Spin-echo small-angle neutron scattering (SESANS) studies of diblock copolymer nanoparticles

Poly(glycerol monomethacrylate)–poly(benzyl methacrylate) (PGMA–PBzMA) diblock copolymer nanoparticles were synthesized via polymerization-induced self-assembly (PISA) using reversible addition–fragmentation chain-transfer (RAFT) aqueous emulsion polymerization in D2O. Such PISA syntheses produce sterically-stabilized nanoparticles in situ and can be performed at relatively high copolymer concentrations (up to 50 wt%). This PGMA–PBzMA formulation is known to form only spherical nanoparticles in water using aqueous emulsion polymerization (Macromolecules, 2014, 47, 5613–5623), which makes it an ideal model system for exploring new characterization methods. The polymer micelles were characterized using small-angle X-ray scattering (SAXS) and a recently developed form of neutron scattering, spin-echo small-angle neutron scattering (SESANS). As far as we are aware, this is the first report of a study of polymer micelles by SESANS, and the data agree well with reciprocal-space scattering. Using this technique enables characterization of the concentrated, as synthesized dispersions directly without dilution, and this will provide a method to study self-assembled polymer systems that have concentration dependent morphologies, while still maintaining the advantages of scattering techniques

Event attribution of Parnaíba River floods in Northeastern Brazil

The climate modeling techniques of event attribution enable systematic assessments of the extent that anthropogenic climate change may be altering the probability or magnitude of extreme events. In the consecutive years of 2018, 2019, and 2020, rainfalls caused repeated flooding impacts in the lower Parnaíba River in Northeastern Brazil. We studied the effect that alterations in precipitation resulting from human influences on the climate had on the likelihood of flooding using two ensembles of the HadGEM3-GA6 atmospheric model: one driven by both natural and anthropogenic forcings; and the other driven only by natural atmospheric forcings, with anthropogenic changes removed from sea surface temperatures and sea ice patterns. We performed hydrological modeling to base our assessments on the peak annual streamflow. The change in the likelihood of flooding was expressed in terms of the ratio between probabilities of threshold exceedance estimated for each model ensemble. With uncertainty estimates at the 90% confidence level, the median (5% 95%) probability ratio at the threshold for flooding impacts in the historical period (1982–2013) was 1.12 (0.97 1.26), pointing to a marginal contribution of anthropogenic emissions by about 12%. For the 2018, 2019, and 2020 events, the median (5% 95%) probability ratios at the threshold for flooding impacts were higher at 1.25 (1.07 1.46), 1.27 (1.12 1.445), and 1.37 (1.19 1.59), respectively; indicating that precipitation change driven by anthropogenic emissions has contributed to the increase of likelihood of these events by about 30%. However, there are other intricate hydrometeorological and anthropogenic processes undergoing long-term changes that affect the flood hazard in the lower Parnaíba River. Trend and flood frequency analyses performed on observations showed a nonsignificant long-term reduction of annual peak flow, likely due to decreasing precipitation from natural climate variability and increasing evapotranspiration and flow regulation

Substantial burden of non-medically attended RSV infection in healthy term infants – an international prospective birth cohort study

Background: During the first year of life, one in four infants develops a symptomatic respiratory syncytial virus (RSV) infection, yet only half seek medical attention. The current focus on medically attended RSV, therefore, underrepresents the true societal burden of RSV. We assessed the burden of non-medically attended RSV infections and compared them with medically attended RSV. Methods: We performed active RSV surveillance until the age of one year in a cohort (n=993) nested within RESCEU, a prospective birth cohort study enrolling healthy term-born infants in five European countries. Parent-reported daily symptoms, medication use, wheezing and impact on family life were analyzed. Results: For 97 of 120 (80.1%) non-medically attended RSV episodes sufficient data were available for analysis. In 50.5% (49/97), symptoms lasted ≥15 days. Parents reported impairment in usual daily activities in 59.8% (58/97), worries in 75.3% (73/97), anxiety in 34.0% (33/97), and work absenteeism in 10.8% (10/93) of episodes. Compared with medically attended RSV (n=102, 9 hospital admissions), ReSViNET severity scores were lower (3.5 vs. 4.6, p<0.001), whereas durations of respiratory symptoms and impairment of usual activities were comparable. Conclusion: Even when medical attendance is not required, RSV infection poses a substantial burden to infants, families and society at large. These findings are important for policymakers when considering the implementation of RSV immunization in national programs

Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP.

We aimed to develop an efficient, flexible and scalable approach to diagnostic genome-wide sequence analysis of genetically heterogeneous clinical presentations. Here we present G2P ( www.ebi.ac.uk/gene2phenotype ) as an online system to establish, curate and distribute datasets for diagnostic variant filtering via association of allelic requirement and mutational consequence at a defined locus with phenotypic terms, confidence level and evidence links. An extension to Ensembl Variant Effect Predictor (VEP), VEP-G2P was used to filter both disease-associated and control whole exome sequence (WES) with Developmental Disorders G2P (G2PDD; 2044 entries). VEP-G2PDD shows a sensitivity/precision of 97.3%/33% for de novo and 81.6%/22.7% for inherited pathogenic genotypes respectively. Many of the missing genotypes are likely false-positive pathogenic assignments. The expected number and discriminative features of background genotypes are defined using control WES. Using only human genetic data VEP-G2P performs well compared to other freely-available diagnostic systems and future phenotypic matching capabilities should further enhance performance

Accrual and drop out in a primary prevention randomised controlled trial: qualitative study

<p>Abstract</p> <p>Background</p> <p>Recruitment and retention of participants are critical to the success of a randomised controlled trial. Gaining the views of potential trial participants who decline to enter a trial and of trial participants who stop the trial treatment is important and can help to improve study processes. Limited research on these issues has been conducted on healthy individuals recruited for prevention trials in the community.</p> <p>Methods</p> <p>Semi-structured interviews with people who were eligible but had declined to participate in the Aspirin for Asymptomatic Atherosclerosis (AAA) trial (N = 11), and AAA trial participants who had stopped taking the trial medication (N = 11). A focus group with further participants who had stopped taking the trial medication (N = 6). (Total participants N = 28).</p> <p>Results</p> <p>Explanations for declining to participate could be divided into two groups: the first group were characterised by a lack of necessity to participate and a tendency to prioritise other largely mundane problems. The second group's concern was with a high level of perceived risk from participating.</p> <p>Explanations for stopping trial medication fell into four categories: side effects attributed to the trial medication; starting on aspirin or medication contraindicating to aspirin; experiencing an outcome event, and changing one's mind.</p> <p>Conclusions</p> <p>These results indicate that when planning trials (especially in preventive medicine) particular attention should be given to designing appropriate recruitment materials and processes that fully inform potential recruits of the risks and benefits of participation.</p> <p>Trial registration</p> <p>ISRCTN66587262</p

Beta Dips in the Gaia Era: Simulation Predictions of the Galactic Velocity Anisotropy Parameter (β) for Stellar Halos

The velocity anisotropy parameter, β, is a measure of the kinematic state of orbits in the stellar halo, which holds promise for constraining the merger history of the Milky Way (MW). We determine global trends for β as a function of radius from three suites of simulations, including accretion-only and cosmological hydrodynamic simulations. We find that the two types of simulations are consistent and predict strong radial anisotropy ($\langle \beta \rangle \sim 0.7$) for Galactocentric radii greater than 10 kpc. Previous observations of β for the MW's stellar halo claim a detection of an isotropic or tangential "dip" at r ~ 20 kpc. Using the N-body+SPH simulations, we investigate the temporal persistence, population origin, and severity of "dips" in β. We find that dips in the in situ stellar halo are long-lived, while dips in the accreted stellar halo are short-lived and tied to the recent accretion of satellite material. We also find that a major merger as early as z ~ 1 can result in a present-day low (isotropic to tangential) value of β over a broad range of radii and angles. While all of these mechanisms are plausible drivers for the β dip observed in the MW, each mechanism in the simulations has a unique metallicity signature associated with it, implying that future spectroscopic surveys could distinguish between them. Since an accurate knowledge of β(r) is required for measuring the mass of the MW halo, we note that significant transient dips in β could cause an overestimate of the halo's mass when using spherical Jeans equation modeling

Transcription restores DNA repair to heterochromatin, determining regional mutation rates in cancer genomes

SummarySomatic mutations in cancer are more frequent in heterochromatic and late-replicating regions of the genome. We report that regional disparities in mutation density are virtually abolished within transcriptionally silent genomic regions of cutaneous squamous cell carcinomas (cSCCs) arising in an XPC−/− background. XPC−/− cells lack global genome nucleotide excision repair (GG-NER), thus establishing differential access of DNA repair machinery within chromatin-rich regions of the genome as the primary cause for the regional disparity. Strikingly, we find that increasing levels of transcription reduce mutation prevalence on both strands of gene bodies embedded within H3K9me3-dense regions, and only to those levels observed in H3K9me3-sparse regions, also in an XPC-dependent manner. Therefore, transcription appears to reduce mutation prevalence specifically by relieving the constraints imposed by chromatin structure on DNA repair. We model this relationship among transcription, chromatin state, and DNA repair, revealing a new, personalized determinant of cancer risk

Impacts of Parasites in Early Life: Contrasting Effects on Juvenile Growth for Different Family Members

Parasitism experienced early in ontogeny can have a major impact on host growth, development and future fitness, but whether siblings are affected equally by parasitism is poorly understood. In birds, hatching asynchrony induced by hormonal or behavioural mechanisms largely under parental control might predispose young to respond to infection in different ways. Here we show that parasites can have different consequences for offspring depending on their position in the family hierarchy. We experimentally treated European Shag (Phalacrocorax aristoteli) nestlings with the broad-spectrum anti-parasite drug ivermectin and compared their growth rates with nestlings from control broods. Average growth rates measured over the period of linear growth (10 days to 30 days of age) and survival did not differ for nestlings from treated and control broods. However, when considering individuals within broods, parasite treatment reversed the patterns of growth for individual family members: last-hatched nestlings grew significantly slower than their siblings in control nests but grew faster in treated nests. This was at the expense of their earlier-hatched brood-mates, who showed an overall growth rate reduction relative to last-hatched nestlings in treated nests. These results highlight the importance of exploring individual variation in the costs of infection and suggest that parasites could be a key factor modulating within-family dynamics, sibling competition and developmental trajectories from an early age

Human Intelligence and Polymorphisms in the DNA Methyltransferase Genes Involved in Epigenetic Marking

Epigenetic mechanisms have been implicated in syndromes associated with mental impairment but little is known about the role of epigenetics in determining the normal variation in human intelligence. We measured polymorphisms in four DNA methyltransferases (DNMT1, DNMT3A, DNMT3B and DNMT3L) involved in epigenetic marking and related these to childhood and adult general intelligence in a population (n = 1542) consisting of two Scottish cohorts born in 1936 and residing in Lothian (n = 1075) or Aberdeen (n = 467). All subjects had taken the same test of intelligence at age 11yrs. The Lothian cohort took the test again at age 70yrs. The minor T allele of DNMT3L SNP 11330C>T (rs7354779) allele was associated with a higher standardised childhood intelligence score; greatest effect in the dominant analysis but also significant in the additive model (coefficient = 1.40additive; 95%CI 0.22,2.59; p = 0.020 and 1.99dominant; 95%CI 0.55,3.43; p = 0.007). The DNMT3L C allele was associated with an increased risk of being below average intelligence (OR 1.25additive; 95%CI 1.05,1.51; p = 0.011 and OR 1.37dominant; 95%CI 1.11,1.68; p = 0.003), and being in the lowest 40th (padditive = 0.009; pdominant = 0.002) and lowest 30th (padditive = 0.004; pdominant = 0.002) centiles for intelligence. After Bonferroni correction for the number variants tested the link between DNMT3L 11330C>T and childhood intelligence remained significant by linear regression and centile analysis; only the additive regression model was borderline significant. Adult intelligence was similarly linked to the DNMT3L variant but this analysis was limited by the numbers studied and nature of the test and the association was not significant after Bonferroni correction. We believe that the role of epigenetics in the normal variation in human intelligence merits further study and that this novel finding should be tested in other cohorts