Bivariate causal mixture model quantifies polygenic overlap between complex traits beyond genetic correlation.

Accumulating evidence from genome wide association studies (GWAS) suggests an abundance of shared genetic influences among complex human traits and disorders, such as mental disorders. Here we introduce a statistical tool, MiXeR, which quantifies polygenic overlap irrespective of genetic correlation, using GWAS summary statistics. MiXeR results are presented as a Venn diagram of unique and shared polygenic components across traits. At 90% of SNP-heritability explained for each phenotype, MiXeR estimates that 8.3 K variants causally influence schizophrenia and 6.4 K influence bipolar disorder. Among these variants, 6.2 K are shared between the disorders, which have a high genetic correlation. Further, MiXeR uncovers polygenic overlap between schizophrenia and educational attainment. Despite a genetic correlation close to zero, the phenotypes share 8.3 K causal variants, while 2.5 K additional variants influence only educational attainment. By considering the polygenicity, discoverability and heritability of complex phenotypes, MiXeR analysis may improve our understanding of cross-trait genetic architectures

Quantitative Comparison of Sinc-Approximating Kernels for Medical Image Interpolation

Abstract. Interpolation is required in many medical image processing operations. From sampling theory, it follows that the ideal interpolation kernel is the sinc function, which is of infinite extent. In the attempt to obtain practical and computationally efficient image processing al-gorithms, many sinc-approximating interpolation kernels have been de-vised. In this paper we present the results of a quantitative comparison of 84 different sinc-approximating kernels, with spatial extents ranging from 2 to 10 grid points in each dimension. The evaluation involves the application of geometrical transformations to medical images from dif-ferent modalities (CT, MR, and PET), using the different kernels. The results show very clearly that, of all kernels with a spatial extent of 2 grid points, the linear interpolation kernel performs best. Of all kernels with an extent of 4 grid points, the cubic convolution kernel is the best (28 %- 75 % reduction of the errors as compared to linear interpolation). Even better results (44 %- 95 % reduction) are obtained with kernels of larger extent, notably the Welch, Cosine, Lanczos, and Kaiser windowed sinc kernels. In general, the truncated sinc kernel is one of the worst performing kernels.

Photodiode read-out of the ALICE photon spectrometer PbWO4PbWO_{4} crystals

Proposal of abstract for LEB99, Snowmass, Colorado, 20-24 September 1999The PHOton Spectrometer of the ALICE experiment is an electromagnetic calorimeter of high granularity consisting of 17280 lead-tungstate (PWO) crystals of dimensions 22x22x180 mm3, read out by large-area PIN-diodes with very low-noise front-end electronics. The crystal assembly is operated at -25C to increase the PWO light yield. A 16.1x17.1 mm2 photodiode, optimized for the PWO emissio spectrum at 400-500 nm, has been developed. The 20x20 mm2 preamplifier PCB is attached to the back side of the diode ceramic frame. The charge sensitive preamplifier is built in discrete logic with two input JFETs for optimum matching with the ~150pF PIN-diode. A prototype shaper has been designed and built in discrete logic. For a detector matrix of 64 units the measured ENCs are between 450-550e at -25C. Beam tests demonstrate that the required energy resolution is reached.Summary:The PHOton Spectrometer of the ALICE experiment is an electromagnetic calorimeter of high granularity consisting of 17280 lead-tungstate (PWO) crystals of dimensions 22x22x180 mm3, coupled to large-area PIN-diodes with matching low-noise preamplifiers. PHOS is optimized for measuring photons, pi0s and eta mesons in the momentum ranges 0.5-10, 1-10 and 2-10 GeV/c, respectively, and is designed for the expected large number of particles that will be produced in central Pb-Pb collisions. Lead tungstate (PWO) is a fast scintillating crystal with a rather complex emission spectrum, consisting of two components: a blue component peaking at 420 nm and a green component peaking at 480-520 nm. The light yield of PWO at room temperature is low compared with other heavy scintillating crystals, for instance BGO. However, the yield depends strongly on the temperature with a coefficient of ~-2 degree. At the selected operating temperature of -25C the yield is about a factor of 3 higher compared to room temperature. Still, in order to reach the required energy resolution for a PHOS channel, an ENC noise of less than 600e for the PIN-diode-preamplifier-shaper stage is required. This is a very low value taking into account the high capacitance of 150-200 pF of the large area PIN-diodes. In collaboration with the PHOS project, the company AME (Horten, Norway) has designed and produced a PIN-photodiode optimized for the cross-section and spectral responsivity of the PHOS PWO crystal. The photodiode has an active area of 17.1x16.1 mm2 and is fabricated on n-type silicon material of thickness 280 um. The wafer specific resistivity is between 3000 and 6000 ohm-cm, which corresponds to a depletion voltage of 70V. The photodiode response is optimized for the spectral region 400-500 nm in order to match the PWO emission spectrum. The PIN-diode is mounted on a ceramic substrate 0.65 mm thick. On this substrate the diode is surrounded by a ceramic frame. The preamplifier PCB of dimension 20x20 mm2 is attached to the back side of the frame. The PIN-diode and bondings to ground and preamplifier input are protected by an optically transparent epoxy layer. The front side of the PIN-diode is glued onto the endface of the PWO crystal with optically transparent glue (Melt-Mount Quick-Stick, Cargille Laboratories, USA). Each crystal is wrapped in White Tyvek to ensure maximum light collection efficiency and optical insulation between the crystals. The PHOS detector consists of four independent modules, each with 4320 channels. The crystal assembly with the photo detectors are operated at -25 +/- 0.3C. The power dissipation per module is ~1 kW. The charge sensitive preamplifier is an operational amplifier built in discrete logic and with two input JFETs (BF861A). Using two JFETs in parallel gives the lowest noise for detector capacitance >100 pF. A prototype shaper, comprising three amplification stages, has been designed and built in discrete logic. For a PIN-diode with capacitance ~150 pF and a leakage current <1 nA under cooling, calculations give optimum time differentiation and integration constants around 3 microsec. For a detector matrix of 64 units the measured ENCs are between 450-550 e at -25C. Beam tests of this matrix show that the required energy resolution for the PHOS is reached

A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer's disease models

Brains are highly metabolically active organs, consuming 20% of a person's energy at resting state. A decline in glucose metabolism is a common feature across a number of neurodegenerative diseases. Another common feature is the progressive accumulation of insoluble protein deposits, it's unclear if the two are linked. Glucose metabolism in the brain is highly coupled between neurons and glia, with glucose taken up by glia and metabolised to lactate, which is then shuttled via transporters to neurons, where it is converted back to pyruvate and fed into the TCA cycle for ATP production. Monocarboxylates are also involved in signalling, and play broad ranging roles in brain homeostasis and metabolic reprogramming. However, the role of monocarboxylates in dementia has not been tested. Here, we find that increasing pyruvate import in Drosophila neurons by over-expression of the transporter bumpel, leads to a rescue of lifespan and behavioural phenotypes in fly models of both frontotemporal dementia and Alzheimer's disease. The rescue is linked to a clearance of late stage autolysosomes, leading to degradation of toxic peptides associated with disease. We propose upregulation of pyruvate import into neurons as potentially a broad-scope therapeutic approach to increase neuronal autophagy, which could be beneficial for multiple dementias

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13

Search for chargino-neutralino production with mass splittings near the electroweak scale in three-lepton final states in √s=13 TeV pp collisions with the ATLAS detector

A search for supersymmetry through the pair production of electroweakinos with mass splittings near the electroweak scale and decaying via on-shell W and Z bosons is presented for a three-lepton final state. The analyzed proton-proton collision data taken at a center-of-mass energy of √s=13  TeV were collected between 2015 and 2018 by the ATLAS experiment at the Large Hadron Collider, corresponding to an integrated luminosity of 139  fb−1. A search, emulating the recursive jigsaw reconstruction technique with easily reproducible laboratory-frame variables, is performed. The two excesses observed in the 2015–2016 data recursive jigsaw analysis in the low-mass three-lepton phase space are reproduced. Results with the full data set are in agreement with the Standard Model expectations. They are interpreted to set exclusion limits at the 95% confidence level on simplified models of chargino-neutralino pair production for masses up to 345 GeV

Search for direct stau production in events with two hadronic tau-leptons in root s=13 TeV pp collisions with the ATLAS detector

A search for the direct production of the supersymmetric partners ofτ-leptons (staus) in final stateswith two hadronically decayingτ-leptons is presented. The analysis uses a dataset of pp collisions corresponding to an integrated luminosity of139fb−1, recorded with the ATLAS detector at the LargeHadron Collider at a center-of-mass energy of 13 TeV. No significant deviation from the expected StandardModel background is observed. Limits are derived in scenarios of direct production of stau pairs with eachstau decaying into the stable lightest neutralino and oneτ-lepton in simplified models where the two staumass eigenstates are degenerate. Stau masses from 120 GeV to 390 GeV are excluded at 95% confidencelevel for a massless lightest neutralino

Cancer and heart attack survivors’ expectations of employment status: results from the English Longitudinal Study of Ageing

Background: Sociodemographic, health- and work-related factors have been found to influence return to work in cancer survivors. It is feasible though that behavioural factors, such as expectation of being at work, could also affect work-related outcomes. Therefore, the effect of earlier identified factors and expectation of being at work on future employment status in cancer survivors was explored. To assess the degree to which these factors specifically concern cancer survivors, a comparison with heart attack survivors was made. Methods: Data from the English Longitudinal Study of Ageing were used. Cancer and heart attack survivors of working age in the UK were included and followed up for 2 years. Baseline characteristics of both cancer and heart attack survivors were compared regarding employment status. Univariate and multivariate regression analyses were performed in survivors at work, and the interaction between independent variables and diagnose group was assessed. Results: In cancer survivors at work (N = 159), alcohol consumption, participating in moderate or vigorous sport activities, general health and participation were univariate associated with employment status at two-year followup. Only fair general health (compared to very good general health) remained statistically significant in the multivariate model (OR 0.31; 95% CI 0.13–0.76; p = 0.010). In heart attack survivors at work (N = 78), gender, general health and expectation of being at work were univariate associated with employment status at follow-up. Female gender (OR 0.03; 95% CI 0.00–0.57; p = 0.018) and high expectation of being at work (OR 10.68; 95% CI 1.23–93.92; p = 0.033) remained significant in the multivariate model. The influence of gender (p = 0.066) and general health (p = 0.020) regarding employment status was found to differ significantly between cancer and heart attack survivors. Conclusions: When predicting future employment status in cancer survivors in the UK, general health is the most relevant factor to consider. While expectation of being at work did not show any significant influence in cancer survivors, in heart attack survivors, it should not be disregarded though, when developing interventions to affect their employment status. Future research should focus on more specific measures for expectation, and additional behavioural factors, such as self-efficacy, and their effect on employment status