Beam tests of a large-scale TORCH time-of-flight demonstrator

The TORCH time-of-flight detector is designed to provide particle identification in the momentum range 2-10 GeV/c over large areas. The detector exploits prompt Cherenkov light produced by charged particles traversing a 10 mm thick quartz plate. The photons propagate via total internal reflection and are focused onto a detector plane comprising position-sensitive Micro-Channel Plate Photo-Multiplier Tubes (MCP-PMT) detectors. The goal is to achieve a single-photon timing resolution of 70 ps, giving a timing precision of 15 ps per charged particle by combining the information from around 30 detected photons. The MCP-PMT detectors have been developed with a commercial partner (Photek Ltd, UK), leading to the delivery of a square tube of active area 53 $\times$ 53mm$^2$ with a granularity of 8 $\times$ 128 pixels equivalent. A large-scale demonstrator of TORCH, having a quartz plate of dimensions 660 $\times$ 1250 $\times$ 10 mm$^3$ and read out by a pair of MCP-PMTs with custom readout electronics, has been verified in a test beam campaign at the CERN PS. Preliminary results indicate that the required performance is close to being achieved. The anticipated performance of a full-scale TORCH detector at the LHCb experiment is presented.Comment: 12 pages, 7 figures, Paper submitted to Nuclear Instruments & Methods in Physics Research, Section A - Special Issue VCI 201

Status of the TORCH time-of-flight project

TORCH is a time-of-flight detector, designed to provide charged pi/K particle identification up to a momentum of 10 GeV/c for a 10 m flight path. To achieve this level of performance, a time resolution of 15 ps per incident particle is required. TORCH uses a plane of quartz of 1 cm thickness as a source of Cherenkov photons, which are then focussed onto square Micro-Channel Plate Photomultipliers (MCP-PMTs) of active area 53 x 53 mm^2, segmented into 8 x 128 pixels equivalent. A small-scale TORCH demonstrator with a customised MCP-PMT and associated readout electronics has been successfully operated in a 5 GeV/c mixed pion/proton beam at the CERN PS facility. Preliminary results indicate that a single-photon resolution better than 100 ps can be achieved. The expected performance of a full-scale TORCH detector for the Upgrade II of the LHCb experiment is also discussed.Comment: 9 pages, 6 figures, Paper submitted to Nuclear and Methods A : Proceedings of the 10th International Workshop on Ring Imaging Cherenkov Detectors (RICH 2018), Moscow, Russia, July 29 to August 4 201

Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.Peer reviewe

Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.</p

Calcium-sensitive fluorescent lifetime imaging using wide field time-resolved detection of emission from optical sections excited by light sheet illumination

Calcium sensitive dyes are valuable tools in the study of intracellular Ca+ signalling. But application of these sensors using conventional wide field fluorescence intensity imaging is limited in model organisms, embryos and other moderately thick tissues by blurring due to detection of emitted light from outside the focal plane, unproductive photobleaching above and below the focal plane as well as depth-dependent variation in intensity. In order to overcome these difficulties we are combining wide field fluorescence lifetime imaging which is intensity-independent with planar illumination orthogonal to the axis of detection. We will demonstrate the accurate calibration of Ca+ sensitivity of the fluorescence lifetime of Oregon Green Bapta1 in buffer systems and its utility in detection of rapid Ca+ dynamics in vivo. In this implementation of our Single Plane Illumination Microscope (SPIM), we are testing a novel detector, the Capacitive Division Imaging Readout (CDIR) detector, consisting of a Microchannel Plate (MCP) vacuum detector with spatial resolution (102 pixels) and timing resolution of the order of 100 ps. The CDIR detector, capacitively couples the charge output of the MCP between four readout nodes. The charge collected at each node is then measured using the NINO ASIC, a charge sensitive amplifier/discriminator, and the HPTDC ASIC, a high time resolution time-to-digital convertor, allowing the charge position to be calculated using a centroiding imaging algorithm

The TORCH time-of-flight detector

The TORCH detector is a time-of-flight system that is being developed for use in particle physics experiments with the aim of providing particle identification, over a wide area, in the momentum range 2 to 10 GeV/c. The detector exploits prompt Cherenkov light produced by charge particles traversing a 10 mm thick quartz plate. Photons propagate via total-internal reflection and are focussed onto a detector plane comprising position-sensitive micro-channel plate photomultiplier (MCP-PMT) detectors. The goal is to achieve a resolution of 15 ps per particle by combining information from around 30 detected photons, given a single-photon resolution of 70 ps. The MCP-PMT detectors have been developed with a commercial partner (Photek), leading to the delivery of a square tube with a 53-by-53 mm active area and 8-by-128 pixel equivalent. A small-scale TORCH demonstrator has been operated in beam tests and preliminary results indicate a single-photon resolution better than 100 ps. Progress towards a larger-scale system with 11 MCP-PMTs is presented

Leveraging Genetic Variability across Populations for the Identification of Causal Variants

Genome-wide association studies have been performed extensively in the last few years, resulting in many new discoveries of genomic regions that are associated with complex traits. It is often the case that a SNP found to be associated with the condition is not the causal SNP, but a proxy to it as a result of linkage disequilibrium. For the identification of the actual causal SNP, fine-mapping follow-up is performed, either with the use of dense genotyping or by sequencing of the region. In either case, if the causal SNP is in high linkage disequilibrium with other SNPs, the fine-mapping procedure will require a very large sample size for the identification of the causal SNP. Here, we show that by leveraging genetic variability across populations, we significantly increase the localization success rate (LSR) for a causal SNP in a follow-up study that involves multiple populations as compared to a study that involves only one population. Thus, the average power for detection of the causal variant will be higher in a joint analysis than that in studies in which only one population is analyzed at a time. On the basis of this observation, we developed a framework to efficiently search for a follow-up study design: our framework searches for the best combination of populations from a pool of available populations to maximize the LSR for detection of a causal variant. This framework and its accompanying software can be used to considerably enhance the power of fine-mapping studies

Test-beam performance of a TORCH prototype module

The TORCH time-of-flight detector is designed to provide a 15 ps timing resolution for charged particles, resulting in $K/\pi$ $(p/K)$ particle identification up to momentum of about 10(15) GeV/$c$ over a 10 m flight distance. Cherenkov photons, produced in a quartz plate of 10 mm thickness, are focused onto an array of micro-channel plate photomultipliers (MCP-PMTs) which measure the photon arrival times and spatial positions. A TORCH demonstrator module instrumented with a customised MCP-PMTs has been tested at the CERN PS. The useful implementation for the particle identification in the LHCb experiment requires single-photon time resolution of 70 ps. The timing performance and photon yields have been measured as a function of beam position in the radiator, giving measurements which are approaching the required resolution. A possible TORCH design of the particle identification system in the LHCb experiment has been simulated and its potential for high luminosity running has been evaluated

Status of the TORCH time-of-flight detector

TORCH is a novel time-of-flight detector, designed to provide $\pi$/K particle identification up to 10$\,\text{GeV}/c$ momentum over a 10$\,$m flight path. Based on the DIRC principle, Cherenkov photons are produced in a quartz plate of 10$\,$mm thickness, where they propagate to the periphery of the plate by total-internal reflection. There the photons are focused onto an array of micro-channel plate photomultipliers (MCP-PMTs) which measure their arrival times and spatial positions. A time resolution of 70 ps per detected Cherenkov photon is expected, which results in a time-of-flight resolution of 15 ps, given typically 30 detected photons per track. For a future application, a full-scale TORCH detector has been proposed for the future LHCb upgrade, which comprises 18 modules with 198 MCP-PMTs. To demonstrate the TORCH principle, a half-height ($1250\times660\times10 \,\text{mm}^3$) prototype module has been tested in a 8$\,\text{GeV}/c$ mixed proton-pion beam at the CERN PS. Customised $53\times53\,\text{mm}^2$ MCP-PMTs of effective granularity $128\times8$ pixels have been employed, which have been developed in collaboration with an industrial partner. The single-photon timing performance and photon yields have been measured and are close to specification, demonstrating the TORCH concept

Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging.

BackgroundBiological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field.ResultsLeveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels.ConclusionThis study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity