GABA(A) receptor phospho-dependent modulation is regulated by phospholipase C-related inactive protein type 1, a novel protein phosphatase 1 anchoring protein

GABA(A) receptors are critical in controlling neuronal activity. Here, we examined the role for phospholipase C-related inactive protein type 1 (PRIP-1), which binds and inactivates protein phosphatase 1alpha (PP1alpha) in facilitating GABA(A) receptor phospho-dependent regulation using PRIP-1(-/-) mice. In wild-type animals, robust phosphorylation and functional modulation of GABA(A) receptors containing beta3 subunits by cAMP-dependent protein kinase was evident, which was diminished in PRIP-1(-/-) mice. PRIP-1(-/-) mice exhibited enhanced PP1alpha activity compared with controls. Furthermore, PRIP-1 was able to interact directly with GABA(A) receptor beta subunits, and moreover, these proteins were found to be PP1alpha substrates. Finally, phosphorylation of PRIP-1 on threonine 94 facilitated the dissociation of PP1alpha-PRIP-1 complexes, providing a local mechanism for the activation of PP1alpha. Together, these results suggest an essential role for PRIP-1 in controlling GABA(A) receptor activity via regulating subunit phosphorylation and thereby the efficacy of neuronal inhibition mediated by these receptors

Dendritic cells cross talk with tumor antigen-specific CD8+T cells, Vγ9γδT cells, and Vα24NKT cells in patients with glioblastoma multiforme and in healthy donors

The finding that dendritic cells (DCs) orchestrate innate and adaptive immune responses has stimulated research on harnessing DCs for developing more effective vaccines for DC therapy. The expression of cytomegalovirus (CMV) antigens in glioblastoma multiforme (GBM) presents a unique opportunity to target these viral proteins for tumor immunotherapy. Here, we demonstrate that Vγ9γδT cells, innate immune cells activated by zoledronate (Z), and Vα24NKT cells, innate/adaptive immune cells activated by α-galactosylceramide (G) can link innate and adaptive immunities through cross talk with IFN-DCs from patients with GBM and healthy donors in a way that can amplify the activation and proliferation of CMVpp65-specific CD8+T cells. The IFN-DCs derived from patients with GBM used in this study express lower levels of programmed death ligand (PDL)1 and PDL2 and higher levels of CCR7 than the most commonly used mature IL-4DCs. The expression level of programmed cell death 1 (PD1) on CD8+ T cells, including CMVpp65-specific CD8+T cells, expanded by IFN-DCs pulsed with the CMVpp65-peptide and Z plus G (IFN-DCs/P+Z+G) was lower than that expanded by IFN-DCs pulsed with the peptide alone (IFN-DCs/P). Multifunctional T cells, including HLA-A*0201-restricted CMVpp65-specific CD8+T cells, Vγ9γδT cells, and Vα24NKT cells, efficiently kill HLA-A*0201 positive GBM cell line expressing CMVpp65 protein (T98G). These findings indicate that DC therapy using IFN-DCs/P+Z+G and/or CTL therapy using CMVpp65-specific CD8+T cells expanded by IFN-DCs/P+Z+G may lead to a good clinical outcome for patients with GBM. This article is protected by copyright. All rights reserved

IL-12 Production Induced by Agaricus blazei Fraction H (ABH) Involves Toll-like Receptor (TLR)

Agaricus blazei Murill is an edible fungus used in traditional medicine, which has various well-documented medicinal properties. In the present study, we investigated the effects of hemicellulase-derived mycelia extract (Agaricus blazei fraction H: ABH) on the immune system. First, we examined the cytokine-inducing activity of ABH on human peripheral mononuclear cells (PBMC). The results indicated that ABH induced expression of IL-12, a cytokine known to be a critical regulator of cellular immune responses. Flow cytometric analysis demonstrated the induction of IL-12 production by the CD14-positive cell population, consisting of monocytes/macrophages (Mo/Mφ). Furthermore, the elimination of Mo/Mφ attenuated IL-12 production in PBMC. ABH-induced IL-12 production was inhibited by anti-CD14 and anti-TLR4 antibodies but not by anti-TLR2 antibody. The activity of ABH was not inhibited by polymyxin B, while the activity of lipopolysaccharide used as a reference was inhibited. Oral administration of ABH enhanced natural killer (NK) activity in the spleen. These findings suggest that ABH activated Mo/Mφ in a manner dependent on CD14/TLR4 and NK activity

High Resolution BPM Upgrade for the ATF Damping Ring at KEK

A beam position monitor (BPM) upgrade at the KEK Accelerator Test Facility (ATF) damping ring has been accomplished, carried out by a KEK/FNAL/SLAC collaboration under the umbrella of the global ILC R&D effort. The upgrade consists of a high resolution, high reproducibility read-out system, based on analog and processing, and also implements a new automatic gain error correction schema. The technical concept and realization as well as results of beam studies are presented.Comment: 3 pp. 10th European Workshop on Beam Diagnostics and Instrumentation for Particle Accelerators DIPAC 2011, 16-18 May 2011. Hamburg, German

Coupling Measurements in ATF2 Extraction Line

THPD080International audienceThe purpose of ATF2 is to deliver a beam with stable very small spotsizes as required for future linear colliders such as ILC or CLIC. To achieve that, precise controls of the aberrations such as dispersion and coupling are necessary. Theoretically, the complete reconstruction of the beam matrix is possible from the measurements of horizontal, vertical and tilted beam sizes, combining skew quadrupole scans at several wire-scanner positions. Such measurements were performed in the extraction line of ATF2 in May 2009. We present analysis results attempting to resolve the 4X4 beam matrix and discuss the experimental limitations of 4D emittance measurements with wire scanner