Theoretical and phenomenological implications of
R-parity violation in supersymmetric theories are discussed in the context of particle physics and cosmology. Fundamental aspects include the relation ...with continuous and discrete symmetries and the various allowed patterns of
R-parity breaking. Recent developments on the generation of neutrino masses and mixings within different scenarios of
R-parity violation are discussed. The possible contribution of
R-parity-violating Yukawa couplings in processes involving virtual supersymmetric particles and the resulting constraints are reviewed. Finally, direct production of supersymmetric particles and their decays in the presence of
R-parity-violating couplings is discussed together with a survey of existing constraints from collider experiments.
The Grenoble Hybrid magnet is a modular platform using resistive and superconducting technologies to produce various DC high magnetic field and flux configurations for the scientific community. They ...range from 43 T in 34 mm diameter with 24 MW electrical power to 9 T in 800 mm diameter when the superconducting coil is used alone. Thanks to the ongoing upgrade of the electrical power installation at LNCMI-Grenoble to 30 MW, and possibly to 36 MW, the opportunity to increase the total field well above 45 T in the near future is anticipated and studied in detail. The key design parameters will be recalled comprising the specifically developed Nb-Ti/Cu conductor, the large-bore outsert superconducting coil, the magnet cryostat with its structure including the eddy-current shield, the cryogenic line for the interconnection with the cryogenic satellite and the dedicated 150 l/h He liquefaction plant. All components of the superconducting part of the hybrid magnet platform have been built, tested and delivered to LNCMI-Grenoble, where integration and final assembly are continuing. The status of the project will be presented with the main problems encountered and solved. It includes the recent commissioning tests of the cryogenic satellite producing the pressurized superfluid He at 1.8 K as well as the successful powering tests of the specially developed current leads at ultimate current and under fully degraded cooling conditions simulating the worst-case accidental scenario.
Monte Carlo simulation is an essential tool in emission tomography that can assist in the design of new medical imaging devices, the optimization of acquisition protocols and the development or ...assessment of image reconstruction algorithms and correction techniques. GATE, the Geant4 Application for Tomographic Emission, encapsulates the Geant4 libraries to achieve a modular, versatile, scripted simulation toolkit adapted to the field of nuclear medicine. In particular, GATE allows the description of time-dependent phenomena such as source or detector movement, and source decay kinetics. This feature makes it possible to simulate time curves under realistic acquisition conditions and to test dynamic reconstruction algorithms. This paper gives a detailed description of the design and development of GATE by the OpenGATE collaboration, whose continuing objective is to improve, document and validate GATE by simulating commercially available imaging systems for PET and SPECT. Large effort is also invested in the ability and the flexibility to model novel detection systems or systems still under design. A public release of GATE licensed under the GNU Lesser General Public License can be downloaded at http:/www-lphe.epfl.ch/GATE/. Two benchmarks developed for PET and SPECT to test the installation of GATE and to serve as a tutorial for the users are presented. Extensive validation of the GATE simulation platform has been started, comparing simulations and measurements on commercially available acquisition systems. References to those results are listed. The future prospects towards the gridification of GATE and its extension to other domains such as dosimetry are also discussed.
Understanding how and when cooperative human behaviour forms in common-pool resource systems is critical to illuminating social–ecological systems and designing governance institutions that promote ...sustainable resource use. Before assessing the full complexity of social dynamics, it is essential to understand, concretely and mechanistically, how resource dynamics and human actions interact to create incentives and pay-offs for social behaviours. Here, we investigated how such incentives for information sharing are affected by spatial dynamics and management in a common-pool resource system. Using interviews with fishermen to inform an agent-based model, we reveal generic mechanisms through which, for a given ecological setting characterized by the spatial dynamics of the resource, the two ‘human factors’ of information sharing and management may heterogeneously impact various members of a group for whom theory would otherwise predict the same strategy. When users can deplete the resource, these interactions are further affected by the management approach. Finally, we discuss the implications of alternative motivations, such as equity among fishermen and consistency of the fleet's output. Our results indicate that resource spatial dynamics, form of management and level of depletion can interact to alter the sociality of people in common-pool resource systems, providing necessary insight for future study of strategic decision processes.
The most common dementia worldwide, Alzheimer's disease is often diagnosed via biomarkers in cerebrospinal fluid, including reduced levels of Aβ1-42, and increases in total tau and phosphorylated ...tau-181. Here we describe results of a Phase 2a study of a promising new drug candidate that significantly reversed all measured biomarkers of Alzheimer's disease, neurodegeneration and neuroinflammation. PTI-125 is an oral small molecule drug candidate that binds and reverses an altered conformation of the scaffolding protein filamin A found in Alzheimer's disease brain. Altered filamin A links to the α7-nicotinic acetylcholine receptor to allow Aβ42's toxic signaling through this receptor to hyperphosphorylate tau. Altered filamin A also links to toll-like receptor 4 to enable Aβ-induced persistent activation of this receptor and inflammatory cytokine release. Restoring the native shape of filamin A prevents or reverses filamin A's linkages to the α7-nicotinic acetylcholine receptor and toll-like receptor 4, thereby blocking Aβ42's activation of these receptors. The result is reduced tau hyperphosphorylation and neuroinflammation, with multiple functional improvements demonstrated in transgenic mice and postmortem Alzheimer's disease brain.
Safety, pharmacokinetics, and cerebrospinal fluid and plasma biomarkers were assessed following treatment with PTI-125 for 28 days. Target engagement and mechanism of action were assessed in patient lymphocytes by measuring 1) the reversal of filamin A's altered conformation, 2) linkages of filamin A with α7-nicotinic acetylcholine receptor or toll-like receptor 4, and 3) levels of Aβ42 bound to α7-nicotinic acetylcholine receptor or CD14, the co-receptor for toll-like receptor 4.
This was a first-in-patient, open-label Phase 2a safety, pharmacokinetics and biomarker study.
Five clinical trial sites in the U.S. under an Investigational New Drug application.
This study included 13 mild-to-moderate Alzheimer's disease patients, age 50-85, Mini Mental State Exam ≥16 and ≤24 with a cerebrospinal fluid total tau/Aβ42 ratio ≥0.30.
PTI-125 oral tablets (100 mg) were administered twice daily for 28 consecutive days.
Safety was assessed by electrocardiograms, clinical laboratory analyses and adverse event monitoring. Plasma levels of PTI-125 were measured in blood samples taken over 12 h after the first and last doses; cerebrospinal fluid levels were measured after the last dose. Commercial enzyme linked immunosorbent assays assessed levels of biomarkers of Alzheimer's disease in cerebrospinal fluid and plasma before and after treatment with PTI-125. The study measured biomarkers of pathology (pT181 tau, total tau and Aβ42), neurodegeneration (neurofilament light chain and neurogranin) and neuroinflammation (YKL-40, interleukin-6, interleukin-1β and tumor necrosis factor α). Plasma levels of phosphorylated and nitrated tau were assessed by immunoprecipitation of tau followed by immunoblotting of three different phospho-epitopes elevated in AD (pT181-tau, pS202-tau and pT231-tau) and nY29-tau. Changes in conformation of filamin A in lymphocytes were measured by isoelectric focusing point. Filamin A linkages to α7-nicotinic acetylcholine receptor and toll-like receptor 4 were assessed by immunoblot detection of α7-nicotinic acetylcholine receptor and toll-like receptor 4 in anti-filamin A immunoprecipitates from lymphocytes. Aβ42 complexed with α7-nicotinic acetylcholine receptor or CD14 in lymphocytes was also measured by co-immunoprecipitation. The trial did not measure cognition.
Consistent with the drug's mechanism of action and preclinical data, PTI-125 reduced cerebrospinal fluid biomarkers of Alzheimer's disease pathology, neurodegeneration and neuroinflammation from baseline to Day 28. All patients showed a biomarker response to PTI-125. Total tau, neurogranin, and neurofilament light chain decreased by 20%, 32% and 22%, respectively. Phospho-tau (pT181) decreased 34%, evidence that PTI-125 suppresses tau hyperphosphorylation induced by Aβ42's signaling through α7-nicotinic acetylcholine receptor. Cerebrospinal fluid biomarkers of neuroinflammation (YKL-40 and inflammatory cytokines) decreased by 5-14%. Biomarker effects were similar in plasma. Aβ42 increased slightly - a desirable result because low Aβ42 indicates Alzheimer's disease. This increase is consistent with PTI-125's 1,000-fold reduction of Aβ42's femtomolar binding affinity to α7-nicotinic acetylcholine receptor. Biomarker reductions were at least p ≤ 0.001 by paired t test. Target engagement was shown in lymphocytes by a shift in filamin A's conformation from aberrant to native: 93% was aberrant on Day 1 vs. 40% on Day 28. As a result, filamin A linkages with α7-nicotinic acetylcholine receptor and toll-like receptor 4, and Aβ42 complexes with α7-nicotinic acetylcholine receptor and CD14, were all significantly reduced by PTI-125. PTI-125 was safe and well-tolerated in all patients. Plasma half-life was 4.5 h and approximately 30% drug accumulation was observed on Day 28 vs. Day 1.
PTI-125 significantly reduced biomarkers of Alzheimer's disease pathology, neurodegeneration, and neuroinflammation in both cerebrospinal fluid and plasma. All patients responded to treatment. The magnitude and consistency of reductions in established, objective biomarkers imply that PTI-125 treatment counteracted disease processes and reduced the rate of neurodegeneration. Based on encouraging biomarker data and safety profile, approximately 60 patients with mild-to-moderate AD are currently being enrolled in a Phase 2b randomized, placebo-controlled confirmatory study to assess the safety, tolerability and efficacy of PTI-125.
A single-photon sensitive ebCMOS camera: The LUSIPHER prototype Barbier, R.; Cajgfinger, T.; Calabria, P. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
08/2011, Letnik:
648, Številka:
1
Journal Article
Recenzirano
Processing high-definition images with single-photon sensitivity acquired above 500 frames per second (fps) will certainly find ground-breaking applications in scientific and industrial domains such ...as nano-photonics. However, current technologies for low light imaging suffer limitations above the standard 30fps to keep providing both excellent spatial resolution and signal-over-noise. This paper presents the state of the art on a promising way to answer this challenge, the electron bombarded CMOS (ebCMOS) detector. A large-scale ultra fast single-photon tracker camera prototype produced with an industrial partner is described. The full characterization of the back-thinned CMOS sensor is presented and a method for Point Spread Function measurements is elaborated. Then the study of the ebCMOS performance is presented for two different multi-alkali cathodes, S20 and S25. Point Spread Function measurements carried out on an optical test bench are analysed to extract the PSF of the tube by deconvolution. The resolution of the tube is studied as a function of temperature, high voltage and incident wavelength. Results are discussed for both multi-alkali cathodes as well as a Maxwellian modelization of the radial initial energy of the photo-electrons.
•Final design of the ITER vacuum vessel (VV).•Procurement of the ITER VV.•Manufacturing results of real scale mock-ups.•Manufacturing status of the VV in domestic agencies.
The ITER vacuum vessel ...(VV) is under manufacturing by four domestic agencies after completion of engineering designs that have been approved by the Agreed Notified Body (ANB). Manufacturing designs of the VV have been being completed, component by component, by accommodating requirements of the RCC-MR 2007 edition. Manufacturing of the VV first sector has been started in February 2012 in Korea and in-wall shielding in May 2013 in India. EU will start manufacturing of its first sector from September 2013 and Russia the upper port by the end of 2013. All DAs have manufactured several mock-ups including real-size ones to justify/qualify and establish manufacturing techniques and procedures.
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