A standard, single dose of inhaled terbutaline attenuates hyperpnoea-induced bronchoconstriction and mast cell activation in athletes

Release of broncho-active mediators from mast cells during exercise hyperpnoea is a key factor in the pathophysiology of exercise-induced bronchoconstriction (EIB). Our aim was to investigate the effect of a standard, single dose of an inhaled β2-adrenoceptor agonist on mast cell activation in response to dry air hyperpnoea in athletes with EIB. Twenty-seven athletes with EIB completed a randomised, double blind, placebo-controlled, crossover study. Terbutaline (0.5 mg) or placebo was inhaled15 min prior to 8 min of eucapnic voluntary hyperpnoea (EVH) with dry air. Pre- and post-bronchial challenge, urine samples were analysed by enzyme immunoassay for 11β-prostaglandin(PG)F2α. The maximum fall in forced expiratory volume in 1 sec(FEV1) of 14 (12-20)% (median and interquartile range) following placebo was attenuated to 7 (5-9)% with the administration of terbutaline (P<0.001). EVH caused a significant increase in 11β-PGF2α from (27-57) ng·mmol creatinine-1 at baseline to (43-72) ng·mmol creatinine-1 at its peak post-EVH following placebo (P=0.002). The rise in 11β-PGF2α was inhibited with administration of terbutaline: 39 (28-44) ng·mmol creatinine-1 at baseline vs. 40 (33-58) ng·mmol creatinine-1 at its peak post-EVH (P=0.118). These data provide novel in vivo evidence of mast cell stabilisation following inhalation of a standard dose of terbutaline prior to bronchial provocation with EVH in athletes with EIB

Evolution in the Volumetric Type Ia Supernova Rate from the Supernova Legacy Survey

We present a measurement of the volumetric Type Ia supernova (SN Ia) rate (SNR_Ia) as a function of redshift for the first four years of data from the Canada-France-Hawaii Telescope (CFHT) Supernova Legacy Survey (SNLS). This analysis includes 286 spectroscopically confirmed and more than 400 additional photometrically identified SNe Ia within the redshift range 0.1<z<1.1. The volumetric SNR_Ia evolution is consistent with a rise to z~1.0 that follows a power-law of the form (1+z)^alpha, with alpha=2.11+/-0.28. This evolutionary trend in the SNLS rates is slightly shallower than that of the cosmic star-formation history over the same redshift range. We combine the SNLS rate measurements with those from other surveys that complement the SNLS redshift range, and fit various simple SN Ia delay-time distribution (DTD) models to the combined data. A simple power-law model for the DTD (i.e., proportional to t^-beta) yields values from beta=0.98+/-0.05 to beta=1.15+/-0.08 depending on the parameterization of the cosmic star formation history. A two-component model, where SNR_Ia is dependent on stellar mass (Mstellar) and star formation rate (SFR) as SNR_Ia(z)=AxMstellar(z) + BxSFR(z), yields the coefficients A=1.9+/-0.1 SNe/yr/M_solar and B=3.3+/-0.2 SNe/yr/(M_solar/yr). More general two-component models also fit the data well, but single Gaussian or exponential DTDs provide significantly poorer matches. Finally, we split the SNLS sample into two populations by the light curve width (stretch), and show that the general behavior in the rates of faster-declining SNe Ia (0.8<s<1.0) is similar, within our measurement errors, to that of the slower objects (1.0<s<1.3) out to z~0.8.Comment: Accepted in A

Supernova rates from the Southern inTermediate Redshift ESO Supernova Search (STRESS)

To measure the supernova (SN) rates at intermediate redshift we performed the Southern inTermediate Redshift ESO Supernova Search (STRESS). Unlike most of the current high redshift SN searches, this survey was specifically designed to estimate the rate for both type Ia and core collapse (CC) SNe. We counted the SNe discovered in a selected galaxy sample measuring SN rate per unit blue band luminosity. Our analysis is based on a sample of ~43000 galaxies and on 25 spectroscopically confirmed SNe plus 64 selected SN candidates. Our approach is aimed at obtaining a direct comparison of the high redshift and local rates and at investigating the dependence of the rates on specific galaxy properties, most notably their colour. The type Ia SN rate, at mean redshift z=0.3, amounts to 0.22^{+0.10+0.16}_{-0.08 -0.14} h_{70}^2 SNu, while the CC SN rate, at z=0.21, is 0.82^{+0.31 +0.30}_{-0.24 -0.26} h_{70}^2 SNu. The quoted errors are the statistical and systematic uncertainties. With respect to local value, the CC SN rate at z=0.2 is higher by a factor of ~2 already at redshift, whereas the type Ia SN rate remains almost constant. This implies that a significant fraction of SN Ia progenitors has a lifetime longer than 2-3 Gyr. We also measured the SN rates in the red and blue galaxies and found that the SN Ia rate seems to be constant in galaxies of different colour, whereas the CC SN rate seems to peak in blue galaxies, as in the local Universe. SN rates per unit volume were found to be consistent with other measurements showing a steeper evolution with redshift for CC SNe with respect to SNe Ia. Finally we have exploited the link between star formation (SF) and SN rates to predict the evolutionary behaviour of the SN rates and compare it with the path indicated by observations.Comment: Accepted for publication in A&A; 25 pages (including on line material), 13 figure

Spectroscopic Observations and Analysis of the Unusual Type Ia SN 1999ac

We present optical spectra of the peculiar Type Ia supernova (SN Ia) 1999ac. The data extend from -15 to +42 days with respect to B-band maximum and reveal an event that is unusual in several respects. Prior to B-band maximum, the spectra resemble those of SN 1999aa, a slowly declining event, but possess stronger SiII and CaII signatures (more characteristic of a spectroscopically normal SN). Spectra after B-band maximum appear more normal. The expansion velocities inferred from the Iron lines appear to be lower than average; whereas, the expansion velocity inferred from Calcium H and K are higher than average. The expansion velocities inferred from SiII are among the slowest ever observed, though SN 1999ac is not particularly dim. The analysis of the parameters v_10, R(SiII), dv(SiII)/dt, and d_m15 further underlines the unique characteristics of SN 1999ac. We find convincing evidence of CII 6580 in the day -15 spectrum with ejection velocity v > 16,000 km/s, but this signature disappears by day -9. This rapid evolution at early times highlights the importance of extremely early-time spectroscopy.Comment: 40 pages, 24 figures, accepted for publication in The Astronomical Journa

Novel endosomolytic compounds enable highly potent delivery of antisense oligonucleotides

The therapeutic and research potentials of oligonucleotides (ONs) have been hampered in part by their inability to effectively escape endosomal compartments to reach their cytosolic and nuclear targets. Splice-switching ONs (SSOs) can be used with endosomolytic small molecule compounds to increase functional delivery. So far, development of these compounds has been hindered by a lack of high-resolution methods that can correlate SSO trafficking with SSO activity. Here we present in-depth characterization of two novel endosomolytic compounds by using a combination of microscopic and functional assays with high spatiotemporal resolution. This system allows the visualization of SSO trafficking, evaluation of endosomal membrane rupture, and quantitates SSO functional activity on a protein level in the presence of endosomolytic compounds. We confirm that the leakage of SSO into the cytosol occurs in parallel with the physical engorgement of LAMP1-positive late endosomes and lysosomes. We conclude that the new compounds interfere with SSO trafficking to the LAMP1-positive endosomal compartments while inducing endosomal membrane rupture and concurrent ON escape into the cytosol. The efficacy of these compounds advocates their use as novel, potent, and quick-acting transfection reagents for antisense ONs

Near-IR search for lensed supernovae behind galaxy clusters: I. Observations and transient detection efficiency

Massive galaxy clusters at intermediate redshift can magnify the flux of distant background sources by several magnitudes and we exploit this effect to search for lensed distant supernovae that may otherwise be too faint to be detected. A supernova search was conducted at near infrared wavelengths using the ISAAC instrument at the VLT. The galaxy clusters Abell 1689, Abell 1835 and AC114 were observed at multiple epochs of 2 hours of exposure time, separated by a month. Image-subtraction techniques were used to search for transient objects with light curve properties consistent with supernovae, both in our new and archival ISAAC/VLT data. The limiting magnitude of the individual epochs was estimated by adding artificial stars to the subtracted images. Most of the epochs reach 90% detection efficiency at SZ(J) ~= 23.8-24.0 mag (Vega). Two transient objects, both in archival images of Abell 1689 and AC114, were detected. The transient in AC114 coincides - within the position uncertainty - with an X-ray source and is likely to be a variable AGN at the cluster redshift. The transient in Abell 1689 was found at SZ=23.24 mag, ~0.5 arcsec away from a galaxy with photometric redshift z=0.6 +/-0.15. The light curves and the colors of the transient are consistent with a reddened Type IIP supernova at redshift z=0.59 +/- 0.05. The lensing model of Abell 1689 predicts ~1.4 mag of magnification at the position of the transient, making it the most magnified supernova ever found and only the second supernova found behind a galaxy cluster. Our pilot survey has demonstrated the feasibility to find distant gravitationally magnified supernovae behind massive galaxy clusters. One likely supernova was found behind Abell 1689, in accordance with the expectations for this survey, as shown in an accompanying analysis paper.Comment: Language-edited version, 9 pages, 6 figures, accepted by A&

Near-IR Search for Lensed Supernovae Behind Galaxy Clusters - II. First Detection and Future Prospects

Powerful gravitational telescopes in the form of massive galaxy clusters can be used to enhance the light collecting power over a limited field of view by about an order of magnitude in flux. This effect is exploited here to increase the depth of a survey for lensed supernovae at near-IR wavelengths. A pilot SN search program conducted with the ISAAC camera at VLT is presented. Lensed galaxies behind the massive clusters A1689, A1835 and AC114 were observed for a total of 20 hours split into 2, 3 and 4 epochs respectively, separated by approximately one month to a limiting magnitude J<24 (Vega). Image subtractions including another 20 hours worth of archival ISAAC/VLT data were used to search for transients with lightcurve properties consistent with redshifted supernovae, both in the new and reference data. The feasibility of finding lensed supernovae in our survey was investigated using synthetic lightcurves of supernovae and several models of the volumetric Type Ia and core-collapse supernova rates as a function of redshift. We also estimate the number of supernova discoveries expected from the inferred star formation rate in the observed galaxies. The methods consistently predict a Poisson mean value for the expected number of SNe in the survey between N_SN=0.8 and 1.6 for all supernova types, evenly distributed between core collapse and Type Ia SN. One transient object was found behind A1689, 0.5" from a galaxy with photometric redshift z_gal=0.6 +- 0.15. The lightcurve and colors of the transient are consistent with being a reddened Type IIP SN at z_SN=0.59. The lensing model predicts 1.4 magnitudes of magnification at the location of the transient, without which this object would not have been detected in the near-IR ground based search described in this paper (unlensed magnitude J~25). (abridged)Comment: Accepted by AA, matches journal versio

Spectroscopic observations and analysis of the peculiar SN 1999aa

We present an extensive new time series of spectroscopic data of the peculiar SN 1999aa in NGC 2595. Our data set includes 25 optical spectra between -11 and +58 days with respect to B-band maximum light, providing an unusually complete time history. The early spectra resemble those of an SN 1991T-like object but with a relatively strong Ca H and K absorption feature. The first clear sign of Si II λ6355, characteristic of Type Ia supernovae, is found at day -7, and its velocity remains constant up to at least the first month after B-band maximum light. The transition to normal-looking spectra is found to occur earlier than in SN 1991T, suggesting SN 1999aa as a possible link between SN 1991T-like and Branch-normal supernovae. Comparing the observations with synthetic spectra, doubly ionized Fe, Si, and Ni are identified at early epochs. These are characteristic of SN 1991T-like objects. Furthermore, in the day -11 spectrum, evidence is found for an absorption feature that could be identified as high velocity C II λ6580 or Hα. At the same epoch C II λ4648.8 at photospheric velocity is probably responsible for the absorption feature at 4500 Å. High-velocity Ca is found around maximum light together with Si II and Fe II confined in a narrow velocity window. Implied constraints on supernovae progenitor systems and explosion hydrodynamic models are briefly discussed

A highly magnified supernova at z=1.703 behind the massive galaxy cluster Abell 1689

Our ability to study the most remote supernova explosions, crucial for the understanding of the evolution of the high-redshift universe and its expansion rate, is limited by the light collection capabilities of telescopes. However, nature offers unique opportunities to look beyond the range within reach of our unaided instruments thanks to the light-focusing power of massive galaxy clusters. Here we report on the discovery of one of the most distant supernovae ever found, at redshift, z=1.703. Due to a lensing magnification factor of 4.3\pm0.3, we are able to measure a lightcurve of the supernova, as well as spectroscopic features of the host galaxy with a precision comparable to what will otherwise only be possible with future generation telescopes.Comment: 19 pages, 4 figures, 1 table, accepted to ApJ

Spectroscopic observations and analysis of the unusual Type Ia SN 1999ac

We present optical spectra of the peculiar Type la supernova (SN Ia) 1999ac. The data extend from -15 to +42 days with respect to B-band maximum and reveal an event that is unusual in several respects. Prior to B-band maximum, the spectra resemble those of SN 1999aa, a slowly declining event, but possess stronger Si II and Ca II signatures (more characteristic of a spectroscopically normal SN). Spectra after the B-band maximum appear more normal. The expansion velocities inferred from the iron lines appear to be lower than average, whereas the expansion velocity inferred from calcium H and K are higher than average. The expansion velocities inferred from Si II are among the slowest ever observed, although SN 1999ac is not particularly dim. The analysis of the parameters v 10(Si II), R(Si II), v̇, and Δm 15 further underlines the unique characteristics of SN 1999ac. We find convincing evidence of C II λ6580 in the day - 15 spectrum with ejection velocity v \u3e 16,000 km s -1, but this signature disappears by day - 9. This rapid evolution at early times highlights the importance of extremely early-time spectroscopy. © 2005. The American Astronomical Society. All rights reserved