Evolution of a beam dynamics model for the transport lines in a proton therapy facility

Despite the fact that the first-order beam dynamics models allow an approximated evaluation of the beam properties, their contribution is essential during the conceptual design of an accelerator or beamline. However, during the commissioning some of their limitations appear in the comparison against measurements. The extension of the linear model to higher order effects is, therefore, demanded. In this paper, the effects of particle-matter interaction have been included in the model of the transport lines in the proton therapy facility at the Paul Scherrer Institut (PSI) in Switzerland. To improve the performance of the facility, a more precise model was required and has been developed with the multi-particle open source beam dynamics code called OPAL (Object oriented Particle Accelerator Library). In OPAL, the Monte Carlo simulations of Coulomb scattering and energy loss are performed seamless with the particle tracking. Beside the linear optics, the influence of the passive elements (e.g. degrader, collimators, scattering foils and air gaps) on the beam emittance and energy spread can be analysed in the new model. This allows for a significantly improved precision in the prediction of beam transmission and beam properties. The accuracy of the OPAL model has been confirmed by numerous measurements.Comment: 17 pages, 19 figure

Transverse-Longitudinal Coupling by Space Charge in Cyclotrons

A method is presented that enables to compute the parameters of matched beams with space charge in cyclotrons with emphasis on the effect of the transverse-longitudinal coupling. Equations describing the transverse-longitudinal coupling and corresponding tune-shifts in first order are derived for the model of an azimuthally symmetric cyclotron. The eigenellipsoid of the beam is calculated and the transfer matrix is transformed into block-diagonal form. The influence of the slope of the phase curve on the transverse-longitudinal coupling is accounted for. The results are generalized and numerical procedures for the case of an AVF cyclotron are presented. The algorithm is applied to the PSI Injector II and Ring cyclotron and the results are compared to TRANSPORT.Comment: 8 pages, 2 figure

On microphysical processes of noctilucent clouds (NLC): Observations and modeling of mean and width of the particle size-distribution

Noctilucent clouds (NLC) in the polar summer mesopause region have been observed in Norway (69° N, 16° E) between 1998 and 2009 by 3-color lidar technique. Assuming a mono-modal Gaussian size distribution we deduce mean and width of the particle sizes throughout the clouds. We observe a quasi linear relationship between distribution width and mean of the particle size at the top of the clouds and a deviation from this behavior for particle sizes larger than 40 nm, most often in the lower part of the layer. The vertically integrated particle properties show that 65% of the data follows the linear relationship with a slope of 0.42±0.02 for mean particle sizes up to 40 nm. For the vertically resolved particle properties (Δz = Combining double low line 0.15 km) the slope is comparable and about 0.39±0.03. For particles larger than 40 nm the distribution width becomes nearly independent of particle size and even decreases in the lower part of the layer. We compare our observations to microphysical modeling of noctilucent clouds and find that the distribution width depends on turbulence, the time that turbulence can act (cloud age), and the sampling volume/time (atmospheric variability). The model results nicely reproduce the measurements and show that the observed slope can be explained by eddy diffusion profiles as observed from rocket measurements. © 2010 Author(s)

Stretch of β1 Integrin Activates an Outwardly Rectifying Chloride Current via FAK and Src in Rabbit Ventricular Myocytes

Osmotic swelling of cardiac myocytes and other types of cells activates an outwardly rectifying, tamoxifen-sensitive Cl− current, ICl,swell, but it is unclear whether Cl− currents also are activated by direct mechanical stretch. We tested whether specific stretch of β1-integrin activates a Cl− current in rabbit left ventricular myocytes. Paramagnetic beads (4.5-μm diameter) coated with mAb to β1-integrin were applied to the surface of myocytes and pulled upward with an electromagnet while recording whole-cell current. In solutions designed to isolate anion currents, β1-integrin stretch elicited an outwardly rectifying Cl− current with biophysical and pharmacological properties similar to those of ICl,swell. Stretch-activated Cl− current activated slowly (t1/2 = 3.5 ± 0.1 min), partially inactivated at positive voltages, reversed near ECl, and was blocked by 10 μM tamoxifen. When stretch was terminated, 64 ± 8% of the stretch-induced current reversed within 10 min. Mechanotransduction involved protein tyrosine kinase. Genistein (100 μM), a protein tyrosine kinase inhibitor previously shown to suppress ICl,swell in myocytes, inhibited stretch-activated Cl− current by 62 ± 6% during continued stretch. Because focal adhesion kinase and Src are known to be activated by cell swelling, mechanical stretch, and clustering of integrins, we tested whether these tyrosine kinases mediated the response to β1-integrin stretch. PP2 (10 μM), a selective blocker of focal adhesion kinase and Src, fully inhibited the stretch-activated Cl− current as well as part of the background Cl− current, whereas its inactive analogue PP3 (10 μM) had no significant effect. In addition to activating Cl− current, stretch of β1-integrin also appeared to activate a nonselective cation current and to suppress IK1. Integrins are the primary mechanical link between the extracellular matrix and cytoskeleton. The present results suggest that integrin stretch may contribute to mechano-electric feedback in heart, modulate electrical activity, and influence the propensity for arrhythmogenesis

EGFR Kinase Regulates Volume-sensitive Chloride Current Elicited by Integrin Stretch via PI-3K and NADPH Oxidase in Ventricular Myocytes

Stretch of β1 integrins activates an outwardly rectifying, tamoxifen-sensitive Cl− current (Cl− SAC) via AT1 receptors, NADPH oxidase, and reactive oxygen species, and Cl− SAC resembles the volume-sensitive Cl− current (ICl,swell). Epidermal growth factor receptor (EGFR) kinase undergoes transactivation upon stretch, integrin engagement, and AT1 receptor activation and, in turn, stimulates NADPH oxidase. Therefore, we tested whether Cl− SAC is regulated by EGFR kinase signaling and is volume sensitive. Paramagnetic beads coated with mAb for β1 integrin were attached to myocytes and pulled with an electromagnet. Stretch activated a Cl− SAC that was 1.13 ± 0.10 pA/pF at +40 mV. AG1478 (10 μM), an EGFR kinase blocker, inhibited 93 ± 13% of Cl− SAC, and intracellular pretreatment with 1 μM AG1478 markedly suppressed Cl− SAC activation. EGF (3.3 nM) directly activated an outwardly rectifying Cl− current (0.81 ± 0.05 pA/pF at +40 mV) that was fully blocked by 10 μM tamoxifen, an ICl,swell blocker. Phosphatidylinositol 3-kinase (PI-3K) is downstream of EGFR kinase. Wortmannin (500 nM) and LY294002 (100 μM), blockers of PI-3K, inhibited Cl− SAC by 67 ± 6% and 91 ± 25% respectively, and the EGF-induced Cl− current also was fully blocked by LY294002. Furthermore, gp91ds-tat (500 nM), a cell-permeable, chimeric peptide that specifically blocks NADPH oxidase assembly, profoundly inhibited the EGF-induced Cl− current. Inactive permeant and active impermeant control peptides had no effect. Myocyte shrinkage with hyperosmotic bathing media inhibited the Cl− SAC and EGF-induced Cl− current by 88 ± 9% and 127 ± 11%, respectively. These results suggest that β1 integrin stretch activates Cl− SAC via EGFR, PI-3K, and NADPH oxidase, and that both the Cl− SAC and the EGF-induced Cl− currents are likely to be the volume-sensitive Cl− current, ICl,swell

Angiotensin II (AT1) Receptors and NADPH Oxidase Regulate Cl− Current Elicited by β1 Integrin Stretch in Rabbit Ventricular Myocytes

Direct stretch of β1 integrin activates an outwardly rectifying, tamoxifen-sensitive Cl− current (Cl− SAC) via focal adhesion kinase (FAK) and/or Src. The characteristics of Cl− SAC resemble those of the volume-sensitive Cl− current, ICl,swell. Because myocyte stretch releases angiotensin II (AngII), which binds AT1 receptors (AT1R) and stimulates FAK and Src in an autocrine-paracrine loop, we tested whether AT1R and their downstream signaling cascade participate in mechanotransduction. Paramagnetic beads coated with mAb for β1-integrin were applied to myocytes and pulled upward with an electromagnet while recording whole-cell anion current. Losartan (5 μM), an AT1R competitive antagonist, blocked Cl− SAC but did not significantly alter the background Cl− current in the absence of integrin stretch. AT1R signaling is mediated largely by H2O2 produced from superoxide generated by sarcolemmal NADPH oxidase. Diphenyleneiodonium (DPI, 60 μM), a potent NADPH oxidase inhibitor, rapidly and completely blocked both Cl− SAC elicited by stretch and the background Cl− current. A structurally unrelated NADPH oxidase inhibitor, 4-(2-aminoethyl) benzenesulfonyl fluoride (AEBSF, 0.5 and 2 mM), also rapidly and completely blocked Cl− SAC as well as a large fraction of the background Cl− current. With continuing integrin stretch, Cl− SAC recovered upon washout of AEBSF (2 mM). In the absence of stretch, exogenous AngII (5 nM) activated an outwardly rectifying Cl− current that was rapidly and completely blocked by DPI (60 μM). Moreover, exogenous H2O2 (10, 100, and 500 μM), the eventual product of NADPH oxidase activity, also activated Cl− SAC in the absence of stretch, whereas catalase (1,000 U/ml), an H2O2 scavenger, attenuated the response to stretch. Application of H2O2 during NADPH oxidase inhibition by either DPI (60 μM) or AEBSF (0.5 mM) did not fully reactivate Cl− SAC, however. These results suggest that stretch of β1-integrin in cardiac myocytes elicits Cl− SAC by activating AT1R and NADPH oxidase and, thereby, producing reactive oxygen species. In addition, NADPH oxidase may be intimately coupled to the channel responsible for Cl− SAC, providing a second regulatory pathway