An update on emerging drugs for asthma

Peer reviewedPreprin

Conditions during adulthood affect cohort-specific reproductive success in an Arctic-nesting goose population

This is the final version of the article. Available from the publisher via the DOI in this record.Variation in fitness between individuals in populations may be attributed to differing environmental conditions experienced among birth (or hatch) years (i.e., between cohorts). In this study, we tested whether cohort fitness could also be explained by environmental conditions experienced in years post-hatch, using 736 lifelong resighting histories of Greenland white-fronted geese (Anser albifrons flavirostris) marked in their first winter. Specifically, we tested whether variation in age at first successful reproduction, the size of the first successful brood and the proportion of successful breeders by cohort was explained by environmental conditions experienced on breeding areas in west Greenland during hatch year, those in adulthood prior to successful reproduction and those in the year of successful reproduction, using North Atlantic Oscillation indices as proxies for environmental conditions during these periods. Fifty-nine (8%) of all marked birds reproduced successfully (i.e., were observed on wintering areas with young) only once in their lifetime and 15 (2%) reproduced successfully twice or thrice. Variation in age at first successful reproduction was explained by the environmental conditions experienced during adulthood in the years prior to successful reproduction. Birds bred earliest (mean age 4) when environmental conditions were 'good' prior to the year of successful reproduction. Conversely, birds successfully reproduced at older ages (mean age 7) if they experienced adverse conditions prior to the year of successful reproduction. Hatch year conditions and an interaction between those experienced prior to and during the year of successful reproduction explained less (marginally significant) variation in age at first successful reproduction. Environmental conditions did not explain variation in the size of the first successful brood or the proportion of successful breeders. These findings show that conditions during adulthood prior to the year of successful reproduction are most important in determining the age at first successful reproduction in Greenland white-fronted geese. Very few birds bred successfully at all (most only once), which suggests that May environmental conditions on breeding areas have cohort effects that influence lifetime (and not just annual) reproductive success.This research was funded through a joint PhD studentship from the Wildfowl & Wetlands Trust and the University of Exeter, and undertaken by MD Weegman. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

The Structure of the Mitotic Spindle and Nucleolus during Mitosis in the Amebo-Flagellate Naegleria

Mitosis in the amebo-flagellate Naegleria pringsheimi is acentrosomal and closed (the nuclear membrane does not break down). The large central nucleolus, which occupies about 20% of the nuclear volume, persists throughout the cell cycle. At mitosis, the nucleolus divides and moves to the poles in association with the chromosomes. The structure of the mitotic spindle and its relationship to the nucleolus are unknown. To identify the origin and structure of the mitotic spindle, its relationship to the nucleolus and to further understand the influence of persistent nucleoli on cellular division in acentriolar organisms like Naegleria, three-dimensional reconstructions of the mitotic spindle and nucleolus were carried out using confocal microscopy. Monoclonal antibodies against three different nucleolar regions and α-tubulin were used to image the nucleolus and mitotic spindle. Microtubules were restricted to the nucleolus beginning with the earliest prophase spindle microtubules. Early spindle microtubules were seen as short rods on the surface of the nucleolus. Elongation of the spindle microtubules resulted in a rough cage of microtubules surrounding the nucleolus. At metaphase, the mitotic spindle formed a broad band completely embedded within the nucleolus. The nucleolus separated into two discreet masses connected by a dense band of microtubules as the spindle elongated. At telophase, the distal ends of the mitotic spindle were still completely embedded within the daughter nucleoli. Pixel by pixel comparison of tubulin and nucleolar protein fluorescence showed 70% or more of tubulin co-localized with nucleolar proteins by early prophase. These observations suggest a model in which specific nucleolar binding sites for microtubules allow mitotic spindle formation and attachment. The fact that a significant mass of nucleolar material precedes the chromosomes as the mitotic spindle elongates suggests that spindle elongation drives nucleolar division

Integrated population modelling reveals a perceived source to be a cryptic sink

This is the final version of the article. Available from the publisher via the DOI in this record.Demographic links among fragmented populations are commonly studied as source-sink dynamics, whereby source populations exhibit net recruitment and net emigration, while sinks suffer net mortality but enjoy net immigration. It is commonly assumed that large, persistent aggregations of individuals must be sources, but this ignores the possibility that they are sinks instead, buoyed demographically by immigration. We tested this assumption using Bayesian integrated population modelling of Greenland white-fronted geese (Anser albifrons flavirostris) at their largest wintering site (Wexford, Ireland), combining capture-mark-recapture, census and recruitment data collected from 1982 to 2010. Management for this subspecies occurs largely on wintering areas; thus, study of source-sink dynamics of discrete regular wintering units provides unprecedented insights into population regulation and enables identification of likely processes influencing population dynamics at Wexford and among 70 other Greenland white-fronted goose wintering subpopulations. Using results from integrated population modelling, we parameterized an age-structured population projection matrix to determine the contribution of movement rates (emigration and immigration), recruitment and mortality to the dynamics of the Wexford subpopulation. Survival estimates for juvenile and adult birds at Wexford and adult birds elsewhere fluctuated over the 29-year study period, but were not identifiably different. However, per capita recruitment rates at Wexford in later years (post-1995) were identifiably lower than in earlier years (pre-1995). The observed persistence of the Wexford subpopulation was only possible with high rates of immigration, which exceeded emigration in each year. Thus, despite its apparent stability, Wexford has functioned as a sink over the entire study period. These results demonstrate that even large subpopulations can potentially be sinks, and that movement dynamics (e.g. immigration) among winters can dramatically obscure key processes driving subpopulation size. Further, novel population models which integrate capture-mark-recapture, census and recruitment data are essential to correctly ascribing source-sink status and accurately informing development of site-safeguard networks.This research was funded through a joint PhD studentship to M.D.W. from the Wildfowl & Wetlands Trust and the University of Exeter, and through a NERC grant (NE/L007770/1) to D.J.

Should I stay or should I go? Fitness costs and benefits of prolonged parent-offspring and sibling-sibling associations in an Arctic-nesting goose population.

This is the final version of the article. Available from the publisher via the DOI in this record.Theory predicts persistence of long-term family relationships in vertebrates will occur until perceived fitness costs exceed benefits to either parents or offspring. We examined whether increased breeding probability and survival were associated with prolonged parent-offspring and sibling-sibling relationships in a long-lived Arctic migrant herbivore, the Greenland white-fronted goose (Anser albifrons flavirostris). Although offspring associated with parents for 1-13 years, 79 % of these associations lasted two or less years. Only 65 (9.9 %) of the 656 marked offspring bred once in their lifetime, and just 16 (2.4 %) bred twice or more. The probability of birds with siblings breeding successfully in a subsequent year was credibly greater than that of independent birds at ages 5, 6, and 7. Survival of offspring with parents was credibly greater than that of independent/nonbreeder birds at all possible ages (i.e., ages 2-7+). A cost-benefit matrix model utilizing breeding and survival probabilities showed that staying with family groups was favored over leaving until age 3, after which there were no credible differences between staying and leaving strategies until the oldest ages, when leaving family groups was favored. Thus, most birds in this study either departed family groups early (e.g., at age 2, when the "stay" strategy was favored) or as predicted by our cost-benefit model (i.e., at age 3). Although extended family associations are a feature of this population, we contend that the survival benefits are not sufficient enough to yield clear fitness benefits, and associations only persist because parents and offspring mutually benefit from their persistence.This research was funded through a joint PhD studentship from the Wildfowl & Wetlands Trust and the University of Exeter undertaken by MDW

A preliminary audit of medical and aid provision in English Rugby union clubs:compliance with Regulation 9

BackgroundGoverning bodies are largely responsible for the monitoring and management of risks associated with a safe playing environment, yet adherence to regulations is currently unknown. The aim of this study was to investigate and evaluate the current status of medical personnel, facilities, and equipment in Rugby Union clubs at regional level in England.MethodsA nationwide cross-sectional survey of 242 registered clubs was undertaken, where clubs were surveyed online on their current medical personnel, facilities, and equipment provision, according to regulation 9 of the Rugby Football Union (RFU).ResultsOverall, 91 (45. 04%) surveys were returned from the successfully contacted recipients. Of the completed responses, only 23.61% (n = 17) were found to be compliant with regulations. Furthermore, 30.56% (n = 22) of clubs were unsure if their medical personnel had required qualifications; thus, compliance could not be determined. There was a significant correlation (p = −0.029, r = 0.295) between club level and numbers of practitioners. There was no significant correlation indicated between the number of practitioners/number of teams and number of practitioners/number of players. There were significant correlations found between club level and equipment score (p = 0.003, r = −0.410), club level and automated external defibrillator (AED) access (p = 0.002, r = −0.352) and practitioner level and AED access (p = 0.0001, r = 0.404). Follow-up, thematic analysis highlighted widespread club concern around funding/cost, awareness, availability of practitioners and AED training.ConclusionThe proportion of clubs not adhering overall compliance with Regulation 9 of the RFU is concerning for player welfare, and an overhaul, nationally, is required

The cometary composition of a protoplanetary disk as revealed by complex cyanides

Observations of comets and asteroids show that the Solar Nebula that spawned our planetary system was rich in water and organic molecules. Bombardment brought these organics to the young Earth's surface, seeding its early chemistry. Unlike asteroids, comets preserve a nearly pristine record of the Solar Nebula composition. The presence of cyanides in comets, including 0.01% of methyl cyanide (CH3CN) with respect to water, is of special interest because of the importance of C-N bonds for abiotic amino acid synthesis. Comet-like compositions of simple and complex volatiles are found in protostars, and can be readily explained by a combination of gas-phase chemistry to form e.g. HCN and an active ice-phase chemistry on grain surfaces that advances complexity[3]. Simple volatiles, including water and HCN, have been detected previously in Solar Nebula analogues - protoplanetary disks around young stars - indicating that they survive disk formation or are reformed in situ. It has been hitherto unclear whether the same holds for more complex organic molecules outside of the Solar Nebula, since recent observations show a dramatic change in the chemistry at the boundary between nascent envelopes and young disks due to accretion shocks[8]. Here we report the detection of CH3CN (and HCN and HC3N) in the protoplanetary disk around the young star MWC 480. We find abundance ratios of these N-bearing organics in the gas-phase similar to comets, which suggests an even higher relative abundance of complex cyanides in the disk ice. This implies that complex organics accompany simpler volatiles in protoplanetary disks, and that the rich organic chemistry of the Solar Nebula was not unique.Comment: Definitive version of the manuscript is published in Nature, 520, 7546, 198, 2015. This is the author's versio

Barriers to enrollment in a randomized controlled trial of hydrocortisone for cardiovascular insufficiency in term and late preterm newborn infants.

ObjectiveTo analyze reasons for low enrollment in a randomized controlled trial (RCT) of the effect of hydrocortisone for cardiovascular insufficiency on survival without neurodevelopmental impairment (NDI) in term/late preterm newborns.Study designThe original study was a multicenter RCT. Eligibility: ⩾34 weeks' gestation, <72 h old, mechanically ventilated, receiving inotrope. Primary outcome was NDI at 2 years; infants with diagnoses at high risk for NDI were excluded. This paper presents an analysis of reasons for low patient enrollment.ResultsTwo hundred and fifty-seven of the 932 otherwise eligible infants received inotropes; however, 207 (81%) had exclusionary diagnoses. Only 12 infants were randomized over 10 months; therefore, the study was terminated. Contributing factors included few eligible infants after exclusions, open-label steroid therapy and a narrow enrollment window.ConclusionDespite an observational study to estimate the population, very few infants were enrolled. Successful RCTs of emergent therapy may require fewer exclusions, a short-term primary outcome, waiver of consent and/or other alternatives

Intrathecal long-term gene expression by self-complementary adeno-associated virus type 1 suitable for chronic pain studies in rats

BACKGROUND: Intrathecal (IT) gene transfer is an attractive approach for targeting spinal mechanisms of nociception but the duration of gene expression achieved by reported methods is short (up to two weeks) impairing their utility in the chronic pain setting. The overall goal of this study was to develop IT gene transfer yielding true long-term transgene expression defined as ≥ 3 mo following a single vector administration. We defined "IT" administration as atraumatic injection into the lumbar cerebrospinal fluid (CSF) modeling a lumbar puncture. Our studies focused on recombinant adeno-associated virus (rAAV), one of the most promising vector types for clinical use. RESULTS: Conventional single stranded rAAV2 vectors performed poorly after IT delivery in rats. Pseudotyping of rAAV with capsids of serotypes 1, 3, and 5 was tested alone or in combination with a modification of the inverted terminal repeat. The former alters vector tropism and the latter allows packaging of self-complementary rAAV (sc-rAAV) vectors. Combining both types of modification led to the identification of sc-rAAV2/l as a vector that performed superiorly in the IT space. IT delivery of 3 × 10e9 sc-rAAV2/l particles per animal led to stable expression of enhanced green fluorescent protein (EGFP) for ≥ 3 mo detectable by Western blotting, quantitative PCR, and in a blinded study by confocal microscopy. Expression was strongest in the cauda equina and the lower sections of the spinal cord and only minimal in the forebrain. Microscopic examination of the SC fixed in situ with intact nerve roots and meninges revealed strong EGFP fluorescence in the nerve roots. CONCLUSION: sc-rAAVl mediates stable IT transgene expression for ≥ 3 mo. Our findings support the underlying hypothesis that IT target cells for gene transfer lack the machinery for efficient conversion of the single-stranded rAAV genome into double-stranded DNA and favor uptake of serotype 1 vectors over 2. Experiments presented here will provide a rational basis for utilizing IT rAAV gene transfer in basic and translational studies on chronic pain