Comparison of Fermi-LAT and CTA in the region between 10-100 GeV

The past decade has seen a dramatic improvement in the quality of data available at both high (HE: 100 MeV to 100 GeV) and very high (VHE: 100 GeV to 100 TeV) gamma-ray energies. With three years of data from the Fermi Large Area Telescope (LAT) and deep pointed observations with arrays of Cherenkov telescope, continuous spectral coverage from 100 MeV to $\sim10$ TeV exists for the first time for the brightest gamma-ray sources. The Fermi-LAT is likely to continue for several years, resulting in significant improvements in high energy sensitivity. On the same timescale, the Cherenkov Telescope Array (CTA) will be constructed providing unprecedented VHE capabilities. The optimisation of CTA must take into account competition and complementarity with Fermi, in particularly in the overlapping energy range 10$-$100 GeV. Here we compare the performance of Fermi-LAT and the current baseline CTA design for steady and transient, point-like and extended sources.Comment: Accepted for Publication in Astroparticle Physic

Prototype 9.7 m Schwarzschild-Couder telescope for the Cherenkov Telescope Array: status of the optical system

The Cherenkov Telescope Array (CTA) is an international project for a next-generation ground-based gamma ray observatory, aiming to improve on the sensitivity of current-generation experiments by an order of magnitude and provide energy coverage from 30 GeV to more than 300 TeV. The 9.7m Schwarzschild-Couder (SC) candidate medium-size telescope for CTA exploits a novel aplanatic two-mirror optical design that provides a large field of view of 8 degrees and substantially improves the off-axis performance giving better angular resolution across all of the field of view with respect to single-mirror telescopes. The realization of the SC optical design implies the challenging production of large aspherical mirrors accompanied by a submillimeter-precision custom alignment system. In this contribution we report on the status of the implementation of the optical system on a prototype 9.7 m SC telescope located at the Fred Lawrence Whipple Observatory in southern Arizona.Comment: Proceedings of the 35th International Cosmic Ray Conference (ICRC 2017), Busan, Korea. All CTA contributions at arXiv:1709.0348

The repertoire of mutational signatures in human cancer

Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature(1). Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium(2) of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses(3-15), enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated-but distinct-DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.Peer reviewe

Brain structure in pediatric Tourette syndrome

Previous studies of brain structure in Tourette syndrome (TS) have produced mixed results, and most had modest sample sizes. In the present multicenter study, we used structural magnetic resonance imaging (MRI) to compare 103 children and adolescents with TS to a well-matched group of 103 children without tics. We applied voxel-based morphometry methods to test gray matter (GM) and white matter (WM) volume differences between diagnostic groups, accounting for MRI scanner and sequence, age, sex and total GM+WM volume. The TS group demonstrated lower WM volume bilaterally in orbital and medial prefrontal cortex, and greater GM volume in posterior thalamus, hypothalamus and midbrain. These results demonstrate evidence for abnormal brain structure in children and youth with TS, consistent with and extending previous findings, and they point to new target regions and avenues of study in TS. For example, as orbital cortex is reciprocally connected with hypothalamus, structural abnormalities in these regions may relate to abnormal decision making, reinforcement learning or somatic processing in TS

In silico karyotyping of chromosomally polymorphic malaria mosquitoes in the Anopheles gambiae complex

Chromosomal inversion polymorphisms play an important role in adaptation to environmental heterogeneities. For mosquito species in the Anopheles gambiae complex that are significant vectors of human malaria, paracentric inversion polymorphisms are abundant and are associated with ecologically and epidemiologically important phenotypes. Improved understanding of these traits relies on determining mosquito karyotype, which currently depends upon laborious cytogenetic methods whose application is limited both by the requirement for specialized expertise and for properly preserved adult females at specific gonotrophic stages. To overcome this limitation, we developed sets of tag single nucleotide polymorphisms (SNPs) inside inversions whose biallelic genotype is strongly correlated with inversion genotype. We leveraged 1,347 fully sequenced An. gambiae and Anopheles coluzzii genomes in the Ag1000G database of natural variation. Beginning with principal components analysis (PCA) of population samples, applied to windows of the genome containing individual chromosomal rearrangements, we classified samples into three inversion genotypes, distinguishing homozygous inverted and homozygous uninverted groups by inclusion of the small subset of specimens in Ag1000G that are associated with cytogenetic metadata. We then assessed the correlation between candidate tag SNP genotypes and PCA-based inversion genotypes in our training sets, selecting those candidates with >80% agreement. Our initial tests both in held-back validation samples from Ag1000G and in data independent of Ag1000G suggest that when used for in silico inversion genotyping of sequenced mosquitoes, these tags perform better than traditional cytogenetics, even for specimens where only a small subset of the tag SNPs can be successfully ascertained

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

Comparing Patterns of Natural Selection across Species Using Selective Signatures

Comparing gene expression profiles over many different conditions has led to insights that were not obvious from single experiments. In the same way, comparing patterns of natural selection across a set of ecologically distinct species may extend what can be learned from individual genome-wide surveys. Toward this end, we show how variation in protein evolutionary rates, after correcting for genome-wide effects such as mutation rate and demographic factors, can be used to estimate the level and types of natural selection acting on genes across different species. We identify unusually rapidly and slowly evolving genes, relative to empirically derived genome-wide and gene family-specific background rates for 744 core protein families in 30 γ-proteobacterial species. We describe the pattern of fast or slow evolution across species as the “selective signature” of a gene. Selective signatures represent a profile of selection across species that is predictive of gene function: pairs of genes with correlated selective signatures are more likely to share the same cellular function, and genes in the same pathway can evolve in concert. For example, glycolysis and phenylalanine metabolism genes evolve rapidly in Idiomarina loihiensis, mirroring an ecological shift in carbon source from sugars to amino acids. In a broader context, our results suggest that the genomic landscape is organized into functional modules even at the level of natural selection, and thus it may be easier than expected to understand the complex evolutionary pressures on a cell

Systematic review and validation of clinical models predicting survival after oesophagectomy for adenocarcinoma

BACKGROUND: Oesophageal adenocarcinoma poses a significant global health burden, yet the staging used to predict survival has limited ability to stratify patients by outcome. This study aimed to identify published clinical models that predict survival in oesophageal adenocarcinoma and to evaluate them using an independent international multicentre dataset. METHODS: A systematic literature search (title and abstract) using the Ovid Embase and MEDLINE databases (from 1947 to 11 July 2020) was performed. Inclusion criteria were studies that developed or validated a clinical prognostication model to predict either overall or disease-specific survival in patients with oesophageal adenocarcinoma undergoing surgical treatment with curative intent. Published models were validated using an independent dataset of 2450 patients who underwent oesophagectomy for oesophageal adenocarcinoma with curative intent. RESULTS: Seventeen articles were eligible for inclusion in the study. Eleven models were suitable for testing in the independent validation dataset and nine of these were able to stratify patients successfully into groups with significantly different survival outcomes. Area under the receiver operating characteristic curves for individual survival prediction models ranged from 0.658 to 0.705, suggesting poor-to-fair accuracy. CONCLUSION: This study highlights the need to concentrate on robust methodologies and improved, independent, validation, to increase the likelihood of clinical adoption of survival predictions models

Imputation-Based Analysis of Association Studies: Candidate Regions and Quantitative Traits

We introduce a new framework for the analysis of association studies, designed to allow untyped variants to be more effectively and directly tested for association with a phenotype. The idea is to combine knowledge on patterns of correlation among SNPs (e.g., from the International HapMap project or resequencing data in a candidate region of interest) with genotype data at tag SNPs collected on a phenotyped study sample, to estimate (“impute”) unmeasured genotypes, and then assess association between the phenotype and these estimated genotypes. Compared with standard single-SNP tests, this approach results in increased power to detect association, even in cases in which the causal variant is typed, with the greatest gain occurring when multiple causal variants are present. It also provides more interpretable explanations for observed associations, including assessing, for each SNP, the strength of the evidence that it (rather than another correlated SNP) is causal. Although we focus on association studies with quantitative phenotype and a relatively restricted region (e.g., a candidate gene), the framework is applicable and computationally practical for whole genome association studies. Methods described here are implemented in a software package, Bim-Bam, available from the Stephens Lab website http://stephenslab.uchicago.edu/software.html