Heart enhancers with deeply conserved regulatory activity are established early in zebrafish development.

During the phylotypic period, embryos from different genera show similar gene expression patterns, implying common regulatory mechanisms. Here we set out to identify enhancers involved in the initial events of cardiogenesis, which occurs during the phylotypic period. We isolate early cardiac progenitor cells from zebrafish embryos and characterize 3838 open chromatin regions specific to this cell population. Of these regions, 162 overlap with conserved non-coding elements (CNEs) that also map to open chromatin regions in human. Most of the zebrafish conserved open chromatin elements tested drive gene expression in the developing heart. Despite modest sequence identity, human orthologous open chromatin regions recapitulate the spatial temporal expression patterns of the zebrafish sequence, potentially providing a basis for phylotypic gene expression patterns. Genome-wide, we discover 5598 zebrafish-human conserved open chromatin regions, suggesting that a diverse repertoire of ancient enhancers is established prior to organogenesis and the phylotypic period

The identification and validation of neural tube defects in the General Practice Research Database

Background: Our objectives were to develop an algorithm for the identification of pregnancies in the General Practice Research Database (GPRD) that could be used to study birth outcomes and pregnancy and to determine if the GPRD could be used to identify cases of neural tube defects (NTDs). Methods: We constructed a pregnancy identification algorithm to identify pregnancies in 15 to 45 year old women between January 1, 1987 and September 14, 2004. The algorithm was evaluated for accuracy through a series of alternate analyses and reviews of electronic records. We then created electronic case definitions of anencephaly, encephalocele, meningocele and spina bifida and used them to identify potential NTD cases. We validated cases by querying general practitioners (GPs) via questionnaire. Results: We analyzed 98,922,326 records from 980,474 individuals and identified 255,400 women who had a total of 374,878 pregnancies. There were 271,613 full-term live births, 2,106 pre- or post-term births, 1,191 multi-fetus deliveries, 55,614 spontaneous abortions or miscarriages, 43,264 elective terminations, 7 stillbirths in combination with a live birth, and 1,083 stillbirths or fetal deaths. A marker of pregnancy care was identifiable for 330,153 pregnancies, eighty-four percent of which had data available at least 180 days prior to the first marker of pregnancy care. From the same population of 980,474 individuals, 217 NTD cases were identified. We attempted to validate all 217 NTD cases and 165 GP questionnaires were returned. We validated a NTD diagnosis for 117 cases, giving our electronic case definitions a positive predictive value of 0.71. The positive predictive value varied by NTD type: 0.81 for anencephaly, 0.83 for cephalocele, 0.64 for meningocele, and 0.47 for spina bifida. Conclusions: We were successful in identifying a large number of pregnancies in the GPRD. Our use of a hierarchical approach to identify pregnancy outcomes builds upon the methods suggested in previous work, while implementing additional steps to minimize potential misclassification of pregnancy outcomes. Our NTD identification algorithm was useful in identifying three of the four types of NTDs studied. Additional information is necessary to accurately identify cases of spina bifida

protocol for a hospital-based registry study

Introduction Obstructive sleep apnoea (OSA), the most common type of sleep- disordered breathing, is associated with significant immediate and long-term morbidity, including fragmented sleep and impaired daytime functioning, as well as more severe consequences, such as hypertension, impaired cognitive function and reduced quality of life. Perioperatively, OSA occurs frequently as a consequence of pre-existing vulnerability, surgery and drug effects. The impact of OSA on postoperative respiratory complications (PRCs) needs to be better characterised. As OSA is associated with significant comorbidities, such as obesity, pulmonary hypertension, myocardial infarction and stroke, it is unclear whether OSA or its comorbidities are the mechanism of PRCs. This project aims to (1) develop a novel prediction score identifying surgical patients at high risk of OSA, (2) evaluate the association of OSA risk on PRCs and (3) evaluate if pharmacological agents used during surgery modify this association. Methods Retrospective cohort study using hospital-based electronic patient data and perioperative data on medications administered and vital signs. We will use data from Partners Healthcare clinical databases, Boston, Massachusetts. First, a prediction model for OSA will be developed using OSA diagnostic codes and polysomnography procedural codes as the reference standard, and will be validated by medical record review. Results of the prediction model will be used to classify patients in the database as high, medium or low risk of OSA, and we will investigate the effect of OSA on risk of PRCs. Finally, we will test whether the effect of OSA on PRCs is modified by the use of intraoperative pharmacological agents known to increase upper airway instability, including neuromuscular blockade, neostigmine, opioids, anaesthetics and sedatives. Ethics and dissemination The Partners Human Research Committee approved this study (protocol number: 2014P000218). Study results will be made available in the form of manuscripts for publication and presentations at national and international meetings

Hepatic decompensation in patients with HIV/Hepatitis B Virus (HBV)/Hepatitis C Virus (HCV) triple infection versus HIV/HCV coinfection and the effect of anti-HBV nucleos(t)ide therapy

Onur Başer (MEF Author)The incidence rate of hepatic decompensation was higher in patients with human immunodeficiency virus (HIV)/hepatitis B virus (HBV)/hepatitis C virus (HCV) triple infection than in those with HIV/HCV coinfection (24.1 vs 10.8 events per 1000 person-years; hazard ratio [HR], 1.89; 95% confidence interval [CI], 1.12–3.18). Compared with HIV/HCVinfected patients, the rate of decompensation was increased among HIV/HBV/HCV-infected patients receiving no anti-HBV therapy (HR, 2.48; 95% CI, 1.37–4.49) but not among those who did receive such therapy (HR, 1.09; 95% CI, .40–2.97)WOS:000343411900019Scopus - Affiliation ID: 60105072PMID: 24944235Science Citation Index ExpandedQ1Editorial MaterialUluslararası işbirliği ile yapılan - EVETEkim2014YÖK - 2014-1

Reducing biting rates of Aedes aegypti with metofluthrin: investigations in time and space

Background: Indoor residual spraying is key to dengue control in Cairns and other parts of northern Queensland, Australia, where Aedes aegypti is prevalent, but the strategy faces challenges with regards to slow application time and, therefore, community coverage. A faster potential improvement might be the use of polyethylene netting impregnated with the volatile pyrethroid metofluthrin (SumiOne™). This formulation was assessed in rooms in three houses in Cairns, Australia. One emanator was placed in each room and cages of 10 female Aedes aegypti were exposed at distances of 1 and 3 m. Knockdown and landings on a human hand were counted before metofluthrin exposure and at 10, 30, 60, 90 and 120 min during exposure. In addition, two trials continued over 48 h of exposure to assess the long-term sublethal effects of metofluthrin on caged mosquitoes. Results: Percentage landing rates fell to 0-2.5% in the first 10 min of exposure. Knockdown was most evident between 10 and 30 min (54% at 1 m and 33% at 3 m). Distance from the emanator strongly affected the results: mosquitoes at 3 m exhibited less knockdown and more landings than those at 1 m. As room volume increased, knockdown decreased and the number of landing increased. There is a cumulative mortality and landing inhibition and, for mosquitoes exposed to metofluthrin for > 48 h, mortality was 100% at 1 m and 90% at 3 m. Of those still alive, a small number continued to land and bite. After being removed from metofluthrin-treated rooms, exposed insect cages were found to reducing landing rates for up to 2 h. Conclusions: Despite only moderate levels of knockdown during the initial hours of exposure, metofluthrin emanators were effective in reducing mosquito landing rates, especially within 1 m, even when exposed on an open veranda. The evaluation methods and results described in this paper will help inform the optimal conditions of deployment of metofluthrin emanators. These devices have the potential to reduce contact between humans and urban disease vectors faster than indoor residual spraying so supplement our current arsenal of dengue control tools

Lasered Graphene Microheaters Modified with Phase-Change Composites: New Approach to Smart Patch Drug Delivery

The combination of paraffin wax and O,O′-bis(2-aminopropyl) polypropylene glycol–block–polyethylene glycol–block–polypropylene glycol was used as a phase-change material (PCM) for the controlled delivery of curcumin. The PCM was combined with a graphene-based heater derived from the laser scribing of polyimide film. This assembly provides a new approach to a smart patch through which release can be electronically controlled, allowing repetitive dosing. Rather than relying on passive diffusion, delivery is induced and terminated through the controlled heating of the PCM with transfer only occurring when the PCM transitions from solid to liquid. The material properties of the device and release characteristics of the strategy under repetitive dosing are critically assessed. The delivery yield of curcumin was found to be 3.5 µg (4.5 µg/cm(2)) per 3 min thermal cycle

Melancholia and conviviality in modern literary Scots : Sanghas, Sengas and Shairs

This paper considers the visions of Scottish identity projected in twenty-first century, post-devolution Scots literature, and seeks to read them against Paul Gilroy’s Postcolonial Melancholia (2005) which examines the protean identities of post-imperial Britain. Gilroy looks particularly at social and artistic manifestations of racial and cultural inequality, although conceding that there is also room for a ‘postcolonial conviviality’ that celebrates diversity. His critique of this ‘Britain’ is, however, selectively constructed, making only passing reference to the constituent nations of the United Kingdom, and no space is devoted to an evaluation of post-colonial Wales, Scotland or Northern Ireland. As yet, no comparable analysis is forthcoming for these ‘home nations’, so this paper attempts to outline the ways in which Scottish—and particularly Scots—literature may provide relevant comparable cultural commentary. Focus is given here to literature written in Scots because the choice to write in Scots is strongly politically motivated and speaks immediately to the question of cultural inequality and loss. Specific attention is paid to Matthew Fitt’s But n Ben A-Go-Go (2000), Suhayl Saadi’s Psychoraag (2004), and Anne Donovan’s Buddha Da (2003), which various engage with questions of personal and national identity as their main characters take part in their personal journeys

Hazards Induced by Breach of Liquid Rocket Fuel Tanks: Conditions and Risks of Cryogenic Liquid Hydrogen-Oxygen Mixture Explosions

We analyze the data of purposeful rupture experiments with LOx and LH2 tanks, the Hydrogen-Oxygen Vertical Impact (HOVI) tests that were performed to clarify the ignition mechanisms, the explosive power of cryogenic H2/Ox mixtures under different conditions, and to elucidate the puzzling source of the initial formation of flames near the intertank section during the Challenger disaster. We carry out a physics-based analysis of general explosions scenarios for cryogenic gaseous H2/Ox mixtures and determine their realizability conditions, using the well-established simplified models from the detonation and deflagration theory. We study the features of aerosol H2/Ox mixture combustion and show, in particular, that aerosols intensify the deflagration flames and can induce detonation for any ignition mechanism. We propose a cavitation-induced mechanism of self-ignition of cryogenic H2/Ox mixtures that may be realized when gaseous H2 and Ox flows are mixed with a liquid Ox turbulent stream, as occurred in all HOVI tests. We present an overview of the HOVI tests to make conclusion on the risk of strong explosions in possible liquid rocket incidents and provide a semi-quantitative interpretation of the HOVI data based on aerosol combustion. We uncover the most dangerous situations and discuss the foreseeable risks which can arise in space missions and lead to tragic outcomes. Our analysis relates to only unconfined mixtures that are likely to arise as a result of liquid propellant space vehicle incidents

Cation complexation by mucoid Pseudomonas aeruginosa extracellular polysaccharide

Mucoid Pseudomonas aeruginosa is a prevalent cystic fibrosis (CF) lung colonizer, producing an extracellular matrix (ECM) composed predominantly of the extracellular polysaccharide (EPS) alginate. The ECM limits antimicrobial penetration and, consequently, CF sufferers are prone to chronic mucoid P. aeruginosa lung infections. Interactions between cations with elevated concentrations in the CF lung and the anionic EPS, enhance the structural rigidity of the biofilm and exacerbates virulence. In this work, two large mucoid P. aeruginosa EPS models, based on β-D-mannuronate (M) and β-D-mannuronate-α-L-guluronate systems (M-G), and encompassing thermodynamically stable acetylation configurations–a structural motif unique to mucoid P. aeruginosa–were created. Using highly accurate first principles calculations, stable coordination environments adopted by the cations have been identified and thermodynamic stability quantified. These models show the weak cross-linking capability of Na+ and Mg2+ ions relative to Ca2+ ions and indicate a preference for cation binding within M-G blocks due to the smaller torsional rearrangements needed to reveal stable binding sites. The geometry of the chelation site influences the stability of the resulting complexes more than electrostatic interactions, and the results show nuanced chemical insight into previous experimental observations

Bringing Virtualization to the x86 Architecture with the Original VMware Workstation

This article describes the historical context, technical challenges, and main implementation techniques used by VMware Workstation to bring virtualization to the x86 architecture in 1999. Although virtual machine monitors (VMMs) had been around for decades, they were traditionally designed as part of monolithic, single-vendor architectures with explicit support for virtualization. In contrast, the x86 architecture lacked virtualization support, and the industry around it had disaggregated into an ecosystem, with different ven- dors controlling the computers, CPUs, peripherals, operating systems, and applications, none of them asking for virtualization. We chose to build our solution independently of these vendors. As a result, VMware Workstation had to deal with new challenges associated with (i) the lack of virtual- ization support in the x86 architecture, (ii) the daunting complexity of the architecture itself, (iii) the need to support a broad combination of peripherals, and (iv) the need to offer a simple user experience within existing environments. These new challenges led us to a novel combination of well-known virtualization techniques, techniques from other domains, and new techniques. VMware Workstation combined a hosted architecture with a VMM. The hosted architecture enabled a simple user experience and offered broad hardware compatibility. Rather than exposing I/O diversity to the virtual machines, VMware Workstation also relied on software emulation of I/O devices. The VMM combined a trap-and-emulate direct execution engine with a system-level dynamic binary translator to ef- ficiently virtualize the x86 architecture and support most commodity operating systems. By relying on x86 hardware segmentation as a protection mechanism, the binary translator could execute translated code at near hardware speeds. The binary translator also relied on partial evaluation and adaptive retranslation to reduce the overall overheads of virtualization. Written with the benefit of hindsight, this article shares the key lessons we learned from building the original system and from its later evolution