Altered m6A Modification of Specific Cellular Transcripts Affects Flaviviridae Infection

The RNA modification N6-methyladenosine (m6A) modulates mRNA fate and thus affects many biological processes. We analyzed m6A across the transcriptome following infection by dengue virus (DENV), Zika virus (ZIKV), West Nile virus (WNV), and hepatitis C virus (HCV). We found that infection by these viruses in the Flaviviridae family alters m6A modification of specific cellular transcripts, including RIOK3 and CIRBP. During viral infection, the addition of m6A to RIOK3 promotes its translation, while loss of m6A in CIRBP promotes alternative splicing. Importantly, viral activation of innate immune sensing or the endoplasmic reticulum (ER) stress response contributes to the changes in m6A in RIOK3 or CIRBP, respectively. Further, several transcripts with infection-altered m6A profiles, including RIOK3 and CIRBP, encode proteins that influence DENV, ZIKV, and HCV infection. Overall, this work reveals that cellular signaling pathways activated during viral infection lead to alterations in m6A modification of host mRNAs to regulate infection. Here, Gokhale, McIntyre et al. identify m6A changes in cellular mRNAs following Flaviviridae infection and demonstrate that infection-activated pathways contribute to these changes. They show that altered m6A modification in RIOK3 and CIRBP mRNAs influence their translation and splicing, respectively, and that RIOK3, CIRBP, and other m6A-altered factors regulate infection

An Exact Diagonalization Demonstration of Incommensurability and Rigid Band Filling for N Holes in the t-J Model

We have calculated S(q) and the single particle distribution function for N holes in the t - J model on a non--square sqrt{8} X sqrt{32} 16--site lattice with periodic boundary conditions; we justify the use of this lattice in compariosn to those of having the full square symmetry of the bulk. This new cluster has a high density of vec k points along the diagonal of reciprocal space, viz. along k = (k,k). The results clearly demonstrate that when the single hole problem has a ground state with a system momentum of vec k = (pi/2,pi/2), the resulting ground state for N holes involves a shift of the peak of the system's structure factor away from the antiferromagnetic state. This shift effectively increases continuously with N. When the single hole problem has a ground state with a momentum that is not equal to k = (pi/2,pi/2), then the above--mentioned incommensurability for N holes is not found. The results for the incommensurate ground states can be understood in terms of rigid--band filling: the effective occupation of the single hole k = (pi/2,pi/2) states is demonstrated by the evaluation of the single particle momentum distribution function . Unlike many previous studies, we show that for the many hole ground state the occupied momentum states are indeed k = (+/- pi/2,+/- pi/2) states.Comment: Revtex 3.0; 23 pages, 1 table, and 13 figures, all include

Use of MRI in the diagnosis of fetal brain abnormalities in utero (MERIDIAN): a multicentre, prospective cohort study.

BACKGROUND: In-utero MRI (iuMRI) has shown promise as an adjunct to ultrasound but the comparative diagnostic performance has been poorly defined. We aimed to assess whether the diagnostic accuracy and confidence of the prenatal diagnosis of fetal brain abnormalities is improved with iuMRI and assess the clinical impact and patient acceptability of iuMRI. METHODS: We did a multicentre, prospective, cohort study in the UK, at 16 fetal medicine centres, of pregnant women aged 16 years or older whose fetus had a brain abnormality detected by ultrasound at a gestational age of 18 weeks or more, had no contraindications to iuMRI, and consented to enter the study. Women carrying a fetus suspected of having a brain anomaly on ultrasound had iuMRI done within 14 days of ultrasound. The findings were reviewed by two independent panels and used to estimate diagnostic accuracy and confidence by comparison with outcome diagnoses. Changes in diagnosis, prognosis, and clinical management brought about by iuMRI and patient acceptability were assessed. FINDINGS: Participants were recruited between July 29, 2011, and Aug 31, 2014. The cohort was subdivided by gestation into the 18 weeks to less than 24 weeks fetus cohort (n=369) and into the 24 weeks or older fetus cohort (n=201). Diagnostic accuracy was improved by 23% (95% CI 18-27) in the 18 weeks to less than 24 weeks group and 29% (23-36) in the 24 weeks and older group (p<0·0001 for both groups). The overall diagnostic accuracy was 68% for ultrasound and 93% for iuMRI (difference 25%, 95% CI 21-29). Dominant diagnoses were reported with high confidence on ultrasound in 465 (82%) of 570 cases compared with 544 (95%) of 570 cases on iuMRI. IuMRI provided additional diagnostic information in 387 (49%) of 783 cases, changed prognostic information in at least 157 (20%), and led to changes in clinical management in more than one in three cases. IuMRI also had high patient acceptability with at least 95% of women saying they would have an iuMRI study if a future pregnancy were complicated by a fetal brain abnormality. INTERPRETATION: iuMRI improves diagnostic accuracy and confidence for fetal brain anomalies and leads to management changes in a high proportion of cases. This finding, along with the high patient acceptability, leads us to propose that any fetus with a suspected brain abnormality on ultrasound should have iuMRI to better inform counselling and management decisions. FUNDING: National Institute for Health Research Health Technology Assessment programme

Systematic review of economic evaluations and cost analyses of guideline implementation strategies

Objectives To appraise the quality of economic studies undertaken as part of evaluations of guideline implementation strategies; determine their resources use; and recommend methods to improve future studies. Methods Systematic review of economic studies undertaken alongside robust study designs of clinical guideline implementation strategies published (1966-1998). Studies assessed against the BMJ economic evaluations guidelines for each stage of the guideline process (guideline development, implementation and treatment). Results 235 studies were identified, 63 reported some information on cost. Only 3 studies provided evidence that their guideline was effective and efficient. 38 reported the treatment costs only, 12 implementation and treatment costs, 11 implementation costs alone, and two guideline development, implementation and treatment costs. No study gave reasonably complete information on costs. Conclusions Very few satisfactory economic evaluations of guideline implementation strategies have been performed. Current evaluations have numerous methodological defects and rarely consider all relevant costs and benefits. Future evaluations should focus on evaluating the implementation of evidence based guidelines. Keywords: Cost-effectiveness analysis, physician (or health care professional) behaviour, practice guidelines, quality improvement, systematic review.Peer reviewedAuthor versio

Antimatter from the cosmological baryogenesis and the anisotropies and polarization of the CMB radiation

We discuss the hypotheses that cosmological baryon asymmetry and entropy were produced in the early Universe by phase transition of the scalar fields in the framework of spontaneous baryogenesis scenario. We show that annihilation of the matter-antimatter clouds during the cosmological hydrogen recombination could distort of the CMB anisotropies and polarization by delay of the recombination. After recombination the annihilation of the antibaryonic clouds (ABC) and baryonic matter can produce peak-like reionization at the high redshifts before formation of quasars and early galaxy formation. We discuss the constraints on the parameters of spontaneous baryogenesis scenario by the recent WMAP CMB anisotropy and polarization data and on possible manifestation of the antimatter clouds in the upcoming PLANCK data.Comment: PRD in press with minor change

Journeying through dementia randomised controlled trial of a psychosocial intervention for people living with early dementia: embedded qualitative study with participants, carers and interventionists

Objective: To identify the barriers and facilitators to the implementation of a complex psychosocial intervention though a study exploring the experiences of participants, carers and interventionists during a trial. Methods: Individual semi-structured interviews were conducted with participants, their carers, and interventionists from a sample of recruiting sites that took part in the Journeying through Dementia randomized controlled trial (RCT). Interview data were transcribed and analysed using framework analysis. Co-researcher data analysis workshops were also conducted to explore researcher interpretations of the data through the lens of those with lived experience of dementia. Triangulation enabled comparison of findings from the interviews with findings from the co-researcher workshops. Results: Three main themes emerged from the interview data: being prepared; intervention engagement; and participation and outcomes from engagement. From these themes, a number of factors that can moderate delivery and receipt of the intervention as intended were identified. These were context and environment; readiness, training, skills and competencies of the workforce; identifying meaningful participation and relationships. Conclusion: This study highlighted that the observed benefit of the intervention was nuanced for each individual. Mechanisms of change were influenced by a range of individual, social and contextual factors. Future research should therefore consider how best to identify and measure the multifaceted interplay of mechanisms of change in complex interventions. Trial Registration: ISRCTN17993825

The Void Abundance with Non-Gaussian Primordial Perturbations

We use a Press-Schechter-like calculation to study how the abundance of voids changes in models with non-Gaussian initial conditions. While a positive skewness increases the cluster abundance, a negative skewness does the same for the void abundance. We determine the dependence of the void abundance on the non-Gaussianity parameter fnl for the local-model bispectrum-which approximates the bispectrum in some multi-field inflation models-and for the equilateral bispectrum, which approximates the bispectrum in e.g. string-inspired DBI models of inflation. We show that the void abundance in large-scale-structure surveys currently being considered should probe values as small as fnl < 10 and fnl^eq < 30, over distance scales ~10 Mpc.Comment: Submitted to JCA

Cosmic Chronometers: Constraining the Equation of State of Dark Energy. I: H(z) Measurements

We present new determinations of the cosmic expansion history from red-envelope galaxies. We have obtained for this purpose high-quality spectra with the Keck-LRIS spectrograph of red-envelope galaxies in 24 galaxy clusters in the redshift range 0.2 < z < 1.0. We complement these Keck spectra with high-quality, publicly available archival spectra from the SPICES and VVDS surveys. We improve over our previous expansion history measurements in Simon et al. (2005) by providing two new determinations of the expansion history: H(z) = 97 +- 62 km/sec/Mpc at z = 0.5 and H(z) = 90 +- 40 km/sec/Mpc at z = 0.8. We discuss the uncertainty in the expansion history determination that arises from uncertainties in the synthetic stellar-population models. We then use these new measurements in concert with cosmic-microwave-background (CMB) measurements to constrain cosmological parameters, with a special emphasis on dark-energy parameters and constraints to the curvature. In particular, we demonstrate the usefulness of direct H(z) measurements by constraining the dark- energy equation of state parameterized by w0 and wa and allowing for arbitrary curvature. Further, we also constrain, using only CMB and H(z) data, the number of relativistic degrees of freedom to be 4 +- 0.5 and their total mass to be < 0.2 eV, both at 1-sigma.Comment: Submitted to JCA

Constraining the expansion rate of the Universe using low-redshift ellipticals as cosmic chronometers

We present a new methodology to determine the expansion history of the Universe analyzing the spectral properties of early type galaxies (ETG). We found that for these galaxies the 4000\AA break is a spectral feature that correlates with the relative ages of ETGs. In this paper we describe the method, explore its robustness using theoretical synthetic stellar population models, and apply it using a SDSS sample of $\sim$14 000 ETGs. Our motivation to look for a new technique has been to minimise the dependence of the cosmic chronometer method on systematic errors. In particular, as a test of our method, we derive the value of the Hubble constant $H_0 = 72.6 \pm 2.8$ (stat) $\pm2.3$ (syst) (68% confidence), which is not only fully compatible with the value derived from the Hubble key project, but also with a comparable error budget. Using the SDSS, we also derive, assuming w=constant, a value for the dark energy equation of state parameter $w = -1 \pm 0.2$ (stat) $\pm0.3$ (syst). Given the fact that the SDSS ETG sample only reaches $z \sim 0.3$, this result shows the potential of the method. In future papers we will present results using the high-redshift universe, to yield a determination of H(z) up to $z \sim 1$.Comment: 25 pages, 17 figures, JCAP accepte

Bending bad—testing caramel wafer bars (#TestATunnocks)

During the coronavirus pandemic, there have been significant challenges in the remote teaching and demonstration of experiments, especially those that require laboratory testing equipment. With a desire to give students a feel for our materials laboratory on open days and allow them to gain a deeper understanding of what materials science and engineering is about, we have designed an experiment focused on composite materials that can be performed remotely and without specialist equipment. This enabled students to experience a bend test sensorily through seeing, hearing and feeling it, creating a strong link to then being able to relate it to the pre-prepared experimental data taken in the laboratory. This fun, easy-to-run and engaging experiment allowed a shared experience and encouraged a discussion about students' observations, differences in results and implications of the bend strength of sandwich composites. We have found it not only works well universally by all ages but can be used with younger children to think about words such as 'stronger', 'stiffer' and 'flexible' and how materials can be different in different directions