Abstract Key challenges faced by all cells include how to spatiotemporally organize complex biochemistry and how to respond to environmental fluctuations. The budding yeast Saccharomyces cerevisiae ...harnesses alternative protein folding mediated by yeast prion domains (PrDs) for rapid evolution of new traits in response to environmental stress. Increasingly, it is appreciated that low complexity domains similar in amino acid composition to yeast PrDs (prion-like domains; PrLDs) found in metazoa have a prominent role in subcellular cytoplasmic organization, especially in relation to RNA homeostasis. In this review, we highlight recent advances in our understanding of the role of prions in enabling rapid adaptation to environmental stress in yeast. We also present the complete list of human proteins with PrLDs and discuss the prevalence of the PrLD in nucleic-acid binding proteins that are often connected to neurodegenerative disease, including: ataxin 1, ataxin 2, FUS, TDP-43, TAF15, EWSR1, hnRNPA1, and hnRNPA2. Recent paradigm-shifting advances establish that PrLDs undergo phase transitions to liquid states, which contribute to the structure and biophysics of diverse membraneless organelles. This structural functionality of PrLDs, however, simultaneously increases their propensity for deleterious protein-misfolding events that drive neurodegenerative disease. We suggest that even these PrLD-misfolding events are not irreversible and can be mitigated by natural or engineered protein disaggregases, which could have important therapeutic applications. This article is part of a Special Issue entitled SI:RNA Metabolism in Disease.
We combine Dark Energy Survey Year 1 clustering and weak lensing data with baryon acoustic oscillations and Big Bang nucleosynthesis experiments to constrain the Hubble constant. Assuming a flat ΛCDM ...model with minimal neutrino mass (∑m_ν = 0.06 eV), we find |$H_0=67.4^{+1.1}_{-1.2}\ \rm {km\,\rm s^{-1}\,\rm Mpc^{-1}}$| (68 per cent CL). This result is completely independent of Hubble constant measurements based on the distance ladder, cosmic microwave background anisotropies (both temperature and polarization), and strong lensing constraints. There are now five data sets that: (a) have no shared observational systematics; and (b) each constrains the Hubble constant with fractional uncertainty at the few-per cent level. We compare these five independent estimates, and find that, as a set, the differences between them are significant at the 2.5σ level (χ^2/dof = 24/11, probability to exceed = 1.1 per cent). Having set the threshold for consistency at 3σ, we combine all five data sets to arrive at |$H_0=69.3^{+0.4}_{-0.6}\ \rm {km\,\mathrm{ s}^{-1}\,\mathrm{ Mpc}^{-1}}$|.
An era of exploring the interactions of high-intensity, hard X-rays with matter has begun with the start-up of a hard-X-ray free-electron laser, the Linac Coherent Light Source (LCLS). Understanding ...how electrons in matter respond to ultra-intense X-ray radiation is essential for all applications. Here we reveal the nature of the electronic response in a free atom to unprecedented high-intensity, short-wavelength, high-fluence radiation (respectively 10(18) W cm(-2), 1.5-0.6 nm, approximately 10(5) X-ray photons per A(2)). At this fluence, the neon target inevitably changes during the course of a single femtosecond-duration X-ray pulse-by sequentially ejecting electrons-to produce fully-stripped neon through absorption of six photons. Rapid photoejection of inner-shell electrons produces 'hollow' atoms and an intensity-induced X-ray transparency. Such transparency, due to the presence of inner-shell vacancies, can be induced in all atomic, molecular and condensed matter systems at high intensity. Quantitative comparison with theory allows us to extract LCLS fluence and pulse duration. Our successful modelling of X-ray/atom interactions using a straightforward rate equation approach augurs favourably for extension to complex systems.
Thousands of eukaryotic protein-coding genes are noncanonically spliced to produce circular RNAs. Bioinformatics has indicated that long introns generally flank exons that circularize in Drosophila, ...but the underlying mechanisms by which these circular RNAs are generated are largely unknown. Here, using extensive mutagenesis of expression plasmids and RNAi screening, we reveal that circularization of the Drosophila laccase2 gene is regulated by both intronic repeats and trans-acting splicing factors. Analogous to what has been observed in humans and mice, base-pairing between highly complementary transposable elements facilitates backsplicing. Long flanking repeats (∼ 400 nucleotides nt) promote circularization cotranscriptionally, whereas pre-mRNAs containing minimal repeats (<40 nt) generate circular RNAs predominately after 3' end processing. Unlike the previously characterized Muscleblind (Mbl) circular RNA, which requires the Mbl protein for its biogenesis, we found that Laccase2 circular RNA levels are not controlled by Mbl or the Laccase2 gene product but rather by multiple hnRNP (heterogeneous nuclear ribonucleoprotein) and SR (serine-arginine) proteins acting in a combinatorial manner. hnRNP and SR proteins also regulate the expression of other Drosophila circular RNAs, including Plexin A (PlexA), suggesting a common strategy for regulating backsplicing. Furthermore, the laccase2 flanking introns support efficient circularization of diverse exons in Drosophila and human cells, providing a new tool for exploring the functional consequences of circular RNA expression across eukaryotes.
Delayed cord clamping has been shown to decrease the need for transfusion in preterm neonates, but may delay resuscitation. The aim of this study was to determine whether umbilical cord milking ...compared with immediate cord clamping in extremely preterm deliveries reduces the need for neonatal red blood cell transfusion.
Women admitted to a tertiary care center and expected to deliver between 24 to 28 completed weeks of gestation were randomized to cord milking before clamping or immediate cord clamping. The primary outcome was the risk of neonatal transfusion, reported as risk ratio (RR) and 95% confidence interval (CI).
Of 113 women who were enrolled and randomized, 56 were assigned to cord milking with 36 remaining eligible and completing the study and 57 were assigned to the control group with 39 remaining eligible and completing the study. Albeit not statistically significant, neonates in the cord milking group were less likely to require transfusion compared with those in the control group (RR: 0.86; 95% CI: 0.73 to 1.0). Neonates whose cords were milked had higher hematocrits at birth (P=0.004) and were less likely to develop an intraventricular hemorrhage (P=0.0195).
Milking the umbilical cord of a preterm neonate is an easy intervention with the potential to improve perinatal outcomes. Our results suggest that milking of the cord increases the neonate's initial hematocrit and may lessen the need for transfusion in the neonatal period. The observed reduction in the incidence of intraventricular hemorrhage may have important long-term implications that warrant further study.
ABSTRACT
We present a simulated cosmology analysis using the second and third moments of the weak lensing mass (convergence) maps. The second moment, or variances, of the convergence as a function of ...smoothing scale contains information similar to standard shear two-point statistics. The third moment, or the skewness, contains additional non-Gaussian information. The analysis is geared towards the third year (Y3) data from the Dark Energy Survey (DES), but the methodology can be applied to other weak lensing data sets. We present the formalism for obtaining the convergence maps from the measured shear and for obtaining the second and third moments of these maps given partial sky coverage. We estimate the covariance matrix from a large suite of numerical simulations. We test our pipeline through a simulated likelihood analyses varying 5 cosmological parameters and 10 nuisance parameters and identify the scales where systematic or modelling uncertainties are not expected to affect the cosmological analysis. Our simulated likelihood analysis shows that the combination of second and third moments provides a 1.5 per cent constraint on S8 ≡ σ8(Ωm/0.3)0.5 for DES Year 3 data. This is 20 per cent better than an analysis using a simulated DES Y3 shear two-point statistics, owing to the non-Gaussian information captured by the inclusion of higher order statistics. This paper validates our methodology for constraining cosmology with DES Year 3 data, which will be presented in a subsequent paper.
We present weak lensing shear catalogues for 139 square degrees of data taken during the Science Verification (SV) time for the new Dark Energy Camera (DECam) being used for the Dark Energy Survey ...(DES). We describe our object selection, point spread function estimation and shear measurement procedures using two independent shear pipelines, im3shape and ngmix, which produce catalogues of 2.12 million and 3.44 million galaxies, respectively. We detail a set of null tests for the shear measurements and find that they pass the requirements for systematic errors at the level necessary for weak lensing science applications using the SV data. We also discuss some of the planned algorithmic improvements that will be necessary to produce sufficiently accurate shear catalogues for the full 5-yr DES, which is expected to cover 5000 square degrees.
Abstract The latest Global Burden of Disease Study, published at the end of 2012, has highlighted the enormous global burden of low back pain. In contrast to the previous study, when it was ranked ...105 out of 136 conditions, low back pain is now the leading cause of disability globally, ahead of 290 other conditions. It was estimated to be responsible for 58.2 million years lived with disability in 1990, increasing to 83 million in 2010. This chapter illustrates the ways that the Global Burden of Disease data can be displayed using the data visualisation tools specifically designed for this purpose. It also considers how best to increase the precision of future global burden of low back pain estimates by identifying limitations in the available data and priorities for further research. Finally, it discusses what should be done at a policy level to militate against the rising burden of this condition.
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