THSD1 (Thrombospondin Type 1 Domain Containing Protein 1) Mutation in the Pathogenesis of Intracranial Aneurysm and Subarachnoid Hemorrhage

Background and Purpose A ruptured intracranial aneurysm (IA) is the leading cause of a subarachnoid hemorrhage (SAH). This study seeks to define a specific gene whose mutation leads to disease. Methods More than 500 IA probands and 100 affected families were enrolled and clinically characterized. Whole exome sequencing was performed on a large family, revealing a segregating THSD1 mutation. THSD1 was sequenced in other probands and controls. Thsd1 loss-of-function studies in zebrafish and mice were used for in vivo analyses, and functional studies performed using an in vitro endothelial cell model. Results A nonsense mutation in THSD1 (thrombospondin type-1 domain-containing protein 1) was identified that segregated with the 9 affected (3 suffered SAH; 6 had unruptured IA) and 13 unaffected family members (LOD score 4.69). Targeted THSD1 sequencing identified mutations in 8 of 507 unrelated IA probands, including 3 who had suffered SAH (1.6% [95% CI, 0.8%–3.1%]). These THSD1 mutations/rare variants were highly enriched in our IA patient cohort relative to 89,040 chromosomes in ExAC database (p\u3c0.0001). In zebrafish and mice, Thsd1 loss-of-function caused cerebral bleeding (which localized to the subarachnoid space in mice) and increased mortality. Mechanistically, THSD1 loss impaired endothelial cell focal adhesion to the basement membrane. These adhesion defects could be rescued by expression of wild-type THSD1 but not THSD1 mutants identified in IA patients. Conclusions This report identifies THSD1 mutations in familial and sporadic IA patients, and shows that THSD1 loss results in cerebral bleeding in two animal models. This finding provides new insight into IA and SAH pathogenesis and provides new understanding of THSD1 function, which includes endothelial cell to extracellular matrix adhesion

What's wrong with the scrum laws in rugby union? - Judgment, truth and refereeing

Officiating and the role of officials in sport are crucial and often decisive factors in sports contests. Notable contributions in philosophy of sport include Collins (2012), Russell (1997; 1999), McFee (2011) & Mumford (2006) have brought a sharp philosophical focus to highlight that justice and desert of sport contests, in part, rely on officiating truths (performances) that arise from an appropriate admixture of epistemic (judgments) and metaphysical (actions) ingredients. This paper provides a rigorous and original philosophical analysis of the problems of obeying the rules and of applying the rules of sport. The paper focuses on a particular phase of play in rugby union, namely the scrum. It is fair to say that the scrum has become a focus of criticism and bewilderment. Elite televised rugby is damaged as a spectacle because too much time is wasted setting and re-setting scrums. Furthermore, our trust in the fairness of games is eroded because the scrum is a ‘lottery’ when it comes to officiating. In this paper, we identify two fundamental structural problems which contribute to the scrum controversy. First, drawing on Mumford (2006) and Collins (2012) we argue that officials cannot make reliable judgments about scrums because they cannot see what they need to see. Secondly, we argue that players cannot follow the laws of the scrum even if they have a strong desire to do so. Laws which can’t be followed are, according to Fuller (2000) defective. Consequently, the scrum is not only potentially dangerous but also flawed in terms of its capacity to actualize an intended part of the game

Improved Techniques for the Surveillance of the Near Earth Space Environment with the Murchison Widefield Array

In this paper we demonstrate improved techniques to extend coherent processing intervals for passive radar processing, with the Murchison Widefield Array. Specifically, we apply a two stage linear range and Doppler migration compensation by utilising Keystone Formatting and a recent dechirping method. These methods are used to further demonstrate the potential for the surveillance of space with the Murchison Widefield Array using passive radar, by detecting objects orders of magnitude smaller than previous work. This paper also demonstrates how the linear Doppler migration methods can be extended to higher order compensation to further increase potential processing intervals.Comment: Presented at the 2019 IEEE Radar Conference in Boston earlier this yea

Testing Reactive Probabilistic Processes

We define a testing equivalence in the spirit of De Nicola and Hennessy for reactive probabilistic processes, i.e. for processes where the internal nondeterminism is due to random behaviour. We characterize the testing equivalence in terms of ready-traces. From the characterization it follows that the equivalence is insensitive to the exact moment in time in which an internal probabilistic choice occurs, which is inherent from the original testing equivalence of De Nicola and Hennessy. We also show decidability of the testing equivalence for finite systems for which the complete model may not be known

Compositionality for Quantitative Specifications

We provide a framework for compositional and iterative design and verification of systems with quantitative information, such as rewards, time or energy. It is based on disjunctive modal transition systems where we allow actions to bear various types of quantitative information. Throughout the design process the actions can be further refined and the information made more precise. We show how to compute the results of standard operations on the systems, including the quotient (residual), which has not been previously considered for quantitative non-deterministic systems. Our quantitative framework has close connections to the modal nu-calculus and is compositional with respect to general notions of distances between systems and the standard operations

Solid foundations? Towards a historical sociology of prison building programmes in England and Wales, 1959–2015

Between 1959 and 2015 the UK government embarked upon five major phases of prison building in England and Wales. Drawing upon detailed archival research, this article offers a historical sociology of prison building programmes. It traces the evolution of prison building as a public policy concern and documents how this key site of penal policymaking was interpreted, and contested, by policy actors who were themselves embedded within deep institutional structures of power and meaning. It argues that prison building has moved from the margins to the mainstream of penal policy, shaped by strongly-held convictions about the liberal-democratic state, the competition for control of finite resources and the complex ?geography of administration? that underpins the British machinery of government

Long-Baseline Neutrino Facility (LBNF) and Deep Underground Neutrino Experiment (DUNE) Conceptual Design Report Volume 2: The Physics Program for DUNE at LBNF

The Physics Program for the Deep Underground Neutrino Experiment (DUNE) at the Fermilab Long-Baseline Neutrino Facility (LBNF) is described

Heavy quarkonium: progress, puzzles, and opportunities

A golden age for heavy quarkonium physics dawned a decade ago, initiated by the confluence of exciting advances in quantum chromodynamics (QCD) and an explosion of related experimental activity. The early years of this period were chronicled in the Quarkonium Working Group (QWG) CERN Yellow Report (YR) in 2004, which presented a comprehensive review of the status of the field at that time and provided specific recommendations for further progress. However, the broad spectrum of subsequent breakthroughs, surprises, and continuing puzzles could only be partially anticipated. Since the release of the YR, the BESII program concluded only to give birth to BESIII; the $B$-factories and CLEO-c flourished; quarkonium production and polarization measurements at HERA and the Tevatron matured; and heavy-ion collisions at RHIC have opened a window on the deconfinement regime. All these experiments leave legacies of quality, precision, and unsolved mysteries for quarkonium physics, and therefore beg for continuing investigations. The plethora of newly-found quarkonium-like states unleashed a flood of theoretical investigations into new forms of matter such as quark-gluon hybrids, mesonic molecules, and tetraquarks. Measurements of the spectroscopy, decays, production, and in-medium behavior of c\bar{c}, b\bar{b}, and b\bar{c} bound states have been shown to validate some theoretical approaches to QCD and highlight lack of quantitative success for others. The intriguing details of quarkonium suppression in heavy-ion collisions that have emerged from RHIC have elevated the importance of separating hot- and cold-nuclear-matter effects in quark-gluon plasma studies. This review systematically addresses all these matters and concludes by prioritizing directions for ongoing and future efforts.Comment: 182 pages, 112 figures. Editors: N. Brambilla, S. Eidelman, B. K. Heltsley, R. Vogt. Section Coordinators: G. T. Bodwin, E. Eichten, A. D. Frawley, A. B. Meyer, R. E. Mitchell, V. Papadimitriou, P. Petreczky, A. A. Petrov, P. Robbe, A. Vair

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

New challenges for BRCA testing:a view from the diagnostic laboratory

Increased demand for BRCA testing is placing pressures on diagnostic laboratories to raise their mutation screening capacity and handle the challenges associated with classifying BRCA sequence variants for clinical significance, for example interpretation of pathogenic mutations or variants of unknown significance, accurate determination of large genomic rearrangements and detection of somatic mutations in DNA extracted from formalin-fixed, paraffin-embedded tumour samples. Many diagnostic laboratories are adopting next-generation sequencing (NGS) technology to increase their screening capacity and reduce processing time and unit costs. However, migration to NGS introduces complexities arising from choice of components of the BRCA testing workflow, such as NGS platform, enrichment method and bioinformatics analysis process. An efficient, cost-effective accurate mutation detection strategy and a standardised, systematic approach to the reporting of BRCA test results is imperative for diagnostic laboratories. This review covers the challenges of BRCA testing from the perspective of a diagnostics laboratory