Constraints on short, hard gamma-ray burst beaming angles from gravitational wave observations

The first detection of a binary neutron star merger, GW170817, and an associated short gamma-ray burst confirmed that neutron star mergers are responsible for at least some of these bursts. The prompt gamma-ray emission from these events is thought to be highly relativistically beamed. We present a method for inferring limits on the extent of this beaming by comparing the number of short gamma-ray bursts (SGRBs) observed electromagnetically with the number of neutron star binary mergers detected in gravitational waves. We demonstrate that an observing run comparable to the expected Advanced LIGO (aLIGO) 2016–2017 run would be capable of placing limits on the beaming angle of approximately \theta \in (2\buildrel{\circ}\over{.} 88,14\buildrel{\circ}\over{.} 15), given one binary neutron star detection, under the assumption that all mergers produce a gamma-ray burst, and that SGRBs occur at an illustrative rate of ${{ \mathcal R }}_{\mathrm{grb}}=10\,{\mathrm{Gpc}}^{-3}\,{\mathrm{yr}}^{-1}$. We anticipate that after a year of observations with aLIGO at design sensitivity in 2020, these constraints will improve to \theta \in (8\buildrel{\circ}\over{.} 10,14\buildrel{\circ}\over{.} 95), under the same efficiency and SGRB rate assumptions

Genesis of ancestral haplotypes: RNA modifications and reverse transcription–mediated polymorphisms

Understanding the genesis of the block haplotype structure of the genome is a major challenge. With the completion of the sequencing of the Human Genome and the initiation of the HapMap project the concept that the chromosomes of the mammalian genome are a mosaic, or patchwork, of conserved extended block haplotype sequences is now accepted by the mainstream genomics research community. Ancestral Haplotypes (AHs) can be viewed as a recombined string of smaller Polymorphic Frozen Blocks (PFBs). How have such variant extended DNA sequence tracts emerged in evolution? Here the relevant literature on the problem is reviewed from various fields of molecular and cell biology particularly molecular immunology and comparative and functional genomics. Based on our synthesis we then advance a testable molecular and cellular model. A critical part of the analysis concerns the origin of the strand biased mutation signatures in the transcribed regions of the human and higher primate genome, A-to-G versus T-to-C (ratio ~1.5 fold) and C-to-T versus G-to-A (≥1.5 fold). A comparison and evaluation of the current state of the fields of immunoglobulin Somatic Hypermutation (SHM) and Transcription-Coupled DNA Repair focused on how mutations in newly synthesized RNA might be copied back to DNA thus accounting for some of the genome-wide strand biases (e.g., the A-to-G vs T-to-C component of the strand biased spectrum). We hypothesize that the genesis of PFBs and extended AHs occurs during mutagenic episodes in evolution (e.g., retroviral infections) and that many of the critical DNA sequence diversifying events occur first at the RNA level, e.g., recombination between RNA strings resulting in tandem and dispersed RNA duplications (retroduplications), RNA mutations via adenosine-to-inosine pre-mRNA editing events as well as error prone RNA synthesis. These are then copied back into DNA by a cellular reverse transcription process (also likely to be error-prone) that we have called "reverse transcription-mediated long DNA conversion." Finally we suggest that all these activities and others can be envisaged as being brought physically under the umbrella of special sites in the nucleus involved in transcription known as "transcription factories."

Structural investigation into the threading intercalation of a chiral dinuclear ruthenium(II) polypyridyl complex through a B-DNA oligonucleotide

Herein we report the separation of the three stereoisomers of the DNA light-switch compound [{Ru(bpy)2}2(tpphz)]4+ (tpphz = tetrapyrido[3,2-a:2',3'-c:3″,2″-h:2‴,3‴-j]phenazine) by column chromatography and the characterization of each stereoisomer by X-ray crystallography. The interaction of these compounds with a DNA octanucleotide d(GCATATCG).d(CGATATGC) has been studied using NMR techniques. Selective deuteration of the bipyridyl rings was needed to provide sufficient spectral resolution to characterize structures. NMR-derived structures for these complexes show a threading intercalation binding mode with slow and chirality-dependent rates. This represents the first solution structure of an intercalated bis-ruthenium ligand. Intriguingly, we find that the binding site selectivity is dependent on the nature of the stereoisomer employed, with Λ RuII centers showing a better intercalation fit

Stakeholder Perspectives of an Approach to Healthcare Leadership Development Through Use of a Multidimensional Leadership Development Conceptual Model

Leadership is often the driver used to transform healthcare services. Healthcare leadership development is often situated around conceptual frameworks or leadership development models. The aim of the study reported here was to evaluate multistakeholder perspectives on leadership development when applying a Multidimensional Leadership Development Conceptual Model to post-graduate healthcare leadership programmes at a university in England. This exploratory qualitative study of healthcare leadership development comprised face-to-face interviews. Six interviews were undertaken with academics from a post-graduate leadership programme team, a family carer and service-user of health care services, and current United Kingdom students and former United Kingdom and international students who had undertaken the leadership development programme. Transcripts were thematically analysed. Three themes emerged: Expectations of the contemporary healthcare leader; Experiences of the Multidimensional Leadership Development Conceptual Model on leadership development; and Improvements to the model. We conclude that framing post-graduate leadership programmes around a conceptual model can aid identification of the key components required for effective leadership development. Evidence-informed recommendations are provided which seek to optimise healthcare leadership development using a leadership development conceptual model which (1) represents the values and beliefs of all stakeholders involved; (2) is reviewed annually to critically explore the internal and external evidence base for leadership development; gain stakeholder consensus of expectations of the healthcare leader; and provide the reality check to ensure a ?fit for purpose? programme; and (3) is constructively aligned to leadership programme curricula with sufficient flexibility to tailor an effective teaching and learning platform for preparing the individual leader, noting unique circumstances and contexts

Ultrasonic Stimulation of Mouse Skin Reverses the Healing Delays in Diabetes and Aging by Activation of Rac1

Chronic skin-healing defects are one of the leading challenges to lifelong well-being, affecting 2–5% of populations. Chronic wound formation is linked to age and diabetes and frequently leads to major limb amputation. Here we identify a strategy to reverse fibroblast senescence and improve healing rates. In healthy skin, fibronectin activates Rac1 in fibroblasts, causing migration into the wound bed, and driving wound contraction. We discover that mechanical stimulation of the skin with ultrasound can overturn healing defects by activating a calcium/CamKinaseII/Tiam1/Rac1 pathway that substitutes for fibronectin-dependent signaling and promotes fibroblast migration. Treatment of diabetic and aged mice recruits fibroblasts to the wound bed and reduces healing times by 30%, restoring healing rates to those observed in young, healthy animals. Ultrasound treatment is equally effective in rescuing the healing defects of animals lacking fibronectin receptors, and can be blocked by pharmacological inhibition of the CamKinaseII pathway. Finally, we discover that the migration defects of fibroblasts from human venous leg ulcer patients can be reversed by ultrasound, demonstrating that the approach is applicable to human chronic samples. By demonstrating that this alternative Rac1 pathway can substitute for that normally operating in the skin, we identify future opportunities for management of chronic wounds

Genomic evolution and polymorphism: Segmental duplications and haplotypes at 108 regions on 21 chromosomes

We describe here extensive, previously unknown, genomic polymorphism in 120 regions, covering 19 autosomes and both sex chromosomes. Each contains duplication within multigene clusters. Of these, 108 are extremely polymorphic with multiple haplotypes.We used the genomic matching technique (GMT), previously used to characterise the major histocompatibility complex (MHC) and regulators of complement activation (RCA).This genome-wide extension of this technique enables the examination of many underlying cis, trans and epistatic interactions responsible for phenotypic differences especially in relation to individuality, evolution and disease susceptibility.The extent of the diversity could not have been predicted and suggests a new model of primate evolution based on conservation of polymorphism rather than de novo mutation

Clinically significant chronic liver disease in people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study

Background: Type 2 diabetes is an independent risk factor for chronic liver disease, however disease burden estimates and knowledge of prognostic indicators are lacking in community populations. Aims: To describe the prevalence and incidence of clinically significant chronic liver disease amongst community-based older people with Type 2 diabetes and to determine risk factors which might assist in discriminating patients with unknown prevalent or incident disease. Design: Prospective cohort study. Methods: Nine hundred and thirty-nine participants in the Edinburgh Type 2 Diabetes Study underwent investigation including liver ultrasound and non-invasive measures of non-alcoholic steatohepatitis (NASH), hepatic fibrosis and systemic inflammation. Over 6-years, cases of cirrhosis and hepatocellular carcinoma were collated from multiple sources. Results: Eight patients had known prevalent disease with 13 further unknown cases identified (prevalence 2.2%) and 15 incident cases (IR 2.9/1000 person-years). Higher levels of systemic inflammation, NASH and hepatic fibrosis markers were associated with both unknown prevalent and incident clinically significant chronic liver disease (all P < 0.001). Conclusions: Our study investigations increased the known prevalence of clinically significant chronic liver disease by over 150%, confirming the suspicion of a large burden of undiagnosed disease. The disease incidence rate was lower than anticipated but still much higher than the general population rate. The ability to identify patients both with and at risk of developing clinically significant chronic liver disease allows for early intervention and clinical monitoring strategies. Ongoing work, with longer follow-up, including analysis of rates of liver function decline, will be used to define optimal risk prediction tools

Analysis of travelling waves associated with the modelling of aerosolised skin grafts

A previous model developed by the authors investigates the growth patterns of keratinocyte cell colonies after they have been applied to a burn site using a spray technique. In this paper, we investigate a simplified one-dimensional version of the model. This model yields travelling wave solutions and we analyse the behaviour of the travelling waves. Approximations for the rate of healing and maximum values for both the active healing and the healed cell densities are obtained

Superscaling analysis of the Coulomb Sum Rule in quasielastic electron-nucleus scattering

The Coulomb sum rule for inclusive quasielastic electron scattering in $^{12}$C, $^{40}$Ca and $^{56}$Fe is analyzed based on scaling and superscaling properties. Results obtained in the relativistic impulse approximation with various descriptions of the final state interactions are shown. A comparison with experimental data measured at Bates and Saclay is provided. The theoretical description based on strong scalar and vector terms present in the relativistic mean field, which has been shown to reproduce the experimental asymmetric superscaling function, leads to results that are in fair agreement with Bates data while it sizeably overestimates Saclay data. We find that the Coulomb sum rule for a momentum transfer $q\geq 500$ $MeV/c$ saturates to a value close to 0.9, being very similar for the three nuclear systems considered. This is in accordance with Bates data, which indicates that these show no significative quenching in the longitudinal response.Comment: 22 pages, 6 figures. To be published in Phys. Lett.

Meson-exchange currents and quasielastic neutrino cross sections in the SuperScaling Approximation model

We evaluate the quasielastic double differential neutrino cross sections obtained in a phenomenological model based on the superscaling behavior of electron scattering data. We compare our results with the recent experimental data for neutrinos of MiniBooNE and estimate the contribution of the vector meson-exchange currents in the 2p-2h sector.Comment: 6 pages, 4 figure