We present a detailed stellar population analysis of 11 bright (H < 26.6) galaxies at z=9−11 (three spectroscopically confirmed) to constrain the chemical enrichment and growth of stellar mass of ...early galaxies. We use the flexible Bayesian spectral energy distribution (SED) fitting code Prospector with a range of star-formation histories (SFHs), a flexible dust attenuation law and a self-consistent modeling of emission lines. This approach allows us to assess how different priors affect our results, and how well we can break degeneracies between dust attenuation, stellar ages, metallicity and emission lines using data which probe only the rest-frame ultraviolet to optical wavelengths. We measure a median observed ultraviolet spectral slope β= −1.87+0.35−0.43 for relatively massive star-forming galaxies (9<log(M?/M)<10), consistent with no change from z=4 to z=9−10 at these stellar masses, implying rapid enrichment. Our SED-fitting results are consistent with a star-forming main sequence with sub-linear slope (0.7±0.2) and specific star-formation rates of 3−10 Gyr−1. However, the stellar ages and SFHs are less well constrained. Using different SFH priors, we cannot distinguish between median mass-weighted ages of ∼50−150 Myr, which corresponds to 50% formation redshifts of z50∼10−12 atz∼9 and is of the order of the dynamical timescales of these systems. Importantly, the models with different SFH priors are able to fit the data equally well. We conclude that the current observational data cannot tightly constrain the mass-buildup timescales of these z=9−11 galaxies, with our results consistent with SFHs implying both a shallow and steep increase of the cosmic SFR density with time at z >10
Late-stage rehabilitation programs often incorporate 'sport-specific' demands, but may not optimally simulate the in-game volume or intensity of such activities as sprinting, cutting, jumping, and ...lateral movement.
The aim of this review was to characterize, quantify, and compare straight-line running and multi-directional demands during sport competition.
A systematic review of PubMed, CINAHL, SPORTDiscus, and Cochrane Central Register of Controlled Trials databases was conducted.
Studies that reported time-motion analysis data on straight-line running, accelerations/decelerations, activity changes, jumping, cutting, or lateral movement over the course of an entire competition in a multi-directional sport (soccer, basketball, lacrosse, handball, field hockey, futsal, volleyball) were included.
Data was organized based on sport, age level, and sex and descriptive statistics of the frequency, intensity, time, and volume of the characteristics of running and multi-directional demands were extracted from each study.
Eighty-one studies were included in the review (n = 47 soccer, n = 11 basketball, n = 9 handball, n = 7 field hockey, n = 3 futsal, n = 4 volleyball). Variability of sport demand data was found across sports, sexes, and age levels. Specifically, soccer and field hockey demanded the most volume of running, while basketball required the highest ratio of high-intensity running to sprinting. Athletes change activity between 500 and 3000 times over the course of a competition, or once every 2-4 s. Studies of soccer reported the most frequent cutting (up to 800 per game), while studies of basketball reported the highest frequency of lateral movement (up to 450 per game). Basketball (42-56 per game), handball (up to 90 per game), and volleyball (up to 35 per game) were found to require the most jumping.
These data may provide an incomplete view of an athlete's straight-line running load, considering that only competition and not practice data was provided.
Considerable variability exists in the demands of straight-line running and multi-directional demands across sports, competition levels, and sexes, indicating the need for sports medicine clinicians to design future rehabilitation programs with improved specificity (including the type of activity and dosage) to these demands.
Background Asthma pathophysiology and treatment responsiveness are predicted by inflammatory phenotype. However, the relationship between airway microbiology and asthma phenotype is poorly ...understood. Objective We aimed to characterize the airway microbiota in patients with symptomatic stable asthma and relate composition to airway inflammatory phenotype and other phenotypic characteristics. Methods The microbial composition of induced sputum specimens collected from adult patients screened for a multicenter randomized controlled trial was determined by using 16S rRNA gene sequencing. Inflammatory phenotypes were defined by sputum neutrophil and eosinophil cell proportions. Microbiota were defined by using α- and β-diversity measures, and interphenotype differences were identified by using similarity of percentages, network analysis, and taxon fold change. Phenotypic predictors of airway microbiology were identified by using multivariate linear regression. Results Microbiota composition was determined in 167 participants and classified as eosinophilic (n = 84), neutrophilic (n = 14), paucigranulocytic (n = 60), or mixed neutrophilic-eosinophilic (n = 9) asthma phenotypes. Airway microbiology was significantly less diverse ( P = .022) and more dissimilar ( P = .005) in neutrophilic compared with eosinophilic participants. Sputum neutrophil proportions, but not eosinophil proportions, correlated significantly with these diversity measures (α-diversity: Spearman r = −0.374, P < .001; β-diversity: r = 0.238, P = .002). Interphenotype differences were characterized by a greater frequency of pathogenic taxa at high relative abundance and reduced Streptococcus , Gemella , and Porphyromonas taxa relative abundance in patients with neutrophilic asthma. Multivariate regression confirmed that sputum neutrophil proportion was the strongest predictor of microbiota composition. Conclusions Neutrophilic asthma is associated with airway microbiology that is significantly different from that seen in patients with other inflammatory phenotypes, particularly eosinophilic asthma. Differences in microbiota composition might influence the response to antimicrobial and steroid therapies and the risk of lung infection.
The macrolide antibiotic azithromycin reduces exacerbations in adults with persistent symptomatic asthma. However, owing to the pleotropic properties of macrolides, unintended bacteriological ...consequences such as augmented pathogen colonization or dissemination of antibiotic-resistant organisms can occur, calling into question the long-term safety of azithromycin maintenance therapy.
To assess the effects of azithromycin on the airway microbiota, pathogen abundance, and carriage of antibiotic resistance genes.
16S rRNA sequencing and quantitative PCR were performed to assess the effect of azithromycin on sputum microbiology from participants of the AMAZES (Asthma and Macrolides: The Azithromycin Efficacy and Safety) trial: a 48-week, double-blind, placebo-controlled trial of thrice-weekly 500 mg oral azithromycin in adults with persistent uncontrolled asthma. Pooled-template shotgun metagenomic sequencing, quantitative PCR, and isolate whole-genome sequencing were performed to assess antibiotic resistance.
Paired sputum samples were available from 61 patients (
= 34 placebo,
= 27 azithromycin). Azithromycin did not affect bacterial load (
= 0.37) but did significantly decrease Faith's phylogenetic diversity (
= 0.026) and
load (
< 0.0001). Azithromycin did not significantly affect levels of
,
,
, or
. Of the 89 antibiotic resistance genes detected, five macrolide resistance genes and two tetracycline resistance genes were increased significantly.
In patients with persistent uncontrolled asthma, azithromycin reduced airway
load compared with placebo but did not change total bacterial load. Macrolide resistance increased, reflecting previous studies. These results highlight the need for studies assessing the efficacy of nonantibiotic macrolides as a long-term therapy for patients with persistent uncontrolled asthma.
Abstract
The selection of high-redshift galaxies often involves spectral energy distribution (SED) fitting to photometric data, an expectation for contamination levels, and measurement of sample ...completeness—all vetted through comparison to spectroscopic redshift measurements of a sub-sample. The first JWST data are now being taken over several extragalactic fields to different depths and across various areas, which will be ideal for the discovery and classification of galaxies out to distances previously uncharted. As spectroscopic redshift measurements for sources in this epoch will not be initially available to compare with the first photometric measurements of
z
> 8 galaxies, robust photometric redshifts are of the utmost importance. Galaxies at
z
> 8 are expected to have bluer rest-frame ultraviolet (UV) colors than typically used model SED templates, which could lead to catastrophic photometric redshift failures. We use a combination of BPASS and
Cloudy
models to create a supporting set of templates that match the predicted rest-UV colors of
z
> 8 simulated galaxies. We test these new templates by fitting simulated galaxies in a mock catalog, Yung et al., which mimic expected field depths and areas of the JWST Cosmic Evolution Early Release Science Survey (
m
5
σ
∼ 28.6 over ∼100 arcmin
2
). We use EAZY to highlight the improvements in redshift recovery with the inclusion of our new template set and suggest criteria for selecting galaxies at 8 <
z
< 10 with the JWST, providing an important test case for observers venturing into this new era of astronomy.
Bronchiectasis guidelines recommend long-term macrolide treatment for patients with three or more exacerbations per year without Pseudomonas aeruginosa infection. Randomised controlled trials suggest ...that long-term macrolide treatment can prevent exacerbations in adult patients with bronchiectasis, but these individual studies have been too small to do meaningful subgroup analyses. We did a systematic review and individual patient data (IPD) meta-analysis to explore macrolide benefit in subpopulations, including those in which macrolide therapy is not currently recommended.
We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science from Jan 1, 2000, to Sept 30, 2018, to identify double blind, randomised, placebo-controlled trials of macrolide antibiotics in adult patients with bronchiectasis. We applied no language restrictions. Randomised controlled trials were eligible if treatment was defined a priori as long term and had a primary or secondary outcome of bronchiectasis exacerbations. Studies in patients with cystic fibrosis bronchiectasis were excluded. The primary outcome of the meta-analysis was frequency of exacerbations requiring treatment with antibiotics. Secondary endpoints were time to first exacerbation, change in quality of life according to the St George's Respiratory Questionnaire (SGRQ), and change in FEV
. IPD meta-analysis was done using fixed effects models adjusting for age, sex, FEV
, and trial. We did prespecified subgroup analyses for each of the primary and secondary endpoints using one-step meta-analysis only. Subgroups were defined by age, sex, previous exacerbation frequency, smoking status, inhaled corticosteroid use at baseline, body-mass index at baseline, cause, C-reactive protein at baseline, baseline FEV
percentage of predicted, SGRQ total score, and Pseudomonas aeruginosa in sputum culture at baseline. The meta-analysis is registered with the PROSPERO international register of systematic reviews, number CRD42018102908.
Of 234 identified studies, we included three randomised controlled trials, and IPD was obtained for 341 participants. Macrolide antibiotics reduced the frequency of exacerbations (adjusted incidence rate ratio IRR 0·49, 95% CI 0·36 to 0·66; p<0·0001). We also found that macrolide treatment improved the time to first exacerbation (adjusted hazard ratio 0·46, 0·34 to 0·61; p<0·0001) and was associated with improved quality of life measured by the SGRQ (mean improvement 2·93 points, 0·03 to 5·83; p=0·048). Macrolides were not associated with a significant improvement in FEV
(67 mL at 1 year, -22 to 112; p=0·14). Effect estimates in prespecified subgroup analyses revealed a reduced frequency of exacerbations in all prespecified subgroups, including a high level of benefit in patients with P aeruginosa infection (IRR 0·36, 0·18-0·72; p=0·0044) and in patients with one to two exacerbations per year (0·37, 0·16-0·88; p=0·025). Studies were rated as low risk of bias across all domains.
Long-term macrolide treatment significantly reduces the frequency of exacerbations in patients with bronchiectasis, with similar benefits observed in all subgroups based on patient characteristics. This finding suggests that macrolides might be considered in patients in whom macrolides are not indicated according to the current guidelines, particularly if alternative approaches to reduce exacerbations have been unsuccessful. However, downsides of long-term macrolide treatment must also be taken into account.
European Respiratory Society.
Exacerbations of asthma cause a substantial global illness burden. Adults with uncontrolled persistent asthma despite maintenance treatment require additional therapy. Since macrolide antibiotics can ...be used to treat persistent asthma, we aimed to assess the efficacy and safety of oral azithromycin as add-on therapy in patients with uncontrolled persistent asthma on medium-to-high dose inhaled corticosteroids plus a long-acting bronchodilator.
We did a randomised, double-blind, placebo controlled parallel group trial to determine whether oral azithromycin decreases the frequency of asthma exacerbations in adults (≥18 years) with symptomatic asthma despite current use of inhaled corticosteroid and long-acting bronchodilator, and who had no hearing impairment or abnormal prolongation of the corrected QT interval. Patients were randomly assigned (1:1) to receive azithromycin 500 mg or placebo three times per week for 48 weeks. Patients were centrally allocated using concealed random allocation from a computer-generated random numbers table with permuted blocks of 4 or 6 and stratification for centre and past smoking. Primary efficacy endpoints were the rate of total (severe and moderate) asthma exacerbations over 48 weeks and asthma quality of life. Data were analysed on an intention-to-treat basis. The trial is registered at the Australian and New Zealand Clinical Trials Registry (ANZCTR), number 12609000197235.
Between June 12, 2009, and Jan 31, 2015, 420 patients were randomly assigned (213 in the azithromycin group and 207 in the placebo group). Azithromycin reduced asthma exacerbations (1·07 per patient-year 95% CI 0·85–1·29) compared with placebo (1·86 per patient-year 1·54–2·18; incidence rate ratio IRR 0·59 95% CI 0·47–0·74; p<0·0001). The proportion of patients experiencing at least one asthma exacerbation was reduced by azithromycin treatment (127 61% patients in the placebo group vs 94 44% patients in the azithromycin group, p<0·0001). Azithromycin significantly improved asthma-related quality of life (adjusted mean difference, 0·36 95% CI 0·21–0·52; p=0·001). Diarrhoea was more common in azithromycin-treated patients (72 34% vs 39 19%; p=0·001).
Adults with persistent symptomatic asthma experience fewer asthma exacerbations and improved quality of life when treated with oral azithromycin for 48 weeks. Azithromycin might be a useful add-on therapy in persistent asthma.
National Health and Medical Research Council of Australia, John Hunter Hospital Charitable Trust.
Significance Events that occur between entry of the HIV-1 capsid into the cytoplasm of the target cell and the delivery of the viral genetic material into the nucleus constitute some of the less well ...understood processes in the viral life cycle. We demonstrated that PF74, a small-molecule inhibitor of HIV-1, and the host proteins CPSF6 and NUP153 bind to a preformed pocket within the CA protein hexamers that exist within the assembled capsid. Our results suggest that key features of the CA hexameric lattice remain intact upon docking at the nuclear pore. In addition, low molecular weight ligands that better mimic virus–host, protein–protein interactions at the intersubunit interfaces within the assembled viral capsid may offer novel avenues for therapeutic intervention.
Upon infection of susceptible cells by HIV-1, the conical capsid formed by ∼250 hexamers and 12 pentamers of the CA protein is delivered to the cytoplasm. The capsid shields the RNA genome and proteins required for reverse transcription. In addition, the surface of the capsid mediates numerous host–virus interactions, which either promote infection or enable viral restriction by innate immune responses. In the intact capsid, there is an intermolecular interface between the N-terminal domain (NTD) of one subunit and the C-terminal domain (CTD) of the adjacent subunit within the same hexameric ring. The NTD–CTD interface is critical for capsid assembly, both as an architectural element of the CA hexamer and pentamer and as a mechanistic element for generating lattice curvature. Here we report biochemical experiments showing that PF-3450074 (PF74), a drug that inhibits HIV-1 infection, as well as host proteins cleavage and polyadenylation specific factor 6 (CPSF6) and nucleoporin 153 kDa (NUP153), bind to the CA hexamer with at least 10-fold higher affinities compared with nonassembled CA or isolated CA domains. The crystal structure of PF74 in complex with the CA hexamer reveals that PF74 binds in a preformed pocket encompassing the NTD–CTD interface, suggesting that the principal inhibitory target of PF74 is the assembled capsid. Likewise, CPSF6 binds in the same pocket. Given that the NTD–CTD interface is a specific molecular signature of assembled hexamers in the capsid, binding of NUP153 at this site suggests that key features of capsid architecture remain intact upon delivery of the preintegration complex to the nucleus.
The derivation of tissue-specific stem cells from human induced pluripotent stem cells (iPSCs) would have broad reaching implications for regenerative medicine. Here, we report the directed ...differentiation of human iPSCs into airway basal cells (“iBCs”), a population resembling the stem cell of the airway epithelium. Using a dual fluorescent reporter system (NKX2-1GFP;TP63tdTomato), we track and purify these cells as they first emerge as developmentally immature NKX2-1GFP+ lung progenitors and subsequently augment a TP63 program during proximal airway epithelial patterning. In response to primary basal cell medium, NKX2-1GFP+/TP63tdTomato+ cells display the molecular and functional phenotype of airway basal cells, including the capacity to self-renew or undergo multi-lineage differentiation in vitro and in tracheal xenografts in vivo. iBCs and their differentiated progeny model perturbations that characterize acquired and genetic airway diseases, including the mucus metaplasia of asthma, chloride channel dysfunction of cystic fibrosis, and ciliary defects of primary ciliary dyskinesia.
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•Directed differentiation of human iPSCs generates airway basal cells (“iBCs”)•iBCs self-renew and display multipotent differentiation in vitro and in vivo•By single-cell RNA-seq, iBCs are highly similar to adult primary airway basal cells•iBCs enable modeling of acquired and genetic airway diseases
Hawkins and colleagues report a directed differentiation protocol enabling the derivation of airway basal cells (“iBCs”) from human iPSCs. iBCs recapitulate hallmark stem cell properties of primary basal cells, including self-renewal and multi-lineage differentiation, thus enabling modeling of airway diseases in vitro and repopulation of tracheal xenografts in vivo.
Abstract
We present the results from a new search for candidate galaxies at
z
≈ 8.5–11 discovered over the 850 arcmin
2
area probed by the Cosmic Assembly Near-Infrared Deep Extragalactic Legacy ...Survey (CANDELS). We use a photometric-redshift selection including both Hubble and Spitzer Space Telescope photometry to robustly identify galaxies in this epoch at
H
160
< 26.6. We use a detailed vetting procedure, including screening against persistence and stellar contamination, and the inclusion of ground-based imaging and follow-up Hubble Space Telescope imaging to build a robust sample of 11 candidate galaxies, three presented here for the first time. The inclusion of Spitzer/IRAC photometry in the selection process reduces contamination, and yields more robust redshift estimates than Hubble alone. We constrain the evolution of the rest-frame ultraviolet luminosity function via a new method of calculating the observed number densities without choosing a prior magnitude bin size. We find that the abundance at our brightest probed luminosities (
M
UV
= − 22.3) is consistent with predictions from simulations that assume that galaxies in this epoch have gas depletion times at least as short as those in nearby starburst galaxies. Due to large Poisson and cosmic variance uncertainties, we cannot conclusively rule out either a smooth evolution of the luminosity function continued from
z
= 4–8, or an accelerated decline at
z
> 8. We calculate that the presence of seven galaxies in a single field Extended Groth Strip is an outlier at the 2
σ
significance level, implying the discovery of a significant over-density. These scenarios will be imminently testable to high confidence within the first year of observations of the James Webb Space Telescope.
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