An Expanded Polyproline Domain Maintains Mutant Huntingtin Soluble in vivo and During Aging.

Funder: Alzheimer’s Research UKFunder: Michael J. Fox Foundation for Parkinson’s ResearchFunder: Medical Research CouncilFunder: Deutsche ForschungsgemeinschaftHuntington's disease is a dominantly inherited neurodegenerative disorder caused by the expansion of a CAG repeat, encoding for the amino acid glutamine (Q), present in the first exon of the protein huntingtin. Over the threshold of Q39 HTT exon 1 (HTTEx1) tends to misfold and aggregate into large intracellular structures, but whether these end-stage aggregates or their on-pathway intermediates are responsible for cytotoxicity is still debated. HTTEx1 can be separated into three domains: an N-terminal 17 amino acid region, the polyglutamine (polyQ) expansion and a C-terminal proline rich domain (PRD). Alongside the expanded polyQ, these flanking domains influence the aggregation propensity of HTTEx1: with the N17 initiating and promoting aggregation, and the PRD modulating it. In this study we focus on the first 11 amino acids of the PRD, a stretch of pure prolines, which are an evolutionary recent addition to the expanding polyQ region. We hypothesize that this proline region is expanding alongside the polyQ to counteract its ability to misfold and cause toxicity, and that expanding this proline region would be overall beneficial. We generated HTTEx1 mutants lacking both flanking domains singularly, missing the first 11 prolines of the PRD, or with this stretch of prolines expanded. We then followed their aggregation landscape in vitro with a battery of biochemical assays, and in vivo in novel models of C. elegans expressing the HTTEx1 mutants pan-neuronally. Employing fluorescence lifetime imaging we could observe the aggregation propensity of all HTTEx1 mutants during aging and correlate this with toxicity via various phenotypic assays. We found that the presence of an expanded proline stretch is beneficial in maintaining HTTEx1 soluble over time, regardless of polyQ length. However, the expanded prolines were only advantageous in promoting the survival and fitness of an organism carrying a pathogenic stretch of Q48 but were extremely deleterious to the nematode expressing a physiological stretch of Q23. Our results reveal the unique importance of the prolines which have and still are evolving alongside expanding glutamines to promote the function of HTTEx1 and avoid pathology

Response of microchannel plates to single particles and to electromagnetic showers

We report on the response of microchannel plates (MCPs) to single relativistic particles and to electromagnetic showers. Particle detection by means of secondary emission of electrons at the MCP surface has long been proposed and is used extensively in ion time-of-flight mass spectrometers. What has not been investigated in depth is their use to detect the ionizing component of showers. The time resolution of MCPs exceeds anything that has been previously used in calorimeters and, if exploited effectively, could aid in the event reconstruction at high luminosity colliders. Several prototypes of photodetectors with the amplification stage based on MCPs were exposed to cosmic rays and to 491 MeV electrons at the INFN-LNF Beam-Test Facility. The time resolution and the efficiency of the MCPs are measured as a function of the particle multiplicity, and the results used to model the response to high-energy showers.Comment: Paper submitted to NIM

Response of microchannel plates in ionization mode to single particles and electromagnetic showers

Hundreds of concurrent collisions per bunch crossing are expected at future hadron colliders. Precision timing calorimetry has been advocated as a way to mitigate the pileup effects and, thanks to their excellent time resolution, microchannel plates (MCPs) are good candidate detectors for this goal. We report on the response of MCPs, used as secondary emission detectors, to single relativistic particles and to electromagnetic showers. Several prototypes, with different geometries and characteristics, were exposed to particle beams at the INFN-LNF Beam Test Facility and at CERN. Their time resolution and efficiency are measured for single particles and as a function of the multiplicity of particles. Efficiencies between 50% and 90% to single relativistic particles are reached, and up to 100% in presence of a large number of particles. Time resolutions between 20ps and 30ps are obtained.Comment: 20 pages, 9 figures. Paper submitted to NIM

Cerium-Doped Fused-Silica Fibers as Wavelength Shifters

We have evaluated the performance of a Ce-doped fused-silica fiber as wavelength shifter coupled to a CeF$_{3}$ crystal using electron beams at CERN. The pulse shape and collection efficiency were measured using irradiated (100 kGy) and un-irradiated fibers. In addition, we evaluated the light yield of various Ce-doped fibers and explored the possibility of using them in the future, including for precision timing applications in a high-luminosity collider environment.Comment: 11 pages, 7 figure

Constraints on the χ_(c1) versus χ_(c2) polarizations in proton-proton collisions at √s = 8 TeV

The polarizations of promptly produced χ_(c1) and χ_(c2) mesons are studied using data collected by the CMS experiment at the LHC, in proton-proton collisions at √s=8  TeV. The χ_c states are reconstructed via their radiative decays χ_c → J/ψγ, with the photons being measured through conversions to e⁺e⁻, which allows the two states to be well resolved. The polarizations are measured in the helicity frame, through the analysis of the χ_(c2) to χ_(c1) yield ratio as a function of the polar or azimuthal angle of the positive muon emitted in the J/ψ → μ⁺μ⁻ decay, in three bins of J/ψ transverse momentum. While no differences are seen between the two states in terms of azimuthal decay angle distributions, they are observed to have significantly different polar anisotropies. The measurement favors a scenario where at least one of the two states is strongly polarized along the helicity quantization axis, in agreement with nonrelativistic quantum chromodynamics predictions. This is the first measurement of significantly polarized quarkonia produced at high transverse momentum