Transcription factor defects causing platelet disorders.

Recent years have seen increasing recognition of a subgroup of inherited platelet function disorders which are due to defects in transcription factors that are required to regulate megakaryopoiesis and platelet production. Thus, germline mutations in the genes encoding the haematopoietic transcription factors RUNX1, GATA-1, FLI1, GFI1b and ETV6 have been associated with both quantitative and qualitative platelet abnormalities, and variable bleeding symptoms in the affected patients. Some of the transcription factor defects are also associated with an increased predisposition to haematologic malignancies (RUNX1, ETV6), abnormal erythropoiesis (GATA-1, GFI1b, ETV6) and immune dysfunction (FLI1). The persistence of MYH10 expression in platelets is a surrogate marker for FLI1 and RUNX1 defects. Characterisation of the transcription factor defects that give rise to platelet function disorders, and of the genes that are differentially regulated as a result, are yielding insights into the roles of these genes in platelet formation and function

Self‑management of overactive bladder at home using transcutaneous tibial nerve stimulation: a qualitative study of women’s experiences

Abstract Background Transcutaneous tibial nerve stimulation (TTNS) has been used to treat overactive bladder (OAB), however patient experiences and views of this treatment are lacking. The aim of this study was to explore women’s experiences of OAB and TTNS treatment and the perceived factors influencing participation and adherence. Methods Semi-structured, individual interviews conducted as part of a mixed-methods, randomised, feasibility trial of self-managed versus HCP-led TTNS. Interviews were audio recorded and transcribed verbatim. Reflexive thematic analysis was undertaken using Booth et al. (Neurourol Urodynam. 2017;37:528–41) approach. Results 16 women were interviewed, 8 self-managing TTNS at home and 8 receiving TTNS in twice-weekly hospital clinic appointments. Women self-managing OAB considered TTNS easy to administer, flexible and favourably ‘convenient’, especially when the participant was bound by work and other life commitments. In contrast to OAB symptoms ‘dominating life’, self-managing bladder treatment was empowering and fitted around home life demands. Flexibility and control engendered by self-management, facilitated women’s willingness to participate in TTNS. Women attending a hospital clinic for TTNS enjoyed the social aspects but found the routine appointments constrained their lives. Motivation to continue TTNS in the longer term was dependent on perception of benefit. Conclusions This study provides novel insights into women’s experiences of self-managing their OAB using TTNS compared to HCP-led management in the clinical setting. It highlights positive experiences self-managing TTNS at home and a willingness to continue in the longer term, facilitated by ease of use and convenience. Trial Registration 1/11/2018: ClinicalTrials.gov Identifier: NCT03727711

Diversity and impact of rare variants in genes encoding the platelet G protein-coupled receptors

Platelet responses to activating agonists are influenced by common population variants within or near G protein-coupled receptor (GPCR) genes that affect receptor activity. However, the impact of rare GPCR gene variants is unknown. We describe the rare single nucleotide variants (SNVs) in the coding and splice regions of 18 GPCR genes in 7,595 exomes from the 1,000-genomes and Exome Sequencing Project databases and in 31 cases with inherited platelet function disorders (IPFDs). In the population databases, the GPCR gene target regions contained 740 SNVs (318 synonymous, 410 missense, 7 stop gain and 6 splice region) of which 70 % had global minor allele frequency (MAF) < 0.05 %. Functional annotation using six computational algorithms, experimental evidence and structural data identified 156/740 (21 %) SNVs as potentially damaging to GPCR function, most commonly in regions encoding the transmembrane and C-terminal intracellular receptor domains. In 31 index cases with IPFDs (Gi-pathway defect n=15; secretion defect n=11; thromboxane pathway defect n=3 and complex defect n=2) there were 256 SNVs in the target regions of 15 stimulatory platelet GPCRs (34 unique; 12 with MAF< 1 % and 22 with MAF≥ 1 %). These included rare variants predicting R122H, P258T and V207A substitutions in the P2Y12 receptor that were annotated as potentially damaging, but only partially explained the platelet function defects in each case. Our data highlight that potentially damaging variants in platelet GPCR genes have low individual frequencies, but are collectively abundant in the population. Potentially damaging variants are also present in pedigrees with IPFDs and may contribute to complex laboratory phenotypes

Sorting Nexin 24 is required for α-granule biogenesis and cargo delivery in megakaryocytes

Germline defects affecting the DNA-binding domain of the transcription factor FLI1 are associated with a bleeding disorder that is characterised by the presence of large, fused α-granules in platelets. We investigated whether the genes showing abnormal expression in FLI1-deficient platelets could be involved in platelet α-granule biogenesis by undertaking transcriptome analysis of control platelets and platelets harbouring a DNA-binding variant of FLI1. Our analysis identified 2276 transcripts that were differentially expressed in FLI1- deficient platelets. Functional annotation clustering of the coding transcripts revealed significant enrichment for gene annotations relating to protein transport, and identified Sorting nexin 24 (SNX24) as a candidate for further investigation. Using an iPSC-derived megakaryocyte model, SNX24 expression was found to be increased during the early stages of megakaryocyte differentiation and downregulated during proplatelet formation, indicating tight regulatory control during megakaryopoiesis. CRISPR-Cas9 mediated knockout (KO) of SNX24 led to decreased expression of immature megakaryocyte markers, CD41 and CD61, and increased expression of the mature megakaryocyte marker CD42b (p=0.0001), without affecting megakaryocyte polyploidisation, or proplatelet formation. Electron microscopic analysis revealed an increase in empty membrane-bound organelles in SNX24 KO megakaryocytes, a reduction in α-granules and an absence of immature and mature multivesicular bodies, consistent with a defect in the intermediate stage of α-granule maturation. Co-localisation studies showed that SNX24 associates with each compartment of α-granule maturation. Reduced expression of CD62P and VWF was observed in SNX24 KO megakaryocytes. We conclude that SNX24 is required for α-granule biogenesis and intracellular trafficking of α-granule cargo within megakaryocytes

Coupled oscillators as models of phantom and scalar field cosmologies

We study a toy model for phantom cosmology recently introduced in the literature and consisting of two oscillators, one of which carries negative kinetic energy. The results are compared with the exact phase space picture obtained for similar dynamical systems describing, respectively, a massive canonical scalar field conformally coupled to the spacetime curvature, and a conformally coupled massive phantom. Finally, the dynamical system describing exactly a minimally coupled phantom is studied and compared with the toy model.Comment: 18 pages, LaTeX, to appear in Physical Review

Generating Sustainable Value from Open Data in a Sharing Society

Part 1: Creating ValueInternational audienceOur societies are in the midst of a paradigm shift that transforms hierarchal markets into an open and networked economy based on digital technology and information. In that context, open data is widely presumed to have a positive effect on social, environmental and economic value; however the evidence to that effect has remained scarce. Subsequently, we address the question how the use of open data can stimulate the generation of sustainable value. We argue that open data sharing and reuse can empower new ways of generating value in the sharing society. Moreover, we propose a model that describes how different mechanisms that take part within an open system generate sustainable value. These mechanisms are enabled by a number of contextual factors that provide individuals with the motivation, opportunity and ability to generate sustainable value

The Metric of the Cosmos from Luminosity and Age Data

This paper presents the algorithm for determining the Lemaitre-Tolman (LT) model that best fits given datasets for maximum stellar ages, and SNIa luminosities, both as functions of redshift. It then applies it to current cosmological data. Special attention must be given to the handling of the origin, and the region of the maximum diameter distances. As with a previous combination of datasets (galaxy number counts and luminosity distances versus redshift), there are relationships that must hold at the region of the maximum diameter distance, which are unlikely to be obeyed exactly by real data. We show how to make corrections that enable a self-consistent solution to be found. We address the questions of the best way to approximate discrete data with smooth functions, and how to estimate the uncertainties of the output - the 3 free functions that determine a specific LT metric. While current data does not permit any confidence in our results, we show that the method works well, and reasonable LT models do fit with or without a cosmological constant.Comment: 25 pages, 8 figures; matches published versio

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie