MEKK1-MKK4-JNK-AP1 Pathway Negatively Regulates Rgs4 Expression in Colonic Smooth Muscle Cells

Background: Regulator of G-protein Signaling 4 (RGS4) plays an important role in regulating smooth muscle contraction, cardiac development, neural plasticity and psychiatric disorder. However, the underlying regulatory mechanisms remain elusive. Our recent studies have shown that upregulation of Rgs4 by interleukin (IL)-1b is mediated by the activation of NFkB signaling and modulated by extracellular signal-regulated kinases, p38 mitogen-activated protein kinase, and phosphoinositide-3 kinase. Here we investigate the effect of the c-Jun N-terminal kinase (JNK) pathway on Rgs4 expression in rabbit colonic smooth muscle cells. Methodology/Principal Findings: Cultured cells at first passage were treated with or without IL-1b (10 ng/ml) in the presence or absence of the selective JNK inhibitor (SP600125) or JNK small hairpin RNA (shRNA). The expression levels of Rgs4 mRNA and protein were determined by real-time RT-PCR and Western blot respectively. SP600125 or JNK shRNA increased Rgs4 expression in the absence or presence of IL-1b stimulation. Overexpression of MEKK1, the key upstream kinase of JNK, inhibited Rgs4 expression, which was reversed by co-expression of JNK shRNA or dominant-negative mutants for MKK4 or JNK. Both constitutive and inducible upregulation of Rgs4 expression by SP600125 was significantly inhibited by pretreatment with the transcription inhibitor, actinomycin D. Dual reporter assay showed that pretreatment with SP600125 sensitized the promoter activity of Rgs4 in response to IL-1b. Mutation of the AP1-binding site within Rgs

Multipass steering protocols at Jefferson lab

The CEBAF recirculating accelerator consists of two CW superconducting RF linacs, through which an electron beam is accelerated for up to 5 passes. Focusing and steering elements affect each pass differently, requiring a multipass steering protocol to correct the orbits. Perturbations include lens misalignments (including long-term ground motion), BPM offsets, and focusing and steering from RF fields inside the cavities. A previous treatment of this problem assumed all perturbations were localized at the quadrupoles and the absence of x-y coupling. Having analyzed the problem and characterized the solutions, we developed an empirical iterative protocol to compare against previous results in the presence of skew fields and cross-plane coupling. We plan to characterize static and acceleration- dependent components of the beam line perturbations to allow systematic and rapid configuration of the accelerator at different linac energy gains

Further analysis of real beam line optics from a synthetic beam

Standard closed-orbit techniques for Twiss parameter measurement are not applicable to the open-ended Continuous Electron Beam Accelerator Facility (CEBAF) at Jefferson Lab. The evolution of selected sets of real orbits in the accelerator models the behavior of a “synthetic” beam. This process will be validated against beam profile-based Twiss parameter measurements and should provide the distributed optical information needed to optimize beamline tuning for an open-ended system. This work will discuss the current and future states of this technique, as well as an example of its use in the CEBAF machine

Challenges and status of tuning simulations for CLIC traditional beam delivery system

The beam delivery system (BDS) for the 3 TeV version of the Compact Linear Collider (CLIC) has two main design types. One type is referred to as the local scheme, as it is approximately one kilometer shorter and corrects the chromaticity in both planes. The other type is referred to as the traditional scheme, and separates the chromaticity correction of each plane into different areas. The expectation early in the studies is that the traditional scheme would be easier to tune. However, it appears that this is not the case. Previous proceedings have shown the complications in tuning the traditional scheme. This work will address the problems experienced in tuning simulations for the traditional BDS and describe the current state of these simulation

Further analysis of real beam line optics from a synthetic beam

Standard closed-orbit techniques for Twiss parameter measurement are not applicable to the open-ended Continuous Electron Beam Accelerator Facility (CEBAF) at Jefferson Lab. The evolution of selected sets of real orbits in the accelerator models the behavior of a “synthetic” beam. This process will be validated against beam profile-based Twiss parameter measurements and should provide the distributed optical information needed to optimize beamline tuning for an open-ended system. This work will discuss the current and future states of this technique, as well as an example of its use in the CEBAF machine

Design and operation of a prototype interaction point beam collision feedback system for the International Linear Collider

A high-resolution, intratrain position feedback system has been developed to achieve and maintain collisions at the proposed future electron-positron International Linear Collider (ILC). A prototype has been commissioned and tested with a beam in the extraction line of the Accelerator Test Facility at the High Energy Accelerator Research Organization in Japan. It consists of a stripline beam position monitor (BPM) with analogue signal-processing electronics, a custom digital board to perform the feedback calculation, and a stripline kicker driven by a high-current amplifier. The closed-loop feedback latency is 148 ns. For a three-bunch train with 154 ns bunch spacing, the feedback system has been used to stabilize the third bunch to 450 nm. The kicker response is linear, and the feedback performance is maintained, over a correction range of over ±60  μm. The propagation of the correction has been confirmed by using an independent stripline BPM located downstream of the feedback system. The system has been demonstrated to meet the BPM resolution, beam kick, and latency requirements for the ILC