1,252 research outputs found

    Direct measurements of mean Reynolds stress and ripple roughness in the presence of energetic forcing by surface waves

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    Author Posting. © American Geophysical Union, 2018. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research: Oceans 123 (2018): 2494-2512, doi:10.1002/2017JC013252.Direct covariance observations of the mean flow Reynolds stress and sonar images of the seafloor collected on a wave‐exposed inner continental shelf demonstrate that the drag exerted by the seabed on the overlying flow is consistent with boundary layer models for wave‐current interaction, provided that the orientation and anisotropy of the bed roughness are appropriately quantified. Large spatial and temporal variations in drag result from nonequilibrium ripple dynamics, ripple anisotropy, and the orientation of the ripples relative to the current. At a location in coarse sand characterized by large two‐dimensional orbital ripples, the observed drag shows a strong dependence on the relative orientation of the mean current to the ripple crests. At a contrasting location in fine sand, where more isotropic sub‐orbital ripples are observed, the sensitivity of the current to the orientation of the ripples is reduced. Further, at the coarse site under conditions when the currents are parallel to the ripple crests and the wave orbital diameter is smaller than the wavelength of the relic orbital ripples, the flow becomes hydraulically smooth. This transition is not observed at the fine site, where the observed wave orbital diameter is always greater than the wavelength of the observed sub‐orbital ripples. Paradoxically, the dominant along‐shelf flows often experience lower drag at the coarse site than at the fine site, despite the larger ripples, highlighting the complex dynamics controlling drag in wave‐exposed environments with heterogeneous roughness.National Science Foundation Ocean Sciences Division Award Grant Number: 1356060; U.S. Geological Survey Coastal and Marine Geology Program2018-09-2

    Developing a Tanshinone IIA Memetic by Targeting MIOS to Regulate mTORC1 and Autophagy in Glioblastoma

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    Tanshinone IIA (T2A) is a bioactive compound that provides promise in the treatment of Glioblastoma multiforme (GBM), with a range of molecular mechanisms including inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) and the induction of autophagy. Recently, T2A has been demonstrated to function through sestrin 2 (SESN) to inhibit mTORC1 activity, but this pathway has not been investigated regarding autophagy. Here we employed the model system Dictyostelium discoideum and GBM cell lines to investigate the role of T2A in autophagy induction, focusing on the regulation of SESN via a GATOR2 component MIOS, to mTORC1. We show that in D. discoideum, T2A treatment induces autophagy, and both this effect and mTORC1 inhibition is lost upon ablation of either SESN (sesn-) or MIOS (mios-). We then investigated targeting MIOS to reproduce this effect of T2A. Here, computational analysis identified 25 novel compounds predicted to strongly bind the human MIOS protein, and one compound (MIOS inhibitor 3; Mi3) that reduced cell proliferation in two GBM cell lines. Furthermore, Mi3 specificity was demonstrated through the reduction of D. discoideum cell proliferation and induced autophagy, dependent upon MIOS. These effects were also confirmed in GBM cells, where Mi3 treatment also inhibited mTORC1 activity and induced autophagy. Thus, we identify a potential T2A mimetic with demonstrated effects on inhibition of mTORC1 and induction of autophagy in GBM cells

    The ORACLE Children Study:Educational outcomes at 11 years of age following antenatal prescription of erythromycin or co-amoxiclav

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    Background Antibiotics used for women in spontaneous preterm labour without overt infection, in contrast to those with preterm rupture of membranes, are associated with altered functional outcomes in their children. Methods From the National Pupil Database, we used Key Stage 2 scores, national test scores in school year 6 at 11 years of age, to explore the hypothesis that erythromycin and co-amoxiclav were associated with poorer educational outcomes within the ORACLE Children Study. Results Anonymised scores for 97% of surviving children born to mothers recruited to ORACLE and resident in England were analysed against treatment group adjusting for key available socio-demographic potential confounders. No association with crude or with adjusted scores for English, mathematics or science was observed by maternal antibiotic group in either women with preterm rupture of membranes or spontaneous preterm labour with intact membranes. While the proportion receiving special educational needs was similar in each group (range 31.6-34.4%), it was higher than the national rate of 19%. Conclusions Despite evidence that antibiotics are associated with increased functional impairment at 7 years, educational test scores and special needs at 11 years of age show no differences between trial groups. Trial registration number ISCRT Number 52995660 (original ORACLE trial number).</p

    C-STICH2: emergency cervical cerclage to prevent miscarriage and preterm birth—study protocol for a randomised controlled trial

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    Abstract Background Cervical cerclage is a recognised treatment to prevent late miscarriage and pre-term birth (PTB). Emergency cervical cerclage (ECC) for cervical dilatation with exposed unruptured membranes is less common and the potential benefits of cerclage are less certain. A randomised control trial is needed to accurately assess the effectiveness of ECC in preventing pregnancy loss compared to an expectant approach. Methods C-STICH2 is a multicentre randomised controlled trial in which women presenting with cervical dilatation and unruptured exposed membranes at 16 + 0 to 27 + 6 weeks gestation are randomised to ECC or expectant management. Trial design includes 18 month internal pilot with embedded qualitative process evaluation, minimal data set and a within-trial health economic analysis. Inclusion criteria are ≄16 years, singleton pregnancy, exposed membranes at the external os, gestation 16 + 0–27 + 6 weeks, and informed consent. Exclusion criteria are contraindication to cerclage, cerclage in situ or previous cerclage in this pregnancy. Randomisation occurs via an online service in a 1:1 ratio, using a minimisation algorithm to reduce chance imbalances in key prognostic variables (site, gestation and dilatation). Primary outcome is pregnancy loss; a composite including miscarriage, termination of pregnancy and perinatal mortality defined as stillbirth and neonatal death in the first week of life. Secondary outcomes include all core outcomes for PTB. Two-year development outcomes will be assessed using general health and Parent Report of Children’s Abilities-Revised (PARCA-R) questionnaires. Intended sample size is 260 participants (130 each arm) based on 60% rate of pregnancy loss in the expectant management arm and 40% in the ECC arm, with 90% power and alpha 0.05. Analysis will be by intention-to-treat. Discussion To date there has been one small trial of ECC in 23 participants which included twin and singleton pregnancies. This small trial along with the largest observational study (n = 161) found ECC to prolong pregnancy duration and reduce deliveries before 34 weeks gestation. It is important to generate high quality evidence on the effectiveness of ECC in preventing pregnancy loss, and improve understanding of the prevalence of the condition and frequency of complications associated with ECC. An adequately powered RCT will provide the highest quality evidence regarding optimum care for these women and their babies. Trial registration ISRCTN Registry ISRCTN12981869 . Registered on 13th June 2018
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