Diverse functions for the semaphorin receptor PlexinD1 in development and disease

AbstractPlexins are a family of single-pass transmembrane proteins that serve as cell surface receptors for Semaphorins during the embryonic development of animals. Semaphorin–Plexin signaling is critical for many cellular aspects of organogenesis, including cell migration, proliferation and survival. Until recently, little was known about the function of PlexinD1, the sole member of the vertebrate-specific PlexinD (PlxnD1) subfamily. Here we review novel findings about PlxnD1's roles in the development of the cardiovascular, nervous and immune systems and salivary gland branching morphogenesis and discuss new insights concerning the molecular mechanisms of PlxnD1 activity

Veliparib in Combination with Carboplatin and Etoposide in Patients with Treatment-Naive Extensive-Stage Small Cell Lung Cancer:A Phase 2 Randomized Study

Purpose: This study investigated the efficacy and safety of oral PARP inhibitor veliparib, plus carboplatin and etoposide in patients with treatment-naive, extensive-stage small cell lung cancer (ED-SCLC). Patients and Methods: Patients were randomized 1:1:1 to veliparib [240 mg twice daily (BID) for 14 days] plus chemotherapy followed by veliparib maintenance (400 mg BID; veliparib throughout), veliparib plus chemotherapy followed by placebo (veliparib combination only), or placebo plus chemotherapy followed by placebo (control). Patients received 4-6 cycles of combination therapy, then maintenance until unacceptable toxicity/progression. The primary endpoint was progression-free survival (PFS) with veliparib throughout versus control. Results: Overall (N = 181), PFS was improved with veliparib throughout versus control [hazard ratio (HR), 0.67; 80% confidence interval (CI), 0.50-0.88; P = 0.059]; median PFS was 5.8 and 5.6 months, respectively. There was a trend toward improved PFS with veliparib throughout versus control in SLFN11-positive patients (HR, 0.6; 80% CI, 0.36-0.97). Median overall survival (OS) was 10.1 versus 12.4 months in the veliparib throughout and control arms, respectively (HR, 1.43; 80% CI, 1.09-1.88). Grade 3/4 adverse events were experienced by 82%, 88%, and 68% of patients in the veliparib throughout, veliparib combination-only and control arms, most commonly hematologic. Conclusions: Veliparib plus platinum chemotherapy followed by veliparib maintenance demonstrated improved PFS as first-line treatment for ED-SCLC with an acceptable safety profile, but there was no corresponding benefit in OS. Further investigation is warranted to define the role of biomarkers in this setting

Virtual Machine Support for Many-Core Architectures: Decoupling Abstract from Concrete Concurrency Models

The upcoming many-core architectures require software developers to exploit concurrency to utilize available computational power. Today's high-level language virtual machines (VMs), which are a cornerstone of software development, do not provide sufficient abstraction for concurrency concepts. We analyze concrete and abstract concurrency models and identify the challenges they impose for VMs. To provide sufficient concurrency support in VMs, we propose to integrate concurrency operations into VM instruction sets. Since there will always be VMs optimized for special purposes, our goal is to develop a methodology to design instruction sets with concurrency support. Therefore, we also propose a list of trade-offs that have to be investigated to advise the design of such instruction sets. As a first experiment, we implemented one instruction set extension for shared memory and one for non-shared memory concurrency. From our experimental results, we derived a list of requirements for a full-grown experimental environment for further research

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

The effects of centralising electoral management board design

The public administration of elections frequently fails. Variation in the performance of electoral management boards around the world has been demonstrated, illustrated by delays in the count, inaccurate or incomplete voter registers, or severe queues at polling stations. Centralising the management of the electoral process has often been proposed as a solution. There has been little theorisation and no empirical investigations into the effects that centralising an already decentralised system would have, however. This article addresses this lacuna by conceptualising centralisation through the literature on bureaucratic control and discretion. It then empirically investigates the effects through a case study of centralisation in two UK referendums. Semi-structured interviews were used with those who devised the policy instrument and those who were subject to it. The introduction of central directions had some of the desired effects such as producing more consistent services and eliminating errors. It also had side effects, however, such as reducing economic efficiency in some areas and overlooking local knowledge. Furthermore, the reforms caused a decline of staff morale, job satisfaction and souring of relations among stakeholder organisations. The process of making organisational change therefore warrants closer attention by policy makers and future scholarship on electoral integrity

Emission of volatile halogenated compounds, speciation and localization of bromine and iodine in the brown algal genome model Ectocarpus siliculosus

This study explores key features of bromine and iodine metabolism in the filamentous brown alga and genomics model Ectocarpus siliculosus. Both elements are accumulated in Ectocarpus, albeit at much lower concentration factors (2-3 orders of magnitude for iodine, and < 1 order of magnitude for bromine) than e.g. in the kelp Laminaria digitata. Iodide competitively reduces the accumulation of bromide. Both iodide and bromide are accumulated in the cell wall (apoplast) of Ectocarpus, with minor amounts of bromine also detectable in the cytosol. Ectocarpus emits a range of volatile halogenated compounds, the most prominent of which by far is methyl iodide. Interestingly, biosynthesis of this compound cannot be accounted for by vanadium haloperoxidase since the latter have not been found to catalyze direct halogenation of an unactivated methyl group or hydrocarbon so a methyl halide transferase-type production mechanism is proposed

A Systematic Review of Fitness Apps and Their Potential Clinical and Sports Utility for Objective and Remote Assessment of Cardiorespiratory Fitness

Key Points The validity and reliability of existing and/or underdevelopment fitness apps should be further investigated. Physiological signals should be incorporated into fitness apps, such as heart rate measures using a smartphone camera, during or after exercise testing. There is a need to develop interoperable fitness apps (e.g., different languages, apps integrated into both app markets, data that is device-independent). Fitness apps should incorporate evidence-based cutpoints of CRF, allowing interpretation of fitness testing resultsWe are grateful to Ms Carmen Sainz-Quinn for assistance with the English language.Background Cardiorespiratory fitness (CRF) assessment provides key information regarding general health status that has high clinical utility. In addition, in the sports setting, CRF testing is needed to establish a baseline level, prescribe an individualized training program and monitor improvement in athletic performance. As such, the assessment of CRF has both clinical and sports utility. Technological advancements have led to increased digitization within healthcare and athletics. Nevertheless, further investigation is needed to enhance the validity and reliability of existing fitness apps for CRF assessment in both contexts. Objectives The present review aimed to (1) systematically review the scientific literature, examining the validity and reliability of apps designed for CRF assessment; and (2) systematically review and qualitatively score available fitness apps in the two main app markets. Lastly, this systematic review outlines evidence-based practical recommendations for developing future apps that measure CRF. Data Sources The following sources were searched for relevant studies: PubMed, Web of Science®, ScopusTM, and SPORTDiscus, and data was also found within app markets (Google Play and the App Store). Study Eligibility Criteria Eligible scientific studies examined the validity and/or reliability of apps for assessing CRF through a field-based fitness test. Criteria for the app markets involved apps that estimated CRF. Study Appraisal and Synthesis Methods The scientific literature search included four major electronic databases and the timeframe was set between 01 January 2000 and 31 October 2018. A total of 2796 articles were identified using a set of fitness-related terms, of which five articles were finally selected and included in this review. The app market search was undertaken by introducing keywords into the search engine of each app market without specified search categories. A total of 691 apps were identified using a set of fitness-related terms, of which 88 apps were finally included in the quantitative and qualitative synthesis. Results Five studies focused on the scientific validity of fitness tests with apps, while only two of these focused on reliability. Four studies used a sub-maximal fitness test via apps. Out of the scientific apps reviewed, the SA-6MWTapp showed the best validity against a criterion measure (r = 0.88), whilst the InterWalk app showed the highest test–retest reliability (ICC range 0.85–0.86). Limitations Levels of evidence based on scientific validity/reliability of apps and on commercial apps could not be robustly determined due to the limited number of studies identified in the literature and the low-to-moderate quality of commercial apps. Conclusions The results from this scientific review showed that few apps have been empirically tested, and among those that have, not all were valid or reliable. In addition, commercial apps were of low-to-moderate quality, suggesting that their potential for assessing CRF has yet to be realized. Lastly, this manuscript has identified evidence-based practical recommendations that apps might potentially offer to objectively and remotely assess CRF as a complementary tool to traditional methods in the clinical and sports settings

Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (, , ) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Juxtaposing BTE and ATE – on the role of the European insurance industry in funding civil litigation

One of the ways in which legal services are financed, and indeed shaped, is through private insurance arrangement. Two contrasting types of legal expenses insurance contracts (LEI) seem to dominate in Europe: before the event (BTE) and after the event (ATE) legal expenses insurance. Notwithstanding institutional differences between different legal systems, BTE and ATE insurance arrangements may be instrumental if government policy is geared towards strengthening a market-oriented system of financing access to justice for individuals and business. At the same time, emphasizing the role of a private industry as a keeper of the gates to justice raises issues of accountability and transparency, not readily reconcilable with demands of competition. Moreover, multiple actors (clients, lawyers, courts, insurers) are involved, causing behavioural dynamics which are not easily predicted or influenced. Against this background, this paper looks into BTE and ATE arrangements by analysing the particularities of BTE and ATE arrangements currently available in some European jurisdictions and by painting a picture of their respective markets and legal contexts. This allows for some reflection on the performance of BTE and ATE providers as both financiers and keepers. Two issues emerge from the analysis that are worthy of some further reflection. Firstly, there is the problematic long-term sustainability of some ATE products. Secondly, the challenges faced by policymakers that would like to nudge consumers into voluntarily taking out BTE LEI