NTRS)

    Aston, G.; Acker, T.

    1990-01-01

    This report describes the results of a program to verify an electrostatic plasma acceleration concept and to identify those parameters most important in optimizing an Electrostatic Plasma Accelerator (EPA) thruster based upon this thrust mechanism. Preliminary performance measurements of thrust, specific impulse and efficiency were obtained using a unique plasma exhaust momentum probe. Reliable EPA thruster operation was achieved using one power supply.

  2. A Survey of Hadron Therapy Accelerator Technologies.

    SciTech Connect

    PEGGS,S.; SATOGATA, T.; FLANZ, J.

    2007-06-25

    Hadron therapy has entered a new age [1]. The number of facilities grows steadily, and 'consumer' interest is high. Some groups are working on new accelerator technology, while others optimize existing designs by reducing capital and operating costs, and improving performance. This paper surveys the current requirements and directions in accelerator technology for hadron therapy.

  3. Multiple time step molecular dynamics in the optimized isokinetic ensemble steered with the molecular theory of solvation: Accelerating with advanced extrapolation of effective solvation forces

    NASA Astrophysics Data System (ADS)

    Omelyan, Igor; Kovalenko, Andriy

    2013-12-01

    We develop efficient handling of solvation forces in the multiscale method of multiple time step molecular dynamics (MTS-MD) of a biomolecule steered by the solvation free energy (effective solvation forces) obtained from the 3D-RISM-KH molecular theory of solvation (three-dimensional reference interaction site model complemented with the Kovalenko-Hirata closure approximation). To reduce the computational expenses, we calculate the effective solvation forces acting on the biomolecule by using advanced solvation force extrapolation (ASFE) at inner time steps while converging the 3D-RISM-KH integral equations only at large outer time steps. The idea of ASFE consists in developing a discrete non-Eckart rotational transformation of atomic coordinates that minimizes the distances between the atomic positions of the biomolecule at different time moments. The effective solvation forces for the biomolecule in a current conformation at an inner time step are then extrapolated in the transformed subspace of those at outer time steps by using a modified least square fit approach applied to a relatively small number of the best force-coordinate pairs. The latter are selected from an extended set collecting the effective solvation forces obtained from 3D-RISM-KH at outer time steps over a broad time interval. The MTS-MD integration with effective solvation forces obtained by converging 3D-RISM-KH at outer time steps and applying ASFE at inner time steps is stabilized by employing the optimized isokinetic Nosé-Hoover chain (OIN) ensemble. Compared to the previous extrapolation schemes used in combination with the Langevin thermostat, the ASFE approach substantially improves the accuracy of evaluation of effective solvation forces and in combination with the OIN thermostat enables a dramatic increase of outer time steps. We demonstrate on a fully flexible model of alanine dipeptide in aqueous solution that the MTS-MD/OIN/ASFE/3D-RISM-KH multiscale method of molecular dynamics

  4. Multiple time step molecular dynamics in the optimized isokinetic ensemble steered with the molecular theory of solvation: Accelerating with advanced extrapolation of effective solvation forces

    SciTech Connect

    Omelyan, Igor E-mail: omelyan@icmp.lviv.ua; Kovalenko, Andriy

    2013-12-28

    We develop efficient handling of solvation forces in the multiscale method of multiple time step molecular dynamics (MTS-MD) of a biomolecule steered by the solvation free energy (effective solvation forces) obtained from the 3D-RISM-KH molecular theory of solvation (three-dimensional reference interaction site model complemented with the Kovalenko-Hirata closure approximation). To reduce the computational expenses, we calculate the effective solvation forces acting on the biomolecule by using advanced solvation force extrapolation (ASFE) at inner time steps while converging the 3D-RISM-KH integral equations only at large outer time steps. The idea of ASFE consists in developing a discrete non-Eckart rotational transformation of atomic coordinates that minimizes the distances between the atomic positions of the biomolecule at different time moments. The effective solvation forces for the biomolecule in a current conformation at an inner time step are then extrapolated in the transformed subspace of those at outer time steps by using a modified least square fit approach applied to a relatively small number of the best force-coordinate pairs. The latter are selected from an extended set collecting the effective solvation forces obtained from 3D-RISM-KH at outer time steps over a broad time interval. The MTS-MD integration with effective solvation forces obtained by converging 3D-RISM-KH at outer time steps and applying ASFE at inner time steps is stabilized by employing the optimized isokinetic Nosé-Hoover chain (OIN) ensemble. Compared to the previous extrapolation schemes used in combination with the Langevin thermostat, the ASFE approach substantially improves the accuracy of evaluation of effective solvation forces and in combination with the OIN thermostat enables a dramatic increase of outer time steps. We demonstrate on a fully flexible model of alanine dipeptide in aqueous solution that the MTS-MD/OIN/ASFE/3D-RISM-KH multiscale method of molecular dynamics

  5. Acceleration modules in linear induction accelerators

    NASA Astrophysics Data System (ADS)

    Wang, Shao-Heng; Deng, Jian-Jun

    2014-05-01

    The Linear Induction Accelerator (LIA) is a unique type of accelerator that is capable of accelerating kilo-Ampere charged particle current to tens of MeV energy. The present development of LIA in MHz bursting mode and the successful application into a synchrotron have broadened LIA's usage scope. Although the transformer model is widely used to explain the acceleration mechanism of LIAs, it is not appropriate to consider the induction electric field as the field which accelerates charged particles for many modern LIAs. We have examined the transition of the magnetic cores' functions during the LIA acceleration modules' evolution, distinguished transformer type and transmission line type LIA acceleration modules, and re-considered several related issues based on transmission line type LIA acceleration module. This clarified understanding should help in the further development and design of LIA acceleration modules.

  6. Progress on plasma accelerators

    SciTech Connect

    Chen, P.

    1986-05-01

    Several plasma accelerator concepts are reviewed, with emphasis on the Plasma Beat Wave Accelerator (PBWA) and the Plasma Wake Field Accelerator (PWFA). Various accelerator physics issues regarding these schemes are discussed, and numerical examples on laboratory scale experiments are given. The efficiency of plasma accelerators is then revealed with suggestions on improvements. Sources that cause emittance growth are discussed briefly.

  7. Vacuum Brazing of Accelerator Components

    NASA Astrophysics Data System (ADS)

    Singh, Rajvir; Pant, K. K.; Lal, Shankar; Yadav, D. P.; Garg, S. R.; Raghuvanshi, V. K.; Mundra, G.

    2012-11-01

    Commonly used materials for accelerator components are those which are vacuum compatible and thermally conductive. Stainless steel, aluminum and copper are common among them. Stainless steel is a poor heat conductor and not very common in use where good thermal conductivity is required. Aluminum and copper and their alloys meet the above requirements and are frequently used for the above purpose. The accelerator components made of aluminum and its alloys using welding process have become a common practice now a days. It is mandatory to use copper and its other grades in RF devices required for accelerators. Beam line and Front End components of the accelerators are fabricated from stainless steel and OFHC copper. Fabrication of components made of copper using welding process is very difficult and in most of the cases it is impossible. Fabrication and joining in such cases is possible using brazing process especially under vacuum and inert gas atmosphere. Several accelerator components have been vacuum brazed for Indus projects at Raja Ramanna Centre for Advanced Technology (RRCAT), Indore using vacuum brazing facility available at RRCAT, Indore. This paper presents details regarding development of the above mentioned high value and strategic components/assemblies. It will include basics required for vacuum brazing, details of vacuum brazing facility, joint design, fixturing of the jobs, selection of filler alloys, optimization of brazing parameters so as to obtain high quality brazed joints, brief description of vacuum brazed accelerator components etc.

  8. Radiation pressure acceleration of ultrathin foils

    NASA Astrophysics Data System (ADS)

    Macchi, Andrea; Veghini, Silvia; Liseykina, Tatyana V.; Pegoraro, Francesco

    2010-04-01

    The acceleration of sub-wavelength, solid-density plasma foils by the ultraintense radiation pressure of circularly polarized laser pulses is investigated analytically and with simulations. An improved 'Light Sail' or accelerating mirror model, accounting for nonlinear self-induced transparency effects, is used for estimating the optimal thickness for acceleration. The model predictions are in good agreement with one-dimensional simulations. These latter are analyzed in detail to unfold the dynamics and self-organization of electrons and ions during the acceleration. Two-dimensional simulations are also performed to address the effects of target bending and of laser intensity inhomogeneity.

  9. Plasma-based accelerator with magnetic compression.

    PubMed

    Schmit, P F; Fisch, N J

    2012-12-21

    Electron dephasing is a major gain-inhibiting effect in plasma-based accelerators. A novel method is proposed to overcome dephasing, in which the modulation of a modest [~O(10 kG)], axial, uniform magnetic field in the acceleration channel leads to densification of the plasma through magnetic compression, enabling direct, time-resolved control of the plasma wave properties. The methodology is broadly applicable and can be optimized to improve the leading acceleration approaches, including plasma beat wave, plasma wakefield, and laser wakefield acceleration. The advantages of magnetic compression are compared to other proposed techniques to overcome dephasing.

  10. Commnity Petascale Project for Accelerator Science And Simulation: Advancing Computational Science for Future Accelerators And Accelerator Technologies

    SciTech Connect

    Spentzouris, Panagiotis; Cary, John; Mcinnes, Lois Curfman; Mori, Warren; Ng, Cho; Ng, Esmond; Ryne, Robert; /LBL, Berkeley

    2011-10-21

    The design and performance optimization of particle accelerators are essential for the success of the DOE scientific program in the next decade. Particle accelerators are very complex systems whose accurate description involves a large number of degrees of freedom and requires the inclusion of many physics processes. Building on the success of the SciDAC-1 Accelerator Science and Technology project, the SciDAC-2 Community Petascale Project for Accelerator Science and Simulation (ComPASS) is developing a comprehensive set of interoperable components for beam dynamics, electromagnetics, electron cooling, and laser/plasma acceleration modelling. ComPASS is providing accelerator scientists the tools required to enable the necessary accelerator simulation paradigm shift from high-fidelity single physics process modeling (covered under SciDAC1) to high-fidelity multiphysics modeling. Our computational frameworks have been used to model the behavior of a large number of accelerators and accelerator R&D experiments, assisting both their design and performance optimization. As parallel computational applications, the ComPASS codes have been shown to make effective use of thousands of processors.

  11. Community petascale project for accelerator science and simulation : Advancing computational science for future accelerators and accelerator technologies.

    SciTech Connect

    Spentzouris, P.; Cary, J.; McInnes, L. C.; Mori, W.; Ng, C.; Ng, E.; Ryne, R.

    2008-01-01

    The design and performance optimization of particle accelerators are essential for the success of the DOE scientific program in the next decade. Particle accelerators are very complex systems whose accurate description involves a large number of degrees of freedom and requires the inclusion of many physics processes. Building on the success of the SciDAC-1 Accelerator Science and Technology project, the SciDAC-2 Community Petascale Project for Accelerator Science and Simulation (ComPASS) is developing a comprehensive set of interoperable components for beam dynamics, electromagnetics, electron cooling, and laser/plasma acceleration modelling. ComPASS is providing accelerator scientists the tools required to enable the necessary accelerator simulation paradigm shift from high-fidelity single physics process modeling (covered under SciDAC1) to high-fidelity multiphysics modeling. Our computational frameworks have been used to model the behavior of a large number of accelerators and accelerator R & D experiments, assisting both their design and performance optimization. As parallel computational applications, the ComPASS codes have been shown to make effective use of thousands of processors.

  12. Commnity Petascale Project for Accelerator Science and Simulation: Advancing Computational Science for Future Accelerators and Accelerator Technologies

    SciTech Connect

    Spentzouris, Panagiotis; Cary, John; Mcinnes, Lois Curfman; Mori, Warren; Ng, Cho; Ng, Esmond; Ryne, Robert; /LBL, Berkeley

    2008-07-01

    The design and performance optimization of particle accelerators is essential for the success of the DOE scientific program in the next decade. Particle accelerators are very complex systems whose accurate description involves a large number of degrees of freedom and requires the inclusion of many physics processes. Building on the success of the SciDAC1 Accelerator Science and Technology project, the SciDAC2 Community Petascale Project for Accelerator Science and Simulation (ComPASS) is developing a comprehensive set of interoperable components for beam dynamics, electromagnetics, electron cooling, and laser/plasma acceleration modeling. ComPASS is providing accelerator scientists the tools required to enable the necessary accelerator simulation paradigm shift from high-fidelity single physics process modeling (covered under SciDAC1) to high-fidelity multi-physics modeling. Our computational frameworks have been used to model the behavior of a large number of accelerators and accelerator R&D experiments, assisting both their design and performance optimization. As parallel computational applications, the ComPASS codes have been shown to make effective use of thousands of processors.

  13. Parametric approach to linear induction accelerator design

    SciTech Connect

    Bresie, D.A.; Andrews, J.A.; Ingram, S.W. . Center for Electromechanics)

    1991-01-01

    Past work on the design of linear induction accelerators has centered on the development of computer codes to analyze accelerator designs, using the current filament method. While these filament models are a very valuable tool for evaluating the performance of an induction launcher design, they provide little insight into the selection of dimensions, materials, and operation points for accelerators with interesting performance. Described in this paper is a parametric approach to defining effective accelerator designs. This method uses a computer optimization routine to iteratively seek out effective designs. The optimization routine is forced to search within a parameter space restricted to interesting and realistic parameters such as size, weight, voltage, and temperature rises. A filament model is used as the filter for the optimizer. Several linear induction accelerators have been designed using this method. The accelerators designed all used a switched capacitor power supply. While the run time of this code on The University of Texas' CRAY XMP-24 computer is moderately long, the resulting designs have good predicted performance. With realistic power supplies and materials, accelerator efficiencies in the 20 to 40% range were easily obtained. This paper describes the effect of armature diameter, length-to-diameter ratio, and weight, as well as other parameters, on the optimum accelerator design.

  14. Muon Acceleration-RLA and FFAG

    SciTech Connect

    Bogacz, S. Alex

    2011-10-06

    Various acceleration schemes for muons are presented. The overall goal of the acceleration systems: large acceptance acceleration to 25 GeV and 'beam shaping' can be accomplished by various fixed field accelerators at different stages. They involve three superconducting linacs: a single pass linear Pre-accelerator followed by a pair of multi-pass Recirculating Linear Accelerators (RLA) and finally a non-scaling FFAG ring. The present baseline acceleration scenario has been optimized to take maximum advantage of appropriate acceleration scheme at a given stage. The solenoid based Pre-accelerator offers very large acceptance and facilitates correction of energy gain across the bunch and significant longitudinal compression trough induced synchrotron motion. However, far off-crest acceleration reduces the effective acceleration gradient and adds complexity through the requirement of individual RF phase control for each cavity. The RLAs offer very efficient usage of high gradient superconducting RF and ability to adjust path-length after each linac pass through individual return arcs with uniformly periodic FODO optics suitable for chromatic compensation of emittace dilution with sextupoles. However, they require spreaders/recombiners switchyards at both linac ends and significant total length of the arcs. The non-scaling Fixed Field Alternating Gradient (FFAG) ring combines compactness with very large chromatic acceptance (twice the injection energy) and it allows for large number of passes through the RF (at least eight, possibly as high as 15).

  15. Design of a nonscaling fixed field alternating gradient accelerator

    NASA Astrophysics Data System (ADS)

    Trbojevic, D.; Courant, E. D.; Blaskiewicz, M.

    2005-05-01

    We present a design of nonscaling fixed field alternating gradient accelerators (FFAG) minimizing the dispersion action function H. The design is considered both analytically and via computer modeling. We present the basic principles of a nonscaling FFAG lattice and discuss optimization strategies so that one can accelerate over a broad range of momentum with reasonable apertures. Acceleration schemes for muons are discussed.

  16. EDITORIAL: Laser and plasma accelerators Laser and plasma accelerators

    NASA Astrophysics Data System (ADS)

    Bingham, Robert

    2009-02-01

    by Chen et al where the driver, instead of being a laser, is a whistler wave known as the magnetowave plasma accelerator. The application to electron--positron plasmas that are found around pulsars is studied in the paper by Shukla, and to muon acceleration by Peano et al. Electron wakefield experiments are now concentrating on control and optimisation of high-quality beams that can be used as drivers for novel radiation sources. Studies by Thomas et al show that filamentation has a deleterious effect on the production of high quality mono-energetic electron beams and is caused by non-optimal choice of focusing geometry and/or electron density. It is crucial to match the focusing with the right plasma parameters and new types of plasma channels are being developed, such as the magnetically controlled plasma waveguide reported by Froula et al. The magnetic field provides a pressure profile shaping the channel to match the guiding conditions of the incident laser, resulting in predicted electron energies of 3GeV. In the forced laser-wakefield experiment Fang et al show that pump depletion reduces or inhibits the acceleration of electrons. One of the earlier laser acceleration concepts known as the beat wave may be revived due to the work by Kalmykov et al who report on all-optical control of nonlinear focusing of laser beams, allowing for stable propagation over several Rayleigh lengths with pre-injected electrons accelerated beyond 100 MeV. With the increasing number of petawatt lasers, attention is being focused on different acceleration regimes such as stochastic acceleration by counterpropagating laser pulses, the relativistic mirror, or the snow-plough effect leading to single-step acceleration reported by Mendonca. During wakefield acceleration the leading edge of the pulse undergoes frequency downshifting and head erosion as the laser energy is transferred to the wake while the trailing edge of the laser pulse undergoes frequency up-shift. This is commonly known

  17. Linac-accelerator-radiosurgery.

    PubMed

    Sturm, V; Schlegel, W; Pastyr, O; Treuer, H; Voges, J; Müller, R P; Lorenz, W J

    1993-01-01

    A survey is given of the actual possibilities and limitations of the use of linear accelerators (Linac radiosurgery systems) for intra = cranial radiosurgery. Depending on the collimator size, spherical fields from 5-54 mm in diameter can be irradiated with dose gradients from 10% (large fields) to 20% (small fields) per millimeter distance between surface and treatment volume. This is comparable to the possibilities of Gamma-Knife and Proton-irradiation. Optimal mechanical adjustment of gantry and linac table are necessary for the required stability of the isocenter. Mechanical inaccuracy should be smaller than 0.8 mm. Advanced computerized 3D-treatment planning systems are indispensable prerequisites for accurate treatment and use of the flexibility of the linac system. Future developments are outlined.

  18. Pulsed Plasma Accelerator Modeling

    NASA Technical Reports Server (NTRS)

    Goodman, M.; Kazeminezhad, F.; Owens, T.

    2009-01-01

    This report presents the main results of the modeling task of the PPA project. The objective of this task is to make major progress towards developing a new computational tool with new capabilities for simulating cylindrically symmetric 2.5 dimensional (2.5 D) PPA's. This tool may be used for designing, optimizing, and understanding the operation of PPA s and other pulsed power devices. The foundation for this task is the 2-D, cylindrically symmetric, magnetohydrodynamic (MHD) code PCAPPS (Princeton Code for Advanced Plasma Propulsion Simulation). PCAPPS was originally developed by Sankaran (2001, 2005) to model Lithium Lorentz Force Accelerators (LLFA's), which are electrode based devices, and are typically operated in continuous magnetic field to the model, and implementing a first principles, self-consistent algorithm to couple the plasma and power circuit that drives the plasma dynamics.

  19. Computational Tools for Accelerating Carbon Capture Process Development

    SciTech Connect

    Miller, David; Sahinidis, N V; Cozad, A; Lee, A; Kim, H; Morinelly, J; Eslick, J; Yuan, Z

    2013-06-04

    This presentation reports development of advanced computational tools to accelerate next generation technology development. These tools are to develop an optimized process using rigorous models. They include: Process Models; Simulation-Based Optimization; Optimized Process; Uncertainty Quantification; Algebraic Surrogate Models; and Superstructure Optimization (Determine Configuration).

  20. ACCELERATION AND THE GIFTED.

    ERIC Educational Resources Information Center

    GIBSON, ARTHUR R.; STEPHANS, THOMAS M.

    ACCELERATION OF PUPILS AND SUBJECTS IS CONSIDERED A MEANS OF EDUCATING THE ACADEMICALLY GIFTED STUDENT. FIVE INTRODUCTORY ARTICLES PROVIDE A FRAMEWORK FOR THINKING ABOUT ACCELERATION. FIVE PROJECT REPORTS OF ACCELERATED PROGRAMS IN OHIO ARE INCLUDED. ACCELERATION IS NOW BEING REGARDED MORE FAVORABLY THAN FORMERLY, BECAUSE METHODS HAVE BEEN…

  1. Future accelerator technology

    SciTech Connect

    Sessler, A.M.

    1986-05-01

    A general discussion is presented of the acceleration of particles. Upon this foundation is built a categorization scheme into which all accelerators can be placed. Special attention is devoted to accelerators which employ a wake-field mechanism and a restricting theorem is examined. It is shown how the theorem may be circumvented. Comments are made on various acceleration schemes.

  2. ACCELERATION AND THE GIFTED.

    ERIC Educational Resources Information Center

    GIBSON, ARTHUR R.; STEPHANS, THOMAS M.

    ACCELERATION OF PUPILS AND SUBJECTS IS CONSIDERED A MEANS OF EDUCATING THE ACADEMICALLY GIFTED STUDENT. FIVE INTRODUCTORY ARTICLES PROVIDE A FRAMEWORK FOR THINKING ABOUT ACCELERATION. FIVE PROJECT REPORTS OF ACCELERATED PROGRAMS IN OHIO ARE INCLUDED. ACCELERATION IS NOW BEING REGARDED MORE FAVORABLY THAN FORMERLY, BECAUSE METHODS HAVE BEEN…

  3. Piezoelectric particle accelerator

    DOEpatents

    Kemp, Mark A.; Jongewaard, Erik N.; Haase, Andrew A.; Franzi, Matthew

    2017-08-29

    A particle accelerator is provided that includes a piezoelectric accelerator element, where the piezoelectric accelerator element includes a hollow cylindrical shape, and an input transducer, where the input transducer is disposed to provide an input signal to the piezoelectric accelerator element, where the input signal induces a mechanical excitation of the piezoelectric accelerator element, where the mechanical excitation is capable of generating a piezoelectric electric field proximal to an axis of the cylindrical shape, where the piezoelectric accelerator is configured to accelerate a charged particle longitudinally along the axis of the cylindrical shape according to the piezoelectric electric field.

  4. Induction linear accelerator technology for SDIO applications

    SciTech Connect

    Birx, D.; Reginato, L.; Rogers, D.; Trimble, D.

    1986-11-01

    The research effort reported concentrated primarily on three major activities. The first was aimed at improvements in the accelerator drive system of an induction linac to meet the high repetition rate requirements of SDI applications. The second activity centered on a redesign of the accelerator cells to eliminate the beam breakup instabilities, resulting in optimized beam transport. The third activity sought to improve the source of electrons to achieve a higher quality beam to satisfy the requirement of the free electron laser. (LEW)

  5. The direction of acceleration

    NASA Astrophysics Data System (ADS)

    Wilhelm, Thomas; Burde, Jan-Philipp; Lück, Stephan

    2015-11-01

    Acceleration is a physical quantity that is difficult to understand and hence its complexity is often erroneously simplified. Many students think of acceleration as equivalent to velocity, a ˜ v. For others, acceleration is a scalar quantity, which describes the change in speed Δ|v| or Δ|v|/Δt (as opposed to the change in velocity). The main difficulty with the concept of acceleration therefore lies in developing a correct understanding of its direction. The free iOS app AccelVisu supports students in acquiring a correct conception of acceleration by showing acceleration arrows directly at moving objects.

  6. Temporal resolution improvement of calibration-free dynamic contrast-enhanced MRI with compressed sensing optimized turbo spin echo: The effects of replacing turbo factor with compressed sensing accelerations.

    PubMed

    Han, SoHyun; Cho, HyungJoon

    2016-07-01

    To enhance the temporal resolution of calibration-free dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) by implementing compressed sensing assisted turbo spin echo (CS-TSE) acquisition. The dynamic sparse sampling variables including acceleration factor, randomized phase encoding distributions, and reconstruction constraints were retrospectively optimized by minimizing the difference from fully sampled dynamic TSE at 7T. The degree of contrast enhancement and the calibration-free quantification of gadolinium (Gd) concentration were evaluated among fast low-angle shot (FLASH), TSE, and CS-TSE acquisitions with multiple phantoms (0.1-6 mM). The kidney-feeding in vivo arterial input function (AIF) was measured at multiple administration doses (0.1-0.3 mmol/kg) to evaluate the benefit of CS-TSE for quantifying rapidly changing high Gd concentrations in C57BL/6 mice (n = 22). In phantom studies, both calibration-free and calibrated conversions estimated equivalent Gd concentrations for CS-TSE (scatterplot slope = 0.9801, r(2)  = 0.9998, P < 0.001). In in vivo studies, 4-fold higher temporal resolution (0.96 sec) of CS-TSE over the corresponding TSE enabled robust measurement of AIF first-pass peak and resulting peak enhancement with CS-TSE were observed, with 1.1439- and 2.1258-fold times higher than those with TSE and FLASH acquisitions, respectively, at the 0.1 mmol/kg dose. Calibration-free estimates of AIF peak concentration with CS-TSE were in good agreement with the calibrated approach at multiple administration doses (scatterplot slope = 0.7800, r(2)  = 0.8014, P < 0.001). Temporal resolution-improved CS-TSE provides practical subsecond (0.96s) calibration-free dynamic MR quantification of high Gd concentration. J. Magn. Reson. Imaging 2016;44:138-147. © 2015 Wiley Periodicals, Inc.

  7. Hardware accelerator for genomic sequence alignment.

    PubMed

    Chiang, Jason; Studniberg, Michael; Shaw, Jack; Seto, Shaw; Truong, Kevin

    2006-01-01

    To infer homology and subsequently gene function, the Smith-Waterman algorithm is used to find the optimal local alignment between two sequences. When searching sequence databases that may contain billions of sequences, this algorithm becomes computationally expensive. Consequently, in this paper, we focused on accelerating the Smith-Waterman algorithm by modifying the computationally repeated portion of the algorithm by FPGA hardware custom instructions. These simple modifications accelerated the algorithm runtime by an average of 287% compared to the pure software implementation. Therefore, further design of FPGA accelerated hardware offers a promising direction to seeking runtime improvement of genomic database searching.

  8. Peak acceleration limiter

    NASA Technical Reports Server (NTRS)

    Chapman, C. P.

    1972-01-01

    Device is described that limits accelerations by shutting off shaker table power very rapidly in acceleration tests. Absolute value of accelerometer signal is used to trigger electronic switch which terminates test and sounds alarm.

  9. Improved plasma accelerator

    NASA Technical Reports Server (NTRS)

    Cheng, D. Y.

    1971-01-01

    Converging, coaxial accelerator electrode configuration operates in vacuum as plasma gun. Plasma forms by periodic injections of high pressure gas that is ionized by electrical discharges. Deflagration mode of discharge provides acceleration, and converging contours of plasma gun provide focusing.

  10. Linear Accelerator (LINAC)

    MedlinePlus

    ... equipment? How is safety ensured? What is this equipment used for? A linear accelerator (LINAC) is the ... Therapy (SBRT) . top of page How does the equipment work? The linear accelerator uses microwave technology (similar ...

  11. Accelerating Particles with Plasma

    SciTech Connect

    Litos, Michael; Hogan, Mark

    2014-11-05

    Researchers at SLAC explain how they use plasma wakefields to accelerate bunches of electrons to very high energies over only a short distance. Their experiments offer a possible path for the future of particle accelerators.

  12. Linear Accelerator (LINAC)

    MedlinePlus

    ... equipment? How is safety ensured? What is this equipment used for? A linear accelerator (LINAC) is the ... Therapy (SBRT) . top of page How does the equipment work? The linear accelerator uses microwave technology (similar ...

  13. Accelerating Particles with Plasma

    ScienceCinema

    Litos, Michael; Hogan, Mark

    2016-07-12

    Researchers at SLAC explain how they use plasma wakefields to accelerate bunches of electrons to very high energies over only a short distance. Their experiments offer a possible path for the future of particle accelerators.

  14. Accelerator Technology Division

    NASA Astrophysics Data System (ADS)

    1992-04-01

    In fiscal year (FY) 1991, the Accelerator Technology (AT) division continued fulfilling its mission to pursue accelerator science and technology and to develop new accelerator concepts for application to research, defense, energy, industry, and other areas of national interest. This report discusses the following programs: The Ground Test Accelerator Program; APLE Free-Electron Laser Program; Accelerator Transmutation of Waste; JAERI, OMEGA Project, and Intense Neutron Source for Materials Testing; Advanced Free-Electron Laser Initiative; Superconducting Super Collider; The High-Power Microwave Program; (Phi) Factory Collaboration; Neutral Particle Beam Power System Highlights; Accelerator Physics and Special Projects; Magnetic Optics and Beam Diagnostics; Accelerator Design and Engineering; Radio-Frequency Technology; Free-Electron Laser Technology; Accelerator Controls and Automation; Very High-Power Microwave Sources and Effects; and GTA Installation, Commissioning, and Operations.

  15. Accelerators, Colliders, and Snakes

    NASA Astrophysics Data System (ADS)

    Courant, Ernest D.

    2003-12-01

    The author traces his involvement in the evolution of particle accelerators over the past 50 years. He participated in building the first billion-volt accelerator, the Brookhaven Cosmotron, which led to the introduction of the "strong-focusing" method that has in turn led to the very large accelerators and colliders of the present day. The problems of acceleration of spin-polarized protons are also addressed, with discussions of depolarizing resonances and "Siberian snakes" as a technique for mitigating these resonances.

  16. Acceleration Apportionment: A Method of Improved 2D SENSE Acceleration Applied to 3D Contrast-Enhanced MR Angiography

    PubMed Central

    Weavers, Paul T.; Borisch, Eric A.; Johnson, Casey P.; Riederer, Stephen J.

    2013-01-01

    Purpose In 2D SENSE-accelerated 3D Cartesian acquisition, the net acceleration factor R is the product of the two individual accelerations, R = RY × RZ. Acceleration Apportionment tailors acceleration parameters (RY, RZ) to improve parallel imaging performance on a patient- and coil-specific basis and is demonstrated in contrast-enhanced MR angiography. Methods A performance metric is defined based on coil sensitivity information which identifies the (RY, RZ) pair that optimally trades off image quality with scan time reduction on a patient-specific basis. Acceleration Apportionment is evaluated using retrospective analysis of contrast-enhanced MR angiography studies, and prospective studies in which optimally apportioned parameters are compared with standard acceleration parameters. Results The retrospective studies show strong variability in optimal acceleration parameters between anatomic regions and between patients. Prospective application of apportionment to foot contrast-enhanced MR angiography with an 8-channel receiver array provides a 20% increase in net acceleration with improved contrast-to-noise ratio. Application to 16-channel contrast-enhanced MR angiography of the feet and calves suggests 10% acceleration increase to R > 13 and no contrast-to-noise ratio loss. The specific implementation allows the optimum (RY, RZ) pair to be determined within one minute. Conclusion Optimum 2D SENSE acceleration parameters can be automatically chosen on a per-exam basis to allow improved performance without disrupting the clinical workflow. PMID:23450817

  17. Acceleration apportionment: a method of improved 2D SENSE acceleration applied to 3D contrast-enhanced MR angiography.

    PubMed

    Weavers, Paul T; Borisch, Eric A; Johnson, Casey P; Riederer, Stephen J

    2014-02-01

    In 2D SENSE-accelerated 3D Cartesian acquisition, the net acceleration factor R is the product of the two individual accelerations, R = RY × RZ. Acceleration Apportionment tailors acceleration parameters (RY, RZ) to improve parallel imaging performance on a patient- and coil-specific basis and is demonstrated in contrast-enhanced MR angiography. A performance metric is defined based on coil sensitivity information which identifies the (RY, RZ) pair that optimally trades off image quality with scan time reduction on a patient-specific basis. Acceleration Apportionment is evaluated using retrospective analysis of contrast-enhanced MR angiography studies, and prospective studies in which optimally apportioned parameters are compared with standard acceleration parameters. The retrospective studies show strong variability in optimal acceleration parameters between anatomic regions and between patients. Prospective application of apportionment to foot contrast-enhanced MR angiography with an 8-channel receiver array provides a 20% increase in net acceleration with improved contrast-to-noise ratio. Application to 16-channel contrast-enhanced MR angiography of the feet and calves suggests 10% acceleration increase to R > 13 and no contrast-to-noise ratio loss. The specific implementation allows the optimum (RY, RZ) pair to be determined within one minute. Optimum 2D SENSE acceleration parameters can be automatically chosen on a per-exam basis to allow improved performance without disrupting the clinical workflow. Copyright © 2013 Wiley Periodicals, Inc.

  18. Acceleration: It's Elementary

    ERIC Educational Resources Information Center

    Willis, Mariam

    2012-01-01

    Acceleration is one tool for providing high-ability students the opportunity to learn something new every day. Some people talk about acceleration as taking a student out of step. In actuality, what one is doing is putting a student in step with the right curriculum. Whole-grade acceleration, also called grade-skipping, usually happens between…

  19. Accelerated test design

    NASA Technical Reports Server (NTRS)

    Mcdermott, P. P.

    1980-01-01

    The design of an accelerated life test program for electric batteries is discussed. A number of observations and suggestions on the procedures and objectives for conducting an accelerated life test program are presented. Equations based on nonlinear regression analysis for predicting the accelerated life test parameters are discussed.

  20. Angular Acceleration without Torque?

    ERIC Educational Resources Information Center

    Kaufman, Richard D.

    2012-01-01

    Hardly. Just as Robert Johns qualitatively describes angular acceleration by an internal force in his article "Acceleration Without Force?" here we will extend the discussion to consider angular acceleration by an internal torque. As we will see, this internal torque is due to an internal force acting at a distance from an instantaneous center.

  1. Acceleration: It's Elementary

    ERIC Educational Resources Information Center

    Willis, Mariam

    2012-01-01

    Acceleration is one tool for providing high-ability students the opportunity to learn something new every day. Some people talk about acceleration as taking a student out of step. In actuality, what one is doing is putting a student in step with the right curriculum. Whole-grade acceleration, also called grade-skipping, usually happens between…

  2. Far field acceleration

    SciTech Connect

    Fernow, R.C.

    1995-07-01

    Far fields are propagating electromagnetic waves far from their source, boundary surfaces, and free charges. The general principles governing the acceleration of charged particles by far fields are reviewed. A survey of proposed field configurations is given. The two most important schemes, Inverse Cerenkov acceleration and Inverse free electron laser acceleration, are discussed in detail.

  3. Angular Acceleration without Torque?

    ERIC Educational Resources Information Center

    Kaufman, Richard D.

    2012-01-01

    Hardly. Just as Robert Johns qualitatively describes angular acceleration by an internal force in his article "Acceleration Without Force?" here we will extend the discussion to consider angular acceleration by an internal torque. As we will see, this internal torque is due to an internal force acting at a distance from an instantaneous center.

  4. Convex Accelerated Maximum Entropy Reconstruction

    PubMed Central

    Worley, Bradley

    2016-01-01

    Maximum entropy (MaxEnt) spectral reconstruction methods provide a powerful framework for spectral estimation of nonuniformly sampled datasets. Many methods exist within this framework, usually defined based on the magnitude of a Lagrange multiplier in the MaxEnt objective function. An algorithm is presented here that utilizes accelerated first-order convex optimization techniques to rapidly and reliably reconstruct nonuniformly sampled NMR datasets using the principle of maximum entropy. This algorithm – called CAMERA for Convex Accelerated Maximum Entropy Reconstruction Algorithm – is a new approach to spectral reconstruction that exhibits fast, tunable convergence in both constant-aim and constant-lambda modes. A high-performance, open source NMR data processing tool is described that implements CAMERA, and brief comparisons to existing reconstruction methods are made on several example spectra. PMID:26894476

  5. Elementary principles of linear accelerators

    SciTech Connect

    Loew, G.A.; Talman, R.

    1983-09-01

    These lectures come in five sections. The first is this introduction. The second is a short chronology of what are viewed as important milestones in the field. The third covers proton linacs. It introduces elementary concepts such as transit time, shunt impedance, and Q. Critical issues such as phase stability and transverse forces are discussed. The fourth section contains an elementary discussion of waveguide accelerating structures. It can be regarded as an introduction to some of the more advanced treatments of the subject. The final section is devoted to electron accelerators. Taking SLAC as an example, various topics are discussed such as structure design, choice of parameters, frequency optimization, beam current, emittance, bunch length and beam loading. Recent developments and future challenges are mentioned briefly. 41 figures, 4 tables.

  6. Convex accelerated maximum entropy reconstruction.

    PubMed

    Worley, Bradley

    2016-04-01

    Maximum entropy (MaxEnt) spectral reconstruction methods provide a powerful framework for spectral estimation of nonuniformly sampled datasets. Many methods exist within this framework, usually defined based on the magnitude of a Lagrange multiplier in the MaxEnt objective function. An algorithm is presented here that utilizes accelerated first-order convex optimization techniques to rapidly and reliably reconstruct nonuniformly sampled NMR datasets using the principle of maximum entropy. This algorithm - called CAMERA for Convex Accelerated Maximum Entropy Reconstruction Algorithm - is a new approach to spectral reconstruction that exhibits fast, tunable convergence in both constant-aim and constant-lambda modes. A high-performance, open source NMR data processing tool is described that implements CAMERA, and brief comparisons to existing reconstruction methods are made on several example spectra. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Convex accelerated maximum entropy reconstruction

    NASA Astrophysics Data System (ADS)

    Worley, Bradley

    2016-04-01

    Maximum entropy (MaxEnt) spectral reconstruction methods provide a powerful framework for spectral estimation of nonuniformly sampled datasets. Many methods exist within this framework, usually defined based on the magnitude of a Lagrange multiplier in the MaxEnt objective function. An algorithm is presented here that utilizes accelerated first-order convex optimization techniques to rapidly and reliably reconstruct nonuniformly sampled NMR datasets using the principle of maximum entropy. This algorithm - called CAMERA for Convex Accelerated Maximum Entropy Reconstruction Algorithm - is a new approach to spectral reconstruction that exhibits fast, tunable convergence in both constant-aim and constant-lambda modes. A high-performance, open source NMR data processing tool is described that implements CAMERA, and brief comparisons to existing reconstruction methods are made on several example spectra.

  8. Compact Plasma Accelerator

    NASA Technical Reports Server (NTRS)

    Foster, John E.

    2004-01-01

    A plasma accelerator has been conceived for both material-processing and spacecraft-propulsion applications. This accelerator generates and accelerates ions within a very small volume. Because of its compactness, this accelerator could be nearly ideal for primary or station-keeping propulsion for spacecraft having masses between 1 and 20 kg. Because this accelerator is designed to generate beams of ions having energies between 50 and 200 eV, it could also be used for surface modification or activation of thin films.

  9. Summary report: working group 2 on 'Plasma Based AccelerationConcepts'

    SciTech Connect

    Esarey, E.; Leemans, Wim

    1998-09-01

    A summary of the talks, papers and discussion sessions presented in the Working Group on Plasma Based Acceleration Concepts is given within the context of the progress towards a 1 GeV laser driven accelerator module. The topics covered within the Working Group were self-modulated laser wakefield acceleration, standard laser wakefield acceleration, plasma beatwave acceleration, laser guiding and wake excitation in plasma channels, plasma wakefield acceleration, plasma lenses and optical injection techniques for laser wakefield accelerators. An overview will be given of the present status of experimental and theoretical progress as well as an outlook towards the future physics and technological challenges for the development of an optimized accelerator module.

  10. Fiber Accelerating Structures

    SciTech Connect

    Hammond, Andrew P.; /Reed Coll. /SLAC

    2010-08-25

    One of the options for future particle accelerators are photonic band gap (PBG) fiber accelerators. PBG fibers are specially designed optical fibers that use lasers to excite an electric field that is used to accelerate electrons. To improve PBG accelerators, the basic parameters of the fiber were tested to maximize defect size and acceleration. Using the program CUDOS, several accelerating modes were found that maximized these parameters for several wavelengths. The design of multiple defects, similar to having closely bound fibers, was studied to find possible coupling or the change of modes. The amount of coupling was found to be dependent on distance separated. For certain distances accelerating coupled modes were found and examined. In addition, several non-periodic fiber structures were examined using CUDOS. The non-periodic fibers produced several interesting results and promised more modes given time to study them in more detail.

  11. High brightness electron accelerator

    DOEpatents

    Sheffield, Richard L.; Carlsten, Bruce E.; Young, Lloyd M.

    1994-01-01

    A compact high brightness linear accelerator is provided for use, e.g., in a free electron laser. The accelerator has a first plurality of acclerating cavities having end walls with four coupling slots for accelerating electrons to high velocities in the absence of quadrupole fields. A second plurality of cavities receives the high velocity electrons for further acceleration, where each of the second cavities has end walls with two coupling slots for acceleration in the absence of dipole fields. The accelerator also includes a first cavity with an extended length to provide for phase matching the electron beam along the accelerating cavities. A solenoid is provided about the photocathode that emits the electons, where the solenoid is configured to provide a substantially uniform magnetic field over the photocathode surface to minimize emittance of the electons as the electrons enter the first cavity.

  12. High brightness electron accelerator

    SciTech Connect

    Sheffield, R.L.; Carlsten, B.E.; Young, L.M.

    1992-12-31

    A compact high brightness linear accelerator is provided for use, e.g., in a free electron laser. The accelerator has a first plurality of acclerating cavities having end walls with four coupling slots for accelerating electrons to high velocities in the absence of quadrupole fields. A second plurality of cavities receives the high velocity electrons for further acceleration, where each of the second cavities has end walls with two coupling slots for acceleration in the absence of dipole fields. The accelerator also includes a first cavity with an extended length to provide for phase matching the electron beam along the accelerating cavities. A solenoid is provided about the photocathode that emits the electrons, where the solenoid is configured to provide a substantially uniform magnetic field over the photocathode surface to minimize emittance of the electrons as the electrons enter the first cavity.

  13. Acceleration in astrophysics

    SciTech Connect

    Colgate, S.A.

    1993-12-31

    The origin of cosmic rays and applicable laboratory experiments are discussed. Some of the problems of shock acceleration for the production of cosmic rays are discussed in the context of astrophysical conditions. These are: The presumed unique explanation of the power law spectrum is shown instead to be a universal property of all lossy accelerators; the extraordinary isotropy of cosmic rays and the limited diffusion distances implied by supernova induced shock acceleration requires a more frequent and space-filling source than supernovae; the near perfect adiabaticity of strong hydromagnetic turbulence necessary for reflecting the accelerated particles each doubling in energy roughly 10{sup 5} to {sup 6} scatterings with negligible energy loss seems most unlikely; the evidence for acceleration due to quasi-parallel heliosphere shocks is weak. There is small evidence for the expected strong hydromagnetic turbulence, and instead, only a small number of particles accelerate after only a few shock traversals; the acceleration of electrons in the same collisionless shock that accelerates ions is difficult to reconcile with the theoretical picture of strong hydromagnetic turbulence that reflects the ions. The hydromagnetic turbulence will appear adiabatic to the electrons at their much higher Larmor frequency and so the electrons should not be scattered incoherently as they must be for acceleration. Therefore the electrons must be accelerated by a different mechanism. This is unsatisfactory, because wherever electrons are accelerated these sites, observed in radio emission, may accelerate ions more favorably. The acceleration is coherent provided the reconnection is coherent, in which case the total flux, as for example of collimated radio sources, predicts single charge accelerated energies much greater than observed.

  14. Feedback: Theory and Accelerator Applications

    NASA Astrophysics Data System (ADS)

    Himel, T.

    The use of feedback to stabilize the beam and improve the performance of accelerators is becoming more common. The methods used to design the feedback algorithms are introduced and some practical implementation details are described. The design of a PID loop using classical control techniques is covered as is the design of an optimal controller using modern control theory. Some adaptive control techniques are also briefly described. Examples are given of multiple-input-multiple-output loops and of how to handle systems of many interacting feedback loops.

  15. Optimized planning of in-service inspections of local flow-accelerated corrosion of pipeline elements used in the secondary coolant circuit of the VVER-440-based units at the Novovoronezh NPP

    NASA Astrophysics Data System (ADS)

    Tomarov, G. V.; Povarov, V. P.; Shipkov, A. A.; Gromov, A. F.; Budanov, V. A.; Golubeva, T. N.

    2015-03-01

    Matters concerned with making efficient use of the information-analytical system on the flow-accelerated corrosion problem in setting up in-service examination of the metal of pipeline elements operating in the secondary coolant circuit of the VVER-440-based power units at the Novovoronezh NPP are considered. The principles used to select samples of pipeline elements in planning ultrasonic thickness measurements for timely revealing metal thinning due to flow-accelerated corrosion along with reducing the total amount of measurements in the condensate-feedwater path are discussed.

  16. Development of the HRIBF 25-MV tandem accelerator as a RIB accelerator

    SciTech Connect

    Meigs, M.J.; Haynes, D.L.; Jones, C.M.; Juras, R.C.

    1995-12-31

    The Holifield Facility 25URC tandem accelerator will begin accelerating radioactive ion beams (RIBs) for nuclear structure and astrophysics research in 1996. This paper addresses the development of the accelerator to allow optimum operation with the particular challenges associated with RIBs. New diagnostics for ultra-low-intensity beams are being installed and the terminal potential stabilization system is being studied to optimize control with these low beam intensities. A new resistor-based voltage-grading system has resulted in more stable operation as well as allowing operation at the very low terminal potentials which are required for some astrophysics experiments. Also addressed is beam transmission optimization, particularly at low terminal potentials, and operation of the accelerator at high terminal potentials.

  17. An introduction to acceleration mechanisms

    SciTech Connect

    Palmer, R.B.

    1987-05-01

    This paper discusses the acceleration of charged particles by electromagnetic fields, i.e., by fields that are produced by the motion of other charged particles driven by some power source. The mechanisms that are discussed include: Ponderamotive Forces, Acceleration, Plasma Beat Wave Acceleration, Inverse Free Electron Laser Acceleration, Inverse Cerenkov Acceleration, Gravity Acceleration, 2D Linac Acceleration and Conventional Iris Loaded Linac Structure Acceleration. (LSP)

  18. Schooling in Times of Acceleration

    ERIC Educational Resources Information Center

    Buddeberg, Magdalena; Hornberg, Sabine

    2017-01-01

    Modern societies are characterised by forms of acceleration, which influence social processes. Sociologist Hartmut Rosa has systematised temporal structures by focusing on three categories of social acceleration: technical acceleration, acceleration of social change, and acceleration of the pace of life. All three processes of acceleration are…

  19. Schooling in Times of Acceleration

    ERIC Educational Resources Information Center

    Buddeberg, Magdalena; Hornberg, Sabine

    2017-01-01

    Modern societies are characterised by forms of acceleration, which influence social processes. Sociologist Hartmut Rosa has systematised temporal structures by focusing on three categories of social acceleration: technical acceleration, acceleration of social change, and acceleration of the pace of life. All three processes of acceleration are…

  20. Binding free energy predictions of farnesoid X receptor (FXR) agonists using a linear interaction energy (LIE) approach with reliability estimation: application to the D3R Grand Challenge 2.

    PubMed

    Rifai, Eko Aditya; van Dijk, Marc; Vermeulen, Nico P E; Geerke, Daan P

    2017-09-09

    Computational protein binding affinity prediction can play an important role in drug research but performing efficient and accurate binding free energy calculations is still challenging. In the context of phase 2 of the Drug Design Data Resource (D3R) Grand Challenge 2 we used our automated eTOX ALLIES approach to apply the (iterative) linear interaction energy (LIE) method and we evaluated its performance in predicting binding affinities for farnesoid X receptor (FXR) agonists. Efficiency was obtained by our pre-calibrated LIE models and molecular dynamics (MD) simulations at the nanosecond scale, while predictive accuracy was obtained for a small subset of compounds. Using our recently introduced reliability estimation metrics, we could classify predictions with higher confidence by featuring an applicability domain (AD) analysis in combination with protein-ligand interaction profiling. The outcomes of and agreement between our AD and interaction-profile analyses to distinguish and rationalize the performance of our predictions highlighted the relevance of sufficiently exploring protein-ligand interactions during training and it demonstrated the possibility to quantitatively and efficiently evaluate if this is achieved by using simulation data only.

  1. Binding free energy predictions of farnesoid X receptor (FXR) agonists using a linear interaction energy (LIE) approach with reliability estimation: application to the D3R Grand Challenge 2

    NASA Astrophysics Data System (ADS)

    Rifai, Eko Aditya; van Dijk, Marc; Vermeulen, Nico P. E.; Geerke, Daan P.

    2017-09-01

    Computational protein binding affinity prediction can play an important role in drug research but performing efficient and accurate binding free energy calculations is still challenging. In the context of phase 2 of the Drug Design Data Resource (D3R) Grand Challenge 2 we used our automated eTOX ALLIES approach to apply the (iterative) linear interaction energy (LIE) method and we evaluated its performance in predicting binding affinities for farnesoid X receptor (FXR) agonists. Efficiency was obtained by our pre-calibrated LIE models and molecular dynamics (MD) simulations at the nanosecond scale, while predictive accuracy was obtained for a small subset of compounds. Using our recently introduced reliability estimation metrics, we could classify predictions with higher confidence by featuring an applicability domain (AD) analysis in combination with protein-ligand interaction profiling. The outcomes of and agreement between our AD and interaction-profile analyses to distinguish and rationalize the performance of our predictions highlighted the relevance of sufficiently exploring protein-ligand interactions during training and it demonstrated the possibility to quantitatively and efficiently evaluate if this is achieved by using simulation data only.

  2. Leaky Fermi accelerators.

    PubMed

    Shah, Kushal; Gelfreich, Vassili; Rom-Kedar, Vered; Turaev, Dmitry

    2015-06-01

    A Fermi accelerator is a billiard with oscillating walls. A leaky accelerator interacts with an environment of an ideal gas at equilibrium by exchange of particles through a small hole on its boundary. Such interaction may heat the gas: we estimate the net energy flow through the hole under the assumption that the particles inside the billiard do not collide with each other and remain in the accelerator for a sufficiently long time. The heat production is found to depend strongly on the type of Fermi accelerator. An ergodic accelerator, i.e., one that has a single ergodic component, produces a weaker energy flow than a multicomponent accelerator. Specifically, in the ergodic case the energy gain is independent of the hole size, whereas in the multicomponent case the energy flow may be significantly increased by shrinking the hole size.

  3. The Dielectric Wall Accelerator

    SciTech Connect

    Caporaso, George J.; Chen, Yu-Jiuan; Sampayan, Stephen E.

    2009-01-01

    The Dielectric Wall Accelerator (DWA), a class of induction accelerators, employs a novel insulating beam tube to impress a longitudinal electric field on a bunch of charged particles. The surface flashover characteristics of this tube may permit the attainment of accelerating gradients on the order of 100 MV/m for accelerating pulses on the order of a nanosecond in duration. A virtual traveling wave of excitation along the tube is produced at any desired speed by controlling the timing of pulse generating modules that supply a tangential electric field to the tube wall. Because of the ability to control the speed of this virtual wave, the accelerator is capable of handling any charge to mass ratio particle; hence it can be used for electrons, protons and any ion. The accelerator architectures, key technologies and development challenges will be described.

  4. Uniformly accelerated black holes

    NASA Astrophysics Data System (ADS)

    Letelier, Patricio S.; Oliveira, Samuel R.

    2001-09-01

    The static and stationary C metric are examined in a generic framework and their interpretations studied in some detail, especially those with two event horizons, one for the black hole and another for the acceleration. We find that (i) the spacetime of an accelerated static black hole is plagued by either conical singularities or a lack of smoothness and compactness of the black hole horizon, (ii) by using standard black hole thermodynamics we show that accelerated black holes have a higher Hawking temperature than Unruh temperature of the accelerated frame, and (iii) the usual upper bound on the product of the mass and acceleration parameters (<1/27) is just a coordinate artifact. The main results are extended to accelerated rotating black holes with no significant changes.

  5. Switched Matrix Accelerator

    SciTech Connect

    Whittum, David H

    2000-10-04

    We describe a new concept for a microwave circuit functioning as a charged-particle accelerator at mm-wavelengths, permitting an accelerating gradient higher than conventional passive circuits can withstand consistent with cyclic fatigue. The device provides acceleration for multiple bunches in parallel channels, and permits a short exposure time for the conducting surface of the accelerating cavities. Our analysis includes scalings based on a smooth transmission line model and a complementary treatment with a coupled-cavity simulation. We provide also an electromagnetic design for the accelerating structure, arriving at rough dimensions for a seven-cell accelerator matched to standard waveguide and suitable for bench tests at low power in air at 91.392. GHz. A critical element in the concept is a fast mm-wave switch suitable for operation at high-power, and we present the considerations for implementation in an H-plane tee. We discuss the use of diamond as the photoconductor switch medium.

  6. Optically pulsed electron accelerator

    DOEpatents

    Fraser, J.S.; Sheffield, R.L.

    1985-05-20

    An optically pulsed electron accelerator can be used as an injector for a free electron laser and comprises a pulsed light source, such as a laser, for providing discrete incident light pulses. A photoemissive electron source emits electron bursts having the same duration as the incident light pulses when impinged upon by same. The photoemissive electron source is located on an inside wall of a radiofrequency-powered accelerator cell which accelerates the electron burst emitted by the photoemissive electron source.

  7. Optically pulsed electron accelerator

    DOEpatents

    Fraser, John S.; Sheffield, Richard L.

    1987-01-01

    An optically pulsed electron accelerator can be used as an injector for a free electron laser and comprises a pulsed light source, such as a laser, for providing discrete incident light pulses. A photoemissive electron source emits electron bursts having the same duration as the incident light pulses when impinged upon by same. The photoemissive electron source is located on an inside wall of a radio frequency powered accelerator cell which accelerates the electron burst emitted by the photoemissive electron source.

  8. ACCELERATION RESPONSIVE SWITCH

    DOEpatents

    Chabrek, A.F.; Maxwell, R.L.

    1963-07-01

    An acceleration-responsive device with dual channel capabilities whereby a first circuit is actuated upon attainment of a predetermined maximum acceleration level and when the acceleration drops to a predetermined minimum acceleriltion level another circuit is actuated is described. A fluid-damped sensing mass slidably mounted in a relatively frictionless manner on a shaft through the intermediation of a ball bushing and biased by an adjustable compression spring provides inertially operated means for actuating the circuits. (AEC)

  9. The foxhole accelerating structure

    SciTech Connect

    Fernow, R.C.; Claus, J.

    1992-07-17

    This report examines some properties of a new type of open accelerating structure. It consists of a series of rectangular cavities, which we call foxholes, joined by a beam channel. The power for accelerating the particles comes from an external radiation source and enters the cavities through their open upper surfaces. Analytic and computer calculations are presented showing that the foxhole is a suitable structure for accelerating relativistic electrons.

  10. GPU-Accelerated Text Mining

    SciTech Connect

    Cui, Xiaohui; Mueller, Frank; Zhang, Yongpeng; Potok, Thomas E

    2009-01-01

    Accelerating hardware devices represent a novel promise for improving the performance for many problem domains but it is not clear for which domains what accelerators are suitable. While there is no room in general-purpose processor design to significantly increase the processor frequency, developers are instead resorting to multi-core chips duplicating conventional computing capabilities on a single die. Yet, accelerators offer more radical designs with a much higher level of parallelism and novel programming environments. This present work assesses the viability of text mining on CUDA. Text mining is one of the key concepts that has become prominent as an effective means to index the Internet, but its applications range beyond this scope and extend to providing document similarity metrics, the subject of this work. We have developed and optimized text search algorithms for GPUs to exploit their potential for massive data processing. We discuss the algorithmic challenges of parallelization for text search problems on GPUs and demonstrate the potential of these devices in experiments by reporting significant speedups. Our study may be one of the first to assess more complex text search problems for suitability for GPU devices, and it may also be one of the first to exploit and report on atomic instruction usage that have recently become available in NVIDIA devices.

  11. Accelerator-based BNCT.

    PubMed

    Kreiner, A J; Baldo, M; Bergueiro, J R; Cartelli, D; Castell, W; Thatar Vento, V; Gomez Asoia, J; Mercuri, D; Padulo, J; Suarez Sandin, J C; Erhardt, J; Kesque, J M; Valda, A A; Debray, M E; Somacal, H R; Igarzabal, M; Minsky, D M; Herrera, M S; Capoulat, M E; Gonzalez, S J; del Grosso, M F; Gagetti, L; Suarez Anzorena, M; Gun, M; Carranza, O

    2014-06-01

    The activity in accelerator development for accelerator-based BNCT (AB-BNCT) both worldwide and in Argentina is described. Projects in Russia, UK, Italy, Japan, Israel, and Argentina to develop AB-BNCT around different types of accelerators are briefly presented. In particular, the present status and recent progress of the Argentine project will be reviewed. The topics will cover: intense ion sources, accelerator tubes, transport of intense beams, beam diagnostics, the (9)Be(d,n) reaction as a possible neutron source, Beam Shaping Assemblies (BSA), a treatment room, and treatment planning in realistic cases.

  12. Superconductivity and future accelerators

    SciTech Connect

    Danby, G.T.; Jackson, J.W.

    1983-08-01

    With the absence, thus far, of charged particle beam accelerators, particle accelerators employing accelerating cavities and deflecting magnets applying superconductivity are still being developed. This paper discusses hadron colliders which involve 20 TeV rings with 40 TeV CM energy with an emphasis to obtain maximum GeV/$, which may be crucial for serious consideration of funding. The accelerator design and operating features are discussed with an emphasis placed on the superconducting magnets. Material and labor costs are discussed. A diagram is given which illustrates magnet superconductor requirements, comparing Fe dominated 2.5T with air core cos theta magnets.

  13. Charged particle accelerator grating

    DOEpatents

    Palmer, Robert B.

    1986-01-01

    A readily disposable and replaceable accelerator grating for a relativistic particle accelerator. The grating is formed for a plurality of liquid droplets that are directed in precisely positioned jet streams to periodically dispose rows of droplets along the borders of a predetermined particle beam path. A plurality of lasers are used to direct laser beams into the droplets, at predetermined angles, thereby to excite the droplets to support electromagnetic accelerating resonances on their surfaces. Those resonances operate to accelerate and focus particles moving along the beam path. As the droplets are distorted or destroyed by the incoming radiation, they are replaced at a predetermined frequency by other droplets supplied through the jet streams.

  14. Charged particle accelerator grating

    DOEpatents

    Palmer, Robert B.

    1986-09-02

    A readily disposable and replaceable accelerator grating for a relativistic particle accelerator. The grating is formed for a plurality of liquid droplets that are directed in precisely positioned jet streams to periodically dispose rows of droplets along the borders of a predetermined particle beam path. A plurality of lasers are used to direct laser beams into the droplets, at predetermined angles, thereby to excite the droplets to support electromagnetic accelerating resonances on their surfaces. Those resonances operate to accelerate and focus particles moving along the beam path. As the droplets are distorted or destroyed by the incoming radiation, they are replaced at a predetermined frequency by other droplets supplied through the jet streams.

  15. Particle acceleration in flares

    NASA Technical Reports Server (NTRS)

    Benz, Arnold O.; Kosugi, Takeo; Aschwanden, Markus J.; Benka, Steve G.; Chupp, Edward L.; Enome, Shinzo; Garcia, Howard; Holman, Gordon D.; Kurt, Victoria G.; Sakao, Taro

    1994-01-01

    Particle acceleration is intrinsic to the primary energy release in the impulsive phase of solar flares, and we cannot understand flares without understanding acceleration. New observations in soft and hard X-rays, gamma-rays and coherent radio emissions are presented, suggesting flare fragmentation in time and space. X-ray and radio measurements exhibit at least five different time scales in flares. In addition, some new observations of delayed acceleration signatures are also presented. The theory of acceleration by parallel electric fields is used to model the spectral shape and evolution of hard X-rays. The possibility of the appearance of double layers is further investigated.

  16. High Gradient Accelerator Research

    SciTech Connect

    Temkin, Richard

    2016-07-12

    The goal of the MIT program of research on high gradient acceleration is the development of advanced acceleration concepts that lead to a practical and affordable next generation linear collider at the TeV energy level. Other applications, which are more near-term, include accelerators for materials processing; medicine; defense; mining; security; and inspection. The specific goals of the MIT program are: • Pioneering theoretical research on advanced structures for high gradient acceleration, including photonic structures and metamaterial structures; evaluation of the wakefields in these advanced structures • Experimental research to demonstrate the properties of advanced structures both in low-power microwave cold test and high-power, high-gradient test at megawatt power levels • Experimental research on microwave breakdown at high gradient including studies of breakdown phenomena induced by RF electric fields and RF magnetic fields; development of new diagnostics of the breakdown process • Theoretical research on the physics and engineering features of RF vacuum breakdown • Maintaining and improving the Haimson / MIT 17 GHz accelerator, the highest frequency operational accelerator in the world, a unique facility for accelerator research • Providing the Haimson / MIT 17 GHz accelerator facility as a facility for outside users • Active participation in the US DOE program of High Gradient Collaboration, including joint work with SLAC and with Los Alamos National Laboratory; participation of MIT students in research at the national laboratories • Training the next generation of Ph. D. students in the field of accelerator physics.

  17. Particle acceleration in flares

    NASA Technical Reports Server (NTRS)

    Benz, Arnold O.; Kosugi, Takeo; Aschwanden, Markus J.; Benka, Steve G.; Chupp, Edward L.; Enome, Shinzo; Garcia, Howard; Holman, Gordon D.; Kurt, Victoria G.; Sakao, Taro

    1994-01-01

    Particle acceleration is intrinsic to the primary energy release in the impulsive phase of solar flares, and we cannot understand flares without understanding acceleration. New observations in soft and hard X-rays, gamma-rays and coherent radio emissions are presented, suggesting flare fragmentation in time and space. X-ray and radio measurements exhibit at least five different time scales in flares. In addition, some new observations of delayed acceleration signatures are also presented. The theory of acceleration by parallel electric fields is used to model the spectral shape and evolution of hard X-rays. The possibility of the appearance of double layers is further investigated.

  18. FFAGS for rapid acceleration

    SciTech Connect

    Carol J. Johnstone and Shane Koscielniak

    2002-09-30

    When large transverse and longitudinal emittances are to be transported through a circular machine, extremely rapid acceleration holds the advantage that the beam becomes immune to nonlinear resonances because there is insufficient time for amplitudes to build up. Uncooled muon beams exhibit large emittances and require fast acceleration to avoid decay losses and would benefit from this style of acceleration. The approach here employs a fixed-field alternating gradient or FFAG magnet structure and a fixed frequency acceleration system. Acceptance is enhanced by the use only of linear lattice elements, and fixed-frequency rf enables the use of cavities with large shunt resistance and quality factor.

  19. Acceleration of polarized protons in circular accelerators

    SciTech Connect

    Courant, E.D.; Ruth, R.D.

    1980-09-12

    The theory of depolarization in circular accelerators is presented. The spin equation is first expressed in terms of the particle orbit and then converted to the equivalent spinor equation. The spinor equation is then solved for three different situations: (1) a beam on a flat top near a resonance, (2) uniform acceleration through an isolated resonance, and (3) a model of a fast resonance jump. Finally, the depolarization coefficient, epsilon, is calculated in terms of properties of the particle orbit and the results are applied to a calculation of depolarization in the AGS.

  20. Acceleration-Augmented LQG Control of an Active Magnetic Bearing

    NASA Technical Reports Server (NTRS)

    Feeley, Joseph J.

    1993-01-01

    A linear-quadratic-gaussian (LQG) regulator controller design for an acceleration-augmented active magnetic bearing (AMB) is outlined. Acceleration augmentation is a key feature in providing improved dynamic performance of the controller. The optimal control formulation provides a convenient method of trading-off fast transient response and force attenuation as control objectives.

  1. Acceleration-augmented LQG control of an active magnetic bearing

    NASA Astrophysics Data System (ADS)

    Feeley, Joseph J.

    A linear-quadratic-gaussian (LQG) regulator controller design for an acceleration-augmented active magnetic bearing (AMB) is outlined. Acceleration augmentation is a key feature in providing improved dynamic performance of the controller. The optimal control formulation provides a convenient method of trading-off fast transient response and force attenuation as control objectives.

  2. RF Gun Optimization Study

    SciTech Connect

    Alicia Hofler; Pavel Evtushenko

    2007-07-03

    Injector gun design is an iterative process where the designer optimizes a few nonlinearly interdependent beam parameters to achieve the required beam quality for a particle accelerator. Few tools exist to automate the optimization process and thoroughly explore the parameter space. The challenging beam requirements of new accelerator applications such as light sources and electron cooling devices drive the development of RF and SRF photo injectors. A genetic algorithm (GA) has been successfully used to optimize DC photo injector designs at Cornell University [1] and Jefferson Lab [2]. We propose to apply GA techniques to the design of RF and SRF gun injectors. In this paper, we report on the initial phase of the study where we model and optimize a system that has been benchmarked with beam measurements and simulation.

  3. RF Gun Optimization Study

    SciTech Connect

    A. S. Hofler; P. Evtushenko; M. Krasilnikov

    2007-08-01

    Injector gun design is an iterative process where the designer optimizes a few nonlinearly interdependent beam parameters to achieve the required beam quality for a particle accelerator. Few tools exist to automate the optimization process and thoroughly explore the parameter space. The challenging beam requirements of new accelerator applications such as light sources and electron cooling devices drive the development of RF and SRF photo injectors. RF and SRF gun design is further complicated because the bunches are space charge dominated and require additional emittance compensation. A genetic algorithm has been successfully used to optimize DC photo injector designs for Cornell* and Jefferson Lab**, and we propose studying how the genetic algorithm techniques can be applied to the design of RF and SRF gun injectors. In this paper, we report on the initial phase of the study where we model and optimize gun designs that have been benchmarked with beam measurements and simulation.

  4. Laser Guiding for GeV Laser-Plasma Accelerators

    SciTech Connect

    Leemans, Wim; Esarey, Eric; Geddes, Cameron; Schroeder, C.B.; Toth, Csaba

    2005-06-06

    Guiding of relativistically intense laser beams in preformed plasma channels is discussed for development of GeV-class laser accelerators. Experiments using a channel guided laser wakefield accelerator (LWFA) at LBNL have demonstrated that near mono-energetic 100 MeV-class electron beams can be produced with a 10 TW laser system. Analysis, aided by particle-in-cell simulations, as well as experiments with various plasma lengths and densities, indicate that tailoring the length of the accelerator, together with loading of the accelerating structure with beam, is the key to production of mono-energetic electron beams. Increasing the energy towards a GeV and beyond will require reducing the plasma density and design criteria are discussed for an optimized accelerator module. The current progress and future directions are summarized through comparison with conventional accelerators, highlighting the unique short term prospects for intense radiation sources based on laser-driven plasma accelerators.

  5. Scaling FFAG accelerator for muon acceleration

    SciTech Connect

    Lagrange, JB.; Planche, T.; Mori, Y.

    2011-10-06

    Recent developments in scaling fixed field alternating gradient (FFAG) accelerators have opened new ways for lattice design, with straight sections, and insertions like dispersion suppressors. Such principles and matching issues are detailed in this paper. An application of these new concepts is presented to overcome problems in the PRISM project.

  6. Scaling FFAG accelerator for muon acceleration

    NASA Astrophysics Data System (ADS)

    Lagrange, JB.; Planche, T.; Mori, Y.

    2011-10-01

    Recent developments in scaling fixed field alternating gradient (FFAG) accelerators have opened new ways for lattice design, with straight sections, and insertions like dispersion suppressors. Such principles and matching issues are detailed in this paper. An application of these new concepts is presented to overcome problems in the PRISM project.

  7. Angular velocities, angular accelerations, and coriolis accelerations

    NASA Technical Reports Server (NTRS)

    Graybiel, A.

    1975-01-01

    Weightlessness, rotating environment, and mathematical analysis of Coriolis acceleration is described for man's biological effective force environments. Effects on the vestibular system are summarized, including the end organs, functional neurology, and input-output relations. Ground-based studies in preparation for space missions are examined, including functional tests, provocative tests, adaptive capacity tests, simulation studies, and antimotion sickness.

  8. Angular velocities, angular accelerations, and coriolis accelerations

    NASA Technical Reports Server (NTRS)

    Graybiel, A.

    1975-01-01

    Weightlessness, rotating environment, and mathematical analysis of Coriolis acceleration is described for man's biological effective force environments. Effects on the vestibular system are summarized, including the end organs, functional neurology, and input-output relations. Ground-based studies in preparation for space missions are examined, including functional tests, provocative tests, adaptive capacity tests, simulation studies, and antimotion sickness.

  9. Accelerators (3/5)

    ScienceCinema

    None

    2016-07-12

    1a) Introduction and motivation 1b) History and accelerator types 2) Transverse beam dynamics 3a) Longitudinal beam dynamics 3b) Figure of merit of a synchrotron/collider 3c) Beam control 4) Main limiting factors 5) Technical challenges Prerequisite knowledge: Previous knowledge of accelerators is not required.

  10. KEK digital accelerator

    NASA Astrophysics Data System (ADS)

    Iwashita, T.; Adachi, T.; Takayama, K.; Leo, K. W.; Arai, T.; Arakida, Y.; Hashimoto, M.; Kadokura, E.; Kawai, M.; Kawakubo, T.; Kubo, Tomio; Koyama, K.; Nakanishi, H.; Okazaki, K.; Okamura, K.; Someya, H.; Takagi, A.; Tokuchi, A.; Wake, M.

    2011-07-01

    The High Energy Accelerator Research Organization KEK digital accelerator (KEK-DA) is a renovation of the KEK 500 MeV booster proton synchrotron, which was shut down in 2006. The existing 40 MeV drift tube linac and rf cavities have been replaced by an electron cyclotron resonance (ECR) ion source embedded in a 200 kV high-voltage terminal and induction acceleration cells, respectively. A DA is, in principle, capable of accelerating any species of ion in all possible charge states. The KEK-DA is characterized by specific accelerator components such as a permanent magnet X-band ECR ion source, a low-energy transport line, an electrostatic injection kicker, an extraction septum magnet operated in air, combined-function main magnets, and an induction acceleration system. The induction acceleration method, integrating modern pulse power technology and state-of-art digital control, is crucial for the rapid-cycle KEK-DA. The key issues of beam dynamics associated with low-energy injection of heavy ions are beam loss caused by electron capture and stripping as results of the interaction with residual gas molecules and the closed orbit distortion resulting from relatively high remanent fields in the bending magnets. Attractive applications of this accelerator in materials and biological sciences are discussed.

  11. Microscale acceleration history discriminators

    DOEpatents

    Polosky, Marc A.; Plummer, David W.

    2002-01-01

    A new class of micromechanical acceleration history discriminators is claimed. These discriminators allow the precise differentiation of a wide range of acceleration-time histories, thereby allowing adaptive events to be triggered in response to the severity (or lack thereof) of an external environment. Such devices have applications in airbag activation, and other safety and surety applications.

  12. Accelerator Science: Why RF?

    SciTech Connect

    Lincoln, Don

    2016-12-21

    Particle accelerators can fire beams of subatomic particles at near the speed of light. The accelerating force is generated using radio frequency technology and a whole lot of interesting features. In this video, Fermilab’s Dr. Don Lincoln explains how it all works.

  13. Measuring Model Rocket Acceleration.

    ERIC Educational Resources Information Center

    Jenkins, Randy A.

    1993-01-01

    Presents an experiment that measures the acceleration and velocity of a model rocket. Lift-off information is transmitted to a computer that creates a graph of the velocity. Discusses the analysis of the computer-generated data and differences between calculated and experimental velocity and acceleration of several rocket types. (MDH)

  14. Induction linear accelerators

    NASA Astrophysics Data System (ADS)

    Birx, Daniel

    1992-03-01

    Among the family of particle accelerators, the Induction Linear Accelerator is the best suited for the acceleration of high current electron beams. Because the electromagnetic radiation used to accelerate the electron beam is not stored in the cavities but is supplied by transmission lines during the beam pulse it is possible to utilize very low Q (typically<10) structures and very large beam pipes. This combination increases the beam breakup limited maximum currents to of order kiloamperes. The micropulse lengths of these machines are measured in 10's of nanoseconds and duty factors as high as 10-4 have been achieved. Until recently the major problem with these machines has been associated with the pulse power drive. Beam currents of kiloamperes and accelerating potentials of megavolts require peak power drives of gigawatts since no energy is stored in the structure. The marriage of liner accelerator technology and nonlinear magnetic compressors has produced some unique capabilities. It now appears possible to produce electron beams with average currents measured in amperes, peak currents in kiloamperes and gradients exceeding 1 MeV/meter, with power efficiencies approaching 50%. The nonlinear magnetic compression technology has replaced the spark gap drivers used on earlier accelerators with state-of-the-art all-solid-state SCR commutated compression chains. The reliability of these machines is now approaching 1010 shot MTBF. In the following paper we will briefly review the historical development of induction linear accelerators and then discuss the design considerations.

  15. Measuring Model Rocket Acceleration.

    ERIC Educational Resources Information Center

    Jenkins, Randy A.

    1993-01-01

    Presents an experiment that measures the acceleration and velocity of a model rocket. Lift-off information is transmitted to a computer that creates a graph of the velocity. Discusses the analysis of the computer-generated data and differences between calculated and experimental velocity and acceleration of several rocket types. (MDH)

  16. Accelerators (4/5)

    ScienceCinema

    None

    2016-07-12

    1a) Introduction and motivation 1b) History and accelerator types 2) Transverse beam dynamics 3a) Longitudinal beam dynamics 3b) Figure of merit of a synchrotron/collider 3c) Beam control 4) Main limiting factors 5) Technical challenges Prerequisite knowledge: Previous knowledge of accelerators is not required.

  17. Accelerators (5/5)

    ScienceCinema

    None

    2016-07-12

    1a) Introduction and motivation 1b) History and accelerator types 2) Transverse beam dynamics 3a) Longitudinal beam dynamics 3b) Figure of merit of a synchrotron/collider 3c) Beam control 4) Main limiting factors 5) Technical challenges Prerequisite knowledge: Previous knowledge of accelerators is not required.

  18. Diagnostics for induction accelerators

    SciTech Connect

    Fessenden, T.J.

    1996-04-01

    The induction accelerator was conceived by N. C. Christofilos and first realized as the Astron accelerator that operated at LLNL from the early 1960`s to the end of 1975. This accelerator generated electron beams at energies near 6 MeV with typical currents of 600 Amperes in 400 ns pulses. The Advanced Test Accelerator (ATA) built at Livermore`s Site 300 produced 10,000 Ampere beams with pulse widths of 70 ns at energies approaching 50 MeV. Several other electron and ion induction accelerators have been fabricated at LLNL and LBNL. This paper reviews the principal diagnostics developed through efforts by scientists at both laboratories for measuring the current, position, energy, and emittance of beams generated by these high current, short pulse accelerators. Many of these diagnostics are closely related to those developed for other accelerators. However, the very fast and intense current pulses often require special diagnostic techniques and considerations. The physics and design of the more unique diagnostics developed for electron induction accelerators are presented and discussed in detail.

  19. Particle Acceleration in Jets

    NASA Technical Reports Server (NTRS)

    Nishikawa, Ken-Ichi

    2005-01-01

    Nonthermal radiation observed from astrophysical systems containing relativistic jets and shocks, e.g., active galactic nuclei (AGNs), gamma ray burst (GRBs), and Galactic microquasar systems usually have power-law emission spectra. Fermi acceleration is the mechanism usually assumed for the acceleration of particles in astrophysical environments.

  20. Accelerators Beyond The Tevatron?

    SciTech Connect

    Lach, Joseph; /Fermilab

    2010-07-01

    Following the successful operation of the Fermilab superconducting accelerator three new higher energy accelerators were planned. They were the UNK in the Soviet Union, the LHC in Europe, and the SSC in the United States. All were expected to start producing physics about 1995. They did not. Why?

  1. Accelerators Beyond The Tevatron?

    SciTech Connect

    Lach, Joseph

    2010-07-29

    Following the successful operation of the Fermilab superconducting accelerator three new higher energy accelerators were planned. They were the UNK in the Soviet Union, the LHC in Europe, and the SSC in the United States. All were expected to start producing physics about 1995. They did not. Why?.

  2. Accelerators, Beams And Physical Review Special Topics - Accelerators And Beams

    SciTech Connect

    Siemann, R.H.; /SLAC

    2011-10-24

    Accelerator science and technology have evolved as accelerators became larger and important to a broad range of science. Physical Review Special Topics - Accelerators and Beams was established to serve the accelerator community as a timely, widely circulated, international journal covering the full breadth of accelerators and beams. The history of the journal and the innovations associated with it are reviewed.

  3. The Atomki accelerator center

    NASA Astrophysics Data System (ADS)

    Vajda, I.; Fülöp, Zs.; Biri, S.

    2017-06-01

    Particle accelerators are the driving forces of nuclear physics laboratories and MTA Atomki, the Institute for Nuclear Research of the Hungarian Academy of Sciences is no exception. The Atomki Accelerator Center (AAC) incorporates several low-energy charged-particle accelerators, offering the possibility of choosing ions with various charge states, energies and beam intensities. Currently, the AAC has six main facilities: a cyclotron (K=20), two Van de Graaff accelerators (1 MV, 5 MV), an ECR ion source, an electromagnetic isotope separator and a 2 MV Tandetron installed in 2015. The accelerators, spanning a range of beam energies from 50 eV to 27 MeV, have been designed for a broad range of research projects and applications in various fields - mainly in nuclear and atomic physics, materials science, environmental research and archaeology. The structure of the laboratory with a short description of the most important topics, education and outreach activities are presented.

  4. Electron acceleration by a propagating laser pulse in vacuum

    SciTech Connect

    Wang Fengchao; Shen Baifei; Zhang Xiaomei; Li Xuemei; Jin Zhangying

    2007-08-15

    Electrons accelerated by a propagating laser pulse of linear or circular polarization in vacuum have been investigated by one-dimensional particle-in-cell simulations and analytical modeling. A stopping target is used to stop the laser pulse and extract the energetic electrons from the laser field. The effect of the reflected light is taken into account. The maximum electron energy depends on the laser intensity and initial electron energy. There is an optimal acceleration length for electrons to gain maximum energy where electrons meet the peak of the laser pulse. The optimal acceleration length depends strongly on the laser pulse duration and amplitude.

  5. Induction technology optimization code

    SciTech Connect

    Caporaso, G.J.; Brooks, A.L.; Kirbie, H.C.

    1992-08-21

    A code has been developed to evaluate relative costs of induction accelerator driver systems for relativistic klystrons. The code incorporates beam generation, transport and pulsed power system constraints to provide an integrated design tool. The code generates an injector/accelerator combination which satisfies the top level requirements and all system constraints once a small number of design choices have been specified (rise time of the injector voltage and aspect ratio of the ferrite induction cores, for example). The code calculates dimensions of accelerator mechanical assemblies and values of all electrical components. Cost factors for machined parts, raw materials and components are applied to yield a total system cost. These costs are then plotted as a function of the two design choices to enable selection of an optimum design based on various criteria. The Induction Technology Optimization Study (ITOS) was undertaken to examine viable combinations of a linear induction accelerator and a relativistic klystron (RK) for high power microwave production. It is proposed, that microwaves from the RK will power a high-gradient accelerator structure for linear collider development. Previous work indicates that the RK will require a nominal 3-MeV, 3-kA electron beam with a 100-ns flat top. The proposed accelerator-RK combination will be a high average power system capable of sustained microwave output at a 300-Hz pulse repetition frequency. The ITOS code models many combinations of injector, accelerator, and pulse power designs that will supply an RK with the beam parameters described above.

  6. Space Acceleration Measurement Systems

    NASA Technical Reports Server (NTRS)

    Foster, William

    2000-01-01

    The Space Acceleration Measurement Systems (SAMS) Project develops and deploys the measurement systems for the Acceleration Measurement Program (AMP). At this time there are two types of measurement systems available, quasi-steady and vibratory. Orbital Acceleration Research Experiment (OARE) and Microgravity Acceleration Measurement System (MAMS) are the current quasi-steady systems available. OARE has flown numerous times supporting STS missions. MAMS has been delivered to Kennedy Space Center (KSC) for its deployment on the International Space Station (ISS). Vibratory measurements have been made and will be made by the Space Acceleration Measurement System (SAMS-I) Generation I, Space Acceleration Measurement System Generation II (SAMS-II), and Space Acceleration Measurement System Free Flyer or Generation III (SAMS-FF). SAMS-I supported 21 STS missions and has been retired. SAMS-II will be delivered to KSC to support ISS-6A launch (currently April 19, 2001). SAMS-FF has replaced SAMS-I in support of STS missions and has been deployed on sounding rockets, the KC-135 and ground facilities. SAMS-FF hardware shall be deployed on ISS in the future to provide a more compact solution.

  7. Large electrostatic accelerators

    SciTech Connect

    Jones, C.M.

    1984-01-01

    The increasing importance of energetic heavy ion beams in the study of atomic physics, nuclear physics, and materials science has partially or wholly motivated the construction of a new generation of large electrostatic accelerators designed to operate at terminal potentials of 20 MV or above. In this paper, the author briefly discusses the status of these new accelerators and also discusses several recent technological advances which may be expected to further improve their performance. The paper is divided into four parts: (1) a discussion of the motivation for the construction of large electrostatic accelerators, (2) a description and discussion of several large electrostatic accelerators which have been recently completed or are under construction, (3) a description of several recent innovations which may be expected to improve the performance of large electrostatic accelerators in the future, and (4) a description of an innovative new large electrostatic accelerator whose construction is scheduled to begin next year. Due to time and space constraints, discussion is restricted to consideration of only tandem accelerators.

  8. Progress Toward NLC/GLC Prototype Accelerator Structures

    SciTech Connect

    Wang, J

    2004-09-13

    The accelerator structure groups for NLC (Next Linear Collider) and GLC (Global Linear Colliders) have successfully collaborated on the research and development of a major series of advanced accelerator structures based on room-temperature technology at X-band frequency. The progress in design, simulation, microwave measurement and high gradient tests are summarized in this paper. The recent effort in design and fabrication of the accelerator structure prototype for the main linac is presented in detail including HOM (High Order Mode) suppression and design of HOM couplers and fundamental mode couplers, optimized accelerator cavities as well as plans for future structures.

  9. Ion beam accelerator system

    NASA Technical Reports Server (NTRS)

    Aston, Graeme (Inventor)

    1984-01-01

    A system is described that combines geometrical and electrostatic focusing to provide high ion extraction efficiency and good focusing of an accelerated ion beam. The apparatus includes a pair of curved extraction grids (16, 18) with multiple pairs of aligned holes positioned to direct a group of beamlets (20) along converging paths. The extraction grids are closely spaced and maintained at a moderate potential to efficiently extract beamlets of ions and allow them to combine into a single beam (14). An accelerator electrode device (22) downstream from the extraction grids, is at a much lower potential than the grids to accelerate the combined beam.

  10. Ion beam accelerator system

    NASA Technical Reports Server (NTRS)

    Aston, G. (Inventor)

    1981-01-01

    A system is described that combines geometrical and electrostatic focusing to provide high ion extraction efficiency and good focusing of an accelerated ion beam. The apparatus includes a pair of curved extraction grids with multiple pairs of aligned holes positioned to direct a group of beamlets along converging paths. The extraction grids are closely spaced and maintained at a moderate potential to efficiently extract beamlets of ions and allow them to combine into a single beam. An accelerator electrode device downstream from the extraction grids is at a much lower potential than the grids to accelerate the combined beam. The application of the system to ion implantation is mentioned.

  11. Vacuum Beat Wave Accelerator

    NASA Astrophysics Data System (ADS)

    Moore, C. I.; Hafizi, B.; Ting, A.; Burris, H. R.; Sprangle, P.; Esarey, E.; Ganguly, A.; Hirshfield, J. L.

    1997-11-01

    The Vacuum Beat Wave Accelerator (VBWA) is a particle acceleration scheme which uses the non-linear ponderomotive beating of two different frequency laser beams to accelerate electrons. A proof-of-principle experiment to demonstrate the VBWA is underway at the Naval Research Laboratory (NRL). This experiment will use the beating of a 1054 nm and 527 nm laser pulse from the NRL T-cubed laser to generate the beat wave and a 4.5 MeV RF electron gun as the electron source. Simulation results and the experimental design will be presented. The suitability of using axicon or higher order Gaussian laser beams will also be discussed.

  12. Laser acceleration of ions: recent results and prospects for applications

    NASA Astrophysics Data System (ADS)

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

    2015-01-01

    We present a brief review of recent theoretical and numerical simulation results on the acceleration of ions from various targets irradiated by high-power femtosecond laser pulses. The results include: the optimization of the laser-plasma acceleration of ions over the thickness of a solid target; a new dependence of the energy of accelerated protons from a semi-transparent foil on the incident pulse energy; a theoretical model of plasma layer expansion in the vacuum for a fixed temperature of heated electrons, describing arbitrary regimes of particle acceleration, from the quasineutral flow of a plasma to Coulomb explosion; analytic theories of the relativistic Coulomb explosion of a spherical microtarget and the radial ponderomotive acceleration of ions from a laser channel in a transparent plasma; and calculations optimizing the production of isotopes for medicine using next-generation lasers.

  13. A beam-matching concept for medical linear accelerators.

    PubMed

    Sjöström, David; Bjelkengren, Ulf; Ottosson, Wiviann; Behrens, Claus F

    2009-01-01

    The flexibility in radiotherapy can be improved if a patient can be moved between any one of the department's medical linear accelerators without the need to change anything in the patient's treatment plan. For this to be possible, the dosimetric characteristics of the various accelerators must be the same, or nearly the same i.e. the accelerators must be beam-matched. During a period of nine months, eight Varian iX accelerators with 6 and 15 MV photon beams and 6-18 MeV electron beams (only four of the eight) were installed at our clinic. All accelerators fulfilled the vendor-defined "fine beam-match" criteria, and a more extensive set of measurements was carried out during commissioning. The measured absorbed dose data for each accelerator were compared with the first accelerator, chosen as reference, and the TPS calculations. Two of the eight accelerators showed a larger discrepancy for the 15 MV beam not revealed by the vendor-defined acceptance criteria, whereas the other six accelerators were satisfactorily matched. The beam-matching acceptance criteria defined by the vendor are not strict enough to guarantee optimal beam-match. Deviations related to dose calculations and to beam-matched accelerators may add up. The safest and most practical way to ensure that all accelerators are within clinical acceptable accuracy is to include TPS calculations in the evaluation. Further, comparisons between measurements and calculations should be done in absolute dose terms.

  14. Accelerating Scientific Computations using FPGAs

    NASA Astrophysics Data System (ADS)

    Pell, O.; Atasu, K.; Mencer, O.

    Field Programmable Gate Arrays (FPGAs) are semiconductor devices that contain a grid of programmable cells, which the user configures to implement any digital circuit of up to a few million gates. Modern FPGAs allow the user to reconfigure these circuits many times each second, making FPGAs fully programmable and general purpose. Recent FPGA technology provides sufficient resources to tackle scientific applications on large-scale parallel systems. As a case study, we implement the Fast Fourier Transform [1] in a flexible floating point implementation. We utilize A Stream Compiler [2] (ASC) which combines C++ syntax with flexible floating point support by providing a 'HWfloat' data-type. The resulting FFT can be targeted to a variety of FPGA platforms in FFTW-style, though not yet completely automatically. The resulting FFT circuit can be adapted to the particular resources available on the system. The optimal implementation of an FFT accelerator depends on the length and dimensionality of the FFT, the available FPGA area, the available hard DSP blocks, the FPGA board architecture, and the precision and range of the application [3]. Software-style object-orientated abstractions allow us to pursue an accelerated pace of development by maximizing re-use of design patterns. ASC allows a few core hardware descriptions to generate hundreds of different circuit variants to meet particular speed, area and precision goals. The key to achieving maximum acceleration of FFT computation is to match memory and compute bandwidths so that maximum use is made of computational resources. Modern FPGAs contain up to hundreds of independent SRAM banks to store intermediate results, providing ample scope for optimizing memory parallelism. At 175Mhz, one of Maxeler's Radix-4 FFT cores computes 4x as many 1024pt FFTs per second as a dual Pentium-IV Xeon machine running FFTW. Eight such parallel cores fit onto the largest FPGA in the Xilinx Virtex-4 family, providing a 32x speed-up over

  15. Graphics Processing Unit Acceleration of Gyrokinetic Turbulence Simulations

    NASA Astrophysics Data System (ADS)

    Hause, Benjamin; Parker, Scott

    2012-10-01

    We find a substantial increase in on-node performance using Graphics Processing Unit (GPU) acceleration in gyrokinetic delta-f particle-in-cell simulation. Optimization is performed on a two-dimensional slab gyrokinetic particle simulation using the Portland Group Fortran compiler with the GPU accelerator compiler directives. We have implemented the GPU acceleration on a Core I7 gaming PC with a NVIDIA GTX 580 GPU. We find comparable, or better, acceleration relative to the NERSC DIRAC cluster with the NVIDIA Tesla C2050 computing processor. The Tesla C 2050 is about 2.6 times more expensive than the GTX 580 gaming GPU. Optimization strategies and comparisons between DIRAC and the gaming PC will be presented. We will also discuss progress on optimizing the comprehensive three dimensional general geometry GEM code.

  16. CLASHING BEAM PARTICLE ACCELERATOR

    DOEpatents

    Burleigh, R.J.

    1961-04-11

    A charged-particle accelerator of the proton synchrotron class having means for simultaneously accelerating two separate contra-rotating particle beams within a single annular magnet structure is reported. The magnet provides two concentric circular field regions of opposite magnetic polarity with one field region being of slightly less diameter than the other. The accelerator includes a deflector means straddling the two particle orbits and acting to collide the two particle beams after each has been accelerated to a desired energy. The deflector has the further property of returning particles which do not undergo collision to the regular orbits whereby the particles recirculate with the possibility of colliding upon subsequent passages through the deflector.

  17. DIELECTRIC WALL ACCELERATOR TECHNOLOGY

    SciTech Connect

    Sampayan, S; Caporaso, G; Chen, Y; Harris, J; Hawkins, S; Holmes, C; Nelson, S; Poole, B; Rhodes, M; Sanders, D; Sullivan, J; Wang, L; Watson, J

    2007-10-18

    The dielectric wall accelerator (DWA) is a compact pulsed power device where the pulse forming lines, switching, and vacuum wall are integrated into a single compact geometry. For this effort, we initiated a extensive compact pulsed power development program and have pursued the study of switching (gas, oil, laser induced surface flashover and photoconductive), dielectrics (ceramics and nanoparticle composites), pulse forming line topologies (asymmetric and symmetric Blumleins and zero integral pulse forming lines), and multilayered vacuum insulator (HGI) technology. Finally, we fabricated an accelerator cell for test on ETAII (a 5.5 MeV, 2 kA, 70 ns pulsewidth electron beam accelerator). We review our past results and report on the progress of accelerator cell testing.

  18. Accelerator on a Chip

    SciTech Connect

    England, Joel

    2014-06-30

    SLAC's Joel England explains how the same fabrication techniques used for silicon computer microchips allowed their team to create the new laser-driven particle accelerator chips. (SLAC Multimedia Communications)

  19. Charged particle accelerator grating

    DOEpatents

    Palmer, R.B.

    1985-09-09

    A readily disposable and replaceable accelerator grating for a relativistic particle accelerator is described. The grating is formed for a plurality of liquid droplets that are directed in precisely positioned jet streams to periodically dispose rows of droplets along the borders of a predetermined particle beam path. A plurality of lasers are used to direct laser beams onto the droplets, at predetermined angles, thereby to excite the droplets to support electromagnetic accelerating resonances on their surfaces. Those resonances operate to accelerate and focus particles moving along the beam path. As the droplets are distorted or destroyed by the incoming radiation, they are replaced at a predetermined frequency by other droplets supplied through the jet streams.

  20. Principles of Induction Accelerators

    NASA Astrophysics Data System (ADS)

    Briggs*, Richard J.

    The basic concepts involved in induction accelerators are introduced in this chapter. The objective is to provide a foundation for the more detailed coverage of key technology elements and specific applications in the following chapters. A wide variety of induction accelerators are discussed in the following chapters, from the high current linear electron accelerator configurations that have been the main focus of the original developments, to circular configurations like the ion synchrotrons that are the subject of more recent research. The main focus in the present chapter is on the induction module containing the magnetic core that plays the role of a transformer in coupling the pulsed power from the modulator to the charged particle beam. This is the essential common element in all these induction accelerators, and an understanding of the basic processes involved in its operation is the main objective of this chapter. (See [1] for a useful and complementary presentation of the basic principles in induction linacs.)

  1. Wake field acceleration experiments

    SciTech Connect

    Simpson, J.D.

    1988-01-01

    Where and how will wake field acceleration devices find use for other than, possibly, accelerators for high energy physics. I don't know that this can be responsibly answered at this time. What I can do is describe some recent results from an ongoing experimental program at Argonne which support the idea that wake field techniques and devices are potentially important for future accelerators. Perhaps this will spawn expanded interest and even new ideas for the use of this new technology. The Argonne program, and in particular the Advanced Accelerator Test Facility (AATF), has been reported in several fairly recent papers and reports. But because this is a substantially new audience for the subject, I will include a brief review of the program and the facility before describing experiments. 10 refs., 7 figs.

  2. TESLA superconducting accelerating structures

    NASA Astrophysics Data System (ADS)

    Sekutowicz, J.

    2007-08-01

    Superconducting standing wave structures have been used for charged particle acceleration for almost 40 years. A brief introduction to this application with examples, test procedures and recently achieved results are discussed in this paper.

  3. HEAVY ION LINEAR ACCELERATOR

    DOEpatents

    Van Atta, C.M.; Beringer, R.; Smith, L.

    1959-01-01

    A linear accelerator of heavy ions is described. The basic contributions of the invention consist of a method and apparatus for obtaining high energy particles of an element with an increased charge-to-mass ratio. The method comprises the steps of ionizing the atoms of an element, accelerating the resultant ions to an energy substantially equal to one Mev per nucleon, stripping orbital electrons from the accelerated ions by passing the ions through a curtain of elemental vapor disposed transversely of the path of the ions to provide a second charge-to-mass ratio, and finally accelerating the resultant stripped ions to a final energy of at least ten Mev per nucleon.

  4. Accelerated immunotherapy schedules.

    PubMed

    Calabria, Christopher W

    2013-08-01

    Rush and cluster immunotherapy schedules are accelerated immunotherapy build-up schedules. A cluster immunotherapy schedule involves the patient receiving several allergen injections (generally 2-4) sequentially in a single day of treatment on nonconsecutive days. The maintenance dose is generally reached in 4-8 weeks. In rush immunotherapy protocols, higher doses are administered at 15- to 60-min intervals over a 1- to 3-day period until the maintenance dose is achieved. This review will serve as an update for accelerated immunotherapy schedules. The review will include recent investigations demonstrating the safety of cluster schedules in atopic dermatitis, pediatric patients, and inhalant allergen mixtures and an accelerated protocol utilizing an infusion pump for allergen delivery. There has also been further elucidation on the immunological changes which occur during accelerated immunotherapy. Finally, new studies analyzing systemic reaction risk factors are discussed.

  5. Accelerator on a Chip

    ScienceCinema

    England, Joel

    2016-07-12

    SLAC's Joel England explains how the same fabrication techniques used for silicon computer microchips allowed their team to create the new laser-driven particle accelerator chips. (SLAC Multimedia Communications)

  6. Dielectric assist accelerating structure

    NASA Astrophysics Data System (ADS)

    Satoh, D.; Yoshida, M.; Hayashizaki, N.

    2016-01-01

    A higher-order TM02 n mode accelerating structure is proposed based on a novel concept of dielectric loaded rf cavities. This accelerating structure consists of ultralow-loss dielectric cylinders and disks with irises which are periodically arranged in a metallic enclosure. Unlike conventional dielectric loaded accelerating structures, most of the rf power is stored in the vacuum space near the beam axis, leading to a significant reduction of the wall loss, much lower than that of conventional normal-conducting linac structures. This allows us to realize an extremely high quality factor and a very high shunt impedance at room temperature. A simulation of a 5 cell prototype design with an existing alumina ceramic indicates an unloaded quality factor of the accelerating mode over 120 000 and a shunt impedance exceeding 650 M Ω /m at room temperature.

  7. Vibration control in accelerators

    SciTech Connect

    Montag, C.

    2011-01-01

    In the vast majority of accelerator applications, ground vibration amplitudes are well below tolerable magnet jitter amplitudes. In these cases, it is necessary and sufficient to design a rigid magnet support structure that does not amplify ground vibration. Since accelerator beam lines are typically installed at an elevation of 1-2m above ground level, special care has to be taken in order to avoid designing a support structure that acts like an inverted pendulum with a low resonance frequency, resulting in untolerable lateral vibration amplitudes of the accelerator components when excited by either ambient ground motion or vibration sources within the accelerator itself, such as cooling water pumps or helium flow in superconducting magnets. In cases where ground motion amplitudes already exceed the required jiter tolerances, for instance in future linear colliders, passive vibration damping or active stabilization may be considered.

  8. Amps particle accelerator definition study

    NASA Technical Reports Server (NTRS)

    Sellen, J. M., Jr.

    1975-01-01

    The Particle Accelerator System of the AMPS (Atmospheric, Magnetospheric, and Plasmas in Space) payload is a series of charged particle accelerators to be flown with the Space Transportation System Shuttle on Spacelab missions. In the configuration presented, the total particle accelerator system consists of an energetic electron beam, an energetic ion accelerator, and both low voltage and high voltage plasma acceleration devices. The Orbiter is illustrated with such a particle accelerator system.

  9. ELECTROMAGNETIC SIMULATIONS OF DIELECTRIC WALL ACCELERATOR STRUCTURES FOR ELECTRON BEAM ACCELERATION

    SciTech Connect

    Nelson, S D; Poole, B R

    2005-05-05

    Dielectric Wall Accelerator (DWA) technology incorporates the energy storage mechanism, the switching mechanism, and the acceleration mechanism for electron beams. Electromagnetic simulations of DWA structures includes these effects and also details of the switch configuration and how that switch time affects the electric field pulse which accelerates the particle beam. DWA structures include both bi-linear and bi-spiral configurations with field gradients on the order of 20MV/m and the simulations include the effects of the beampipe, the beampipe walls, the DWA High Gradient Insulator (HGI) insulating stack, wakefield impedance calculations, and test particle trajectories with low emittance gain. Design trade-offs include the transmission line impedance (typically a few ohms), equilibration ring optimization, driving switch inductances, and layer-to-layer coupling effects and the associated affect on the acceleration pulse's peak value.

  10. Rolamite acceleration sensor

    DOEpatents

    Abbin, Joseph P.; Briner, Clifton F.; Martin, Samuel B.

    1993-01-01

    A rolamite acceleration sensor which has a failsafe feature including a housing, a pair of rollers, a tension band wrapped in an S shaped fashion around the rollers, wherein the band has a force-generation cut out and a failsafe cut out or weak portion. The failsafe cut out or weak portion breaks when the sensor is subjected to an excessive acceleration so that the sensor fails in an open circuit (non-conducting) state permanently.

  11. Rolamite acceleration sensor

    DOEpatents

    Abbin, J.P.; Briner, C.F.; Martin, S.B.

    1993-12-21

    A rolamite acceleration sensor is described which has a failsafe feature including a housing, a pair of rollers, a tension band wrapped in an S shaped fashion around the rollers, wherein the band has a force-generation cut out and a failsafe cut out or weak portion. The failsafe cut out or weak portion breaks when the sensor is subjected to an excessive acceleration so that the sensor fails in an open circuit (non-conducting) state permanently. 6 figures.

  12. Accelerated Corrosion Testing

    DTIC Science & Technology

    1982-12-01

    conducted on high-strength 4340 steel and 7075-T6 aluminum alloy usina accelerating pollutants such as sulfur dinxide, nitrogen dioxide, surface salt...CONTROLLED 100 ATMOSPHERES APPiENDIX B - ACCELERATED ATMDSPHERIC-CORROSION TESTING 128 v I. LIST OF ILLUSTRATIONS Ficure Page 1 Schematic Diagram of Applied...Static-Load Crack-Growth Rate (from ref. 17). 26 12 Environmental-System Flow Diagram . 33 13 Compact-Tension Plane-Strain Fracture-Toughness Specimen

  13. Microgravity Acceleration Measurement System

    NASA Technical Reports Server (NTRS)

    Foster, William

    2009-01-01

    Microgravity Acceleration Measurement System (MAMS) is an ongoing study of the small forces (vibrations and accelerations) on the ISS that result from the operation of hardware, crew activities, as well as dockings and maneuvering. Results will be used to generalize the types of vibrations affecting vibration-sensitive experiments. Investigators seek to better understand the vibration environment on the space station to enable future research.

  14. Designing reliability into accelerators

    NASA Astrophysics Data System (ADS)

    Hutton, A.

    1992-07-01

    Future accelerators will have to provide a high degree of reliability. Quality must be designed in right from the beginning and must remain a central theme throughout the project. The problem is similar to the problems facing US industry today, and examples of the successful application of quality engineering will be given. Different aspects of an accelerator project will be addressed: Concept, Design, Motivation, Management Techniques, and Fault Diagnosis. The importance of creating and maintaining a coherent team will be stressed.

  15. Accelerator Experiments for Astrophysics

    SciTech Connect

    Ng, J

    2003-10-15

    Many recent discoveries in astrophysics involve phenomena that are highly complex. Carefully designed experiments, together with sophisticated computer simulations, are required to gain insights into the underlying physics. We show that particle accelerators are unique tools in this area of research, by providing precision calibration data and by creating extreme experimental conditions relevant for astrophysics. In this paper we discuss laboratory experiments that can be carried out at the Stanford Linear Accelerator Center and implications for astrophysics.

  16. Collective field accelerator

    DOEpatents

    Luce, John S.

    1978-01-01

    A collective field accelerator which operates with a vacuum diode and utilizes a grooved cathode and a dielectric anode that operates with a relativistic electron beam with a .nu./.gamma. of .about. 1, and a plurality of dielectric lenses having an axial magnetic field thereabout to focus the collectively accelerated electrons and ions which are ejected from the anode. The anode and lenses operate as unoptimized r-f cavities which modulate and focus the beam.

  17. Accelerators for America's Future

    NASA Astrophysics Data System (ADS)

    Bai, Mei

    2016-03-01

    Particle accelerator, a powerful tool to energize beams of charged particles to a desired speed and energy, has been the working horse for investigating the fundamental structure of matter and fundermental laws of nature. Most known examples are the 2-mile long Stanford Linear Accelerator at SLAC, the high energy proton and anti-proton collider Tevatron at FermiLab, and Large Hadron Collider that is currently under operation at CERN. During the less than a century development of accelerator science and technology that led to a dazzling list of discoveries, particle accelerators have also found various applications beyond particle and nuclear physics research, and become an indispensible part of the economy. Today, one can find a particle accelerator at almost every corner of our lives, ranging from the x-ray machine at the airport security to radiation diagnostic and therapy in hospitals. This presentation will give a brief introduction of the applications of this powerful tool in fundermental research as well as in industry. Challenges in accelerator science and technology will also be briefly presented

  18. APT accelerator technology

    SciTech Connect

    Schneider, J.D.

    1996-09-01

    Proposed accelerator production of tritium (APT) project requires an accelerator providing a cw proton beam of 100 mA at 1300 MeV. Since most of the technical risk of a high-current cw (continuous-wave, 100% DF) accelerator resides in the low-energy section, Los Alamos is building a 20 MeV duplicate of the accelerator front end to confirm design codes, beam performance, and demonstrate operaional reliability. We report on design details of this low-energy demonstration accelerator (LEDA) and discuss the integrated design of the full accelerator for the APT plant. LEDA`s proton injector is under test and has produced more than 130 mA at 75 keV. Fabrication is proceeding on a 6.7-KeV, 8-m long RFQ, and detailed design is underway on coupled-cavity drift-tube linac (CCDTL) structures. Detailed design and technology experiments are underway on medium-beta superconducting cavities to assess feasibility of replacing the conventional (room-temperature copper) high-energy linac with a linac made of niobium superconducting RF cavities.

  19. Precession dynamics of the relativistic electron spin in laser-plasma acceleration

    SciTech Connect

    Pugacheva, D V; Andreev, N E

    2016-01-31

    A model is developed to study the precession dynamics of the relativistic electron spin in a laser-plasma accelerator versus the initial energy of the electron and its injection phase. Optimal parameters providing minimum depolarisation of the electron in the acceleration process are determined. (laser -plasma acceleration of electrons)

  20. Multileaf collimator for Coline medical accelerators

    NASA Astrophysics Data System (ADS)

    Harasimowicz, Janusz; Plebański, Grzegorz; Sajna, Krzysztof

    2008-01-01

    Multileaf collimator (MLC) allows advanced field shaping for radiation therapy delivered with medical accelerators. In this paper theoretical considerations and scientific studies of a new MLC design are described. Considered multileaf collimator model comprises of a multiplicity of tungsten leaves of 1 cm width projected at isocenter plane. To ensure compatibility of a new MLC solution with different accelerator types as well as to assure high reliability in irradiated environment and presence of strong magnetic field, a complex and independent control system had to be developed. It comprises of two modules - one placed in the accelerator treatment head and the other one placed in the control room. Both of them ensure high reliability and treatment quality while working in harsh conditions. Mechanical design and leaf shape optimization algorithm based on a ray tracing method are also described in details. Adapted solutions allowed providing minimized and uniform radiation penumbrae in the full range of leaves positions which is crucial for modern advanced radiotherapy.

  1. Method for computationally efficient design of dielectric laser accelerator structures.

    PubMed

    Hughes, Tyler; Veronis, Georgios; Wootton, Kent P; Joel England, R; Fan, Shanhui

    2017-06-26

    Dielectric microstructures have generated much interest in recent years as a means of accelerating charged particles when powered by solid state lasers. The acceleration gradient (or particle energy gain per unit length) is an important figure of merit. To design structures with high acceleration gradients, we explore the adjoint variable method, a highly efficient technique used to compute the sensitivity of an objective with respect to a large number of parameters. With this formalism, the sensitivity of the acceleration gradient of a dielectric structure with respect to its entire spatial permittivity distribution is calculated by the use of only two full-field electromagnetic simulations, the original and 'adjoint'. The adjoint simulation corresponds physically to the reciprocal situation of a point charge moving through the accelerator gap and radiating. Using this formalism, we perform numerical optimizations aimed at maximizing acceleration gradients, which generate fabricable structures of greatly improved performance in comparison to previously examined geometries.

  2. Beam dynamics simulation of a double pass proton linear accelerator

    NASA Astrophysics Data System (ADS)

    Hwang, Kilean; Qiang, Ji

    2017-04-01

    A recirculating superconducting linear accelerator with the advantage of both straight and circular accelerator has been demonstrated with relativistic electron beams. The acceleration concept of a recirculating proton beam was recently proposed [J. Qiang, Nucl. Instrum. Methods Phys. Res., Sect. A 795, 77 (2015, 10.1016/j.nima.2015.05.056)] and is currently under study. In order to further support the concept, the beam dynamics study on a recirculating proton linear accelerator has to be carried out. In this paper, we study the feasibility of a two-pass recirculating proton linear accelerator through the direct numerical beam dynamics design optimization and the start-to-end simulation. This study shows that the two-pass simultaneous focusing without particle losses is attainable including fully 3D space-charge effects through the entire accelerator system.

  3. GPU Accelerated Vector Median Filter

    NASA Technical Reports Server (NTRS)

    Aras, Rifat; Shen, Yuzhong

    2011-01-01

    Noise reduction is an important step for most image processing tasks. For three channel color images, a widely used technique is vector median filter in which color values of pixels are treated as 3-component vectors. Vector median filters are computationally expensive; for a window size of n x n, each of the n(sup 2) vectors has to be compared with other n(sup 2) - 1 vectors in distances. General purpose computation on graphics processing units (GPUs) is the paradigm of utilizing high-performance many-core GPU architectures for computation tasks that are normally handled by CPUs. In this work. NVIDIA's Compute Unified Device Architecture (CUDA) paradigm is used to accelerate vector median filtering. which has to the best of our knowledge never been done before. The performance of GPU accelerated vector median filter is compared to that of the CPU and MPI-based versions for different image and window sizes, Initial findings of the study showed 100x improvement of performance of vector median filter implementation on GPUs over CPU implementations and further speed-up is expected after more extensive optimizations of the GPU algorithm .

  4. Photon acceleration in laser wakefield accelerators

    SciTech Connect

    Trines, R. M. G. M.

    2007-07-11

    If the index of a refraction of a dispersive medium, such as a plasma, changes in time, it can be used to change the frequency of light propagating through the medium. This effect is called photon acceleration. It has been predicted in both theory and simulations, and also been demonstrated experimentally for the case of moving ionization fronts in gases (the so-called ionization blueshift) as well as for laser-driven wakefields.Here, we present studies of photon acceleration in laser-driven plasma wakefields. The unique spectral characteristics of this process will be discussed, to distinguish it from e.g. photon acceleration by ionization fronts, frequency domain interferometry or self-phase modulation. The dynamics of the photons in laser-wakefield interaction are studied through both regular particle-in-cell and wave-kinetic simulations. The latter approach provides a powerful, versatile, and easy-to-use method to track the propagation of individual spectral components, providing new insight into the physics of laser-plasma interaction. Theory, simulations and experimental results will be brought together to provide a full understanding of the dynamics of a laser pulse in its own wakefield.Even though the wave-kinetic approach mentioned above has mainly been developed for the description of laser-plasma interaction, it can be applied to a much wider range of fast wave-slow wave interaction processes: Langmuir waves-ion acoustic waves, drift waves-zonal flow, Rossby waves-zonal flow, or even photons-gravitational waves. Several recent results in these areas will be shown, often with surprising results.

  5. Diffusive Shock Acceleration and Reconnection Acceleration Processes

    NASA Astrophysics Data System (ADS)

    Zank, G. P.; Hunana, P.; Mostafavi, P.; Le Roux, J. A.; Li, Gang; Webb, G. M.; Khabarova, O.; Cummings, A.; Stone, E.; Decker, R.

    2015-12-01

    Shock waves, as shown by simulations and observations, can generate high levels of downstream vortical turbulence, including magnetic islands. We consider a combination of diffusive shock acceleration (DSA) and downstream magnetic-island-reconnection-related processes as an energization mechanism for charged particles. Observations of electron and ion distributions downstream of interplanetary shocks and the heliospheric termination shock (HTS) are frequently inconsistent with the predictions of classical DSA. We utilize a recently developed transport theory for charged particles propagating diffusively in a turbulent region filled with contracting and reconnecting plasmoids and small-scale current sheets. Particle energization associated with the anti-reconnection electric field, a consequence of magnetic island merging, and magnetic island contraction, are considered. For the former only, we find that (i) the spectrum is a hard power law in particle speed, and (ii) the downstream solution is constant. For downstream plasmoid contraction only, (i) the accelerated spectrum is a hard power law in particle speed; (ii) the particle intensity for a given energy peaks downstream of the shock, and the distance to the peak location increases with increasing particle energy, and (iii) the particle intensity amplification for a particular particle energy, f(x,c/{c}0)/f(0,c/{c}0), is not 1, as predicted by DSA, but increases with increasing particle energy. The general solution combines both the reconnection-induced electric field and plasmoid contraction. The observed energetic particle intensity profile observed by Voyager 2 downstream of the HTS appears to support a particle acceleration mechanism that combines both DSA and magnetic-island-reconnection-related processes.

  6. Optimally Stopped Optimization

    NASA Astrophysics Data System (ADS)

    Vinci, Walter; Lidar, Daniel A.

    2016-11-01

    We combine the fields of heuristic optimization and optimal stopping. We propose a strategy for benchmarking randomized optimization algorithms that minimizes the expected total cost for obtaining a good solution with an optimal number of calls to the solver. To do so, rather than letting the objective function alone define a cost to be minimized, we introduce a further cost-per-call of the algorithm. We show that this problem can be formulated using optimal stopping theory. The expected cost is a flexible figure of merit for benchmarking probabilistic solvers that can be computed when the optimal solution is not known and that avoids the biases and arbitrariness that affect other measures. The optimal stopping formulation of benchmarking directly leads to a real-time optimal-utilization strategy for probabilistic optimizers with practical impact. We apply our formulation to benchmark simulated annealing on a class of maximum-2-satisfiability (MAX2SAT) problems. We also compare the performance of a D-Wave 2X quantum annealer to the Hamze-Freitas-Selby (HFS) solver, a specialized classical heuristic algorithm designed for low-tree-width graphs. On a set of frustrated-loop instances with planted solutions defined on up to N =1098 variables, the D-Wave device is 2 orders of magnitude faster than the HFS solver, and, modulo known caveats related to suboptimal annealing times, exhibits identical scaling with problem size.

  7. Gait analysis using gravitational acceleration measured by wearable sensors.

    PubMed

    Takeda, Ryo; Tadano, Shigeru; Todoh, Masahiro; Morikawa, Manabu; Nakayasu, Minoru; Yoshinari, Satoshi

    2009-02-09

    A novel method for measuring human gait posture using wearable sensor units is proposed. The sensor units consist of a tri-axial acceleration sensor and three gyro sensors aligned on three axes. The acceleration and angular velocity during walking were measured with seven sensor units worn on the abdomen and the lower limb segments (both thighs, shanks and feet). The three-dimensional positions of each joint are calculated from each segment length and joint angle. Joint angle can be estimated mechanically from the gravitational acceleration along the anterior axis of the segment. However, the acceleration data during walking includes three major components; translational acceleration, gravitational acceleration and external noise. Therefore, an optimization analysis was represented to separate only the gravitational acceleration from the acceleration data. Because the cyclic patterns of acceleration data can be found during constant walking, a FFT analysis was applied to obtain some characteristic frequencies in it. A pattern of gravitational acceleration was assumed using some parts of these characteristic frequencies. Every joint position was calculated from the pattern under the condition of physiological motion range of each joint. An optimized pattern of the gravitational acceleration was selected as a solution of an inverse problem. Gaits of three healthy volunteers were measured by walking for 20s on a flat floor. As a result, the acceleration data of every segment was measured simultaneously. The characteristic three-dimensional walking could be shown by the expression using a stick figure model. In addition, the trajectories of the knee joint in the horizontal plane could be checked by visual imaging on a PC. Therefore, this method provides important quantitive information for gait diagnosis.

  8. Multi-Mode Cavity Accelerator Structure

    SciTech Connect

    Jiang, Yong; Hirshfield, Jay Leonard

    2016-11-10

    This project aimed to develop a prototype for a novel accelerator structure comprising coupled cavities that are tuned to support modes with harmonically-related eigenfrequencies, with the goal of reaching an acceleration gradient >200 MeV/m and a breakdown rate <10-7/pulse/meter. Phase I involved computations, design, and preliminary engineering of a prototype multi-harmonic cavity accelerator structure; plus tests of a bimodal cavity. A computational procedure was used to design an optimized profile for a bimodal cavity with high shunt impedance and low surface fields to maximize the reduction in temperature rise ΔT. This cavity supports the TM010 mode and its 2nd harmonic TM011 mode. Its fundamental frequency is at 12 GHz, to benchmark against the empirical criteria proposed within the worldwide High Gradient collaboration for X-band copper structures; namely, a surface electric field Esurmax< 260 MV/m and pulsed surface heating ΔTmax< 56 °K. With optimized geometry, amplitude and relative phase of the two modes, reductions are found in surface pulsed heating, modified Poynting vector, and total RF power—as compared with operation at the same acceleration gradient using only the fundamental mode.

  9. Three-directional acceleration phase mapping of myocardial function.

    PubMed

    Staehle, Felix; Jung, Bernd A; Bauer, Simon; Leupold, Jochen; Bock, Jelena; Lorenz, Ramona; Föll, Daniela; Markl, Michael

    2011-05-01

    An optimized acceleration encoded phase contrast method termed "acceleration phase mapping" for the assessment of regional myocardial function is presented. Based on an efficient gradient waveform design using two-sided encoding for in vivo three-directional acceleration mapping, echo and repetition times TE = 12-14 ms and TR = 15-17 ms for low accelerations sensitivity aenc = 5-8 m/s(2) were achieved. In addition to phantom validation, the technique was applied in a study with 10 healthy volunteers at 1.5T and 3T to evaluate its feasibility to assess regional myocardial acceleration at 1.5T and 3T. Results of the acceleration measurements were compared with the temporal derivative of myocardial velocities from three-directional velocity encoded standard phase contrast MRI in the same volunteers. The feasibility to assess myocardial acceleration along the radial, circumferential, and longitudinal direction of the left ventricle was demonstrated. Despite improved signal-to-noise-ratio at 3T (34% increase compared with 1.5T), image quality with respect to susceptibility artifacts was better 1.5T compared with 3T. Analysis of global and regional left ventricular acceleration showed characteristic patterns of systolic and diastolic acceleration and deceleration. Comparisons of directly measured and derived myocardial acceleration dynamics over the cardiac cycle revealed good correlation (r = 0.45-0.68, P < 0.01) between both methods. Copyright © 2010 Wiley-Liss, Inc.

  10. New Advanced Dielectric Materials for Accelerator Applications

    SciTech Connect

    Kanareykin, A.

    2010-11-04

    We present our recent results on the development and experimental testing of advanced dielectric materials that are capable of supporting the high RF electric fields generated by electron beams or pulsed high power microwaves. These materials have been optimized or specially designed for accelerator applications. The materials discussed here include low loss microwave ceramics, quartz, Chemical Vapor Deposition diamonds and nonlinear Barium Strontium Titanate based ferroelectrics.

  11. Emittance measurements from the LLUMC proton accelerator

    NASA Astrophysics Data System (ADS)

    Coutrakon, G.; Gillespie, G. H.; Hubbard, J.; Sanders, E.

    2005-12-01

    A new method of calculating beam emittances at the extraction point of a particle accelerator is presented. The technique uses the optimization programs NPSOL and MINOS developed at Stanford University in order to determine the initial values of beam size, divergence and correlation parameters (i.e. beam sigma matrix, σij) that best fit measured beam parameters. These σij elements are then used to compute the Twiss parameters α, β, and the phase space area, ε, of the beam at the extraction point. Beam size measurements in X and Y throughout the transport line were input to the optimizer along with the magnetic elements of bends, quads, and drifts. The σij parameters were optimized at the accelerator's extraction point by finding the best agreement between these measured beam sizes and those predicted by TRANSPORT. This expands upon a previous study in which a "trial and error" technique was used instead of the optimizer software, and which yielded similar results. The Particle Beam Optics Laboratory (PBO Lab™) program used for this paper integrates particle beam optics and other codes into a single intuitive graphically-based computing environment. This new software provides a seamless interface between the NPSOL and MINOS optimizer and TRANSPORT calculations. The results of these emittance searches are presented here for the eight clinical energies between 70 and 250 MeV currently being used at LLUMC.

  12. Dielectric laser accelerators

    NASA Astrophysics Data System (ADS)

    England, R. Joel; Noble, Robert J.; Bane, Karl; Dowell, David H.; Ng, Cho-Kuen; Spencer, James E.; Tantawi, Sami; Wu, Ziran; Byer, Robert L.; Peralta, Edgar; Soong, Ken; Chang, Chia-Ming; Montazeri, Behnam; Wolf, Stephen J.; Cowan, Benjamin; Dawson, Jay; Gai, Wei; Hommelhoff, Peter; Huang, Yen-Chieh; Jing, Chunguang; McGuinness, Christopher; Palmer, Robert B.; Naranjo, Brian; Rosenzweig, James; Travish, Gil; Mizrahi, Amit; Schachter, Levi; Sears, Christopher; Werner, Gregory R.; Yoder, Rodney B.

    2014-10-01

    The use of infrared lasers to power optical-scale lithographically fabricated particle accelerators is a developing area of research that has garnered increasing interest in recent years. The physics and technology of this approach is reviewed, which is referred to as dielectric laser acceleration (DLA). In the DLA scheme operating at typical laser pulse lengths of 0.1 to 1 ps, the laser damage fluences for robust dielectric materials correspond to peak surface electric fields in the GV /m regime. The corresponding accelerating field enhancement represents a potential reduction in active length of the accelerator between 1 and 2 orders of magnitude. Power sources for DLA-based accelerators (lasers) are less costly than microwave sources (klystrons) for equivalent average power levels due to wider availability and private sector investment. Because of the high laser-to-particle coupling efficiency, required pulse energies are consistent with tabletop microJoule class lasers. Combined with the very high (MHz) repetition rates these lasers can provide, the DLA approach appears promising for a variety of applications, including future high-energy physics colliders, compact light sources, and portable medical scanners and radiative therapy machines.

  13. Electrostatic Plasma Accelerator (EPA)

    NASA Technical Reports Server (NTRS)

    Brophy, John R.; Aston, Graeme

    1989-01-01

    The Electrostatic Plasma Accelerator (EPA) is a thruster concept which promises specific impulse levels between low power arcjets and those of the ion engine while retaining the relative simplicity of the arcjet. The EPA thruster produces thrust through the electrostatic acceleration of a moderately dense plasma. No accelerating electrodes are used and the specific impulse is a direct function of the applied discharge voltage and the propellant atomic mass. The goal of the present program is to demonstrate feasibility of the EPA thruster concept through experimental and theoretical investigations of the EPA acceleration mechanism and discharge chamber performance. Experimental investigations will include operating the test bed ion (TBI) engine as an EPA thruster and parametrically varying the thruster geometry and operating conditions to quantify the electrostatic plasma acceleration effect. The theoretical investigations will include the development of a discharge chamber model which describes the relationships between the engine size, plasma properties, and overall performance. For the EPA thruster to be a viable propulsion concept, overall thruster efficiencies approaching 30% with specific impulses approaching 1000 s must be achieved.

  14. Laser Ion Acceleration Control

    NASA Astrophysics Data System (ADS)

    Kawata, Shigeo; Nagashima, T.; Izumiyama, T.; Sato, D.; Takano, M.; Barada, D.; Ma, Y. Y.; Gu, Y. J.; Kong, Q.; Wang, P. X.; Wang, W. M.

    2013-10-01

    An intense femtosecond pulsed laser is employed to accelerate ions. The issues in the laser ion accelerator include the energy efficiency from the laser to the ions, the ion beam collimation, the ion energy spectrum control, the ion beam bunching, the ion particle energy control, etc. In the study particle computer simulations were performed to solve the issues, and each component was designed to control the ion beam quality. When an intense laser illuminates a target, electrons in the target are accelerated and leave from the target; temporarily a strong electric field is formed between the high-energy electrons and the target ions, and the target ions are accelerated. The energy efficiency from the laser to ions was improved by using a solid target with a fine sub-wavelength structure or by a near critical density gas plasma. The ion beam collimation was realized by holes behind the solid target. The control of the ion energy spectrum and the ion particle energy, and the ion beam bunching were successfully realized by a multi-stage laser-target interaction. The present study proposed a novel concept for a future compact laser ion accelerator, based on each component study required to control the ion beam quality and parameters. Partly supported by JSPS, MEXT, CORE, Japan/US Cooperation program, ASHULA and ILE/Osaka University.

  15. Surfzone alongshore advective accelerations: observations and modeling

    NASA Astrophysics Data System (ADS)

    Hansen, J.; Raubenheimer, B.; Elgar, S.

    2014-12-01

    The sources, magnitudes, and impacts of non-linear advective accelerations on alongshore surfzone currents are investigated with observations and a numerical model. Previous numerical modeling results have indicated that advective accelerations are an important contribution to the alongshore force balance, and are required to understand spatial variations in alongshore currents (which may result in spatially variable morphological change). However, most prior observational studies have neglected advective accelerations in the alongshore force balance. Using a numerical model (Delft3D) to predict optimal sensor locations, a dense array of 26 colocated current meters and pressure sensors was deployed between the shoreline and 3-m water depth over a 200 by 115 m region near Duck, NC in fall 2013. The array included 7 cross- and 3 alongshore transects. Here, observational and numerical estimates of the dominant forcing terms in the alongshore balance (pressure and radiation-stress gradients) and the advective acceleration terms will be compared with each other. In addition, the numerical model will be used to examine the force balance, including sources of velocity gradients, at a higher spatial resolution than possible with the instrument array. Preliminary numerical results indicate that at O(10-100 m) alongshore scales, bathymetric variations and the ensuing alongshore variations in the wave field and subsequent forcing are the dominant sources of the modeled velocity gradients and advective accelerations. Additional simulations and analysis of the observations will be presented. Funded by NSF and ASDR&E.

  16. Backward Raman Amplifier for Laser Wakefield Accelerator

    NASA Astrophysics Data System (ADS)

    Ludwig, Joshua; Masson-Laborde, Paul-Edouard; Huller, Stefan; Rozmus, Wojciech; Wilks, Scott C.

    2016-10-01

    Particle in cell simulations via SCPIC and theoretical work on Raman amplification and laser wake field acceleration will be presented. Laser energy depletion has been shown to be a limiting factor during wake field acceleration. This work focuses on optimizing parameters for Raman amplification to work in conjunction with wake field acceleration in order in order to sustain an accelerating laser pulse as it generates plasma waves. It has been shown that laser pulses undergo red shifting during wake generation. Our work demonstrates that this red shifting results in a detuning between pump and seed in the backward Raman Amplifier. This detuning limits the amount of energy that can be transferred from the pump to the seed, and places new limits on backward Raman amplification. To overcome this limiting factor, this study makes use of a chirped pump allowing for extended coupling to the accelerating pulse. Three wave coupling model of Raman amplifier with a frequency shift term due to wake field will also be discussed and compared with PIC simulations.

  17. Induction accelerator development for heavy ion fusion

    SciTech Connect

    Reginato, L.L.

    1993-05-01

    For approximately a decade, the Heavy Ion Fusion Accelerator Research (HIFAR) group at LBL has been exploring the use of induction accelerators with multiple beams as the driver for inertial fusion targets. Scaled experiments have investigated the transport of space charge dominated beams (SBTE), and the current amplification and transverse emittance control in induction linacs (MBE-4) with very encouraging results. In order to study many of the beam manipulations required by a driver and to further develop economically competitive technology, a proposal has been made in partnership with LLNL to build a 10 MeV accelerator and to conduct a series of experiments collectively called the Induction Linac System Experiments (ILSE). The major components critical to the ILSE accelerator are currently under development. We have constructed a full scale induction module and we have tested a number of amorphous magnetic materials developed by Allied Signal to establish an overall optimal design. The electric and magnetic quadrupoles critical to the transport and focusing of heavy ion beams are also under development The hardware is intended to be economically competitive for a driver without sacrificing any of the physics or performance requirements. This paper will concentrate on the recent developments and tests of the major components required by the ILSE accelerator.

  18. AESS: Accelerated Exact Stochastic Simulation

    NASA Astrophysics Data System (ADS)

    Jenkins, David D.; Peterson, Gregory D.

    2011-12-01

    The Stochastic Simulation Algorithm (SSA) developed by Gillespie provides a powerful mechanism for exploring the behavior of chemical systems with small species populations or with important noise contributions. Gene circuit simulations for systems biology commonly employ the SSA method, as do ecological applications. This algorithm tends to be computationally expensive, so researchers seek an efficient implementation of SSA. In this program package, the Accelerated Exact Stochastic Simulation Algorithm (AESS) contains optimized implementations of Gillespie's SSA that improve the performance of individual simulation runs or ensembles of simulations used for sweeping parameters or to provide statistically significant results. Program summaryProgram title: AESS Catalogue identifier: AEJW_v1_0 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AEJW_v1_0.html Program obtainable from: CPC Program Library, Queen's University, Belfast, N. Ireland Licensing provisions: University of Tennessee copyright agreement No. of lines in distributed program, including test data, etc.: 10 861 No. of bytes in distributed program, including test data, etc.: 394 631 Distribution format: tar.gz Programming language: C for processors, CUDA for NVIDIA GPUs Computer: Developed and tested on various x86 computers and NVIDIA C1060 Tesla and GTX 480 Fermi GPUs. The system targets x86 workstations, optionally with multicore processors or NVIDIA GPUs as accelerators. Operating system: Tested under Ubuntu Linux OS and CentOS 5.5 Linux OS Classification: 3, 16.12 Nature of problem: Simulation of chemical systems, particularly with low species populations, can be accurately performed using Gillespie's method of stochastic simulation. Numerous variations on the original stochastic simulation algorithm have been developed, including approaches that produce results with statistics that exactly match the chemical master equation (CME) as well as other approaches that approximate the CME. Solution

  19. Plasma-based accelerator structures

    SciTech Connect

    Schroeder, Carl B.

    1999-12-01

    Plasma-based accelerators have the ability to sustain extremely large accelerating gradients, with possible high-energy physics applications. This dissertation further develops the theory of plasma-based accelerators by addressing three topics: the performance of a hollow plasma channel as an accelerating structure, the generation of ultrashort electron bunches, and the propagation of laser pulses is underdense plasmas.

  20. Uniform acceleration in general relativity

    NASA Astrophysics Data System (ADS)

    Friedman, Yaakov; Scarr, Tzvi

    2015-10-01

    We extend de la Fuente and Romero's (Gen Relativ Gravit 47:33, 2015) defining equation for uniform acceleration in a general curved spacetime from linear acceleration to the full Lorentz covariant uniform acceleration. In a flat spacetime background, we have explicit solutions. We use generalized Fermi-Walker transport to parallel transport the Frenet basis along the trajectory. In flat spacetime, we obtain velocity and acceleration transformations from a uniformly accelerated system to an inertial system. We obtain the time dilation between accelerated clocks. We apply our acceleration transformations to the motion of a charged particle in a constant electromagnetic field and recover the Lorentz-Abraham-Dirac equation.