Rocaglates convert DEAD-box protein eIF4A into a sequence-selective translational repressor.

Rocaglamide A (RocA) typifies a class of protein synthesis inhibitors that selectively kill aneuploid tumour cells and repress translation of specific messenger RNAs. RocA targets eukaryotic initiation factor 4A (eIF4A), an ATP-dependent DEAD-box RNA helicase; its messenger RNA selectivity is proposed to reflect highly structured 5' untranslated regions that depend strongly on eIF4A-mediated unwinding. However, rocaglate treatment may not phenocopy the loss of eIF4A activity, as these drugs actually increase the affinity between eIF4A and RNA. Here we show that secondary structure in 5' untranslated regions is only a minor determinant for RocA selectivity and that RocA does not repress translation by reducing eIF4A availability. Rather, in vitro and in cells, RocA specifically clamps eIF4A onto polypurine sequences in an ATP-independent manner. This artificially clamped eIF4A blocks 43S scanning, leading to premature, upstream translation initiation and reducing protein expression from transcripts bearing the RocA-eIF4A target sequence. In elucidating the mechanism of selective translation repression by this lead anti-cancer compound, we provide an example of a drug stabilizing sequence-selective RNA-protein interactions

Simulated Versus Observed Cluster Eccentricity Evolution

The rate of galaxy cluster eccentricity evolution is useful in understanding large scale structure. Rapid evolution for $z <$ 0.13 has been found in two different observed cluster samples. We present an analysis of projections of 41 clusters produced in hydrodynamic simulations augmented with radiative cooling and 43 clusters from adiabatic simulations. This new, larger set of simulated clusters strengthens the claims of previous eccentricity studies. We find very slow evolution in simulated clusters, significantly different from the reported rates of observational eccentricity evolution. We estimate the rate of change of eccentricity with redshift and compare the rates between simulated and observed clusters. We also use a variable aperture radius to compute the eccentricity, r$_{200}$. This method is much more robust than the fixed aperture radius used in previous studies. Apparently radiative cooling does not change cluster morphology on scales large enough to alter eccentricity. The discrepancy between simulated and observed cluster eccentricity remains. Observational bias or incomplete physics in simulations must be present to produce halos that evolve so differently.Comment: ApJ, in press, minor revision

STROOPWAFEL: Simulating rare outcomes from astrophysical populations, with application to gravitational-wave sources

Gravitational-wave observations of double compact object (DCO) mergers are providing new insights into the physics of massive stars and the evolution of binary systems. Making the most of expected near-future observations for understanding stellar physics will rely on comparisons with binary population synthesis models. However, the vast majority of simulated binaries never produce DCOs, which makes calculating such populations computationally inefficient. We present an importance sampling algorithm, STROOPWAFEL, that improves the computational efficiency of population studies of rare events, by focusing the simulation around regions of the initial parameter space found to produce outputs of interest. We implement the algorithm in the binary population synthesis code COMPAS, and compare the efficiency of our implementation to the standard method of Monte Carlo sampling from the birth probability distributions. STROOPWAFEL finds $\sim$25-200 times more DCO mergers than the standard sampling method with the same simulation size, and so speeds up simulations by up to two orders of magnitude. Finding more DCO mergers automatically maps the parameter space with far higher resolution than when using the traditional sampling. This increase in efficiency also leads to a decrease of a factor $\sim$3-10 in statistical sampling uncertainty for the predictions from the simulations. This is particularly notable for the distribution functions of observable quantities such as the black hole and neutron star chirp mass distribution, including in the tails of the distribution functions where predictions using standard sampling can be dominated by sampling noise.Comment: Accepted. Data and scripts to reproduce main results is publicly available. The code for the STROOPWAFEL algorithm will be made publicly available. Early inquiries can be addressed to the lead autho

N-terminal truncated RHT-1 proteins generated by translational reinitiation cause semi-dwarfing of wheat Green Revolution alleles

The unprecedented wheat yield increases during the Green Revolution were achieved through the introduction of the Reduced height (Rht)-B1b and Rht-D1b semi-dwarfing alleles. These Rht-1 alleles encode growth-repressing DELLA genes containing a stop codon within their open reading frame that confers gibberellin (GA)-insensitive semi-dwarfism. In this study, we successfully took the hurdle of detecting wild-type RHT-1 proteins in different wheat organs and confirmed their degradation in response to GAs. We further demonstrated that Rht-B1b and Rht-D1b produce N-terminal truncated proteins through translational reinitiation. Expression of these N-terminal truncated proteins in transgenic lines and in Rht-D1c, an allele containing multiple Rht-D1b copies, demonstrated their ability to cause strong dwarfism, resulting from their insensitivity to GA-mediated degradation. N-terminal truncated proteins were detected in spikes and nodes, but not in the aleurone layers. Since Rht-B1b and Rht-D1b alleles cause dwarfism but have wild-type dormancy, this finding suggests that tissue-specific differences in translational reinitiation may explain why the Rht-1 alleles reduce plant height without affecting dormancy. Taken together, our findings not only reveal the molecular mechanism underlying the Green Revolution but also demonstrate that translational reinitiation in the main open reading frame occurs in plants

Common-Envelope Episodes that lead to Double Neutron Star formation

Close double neutron stars have been observed as Galactic radio pulsars, while their mergers have been detected as gamma-ray bursts and gravitational-wave sources. They are believed to have experienced at least one common-envelope episode during their evolution prior to double neutron star formation. In the last decades there have been numerous efforts to understand the details of the common-envelope phase, but its computational modelling remains challenging. We present and discuss the properties of the donor and the binary at the onset of the Roche-lobe overflow leading to these common-envelope episodes as predicted by rapid binary population synthesis models. These properties can be used as initial conditions for detailed simulations of the common-envelope phase. There are three distinctive populations, classified by the evolutionary stage of the donor at the moment of the onset of the Roche-lobe overflow: giant donors with fully-convective envelopes, cool donors with partially-convective envelopes, and hot donors with radiative envelopes. We also estimate that, for standard assumptions, tides would not circularise a large fraction of these systems by the onset of Roche-lobe overflow. This makes the study and understanding of eccentric mass-transferring systems relevant for double neutron star populations.Comment: 26 pages, 10 figures. Includes bug fix. Two new figures and an appendix adde

International Wildlife Law : Understanding and Enhancing Its Role in Conservation

We gratefully acknowledge valuable input by Kees Bastmeijer, Sanja Bogojevic, Jennifer Dubrulle, and Han Somsen.Peer reviewedPublisher PD

Eccentricity Evolution in Simulated Galaxy Clusters

Strong cluster eccentricity evolution for $z \le 0.13$ has appeared in a variety of observational data sets. We examine the evolution of eccentricity in simulated galaxy clusters using a variety of simulation methodologies, amplitude normalizations, and background cosmologies. We do not find find such evolution for $z < 0.1$ in any of our simulation ensembles. We suggest a systematic error in the form of a redshift-dependent selection effect in cluster catalogs or missing physics in cluster simulations important enough to modify the cluster morphology.Comment: Revised version to be published in ApJ. Moderate revisions, including additional N-body simulations with varying amplitude normalization and background matter density within OCDM and $\lambda$CDM scenarios reinforce our conclusion that observed clusters have recently relaxed much more rapidly than simulated one

Qualitative analysis of the impact of the SARS-CoV-2 pandemic response on paediatric health services in North of Scotland and North of England

Objective To capture the extent and impact of changes in the delivery of child health services in the UK, resulting from the SARS-CoV-2 pandemic response, from the perspectives of a range of child healthcare providers. Setting National Health Service commissioned/delivered healthcare services in two regional settings in the UK: North of Scotland (NOS) and North East and North Cumbria (NENC) in England. Participants Purposive sample of 39 child healthcare professionals including paediatricians, community/specialist nurses, allied health professionals and mental health professionals, from across the two regions (22 in NOS, 17 in NENC). Methods Semistructured qualitative interviews conducted via telephone between June and October 2020, fully transcribed and analysed in NVivo V.11 using thematic analysis. Results Extensive changes across a range of paediatric services were rapidly implemented to support the pandemic response and ongoing healthcare delivery. New ways of working emerged, principally to control the spread of the virus. Keeping users and their families out of hospital was an urgent driver for change. The changes had considerable impact on the health and well-being of staff with many experiencing radical changes to their working conditions and roles. However, there were some positive changes noted: some practitioners felt empowered and listened to by decision makers; some of the usual bureaucratic barriers to change were lifted; staff saw improved collaboration and joint working across the system; and some new ways of working were seen to be more efficient. Interviewees perceived the implications for children and their families to be profound, particularly with regard to self-care, relationships with practitioners and timely access to services. Conclusions Despite the challenges experienced by staff, the pandemic provided an opportunity for positive, lasting change. It is vital to capitalise on this opportunity to benefit patient outcomes and to ‘build back’ services in a more sustainable way

Impact of Massive Binary Star and Cosmic Evolution on Gravitational Wave Observations I: Black Hole-Neutron Star Mergers

Mergers of black hole-neutron star (BHNS) binaries have now been observed by GW detectors with the recent announcement of GW200105 and GW200115. Such observations not only provide confirmation that these systems exist, but will also give unique insights into the death of massive stars, the evolution of binary systems and their possible association with gamma-ray bursts, $r$-process enrichment and kilonovae. Here we perform binary population synthesis of isolated BHNS systems in order to present their merger rate and characteristics for ground-based GW observatories. We present the results for 420 different model permutations that explore key uncertainties in our assumptions about massive binary star evolution (e.g. mass transfer, common-envelope evolution, supernovae), and the metallicity-specific star formation rate density, and characterize their relative impacts on our predictions. We find intrinsic local BHNS merger rates spanning $\mathcal{R}_{\rm{m}}^0 \approx 4$-$830\,\rm{Gpc}^{-3}\,\rm{yr}^{-1}$ for our full range of assumptions. This encompasses the rate inferred from recent BHNS GW detections, and would yield detection rates of $\mathcal{R}_{\rm{det}} \approx 1$-$180\, \rm{yr}^{-1}$ for a GW network consisting of LIGO, Virgo and KAGRA at design sensitivity. We find that the binary evolution and metallicity-specific star formation rate density each impact the predicted merger rates by order $\mathcal{O}(10)$. We also present predictions for the GW detected BHNS merger properties and find that all 420 model variations predict that $\lesssim 5\%$ of the BHNS mergers have BH masses $\gtrsim 18\,M_{\odot}$, total masses $\gtrsim 20\,M_{\odot}$, chirp masses $\gtrsim 5.5\,M_{\odot}$, mass ratios $\gtrsim 12$ or $\lesssim 2$. Moreover, we find that massive NSs $\gtrsim 2\,M_{\odot}$ are expected to be commonly detected in BHNS mergers in almost all our model variations.Comment: 38 pages, 18 figures, accepted to MNRAS. The authors welcome suggestions and feedback. All data and code to reproduce the results in this paper are publicly availabl