Monte Carlo Performance Studies of Candidate Sites for the Cherenkov Telescope Array

The Cherenkov Telescope Array (CTA) is the next-generation gamma-ray observatory with sensitivity in the energy range from 20 GeV to beyond 300 TeV. CTA is proposed to consist of two arrays of 40-100 imaging atmospheric Cherenkov telescopes, with one site located in each of the Northern and Southern Hemispheres. The evaluation process for the candidate sites for CTA is supported by detailed Monte Carlo simulations, which take different attributes like site altitude and geomagnetic field configuration into account. In this contribution we present the comparison of the sensitivity and performance of the different CTA site candidates for the measurement of very-high energy gamma rays.Comment: In Proceedings of the 34th International Cosmic Ray Conference (ICRC2015), The Hague, The Netherlands. All CTA contributions at arXiv:1508.0589

EU External Relations: Exclusive Competence Revisited

This Article will focus on the question of exclusive competence in the field of EU external relations, especially in the light of recent developments. After a brief discussion on the origins and development of exclusive competence, a distinction will be made between common commercial policy, which has traditionally been the most important area of an explicit “a priori” exclusive competence, and what is often called an implicit exclusive competence, which, as it is today based on some general criteria enshrined in TFEU Article 3(2), may be called “supervening” exclusive competence. With regard to both categories, the main focus will be on recent developments, notably the impact of the Treaty of Lisbon, which introduced the TFEU and its Articles 2 and 3, as well as the case law of the European Court of Justice (“ECJ” or the “Court”) following the entry into force of the Treaty of Lisbon, on December 1, 2009

PacBio assembly of a Plasmodium knowlesi genome sequence with Hi-C correction and manual annotation of the SICAvar gene family.

Plasmodium knowlesi has risen in importance as a zoonotic parasite that has been causing regular episodes of malaria throughout South East Asia. The P. knowlesi genome sequence generated in 2008 highlighted and confirmed many similarities and differences in Plasmodium species, including a global view of several multigene families, such as the large SICAvar multigene family encoding the variant antigens known as the schizont-infected cell agglutination proteins. However, repetitive DNA sequences are the bane of any genome project, and this and other Plasmodium genome projects have not been immune to the gaps, rearrangements and other pitfalls created by these genomic features. Today, long-read PacBio and chromatin conformation technologies are overcoming such obstacles. Here, based on the use of these technologies, we present a highly refined de novo P. knowlesi genome sequence of the Pk1(A+) clone. This sequence and annotation, referred to as the 'MaHPIC Pk genome sequence', includes manual annotation of the SICAvar gene family with 136 full-length members categorized as type I or II. This sequence provides a framework that will permit a better understanding of the SICAvar repertoire, selective pressures acting on this gene family and mechanisms of antigenic variation in this species and other pathogens

E.U. paediatric MOG consortium consensus: Part 3 - Biomarkers of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders.

A first episode of acquired demyelinating disorder (ADS) in children is a diagnostic challenge as different diseases can express similar clinical features. Recently, antibodies against myelin oligodendrocyte glycoprotein (MOG) have emerged as a new ADS biomarker, which clearly allow the identification of monophasic and relapsing ADS forms different from MS predominantly in children. Due to the novelty of this antibody there are still challenges and controversies about its pathogenicity and best technique to detect it. In this manuscript we will discuss the recommendations and caveats on MOG antibody assays, role in the pathogenesis, and additionally discuss the usefulness of other potential new biomarkers in MOG-antibody associated disorders (MOGAD)

Law of Genome Evolution Direction : Coding Information Quantity Grows

The problem of the directionality of genome evolution is studied. Based on the analysis of C-value paradox and the evolution of genome size we propose that the function-coding information quantity of a genome always grows in the course of evolution through sequence duplication, expansion of code, and gene transfer from outside. The function-coding information quantity of a genome consists of two parts, p-coding information quantity which encodes functional protein and n-coding information quantity which encodes other functional elements except amino acid sequence. The evidences on the evolutionary law about the function-coding information quantity are listed. The needs of function is the motive force for the expansion of coding information quantity and the information quantity expansion is the way to make functional innovation and extension for a species. So, the increase of coding information quantity of a genome is a measure of the acquired new function and it determines the directionality of genome evolution.Comment: 16 page

Gamma-ray signatures of cosmic ray acceleration, propagation, and confinement in the era of CTA

Galactic cosmic rays are commonly believed to be accelerated at supernova remnants via diffusive shock acceleration. Despite the popularity of this idea, a conclusive proof for its validity is still missing. Gamma-ray astronomy provides us with a powerful tool to tackle this problem, because gamma rays are produced during cosmic ray interactions with the ambient gas. The detection of gamma rays from several supernova remnants is encouraging, but still does not constitute a proof of the scenario, the main problem being the difficulty in disentangling the hadronic and leptonic contributions to the emission. Once released by their sources, cosmic rays diffuse in the interstellar medium, and finally escape from the Galaxy. The diffuse gamma-ray emission from the Galactic disk, as well as the gamma-ray emission detected from a few galaxies is largely due to the interactions of cosmic rays in the interstellar medium. On much larger scales, cosmic rays are also expected to permeate the intracluster medium, since they can be confined and accumulated within clusters of galaxies for cosmological times. Thus, the detection of gamma rays from clusters of galaxies, or even upper limits on their emission, will allow us to constrain the cosmic ray output of the sources they contain, such as normal galaxies, AGNs, and cosmological shocks. In this paper, we describe the impact that the Cherenkov Telescope Array, a future ground-based facility for very-high energy gamma-ray astronomy, is expected to have in this field of research.Comment: accepted to Astroparticle Physics, special issue on Physics with the Cherenkov Telescope Arra

Binaries with the eyes of CTA

The binary systems that have been detected in gamma rays have proven very useful to study high-energy processes, in particular particle acceleration, emission and radiation reprocessing, and the dynamics of the underlying magnetized flows. Binary systems, either detected or potential gamma-ray emitters, can be grouped in different subclasses depending on the nature of the binary components or the origin of the particle acceleration: the interaction of the winds of either a pulsar and a massive star or two massive stars; accretion onto a compact object and jet formation; and interaction of a relativistic outflow with the external medium. We evaluate the potentialities of an instrument like the Cherenkov telescope array (CTA) to study the non-thermal physics of gamma-ray binaries, which requires the observation of high-energy phenomena at different time and spatial scales. We analyze the capability of CTA, under different configurations, to probe the spectral, temporal and spatial behavior of gamma-ray binaries in the context of the known or expected physics of these sources. CTA will be able to probe with high spectral, temporal and spatial resolution the physical processes behind the gamma-ray emission in binaries, significantly increasing as well the number of known sources. This will allow the derivation of information on the particle acceleration and emission sites qualitatively better than what is currently available.Comment: 23 pages, 13 figures, accepted for publication in Astroparticle Physics, special issue on Physics with the Cherenkov Telescope Arra

Genome-Wide Methylation Profiling in 229 Patients With Crohn's Disease Requiring Intestinal Resection: Epigenetic Analysis of the Trial of Prevention of Post-operative Crohn's Disease (TOPPIC).

Background &amp; Aims: DNA methylation alterations may provide important insights into gene-environment interaction in cancer, aging, and complex diseases, such as inflammatory bowel disease (IBD). We aim first to determine whether the circulating DNA methylome in patients requiring surgery may predict Crohn's disease (CD) recurrence following intestinal resection; and second to compare the circulating methylome seen in patients with established CD with that we had reported in a series of inception cohorts. Methods: TOPPIC was a placebo-controlled, randomized controlled trial of 6-mercaptopurine at 29 UK centers in patients with CD undergoing ileocolic resection between 2008 and 2012. Genomic DNA was extracted from whole blood samples from 229 of the 240 patients taken before intestinal surgery and analyzed using 450KHumanMethylation and Infinium Omni Express Exome arrays (Illumina, San Diego, CA). Coprimary objectives were to determine whether methylation alterations may predict clinical disease recurrence; and to assess whether the epigenetic alterations previously reported in newly diagnosed IBD were present in the patients with CD recruited into the TOPPIC study. Differential methylation and variance analysis was performed comparing patients with and without clinical evidence of recurrence. Secondary analyses included investigation of methylation associations with smoking, genotype (MeQTLs), and chronologic age. Validation of our previously published case-control observation of the methylome was performed using historical control data (CD, n = 123; Control, n = 198). Results: CD recurrence in patients following surgery is associated with 5 differentially methylated positions (Holm P &lt;.05), including probes mapping to WHSC1 (P = 4.1 × 10 -9, Holm P =.002) and EFNA3 (P = 4.9 × 10 -8, Holm P =.02). Five differentially variable positions are demonstrated in the group of patients with evidence of disease recurrence including a probe mapping to MAD1L1 (P = 6.4 × 10 -5). DNA methylation clock analyses demonstrated significant age acceleration in CD compared with control subjects (GrimAge + 2 years; 95% confidence interval, 1.2–2.7 years), with some evidence for accelerated aging in patients with CD with disease recurrence following surgery (GrimAge +1.04 years; 95% confidence interval, -0.04 to 2.22). Significant methylation differences between CD cases and control subjects were seen by comparing this cohort in conjunction with previously published control data, including validation of our previously described differentially methylated positions (RPS6KA2 P = 1.2 × 10 -19, SBNO2 = 1.2 × 10 -11) and regions (TXK [false discovery rate, P = 3.6 × 10 -14], WRAP73 [false discovery rate, P = 1.9 × 10 -9], VMP1 [false discovery rate, P = 1.7 × 10 -7], and ITGB2 [false discovery rate, P = 1.4 × 10 -7]). Conclusions: We demonstrate differential methylation and differentially variable methylation in patients developing clinical recurrence within 3 years of surgery. Moreover, we report replication of the CD-associated methylome, previously characterized only in adult and pediatric inception cohorts, in patients with medically refractory disease needing surgery.</p

Protocol for the development and validation procedure of the managing the link and strengthening transition from child to adult mental health care (MILESTONE) suite of measures

Background: Mental health disorders in the child and adolescent population are a pressing public health concern. Despite the high prevalence of psychopathology in this vulnerable population, the transition from Child and Adolescent Mental Health Services (CAMHS) to Adult Mental Health Services (AMHS) has many obstacles such as deficiencies in planning, organisational readiness and policy gaps. All these factors contribute to an inadequate and suboptimal transition process. A suite of measures is required that would allow young people to be assessed in a structured and standardised way to determine the on-going need for care and to improve communication across clinicians at CAMHS and AMHS. This will have the potential to reduce the overall health economic burden and could also improve the quality of life for patients travelling across the transition boundary. The MILESTONE (Managing the Link and Strengthening Transition from Child to Adult Mental Health Care) project aims to address the significant socioeconomic and societal challenge related to the transition process. This protocol paper describes the development of two MILESTONE transition-related measures: The Transition Readiness and Appropriateness Measure (TRAM), designed to be a decision-making aide for clinicians, and the Transition Related Outcome Measure (TROM), for examining the outcome of transition. Methods: The TRAM and TROM have been developed and were validated following the US FDA Guidance for Patient-reported Outcome Measures which follows an incremental stepwise framework. The study gathers information from service users, parents, families and mental health care professionals who have experience working with young people undergoing the transition process from eight European countries. Discussion: There is an urgent need for comprehensive measures that can assess transition across the CAMHS/AMHS boundary. This study protocol describes the process of development of two new transition measures: the TRAM and TROM. The TRAM has the potential to nurture better transitions as the findings can be summarised and provided to clinicians as a clinician-decision making support tool for identifying cases who need to transition and the TROM can be used to examine the outcomes of the transition process. Trial registration: MILESTONE study registration: ISRCTN83240263 Registered 23-July-2015 - ClinicalTrials.gov NCT03013595 Registered 6 January 2017