The TORCH PMT: a close packing, multi-anode, long life MCP-PMT for Cherenkov applications

Photek (U.K.) and the TORCH collaboration are undertaking a three year development program to produce a novel square MCP-PMT for single photon detection. The TORCH detector aims to provide particle identification in the 2-10 GeV/c momentum range, using a Time-of-Flight method based on Cherenkov light. It is a stand-alone R&D; project with possible application in LHCb, and has been proposed for the LHCb Upgrade. The Microchannel Plate (MCP) detector will provide a single photon timing accuracy of 40 ps, and its development will include the following properties: (i) Long lifetime up to at least 5 C/cm2; (ii) Multi-anode output with a spatial resolution of 6 mm and 0.4 mm respectively in the horizontal and vertical directions, incorporating a novel charge-sharing technique; (iii) Close packing on two opposing sides with an active area fill factor of 88% in the horizontal direction. Results from simulations modelling the MCP detector performance factoring in the pulse height variation from the detector, NINO threshold levels and potential charge sharing techniques that enhance the position resolution beyond the physical pitch of the pixel layout will be discussed. Also, a novel method of coupling the MCP-PMT output pads using Anisotropic Conductive Film (ACF) will be described. This minimises parasitic input capacitance by allowing very close proximity between the frontend electronics and the MCP detector

Testbeam studies of a TORCH prototype detector

TORCH is a novel time-of-flight detector that has been developed to provide charged-particle identification between 2 and 10 GeV/c momentum. TORCH combines arrival times from multiple Cherenkov photons produced within a 10 mm-thick quartz radiator plate, to achieve a 15 ps time-of-flight resolution per incident particle. A customised Micro-Channel Plate photomultiplier tube (MCP-PMT) and associated readout system utilises an innovative charge-sharing technique between adjacent pixels to obtain the necessary 70 ps time resolution of each Cherenkov photon. A five-year R&D programme has been undertaken, culminating in the construction of a small-scale prototype TORCH module. In testbeams at CERN, this prototype operated successfully with customised electronics and readout system. A full analysis chain has been developed to reconstruct the data and to calibrate the detector. Results are compared to those using a commercial Planacon MCP-PMT, and single photon resolutions approaching 80 ps have been achieved. The photon counting efficiency was found to be in reasonable agreement with a GEANT4 Monte Carlo simulation of the detector. The small-scale demonstrator is a precursor to a full-scale TORCH module (with a radiator plate of 660×1250×10mm3), which is currently under construction

Acceleration of Age-Associated Methylation Patterns in HIV-1-Infected Adults

Patients with treated HIV-1-infection experience earlier occurrence of aging-associated diseases, raising speculation that HIV-1-infection, or antiretroviral treatment, may accelerate aging. We recently described an age-related co-methylation module comprised of hundreds of CpGs; however, it is unknown whether aging and HIV-1-infection exert negative health effects through similar, or disparate, mechanisms. We investigated whether HIV-1-infection would induce age-associated methylation changes. We evaluated DNA methylation levels at >450,000 CpG sites in peripheral blood mononuclear cells (PBMC) of young (20-35) and older (36-56) adults in two separate groups of participants. Each age group for each data set consisted of 12 HIV-1-infected and 12 age-matched HIV-1-uninfected samples for a total of 96 samples. The effects of age and HIV-1 infection on methylation at each CpG revealed a strong correlation of 0.49, p<1 x 10(-200) and 0.47, p<1 x 10(-200). Weighted gene correlation network analysis (WGCNA) identified 17 co-methylation modules; module 3 (ME3) was significantly correlated with age (cor=0.70) and HIV-1 status (cor=0.31). Older HIV-1+ individuals had a greater number of hypermethylated CpGs across ME3 (p=0.015). In a multivariate model, ME3 was significantly associated with age and HIV status (Data set 1: βage=0.007088, p=2.08 x 10(-9); βHIV=0.099574, p=0.0011; Data set 2: βage=0.008762, p=1.27 x 10(-5); βHIV=0.128649, p=0.0001). Using this model, we estimate that HIV-1 infection accelerates age-related methylation by approximately 13.7 years in data set 1 and 14.7 years in data set 2. The genes related to CpGs in ME3 are enriched for polycomb group target genes known to be involved in cell renewal and aging. The overlap between ME3 and an aging methylation module found in solid tissues is also highly significant (Fisher-exact p=5.6 x 10(-6), odds ratio=1.91). These data demonstrate that HIV-1 infection is associated with methylation patterns that are similar to age-associated patterns and suggest that general aging and HIV-1 related aging work through some common cellular and molecular mechanisms. These results are an important first step for finding potential therapeutic targets and novel clinical approaches to mitigate the detrimental effects of both HIV-1-infection and aging

The Galanin Receptor 1 Gene Associates with Tobacco Craving in Smokers Seeking Cessation Treatment

Craving for tobacco is a major challenge for people with nicotine dependence (ND) who try to quit smoking. Galanin (GAL) and its receptors (GALRs) can alter addiction-related behaviors and are therefore good candidates for modulators of behavioral parameters associated with smoking. We performed a genetic association study in 486 subjects (432 European American, EA) recruited for smoking cessation trials. Twenty-six candidate genes for ND-related phenotypes were selected based on the literature. Subjects were assessed using the Minnesota Withdrawal Scale (MWS), which included a specific item for craving, the Fagerström Scale of Nicotine Dependence (FTND), and other ND-related instruments. One single-nucleotide polymorphism (SNP) in GALR1, rs2717162, significantly associated with severity of craving in EA samples (p=6.48 × 10−6) and in the combined sample (p=9.23 × 10−6). Individuals with TT and TC genotypes had significantly higher craving scores than CC subjects. We also observed that SNPs in the CHRNA5 locus, rs16969968 and rs684513, which have been associated with ND-related phenotypes in previous studies, were nominally associated with FTND scores, although these results did not meet Bonferroni-adjusted criteria for experiment-wide significance. Our findings suggest that variation at GALR1 associates with differences in the severity of past craving for tobacco among smokers motivated to quit. Taken together with preclinical evidence, these results, if replicated, suggest that GAL and GALRs may be useful therapeutic targets for the pharmacological treatment of ND. Our results also confirm previously reported associations between variation at CHRNA5 and ND