PinAPL-Py: A comprehensive web-application for the analysis of CRISPR/Cas9 screens.

Large-scale genetic screens using CRISPR/Cas9 technology have emerged as a major tool for functional genomics. With its increased popularity, experimental biologists frequently acquire large sequencing datasets for which they often do not have an easy analysis option. While a few bioinformatic tools have been developed for this purpose, their utility is still hindered either due to limited functionality or the requirement of bioinformatic expertise. To make sequencing data analysis of CRISPR/Cas9 screens more accessible to a wide range of scientists, we developed a Platform-independent Analysis of Pooled Screens using Python (PinAPL-Py), which is operated as an intuitive web-service. PinAPL-Py implements state-of-the-art tools and statistical models, assembled in a comprehensive workflow covering sequence quality control, automated sgRNA sequence extraction, alignment, sgRNA enrichment/depletion analysis and gene ranking. The workflow is set up to use a variety of popular sgRNA libraries as well as custom libraries that can be easily uploaded. Various analysis options are offered, suitable to analyze a large variety of CRISPR/Cas9 screening experiments. Analysis output includes ranked lists of sgRNAs and genes, and publication-ready plots. PinAPL-Py helps to advance genome-wide screening efforts by combining comprehensive functionality with user-friendly implementation. PinAPL-Py is freely accessible at http://pinapl-py.ucsd.edu with instructions and test datasets

Disk Diffusion Propagation Model for the Outburst of XTE J1118+480

We present a linear diffusion model for the evolution of the double-peaked outburst in the transient source XTEJ1118+480. The model treats the two outbursts as episodic mass deposition at the outer radius of the disk followed by evolution of disk structure according to a diffusion process. We demonstrate that light curves with fast-rise, exponential decay profile are a general consequence of the diffusion process. Deconvolution of the light curve proves to be feasible and gives an input function specifying mass deposition at the outer disk edge as well as the total mass of the disk, both as functions of time. The derived evolution of total disk mass can be correlated with the observed evolution of the ~0.1 Hz QPO in the source reported in Wood et al. (2000).Comment: 26 pages, 6 figures, accepted for publication in Ap

The Effects of Midline Cerebellar rTMS on Human Pharyngeal Cortical Activity in the Intact Swallowing Motor System

We sought to compare the effects of 10 Hz cerebellar vermis (vs. unilateral hemispheric and sham) repetitive transcranial magnetic stimulation (rTMS) on cortical neuroelectrical activity and thereafter 10 Hz cerebellar vermis (vs. sham) rTMS on swallowing behaviour. Healthy participants (n = 25) were randomly allocated to receive vermis, unilateral hemisphere or sham 10 Hz cerebellar rTMS. Recordings were made using pharyngeal electromyography and manometry catheters, obtaining motor-evoked potentials (MEPs) and pressure recordings. The amplitudes of MEPs elicited using single-pulse TMS delivered to the pharyngeal areas of the motor cortex bilaterally were measured pre- and post-cerebellar stimulation. As in previous studies, abductor policis brevis (APB) MEPs were measured to assess post-rTMS modulation specificity. Swallowing was assessed using a swallowing accuracy task. Measurements were made at baseline and 15-min intervals for an hour post-intervention. Measurements involved TMS being used to elicit 10 MEPs bilaterally over the pharyngeal areas of the motor cortex, over the APB cortical representation adjacent to the pharyngeal area with the lowest resting motor threshold and 5 MEPs bilaterally over pharyngeal areas of the cerebellar hemispheres. Swallowing accuracy was assessed by giving participants 10 attempts to swallow and hit a digital target. Cerebellar vermis rTMS caused significant suppression of cortical pharyngeal MEP amplitudes compared with unilateral rTMS and sham (P = 0.0005, 0.002). APB and cerebellar MEP amplitudes were unaffected as were pharyngeal and APB MEP latencies. Following cerebellar vermis rTMS there was a significant reduction in swallowing accuracy compared with sham (P = 0.001). Our findings demonstrate cerebellar vermis rTMS exerts a suppressive effect on pharyngeal motor cortical activity and swallowing behaviour

ORFEUS II and IUE Spectroscopy of EX Hydrae

Using ORFEUS-SPAS II FUV spectra, IUE UV spectra, and archival EUVE deep survey photometry, we present a detailed picture of the behavior of the magnetic cataclysmic variable EX Hydrae. Like HUT spectra of this source, the FUV and UV spectra reveal broad emission lines of He II, C II-IV, N III and V, O VI, Si III-IV, and Al III superposed on a continuum which is blue in the UV and nearly flat in the FUV. Like ORFEUS spectra of AM Her, the O VI doublet is resolved into broad and narrow emission components. Consistent with its behavior in the optical, the FUV and UV continuum flux densities, the FUV and UV broad emission line fluxes, and the radial velocity of the O VI broad emission component all vary on the spin phase of the white dwarf, with the maximum of the FUV and UV continuum and broad emission line flux light curves coincident with maximum blueshift of the broad O VI emission component. On the binary phase, the broad dip in the EUV light curve is accompanied by strong eclipses of the UV emission lines and by variations in both the flux and radial velocity of the O VI narrow emission component. The available data are consistent with the accretion funnel being the source of the FUV and UV continuum and the O VI broad emission component, and the white dwarf being the source of the O VI narrow emission component.Comment: 21 pages, 10 Postscript figures; LaTeX format, uses aaspp4.sty; table2.tex included separately because it must be printed sideways - see instructions in the file; accepted on 1999 Feb 20 for publication in The Astrophysical Journa

Design of hidden thermodynamic driving for non-equilibrium systems via mismatch elimination during DNA strand displacement

Recent years have seen great advances in the development of synthetic self-assembling molecular systems. Designing out-of-equilibrium architectures, however, requires a more subtle control over the thermodynamics and kinetics of reactions. We propose a mechanism for enhancing the thermodynamic drive of DNA strand-displacement reactions whilst barely perturbing forward reaction rates: the introduction of mismatches within the initial duplex. Through a combination of experiment and simulation, we demonstrate that displacement rates are strongly sensitive to mismatch location and can be tuned by rational design. By placing mismatches away from duplex ends, the thermodynamic drive for a strand-displacement reaction can be varied without significantly affecting the forward reaction rate. This hidden thermodynamic driving motif is ideal for the engineering of non-equilibrium systems that rely on catalytic control and must be robust to leak reactions

The incidence of first stroke in pregnant and non-pregnant women of childbearing age: a population-based cohort study from England

Background: Pregnant women may have an increased risk of stroke compared to non-pregnant women of similar age, but the magnitude and the timing of such risk are unclear. We examined the risk of first stroke event in women of childbearing age and compared the risk during pregnancy and in the early postpartum period to background risk outside these periods. Methods and Results: We conducted an open cohort study of 2,046,048 women aged 15-49 years between 1st April 1997 and 31th March 2014 using linked primary (Clinical Practice Research Datalink) and secondary (Hospital Episode Statistics) care records in England. Risk of first stroke was assessed by calculating the incidence rate of stroke in antepartum, peripartum (2 days before until 1 day after delivery), early (first six weeks) and late (second six weeks) postpartum periods, compared with non-pregnant time using a Poisson regression model with adjustment for maternal age, socioeconomic group and calendar time. A total of 2,511 women had a first stroke. The incidence rate of stroke was 25.0 per 100,000 person-years (95% confidence interval 24.0-26.0) in non-pregnant time. The rate was lower antepartum (10.7/100,000 person-years, 7.6-15.1), but 9-fold higher peripartum (161.1/100,000 person-years, 80.6-322.1) and 3-fold higher early postpartum (47.1/100,000 person-years, 31.3-70.9). Rates of ischaemic and haemorrhagic stroke both increased peripartum and early postpartum. Conclusions: Although the absolute risk of first stroke is low in women of childbearing age, health care professionals should be aware of a considerable increase in relative risk during the peripartum and early postpartum periods

Attitudes and perceived social norms towards drug use among gay and bisexual men in Australia

Background: Gay and bisexual men (GBM) report distinctive patterns and contexts of drug use, yet little has been published about their attitudes towards drug use. Objectives: We developed measures of attitudes and perceived social norms towards drug use, and examined covariates of more accepting attitudes and norms among GBM in Australia. Methods: We analysed baseline data from the [removed for blinded review] study. This is an online prospective observational study of drug use among Australian GBM. We used principal components factor analysis to generate two attitudinal scales assessing “drug use for social and sexual enhancement” and “perceptions of drug risk”. A third perceived social norms scale examined “acceptability of drug use among gay friends”. Results: Among 2,112 participants, 61% reported illicit drug use in the preceding 6 months. Stronger endorsement of drug use for social and sexual engagement and lower perceptions of drug risk were found among men who were more socially engaged with other gay men and reported regular drug use and drug use for sex. In multivariate analyses, all three scales were associated with recent drug use (any use in the previous six months), but only the drug use for social and sexual enhancement scale was associated with regular (at least monthly) use. Conclusions: Drug use and sex are difficult to disentangle for some GBM, and health services and policies could benefit from a better understanding of attitudinal and normative factors associated with drug use in gay social networks, while recognising the role of pleasure in substance use

The influence of nova nucleosynthesis on the chemical evolution of the Galaxy

We adopt up-to-date yields of 7Li, 13C, 15N from classical novae and use a well tested model for the chemical evolution of the Milky Way in order to predict the temporal evolution of these elemental species in the solar neighborhood. In spite of major uncertainties due to our lack of knowledge of metallicity effects on the final products of explosive nucleosynthesis in nova outbursts, we find a satisfactory agreement between theoretical predictions and observations for 7Li and 13C. On the contrary, 15N turns out to be overproduced by about an order of magnitude.Comment: 8 pages, latex, 3 figures. To appear in "The Chemical Evolution of the Milky Way: Stars versus Clusters", eds. F. Giovannelli and F. Matteucci (Kluwer: Dordrecht

The Virtual International Stroke Trials Archive

BACKGROUND AND PURPOSE: Stroke has global importance and it causes an increasing amount of human suffering and economic burden, but its management is far from optimal. The unsuccessful outcome of several research programs highlights the need for reliable data on which to plan future clinical trials. The Virtual International Stroke Trials Archive aims to aid the planning of clinical trials by collating and providing access to a rich resource of patient data to perform exploratory analyses. METHODS: Data were contributed by the principal investigators of numerous trials from the past 16 years. These data have been centrally collated and are available for anonymized analysis and hypothesis testing. RESULTS: Currently, the Virtual International Stroke Trials Archive contains 21 trials. There are data on \u3e15,000 patients with both ischemic and hemorrhagic stroke. Ages range between 18 and 103 years, with a mean age of 69+/-12 years. Outcome measures include the Barthel Index, Scandinavian Stroke Scale, National Institutes of Health Stroke Scale, Orgogozo Scale, and modified Rankin Scale. Medical history and onset-to-treatment time are readily available, and computed tomography lesion data are available for selected trials. CONCLUSIONS: This resource has the potential to influence clinical trial design and implementation through data analyses that inform planning

Therapeutic potential of transdermal glyceryl trinitrate in the management of acute stroke

The nitric oxide donor, glyceryl trinitrate (GTN), is a candidate treatment for the management of acute stroke with haemodynamic and potential reperfusion and neuroprotective effects. When administered as a transdermal patch during the acute and subacute phases after stroke, GTN was safe, lowered blood pressure, maintained cerebral blood flow, and did not induce cerebral steal or alter functional outcome. However, when given within 6 h of stroke onset, GTN reduced death and dependency (odds ratio 0.52; 95% confidence interval 0.34–0.78), death, disability, cognitive impairment and mood disturbance, and improved quality of life (data from two trials, n = 312). In a pooled analysis of four studies (n = 186), GTN reduced between-visit systolic blood pressure variability over days 1–7 compared with no GTN (mean difference -2.09; 95% confidence interval -3.83 to -0.35; p = 0.019). The efficacy of GTN given in the ultra-acute/pre-hospital setting is currently being assessed and, if found to be beneficial, the implications for hyperacute stroke practice are significant. Here, we discuss the evidence to date, potential mechanisms of action and future possibilities, including unanswered questions, for the therapeutic potential of GTN in acute stroke