End-to-End Scheduling Strategies for Aperiodic Tasks in Middleware

Many mission-critical distributed real-time applicationsmust handle aperiodic tasks with hard end-to-end dead-lines. Existing middleware such as RT-CORBA lacksschedulability analysis and run-time scheduling mecha-nisms that can provide real-time guarantees to aperiodictasks. This paper makes the following contributions to thestate of the art for end-to-end aperiodic scheduling in mid-dleware. First, we compare two approaches to aperiodicscheduling, the deferrable server and the aperiodic utiliza-tion bound, using representative workloads. Numerical re-sults show that the deferrable server analysis is less pes-simistic than the aperiodic utilization bounds when appliedoffline. Second, we propose a practical approach to tuningdeferrable servers for end-to-end tasks. Third, we describedeferrable server mechanisms we have developed for TAO’sfederated event channel. Finally, we present empirical re-sults from a Linux testbed that demonstrate the efficiency ofthose deferrable server mechanisms

Precision near-infrared radial velocity instrumentation II: Non-Circular Core Fiber Scrambler

We have built and commissioned a prototype agitated non-circular core fiber scrambler for precision spectroscopic radial velocity measurements in the near-infrared H band. We have collected the first on-sky performance and modal noise tests of these novel fibers in the near-infrared at H and K bands using the CSHELL spectrograph at the NASA InfraRed Telescope Facility (IRTF). We discuss the design behind our novel reverse injection of a red laser for co-alignment of star-light with the fiber tip via a corner cube and visible camera. We summarize the practical details involved in the construction of the fiber scrambler, and the mechanical agitation of the fiber at the telescope. We present radial velocity measurements of a bright standard star taken with and without the fiber scrambler to quantify the relative improvement in the obtainable blaze function stability, the line spread function stability, and the resulting radial velocity precision. We assess the feasibility of applying this illumination stabilization technique to the next generation of near-infrared spectrographs such as iSHELL on IRTF and an upgraded NIRSPEC at Keck. Our results may also be applied in the visible for smaller core diameter fibers where fiber modal noise is a significant factor, such as behind an adaptive optics system or on a small < 1 meter class telescope such as is being pursued by the MINERVA and LCOGT collaborations.Comment: Proceedings of the SPIE Optics and Photonics Conference "Techniques and Instrumentation for Detection of Exoplanets VI" held in San Diego, CA, August 25-29, 201

Absence of α-Syntrophin Leads to Structurally Aberrant Neuromuscular Synapses Deficient in Utrophin

The syntrophins are a family of structurally related proteins that contain multiple protein interaction motifs. Syntrophins associate directly with dystrophin, the product of the Duchenne muscular dystrophy locus, and its homologues. We have generated α-syntrophin null mice by targeted gene disruption to test the function of this association. The α-Syn−/− mice show no evidence of myopathy, despite reduced levels of α-dystrobrevin–2. Neuronal nitric oxide synthase, a component of the dystrophin protein complex, is absent from the sarcolemma of the α-Syn−/− mice, even where other syntrophin isoforms are present. α-Syn−/− neuromuscular junctions have undetectable levels of postsynaptic utrophin and reduced levels of acetylcholine receptor and acetylcholinesterase. The mutant junctions have shallow nerve gutters, abnormal distributions of acetylcholine receptors, and postjunctional folds that are generally less organized and have fewer openings to the synaptic cleft than controls. Thus, α-syntrophin has an important role in synapse formation and in the organization of utrophin, acetylcholine receptor, and acetylcholinesterase at the neuromuscular synapse

Architecture design study and technology road map for the Planet Formation Imager (PFI)

The Planet Formation Imager (PFI) Project has formed a Technical Working Group (TWG) to explore possible facility architectures to meet the primary PFI science goal of imaging planet formation $\textit{in situ}$ in nearby star-forming regions. The goals of being sensitive to dust emission on solar system scales and resolving the Hill-sphere around forming giant planets can best be accomplished through sub-milliarcsecond imaging in the thermal infrared. Exploiting the 8-13 micron atmospheric window, a ground-based long-baseline interferometer with approximately 20 apertures including 10km baselines will have the necessary resolution to image structure down 0.1 milliarcseconds (0.014 AU) for T Tauri disks in Taurus. Even with large telescopes, this array will not have the sensitivity to directly track fringes in the mid-infrared for our prime targets and a fringe tracking system will be necessary in the near-infrared. While a heterodyne architecture using modern mid-IR laser comb technology remains a competitive option (especially for the intriguing 24 and 40µm atmospheric windows), the prioritization of 3-5µm observations of CO/H$_2$O vibrotational levels by the PFI-Science Working Group (SWG) pushes the TWG to require vacuum pipe beam transport with potentially cooled optics. We present here a preliminary study of simulated L- and N-band PFI observations of a realistic 4-planet disk simulation, finding 21x2.5m PFI can easily detect the accreting protoplanets in both L and N-band but can see non-accreting planets only in L band. We also find that even an ambitious PFI will lack sufficient surface brightness sensitivity to image details of the fainter emission from dust structures beyond ~5 AU, unless directly illuminated or heated by local energy sources. That said, the utility of PFI at N-band is highly dependent on the stage of planet formation in the disk and we require additional systematic studies in conjunction with the PFI-SWG to better understand the science capabilities of PFI, including the potential to resolve protoplanetary disks in emission lines to measure planet masses using position-velocity diagrams. We advocate for a specific technology road map in order to reduce the current cost driver (telescopes) and to validate high accuracy fringe tracking and high dynamic range imaging at L, M band. In conclusion, no technology show-stoppers have been identified for PFI to date, however there is high potential for breakthroughs in medium-aperture (4-m class) telescopes architecture that could reduce the cost of PFI by a factor of 2 or more.This is the author accepted manuscript. The final version is available from SPIE via http://dx.doi.org/10.1117/12.223331

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation

Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.JW is supported by a Cancer Research UK Cambridge Cancer Centre Clinical Research Training Fellowship. Funding for the NIHR BioResource – Rare diseases project was provided by the National Institute for Health Research (NIHR, grant number RG65966). ERM acknowledges support from the European Research Council (Advanced Researcher Award), NIHR (Senior Investigator Award and Cambridge NIHR Biomedical Research Centre), Cancer Research UK Cambridge Cancer Centre and Medical Research Council Infrastructure Award. The University of Cambridge has received salary support in respect of EM from the NHS in the East of England through the Clinical Academic Reserve. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health. DGE is an NIHR Senior Investigator and is supported by the all Manchester NIHR Biomedical Research Centre

Phenotypic Characterization of <i>EIF2AK4</i> Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension

Background: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 ( BMPR2 ) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene ( EIF2AK4 ) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. Methods: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource–Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of &lt;1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. Results: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (K co ; 33% [interquartile range, 30%–35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23–38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. Conclusions: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low K co and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation. </jats:sec

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.This work was supported by The National Institute for Health Research England (NIHR) for the NIHR BioResource – Rare Diseases project (grant number RG65966). The Moorfields Eye Hospital cohort of patients and clinical and imaging data were ascertained and collected with the support of grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Foundation Fighting Blindness (USA), and Retinitis Pigmentosa Fighting Blindness. M.M. is a recipient of an FFB Career Development Award. E.M. is supported by UCLH/UCL NIHR Biomedical Research Centre. F.L.R. and D.G. are supported by Cambridge NIHR Biomedical Research Centre

Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data.

Telomere length is a risk factor in disease and the dynamics of telomere length are crucial to our understanding of cell replication and vitality. The proliferation of whole genome sequencing represents an unprecedented opportunity to glean new insights into telomere biology on a previously unimaginable scale. To this end, a number of approaches for estimating telomere length from whole-genome sequencing data have been proposed. Here we present Telomerecat, a novel approach to the estimation of telomere length. Previous methods have been dependent on the number of telomeres present in a cell being known, which may be problematic when analysing aneuploid cancer data and non-human samples. Telomerecat is designed to be agnostic to the number of telomeres present, making it suited for the purpose of estimating telomere length in cancer studies. Telomerecat also accounts for interstitial telomeric reads and presents a novel approach to dealing with sequencing errors. We show that Telomerecat performs well at telomere length estimation when compared to leading experimental and computational methods. Furthermore, we show that it detects expected patterns in longitudinal data, repeated measurements, and cross-species comparisons. We also apply the method to a cancer cell data, uncovering an interesting relationship with the underlying telomerase genotype