Signal-to-Noise Measurements on Irradiated CMS Tracker Detector Modules in an Electron Testbeam

The CMS experiment at the Large Hadron Collider at CERN is in the last phase of its construction. The harsh radiation environment at LHC will put strong demands in radiation hardness to the innermost parts of the detector. To assess the performance of irradiated microstrip detector modules, a testbeam was conducted at the Testbeam 22 facility of the DESY research center. The primary objective was the signal-to-noise measurement of irradiated CMS Tracker modules to ensure their functionality up to 10 years of LHC operation. The paper briefly summarises the basic setup at the facility and the hardware and software used to collect and analyse the data. Some interesting subsidiary results are shown, which confirm the expected behaviour of the detector with respect to the signal-to-noise performance over the active detector area and for different electron energies. The main focus of the paper are the results of the signal-to-noise measurements for CMS Tracker Modules which were exposed to different radiation doses

Dysregulation of the PDGFRA gene causes inflow tract anomalies including TAPVR: integrating evidence from human genetics and model organisms

Total anomalous pulmonary venous return (TAPVR) is a congenital heart defect inherited via complex genetic and/or environmental factors. We report detailed mapping in extended TAPVR kindreds and mutation analysis in TAPVR patients that implicate the PDGFRA gene in the development of TAPVR. Gene expression studies in mouse and chick embryos for both the Pdgfra receptor and its ligand Pdgf-a show temporal and spatial patterns consistent with a role in pulmonary vein (PV) development. We used an in ovo function blocking assay in chick and a conditional knockout approach in mouse to knock down Pdgfra expression in the developing venous pole during the period of PV formation. We observed that loss of PDGFRA function in both organisms causes TAPVR with low penetrance (∼7%) reminiscent of that observed in our human TAPVR kindreds. Intermediate inflow tract anomalies occurred in a higher percentage of embryos (∼30%), suggesting that TAPVR occurs at one end of a spectrum of defects. We show that the anomalous pulmonary venous connection seen in chick and mouse is highly similar to TAPVR discovered in an abnormal early stage embryo from the Kyoto human embryo collection. Whereas the embryology of the normal venous pole and PV is becoming understood, little is known about the embryogenesis or molecular pathogenesis of TAPVR. These models of TAPVR provide important insight into the pathogenesis of PV defects. Taken together, these data from human genetics and animal models support a role for PDGF-signaling in normal PV development, and in the pathogenesis of TAPVR

Shared Segment Analysis and Next-Generation Sequencing Implicates the Retinoic Acid Signaling Pathway in Total Anomalous Pulmonary Venous Return (TAPVR)

<div><p>Most isolated congenital heart defects are thought to be sporadic and are often ascribed to multifactorial mechanisms with poorly understood genetics. Total Anomalous Pulmonary Venous Return (TAPVR) occurs in 1 in 15,000 live-born infants and occurs either in isolation or as part of a syndrome involving aberrant left-right development. Previously, we reported causative links between TAVPR and the <i>PDGFRA</i> gene. TAPVR has also been linked to the <i>ANKRD1/CARP</i> genes. However, these genes only explain a small fraction of the heritability of the condition. By examination of phased single nucleotide polymorphism genotype data from 5 distantly related TAPVR patients we identified a single 25 cM shared, Identical by Descent genomic segment on the short arm of chromosome 12 shared by 3 of the patients and their obligate-carrier parents. Whole genome sequence (WGS) analysis identified a non-synonymous variant within the shared segment in the <i>retinol binding protein 5</i> (<i>RBP5</i>) gene. The <i>RBP5</i> variant is predicted to be deleterious and is overrepresented in the TAPVR population. Gene expression and functional analysis of the zebrafish orthologue, <i>rbp7</i>, supports the notion that <i>RBP5</i> is a TAPVR susceptibility gene. Additional sequence analysis also uncovered deleterious variants in genes associated with retinoic acid signaling, including <i>NODAL</i> and <i>retinol dehydrogenase 10</i>. These data indicate that genetic variation in the retinoic acid signaling pathway confers, in part, susceptibility to TAPVR.</p></div

<i>rbp7a</i> expression in the developing Zebrafish.

<p><i>rbp7a</i> is strongly expressed within the dorsal forerunner cells (DFCs) and Kupffer’s vesicle (KV) in the developing zebrafish embryo: Panel A. 75% epiboly; Panel B. tailbud stage; Panel C. 8 somite stage.</p

Variants in the chromosome 12 SGS predicted damaging/deleterious by MutationTaster/Polyphen2 and SIFT.

<p>Variants in the chromosome 12 SGS predicted damaging/deleterious by MutationTaster/Polyphen2 and SIFT.</p

VAAST Analysis of the WGS variants identified in the chromosome 12 SGS.

<p>VAAST Analysis of the WGS variants identified in the chromosome 12 SGS.</p

Comparison of the allelic frequency of rs7969705 in 64 TAPVR cases and 149 heterotaxy cases versus non-Finnish Europeans in the ExAC database.

<p>Comparison of the allelic frequency of rs7969705 in 64 TAPVR cases and 149 heterotaxy cases versus non-Finnish Europeans in the ExAC database.</p

KV cilia are shortened in <i>rbp7a</i> morphants.

<p>Panels A and B: Immunohistochemical staining of representative WT and morphant KV and cilia. Panel C: <i>rbp7a</i> morphants have shorter but not fewer KV cilia than WT embryos. * p<0.05.</p

<i>rbp7a</i> and <i>spaw</i> function together in left-right development.

<p>Panel A: Injection of <i>rbp7a</i> (blue bars) or <i>spaw</i> (purple bars) morpholinos at standard concentrations results in significantly altered <i>spaw</i> expression. Panel B: Injection of either morpholino at subthreshold doses (<i>rbp7a</i>: blue bars; <i>spaw</i>: purple bars) results in more normal left-sided <i>spaw</i> expression. However, co-injection of both morpholinos at subthreshold doses leads to significantly altered <i>spaw</i> expression, similar to the higher dose <i>spaw</i> morphants.</p