Impact of DNA ligase IV on the fidelity of end joining in human cells

A DNA ligase IV (LIG4)‐null human pre‐B cell line and human cell lines with hypomorphic mutations in LIG4 are significantly impaired in the frequency and fidelity of end joining using an in vivo plasmid assay. Analysis of the null line demonstrates the existence of an error‐prone DNA ligase IV‐independent rejoining mechanism in mammalian cells. Analysis of lines with hypomorphic mutations demonstrates that residual DNA ligase IV activity, which is sufficient to promote efficient end joining, nevertheless can result in decreased fidelity of rejoining. Thus, DNA ligase IV is an important factor influencing the fidelity of end joining in vivo. The LIG4‐defective cell lines also showed impaired end joining in an in vitro assay using cell‐free extracts. Elevated degradation of the terminal nucleotide was observed in a LIG4‐defective line, and addition of the DNA ligase IV–XRCC4 complex restored end protection. End protection by DNA ligase IV was not dependent upon ligation. Finally, using purified proteins, we demonstrate that DNA ligase IV–XRCC4 is able to protect DNA ends from degradation by T7 exonuclease. Thus, the ability of DNA ligase IV–XRCC4 to protect DNA ends may contribute to the ability of DNA ligase IV to promote accurate rejoining in vivo

Classifying High-cadence Microlensing Light Curves I; Defining Features

Microlensing is a powerful tool for discovering cold exoplanets, and the The Roman Space Telescope microlensing survey will discover over 1000 such planets. Rapid, automated classification of Roman's microlensing events can be used to prioritize follow-up observations of the most interesting events. Machine learning is now often used for classification problems in astronomy, but the success of such algorithms can rely on the definition of appropriate features that capture essential elements of the observations that can map to parameters of interest. In this paper, we introduce tools that we have developed to capture features in simulated Roman light curves of different types of microlensing events, and evaluate their effectiveness in classifying microlensing light curves. These features are quantified as parameters that can be used to decide the likelihood that a given light curve is due to a specific type of microlensing event. This method leaves us with a list of parameters that describe features like the smoothness of the peak, symmetry, the number of peaks, and width and height of small deviations from the main peak. This will allow us to quickly analyze a set of microlensing light curves and later use the resulting parameters as input to machine learning algorithms to classify the events.Comment: 29 Pages, 30 Figures, 3 Tables, Accepted to the Astronomical Journa

The White Dwarf Distance to the Globular Cluster 47 Tucanae and its Age

We present a new determination of the distance (and age) of the Galactic globular cluster 47 Tucanae (NGC 104) based on the fit of its white dwarf (WD) cooling sequence with the empirical fiducial sequence of local WD with known trigonometric parallax, following the method described in Renzini et al. (1996). Both the cluster and the local WDs were imaged with HST+WFPC2 using the same instrument setup. We obtained an apparent distance modulus of $(m-M)_V=13.27\pm0.14$ consistent with previous ground-based determinations and shorter than that found using HIPPARCOS subdwarfs. Coupling our distance determination with a new measure of the apparent magnitude of the main sequence turnoff, based on our HST data, we derive an age of $13\pm2.5$ Gyr.Comment: Accepted for publication on the Astrophysical Journa

Comparing families of dynamic causal models

Mathematical models of scientific data can be formally compared using Bayesian model evidence. Previous applications in the biological sciences have mainly focussed on model selection in which one first selects the model with the highest evidence and then makes inferences based on the parameters of that model. This “best model” approach is very useful but can become brittle if there are a large number of models to compare, and if different subjects use different models. To overcome this shortcoming we propose the combination of two further approaches: (i) family level inference and (ii) Bayesian model averaging within families. Family level inference removes uncertainty about aspects of model structure other than the characteristic of interest. For example: What are the inputs to the system? Is processing serial or parallel? Is it linear or nonlinear? Is it mediated by a single, crucial connection? We apply Bayesian model averaging within families to provide inferences about parameters that are independent of further assumptions about model structure. We illustrate the methods using Dynamic Causal Models of brain imaging data

First Astronomical Application of a Cryogenic TES Spectrophotometer

We report on the first astronomical observations with a photon counting pixel detector that provides arrival time- (delta t = 100ns) and energy- (delta E_gamma < 0.15eV) resolved measurements from the near IR through the near UV. Our test observations were performed by coupling this Transition Edge Sensor (TES) device to a 0.6m telescope; we have obtained the first simultaneous optical near-IR phase-resolved spectra of the Crab pulsar. A varying infrared turnover gives evidence of self-absorption in the pulsar plasma. The potential of such detectors in imaging arrays from a space platform are briefly described.Comment: 4 pages, 5 figure

Phase light curves for extrasolar Jupiters and Saturns

We predict how a remote observer would see the brightness variations of giant planets similar to Jupiter and Saturn as they orbit their central stars. We model the geometry of Jupiter, Saturn and Saturn's rings for varying orbital and viewing parameters. Scattering properties for the planets and rings at wavelenghts 0.6-0.7 microns follow Pioneer and Voyager observations, namely, planets are forward scattering and rings are backward scattering. Images of the planet with or without rings are simulated and used to calculate the disk-averaged luminosity varying along the orbit, that is, a light curve is generated. We find that the different scattering properties of Jupiter and Saturn (without rings) make a substantial difference in the shape of their light curves. Saturn-size rings increase the apparent luminosity of the planet by a factor of 2-3 for a wide range of geometries. Rings produce asymmetric light curves that are distinct from the light curve of the planet without rings. If radial velocity data are available for the planet, the effect of the ring on the light curve can be distinguished from effects due to orbital eccentricity. Non-ringed planets on eccentric orbits produce light curves with maxima shifted relative to the position of the maximum planet's phase. Given radial velocity data, the amount of the shift restricts the planet's unknown orbital inclination and therefore its mass. Combination of radial velocity data and a light curve for a non-ringed planet on an eccentric orbit can also be used to constrain the surface scattering properties of the planet. To summarize our results for the detectability of exoplanets in reflected light, we present a chart of light curve amplitudes of non-ringed planets for different eccentricities, inclinations, and the viewing azimuthal angles of the observer.Comment: 40 pages, 13 figures, submitted to Ap.

Photometry of K2 Campaign 9 bulge data

In its Campaign 9, K2 observed dense regions toward the Galactic bulge in order to constrain the microlensing parallaxes and probe for free-floating planets. Photometric reduction of the \emph{K2} bulge data poses a significant challenge due to a combination of the very high stellar density, large pixels of the Kepler camera, and the pointing drift of the spacecraft. Here we present a new method to extract K2 photometry in dense stellar regions. We extended the Causal Pixel Model developed for less-crowded fields, first by using the pixel response function together with accurate astrometric grids, second by combining signals from a few pixels, and third by simultaneously fitting for an astrophysical model. We tested the method on two microlensing events and a long-period eclipsing binary. The extracted K2 photometry is an order of magnitude more precise than the photometry from other method

Polyclonal and monoclonal antibodies for induction therapy in kidney transplant recipients

Background Prolonging kidney transplant survival is an important clinical priority. Induction immunosuppression with antibody therapy is recommended at transplantation and non‐depleting interleukin‐2 receptor monoclonal antibodies (IL2Ra) are considered first line. It is suggested that recipients at high risk of rejection should receive lymphocyte‐depleting antibodies but the relative benefits and harms of the available agents are uncertain. Objectives We aimed to: evaluate the relative and absolute effects of different antibody preparations (except IL2Ra) when used as induction therapy in kidney transplant recipients; determine how the benefits and adverse events vary for each antibody preparation; determine how the benefits and harms vary for different formulations of antibody preparation; and determine whether the benefits and harms vary in specific subgroups of recipients (e.g. children and sensitised recipients). Search methods We searched the Cochrane Kidney and Transplant's Specialised Register to 29 August 2016 through contact with the Information Specialist using search terms relevant to this review. Selection criteria Randomised controlled trials (RCTs) comparing monoclonal or polyclonal antibodies with placebo, no treatment, or other antibody therapy in adults and children who had received a kidney transplant. Data collection and analysis Two authors independently extracted data and assessed risk of bias. Dichotomous outcomes are reported as relative risk (RR) and continuous outcomes as mean difference (MD) together with their 95% confidence intervals (CI). Main results We included 99 studies (269 records; 8956 participants; 33 with contemporary agents). Methodology was incompletely reported in most studies leading to lower confidence in the treatment estimates. Antithymocyte globulin (ATG) prevented acute graft rejection (17 studies: RR 0.63, 95% CI 0.51 to 0.78). The benefits of ATG on graft rejection were similar when used with (12 studies: RR 0.61, 0.49 to 0.76) or without (5 studies: RR 0.65, 0.43 to 0.98) calcineurin inhibitor (CNI) treatment. ATG (with CNI therapy) had uncertain effects on death (3 to 6 months, 3 studies: RR 0.41, 0.13 to 1.22; 1 to 2 years, 5 studies: RR 0.75, 0.27 to 2.06; 5 years, 2 studies: RR 0.94, 0.11 to 7.81) and graft loss (3 to 6 months, 4 studies: RR 0.60, 0.34 to 1.05; 1 to 2 years, 3 studies: RR 0.65, 0.36 to 1.19). The effect of ATG on death‐censored graft loss was uncertain at 1 to 2 years and 5 years. In non‐CNI studies, ATG had uncertain effects on death but reduced death‐censored graft loss (6 studies: RR 0.55, 0.38 to 0.78). When CNI and older non‐CNI studies were combined, a benefit was seen with ATG at 1 to 2 years for both all‐cause graft loss (7 studies: RR 0.71, 0.53 to 0.95) and death‐censored graft loss (8 studies: RR 0.55, 0.39 to 0.77) but not sustained longer term. ATG increased cytomegalovirus (CMV) infection (6 studies: RR 1.55, 1.24 to 1.95), leucopenia (4 studies: RR 3.86, 2.79 to 5.34) and thrombocytopenia (4 studies: RR 2.41, 1.61 to 3.61) but had uncertain effects on delayed graft function, malignancy, post‐transplant lymphoproliferative disorder (PTLD), and new onset diabetes after transplantation (NODAT). Alemtuzumab was compared to ATG in six studies (446 patients) with early steroid withdrawal (ESW) or steroid minimisation. Alemtuzumab plus steroid minimisation reduced acute rejection compared to ATG at one year (4 studies: RR 0.57, 0.35 to 0.93). In the two studies with ESW only in the alemtuzumab arm, the effect of alemtuzumab on acute rejection at 1 year was uncertain compared to ATG (RR 1.27, 0.50 to 3.19). Alemtuzumab had uncertain effects on death (1 year, 2 studies: RR 0.39, 0.06 to 2.42; 2 to 3 years, 3 studies: RR 0.67, 95% CI 0.15 to 2.95), graft loss (1 year, 2 studies: RR 0.39, 0.13 to 1.30; 2 to 3 years, 3 studies: RR 0.98, 95% CI 0.47 to 2.06), and death‐censored graft loss (1 year, 2 studies: RR 0.38, 0.08 to 1.81; 2 to 3 years, 3 studies: RR 2.45, 95% CI 0.67 to 8.97) compared to ATG. Creatinine clearance was lower with alemtuzumab plus ESW at 6 months (2 studies: MD ‐13.35 mL/min, ‐23.91 to ‐2.80) and 2 years (2 studies: MD ‐12.86 mL/min, ‐23.73 to ‐2.00) compared to ATG plus triple maintenance. Across all 6 studies, the effect of alemtuzumab versus ATG was uncertain on all‐cause infection, CMV infection, BK virus infection, malignancy, and PTLD. The effect of alemtuzumab with steroid minimisation on NODAT was uncertain, compared to ATG with steroid maintenance. Alemtuzumab plus ESW compared with triple maintenance without induction therapy had uncertain effects on death and all‐cause graft loss at 1 year, acute rejection at 6 months and 1 year. CMV infection was increased (2 studies: RR 2.28, 1.18 to 4.40). Treatment effects were uncertain for NODAT, thrombocytopenia, and malignancy or PTLD. Rituximab had uncertain effects on death, graft loss, acute rejection and all other adverse outcomes compared to placebo. Authors' conclusions ATG reduces acute rejection but has uncertain effects on death, graft survival, malignancy and NODAT, and increases CMV infection, thrombocytopenia and leucopenia. Given a 45% acute rejection risk without ATG induction, seven patients would need treatment to prevent one having rejection, while incurring an additional patient experiencing CMV disease for every 12 treated. Excluding non‐CNI studies, the risk of rejection was 37% without induction with six patients needing treatment to prevent one having rejection. In the context of steroid minimisation, alemtuzumab prevents acute rejection at 1 year compared to ATG. Eleven patients would require treatment with alemtuzumab to prevent 1 having rejection, assuming a 21% rejection risk with ATG. Triple maintenance without induction therapy compared to alemtuzumab combined with ESW had similar rates of acute rejection but adverse effects including NODAT were poorly documented. Alemtuzumab plus steroid withdrawal would cause one additional patient experiencing CMV disease for every six patients treated compared to no induction and triple maintenance, in the absence of any clinical benefit. Overall, ATG and alemtuzumab decrease acute rejection at a cost of increased CMV disease while patient‐centred outcomes (reduced death or lower toxicity) do not appear to be improved

ExELS: an exoplanet legacy science proposal for the ESA Euclid mission. II. Hot exoplanets and sub-stellar systems

The Exoplanet Euclid Legacy Survey (ExELS) proposes to determine the frequency of cold exoplanets down to Earth mass from host separations of ~1 AU out to the free-floating regime by detecting microlensing events in Galactic Bulge. We show that ExELS can also detect large numbers of hot, transiting exoplanets in the same population. The combined microlensing+transit survey would allow the first self-consistent estimate of the relative frequencies of hot and cold sub-stellar companions, reducing biases in comparing "near-field" radial velocity and transiting exoplanets with "far-field" microlensing exoplanets. The age of the Bulge and its spread in metallicity further allows ExELS to better constrain both the variation of companion frequency with metallicity and statistically explore the strength of star-planet tides. We conservatively estimate that ExELS will detect ~4100 sub-stellar objects, with sensitivity typically reaching down to Neptune-mass planets. Of these, ~600 will be detectable in both Euclid's VIS (optical) channel and NISP H-band imager, with ~90% of detections being hot Jupiters. Likely scenarios predict a range of 2900-7000 for VIS and 400-1600 for H-band. Twice as many can be expected in VIS if the cadence can be increased to match the 20-minute H-band cadence. The separation of planets from brown dwarfs via Doppler boosting or ellipsoidal variability will be possible in a handful of cases. Radial velocity confirmation should be possible in some cases, using 30-metre-class telescopes. We expect secondary eclipses, and reflection and emission from planets to be detectable in up to ~100 systems in both VIS and NISP-H. Transits of ~500 planetary-radius companions will be characterised with two-colour photometry and ~40 with four-colour photometry (VIS,YJH), and the albedo of (and emission from) a large sample of hot Jupiters in the H-band can be explored statistically.Comment: 18 pages, 16 figures, accepted MNRA