Rad GTPase Deletion Atenuates Post-Ischemic Cardiac Dysfunction and Remodeling

The protein Rad interacts with the L-type calcium channel complex to modulate trigger Ca2+ and hence to govern contractility. Reducing Rad levels increases cardiac output. Ablation of Rad also attenuated the inflammatory response following acute myocardial infarction. Future studies to target deletion of Rad in the heart could be conducted to establish a novel treatment paradigm whereby pathologically stressed hearts would be given safe, stable positive inotropic support without arrhythmias and without pathological structural remodeling. Future investigations will also focus on establishing inhibitors of Rad and testing the efficacy of Rad deletion in cardioprotection relative to the time of onset of acute myocardial infarction

Current- and wave- generated bedforms on mixed sand-clay intertidal flats : a new bedform phase diagram and implications for bed roughness and preservation potential

Funding: This work was supported by the United Kingdom’s Natural Environment Research Council (NERC) under Grant NE/I027223/1 (COHBED). JM, Julie Hope, and Daniel Parsons were partially funded by a Horizon 2020 European Research Council Consolidator Award (GEOSTICK, Grant 725955). The GEOSTICK project also kindly contributed the article processing fees. Andrew Manning’s contribution toward this research was partly supported by the National Science Foundation grants OCE-1924532 and OCE-1736668, TKI-MUSA project 11204950-000-ZKS-0002, and the HR Wallingford company research project FineScale (Grant Nos. ACK3013_62). DP received funding from the MASTS pooling initiative (The Marine Alliance for Science and Technology for Scotland) and their support is gratefully acknowledged. MASTS is funded by the Scottish Funding Council (Grant reference HR09011) and contributing institutions.The effect of bedforms on frictional roughness felt by the overlying flow is crucial to the regional modelling of estuaries and coastal seas. Bedforms are also a key marker of palaeoenvironments. Experiments have shown that even modest biotic and abiotic cohesion in sand inhibits bedform formation, modifies bedform size, and slows bedform development, but this has rarely been tested in nature. The present study used a comprehensive dataset recorded over a complete spring–neap cycle on an intertidal flat to investigate bedform dynamics controlled by a wide range of wave and current conditions, including the effects of wave–current angle and bed cohesion. A detailed picture of different bedform types and their relationship to the flow, be they equilibrium, non-equilibrium, or relict, was produced, and captured in a phase diagram that integrates wave-dominated, current-dominated, and combined wave–current bedforms. This bedform phase diagram incorporates a substantially wider range of flow conditions than previous phase diagrams, including bedforms related to near-orthogonal wave–current angles, such as ladderback ripples. Comparison with laboratory-derived bedform phase diagrams indicates that washed-out ripples, lunate interference ripples and upper-stage plane beds replace the subaqueous dune field; such bedform distributions may be a key characteristic of intertidal flats. The field data also provide a means of predicting the dimensions of these bedforms, which can be transferred to other areas and grain sizes. We show that an equation for the prediction of equilibrium bedform size is sufficient to predict the roughness, even though the bedforms are highly variable in character and only in equilibrium with the flow for approximately half the time. Whilst the effect of cohesive clay is limited under more active spring conditions, clay does play a role in reducing the bedform dimensions under more quiescent neap conditions. We also investigated which combinations of waves, currents, and bed clay contents in the intertidal zone have the highest potential for bedform preservation in the geological record. This shows that combined wave–current bedforms have the lowest preservation potential and equilibrium current ripples have the highest preservation potential, even in the presence of moderate and storm waves. Hence, the absence of wave ripples and combined-flow bedforms and their primary stratification in sedimentary successions cannot be taken as evidence that waves were absent at the time of deposition.Publisher PDFPeer reviewe

Glucocorticoids accelerate maturation of the heme pathway in fetal liver through effects on transcription and DNA methylation

<p>Glucocorticoids are widely used in threatened preterm labor to promote maturation in many organ systems in preterm babies and have significant beneficial effects on morbidity and mortality. We performed transcriptional profiling in fetal liver in a rat model of prenatal glucocorticoid exposure and identified marked gene expression changes in heme biosynthesis, utilization, and degradation pathways in late gestation. These changes in gene expression associated with alterations in DNA methylation and with a reduction in hepatic heme concentration. There were no persistent differences in gene expression, DNA methylation, or heme concentrations at 4 weeks of age, suggesting that these are transient effects. Our findings are consistent with glucocorticoid-induced accelerated maturation of the haematopoietic system and support the hypothesis that glucocorticoids can drive changes in gene expression in association with alterations in DNA methylation.</p

Treatment effect of switching from intravenous to subcutaneous C1-inhibitor for prevention of hereditary angioedema attacks: COMPACT subgroup findings

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Development of the IntCal database

The IntCal family of radiocarbon (14C) calibration curves is based on research spanning more than three decades. The IntCal group have collated the 14C and calendar age data (mostly derived from primary publications with other types of data and meta-data) and, since 2010, made them available for other sorts of analysis through an open-access database. This has ensured transparency in terms of the data used in the construction of the ratified calibration curves. As the IntCal database expands, work is underway to facilitate best practice for new data submissions, make more of the associated metadata available in a structured form, and help those wishing to process the data with programming languages such as R, Python, and MATLAB. The data and metadata are complex because of the range of different types of archives. A restructured interface, based on the “IntChron” open-access data model, includes tools which allow the data to be plotted and compared without the need for export. The intention is to include complementary information which can be used alongside the main 14C series to provide new insights into the global carbon cycle, as well as facilitating access to the data for other research applications. Overall, this work aims to streamline the generation of new calibration curves

The role of biophysical cohesion on subaqueous bed form size

Biologically active, fine-grained sediment forms abundant sedimentary deposits on Earth's surface, and mixed mud-sand dominates many coasts, deltas, and estuaries. Our predictions of sediment transport and bed roughness in these environments presently rely on empirically based bed form predictors that are based exclusively on biologically inactive cohesionless silt, sand, and gravel. This approach underpins many paleoenvironmental reconstructions of sedimentary successions, which rely on analysis of cross-stratification and bounding surfaces produced by migrating bed forms. Here we present controlled laboratory experiments that identify and quantify the influence of physical and biological cohesion on equilibrium bed form morphology. The results show the profound influence of biological cohesion on bed form size and identify how cohesive bonding mechanisms in different sediment mixtures govern the relationships. The findings highlight that existing bed form predictors require reformulation for combined biophysical cohesive effects in order to improve morphodynamic model predictions and to enhance the interpretations of these environments in the geological record

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels

Artemisinin-Naphthoquine versus Artemether-Lumefantrine for Uncomplicated Malaria in Papua New Guinean Children: An Open-Label Randomized Trial

© 2014 Laman et al. Artemisinin combination therapies (ACTs) with broad efficacy are needed where multiple Plasmodium species are transmitted, especially in children, who bear the brunt of infection in endemic areas. In Papua New Guinea (PNG), artemether-lumefantrine is the first-line treatment for uncomplicated malaria, but it has limited efficacy against P. vivax. Artemisinin-naphthoquine should have greater activity in vivax malaria because the elimination of naphthoquine is slower than that of lumefantrine. In this study, the efficacy, tolerability, and safety of these ACTs were assessed in PNG children aged 0.5–5 y.An open-label, randomized, parallel-group trial of artemether-lumefantrine (six doses over 3 d) and artemisinin-naphthoquine (three daily doses) was conducted between 28 March 2011 and 22 April 2013. Parasitologic outcomes were assessed without knowledge of treatment allocation. Primary endpoints were the 42-d P. falciparum PCR-corrected adequate clinical and parasitologic response (ACPR) and the P. vivax PCR-uncorrected 42-d ACPR. Non-inferiority and superiority designs were used for falciparum and vivax malaria, respectively. Because the artemisinin-naphthoquine regimen involved three doses rather than the manufacturer-specified single dose, the first 188 children underwent detailed safety monitoring. Of 2,542 febrile children screened, 267 were randomized, and 186 with falciparum and 47 with vivax malaria completed the 42-d follow-up. Both ACTs were safe and well tolerated. P. falciparum ACPRs were 97.8% and 100.0% in artemether-lumefantrine and artemisinin-naphthoquine-treated patients, respectively (difference 2.2% [95% CI -3.0% to 8.4%] versus -5.0% non-inferiority margin, p?=?0.24), and P. vivax ACPRs were 30.0% and 100.0%, respectively (difference 70.0% [95% CI 40.9%–87.2%], p&lt;0.001). Limitations included the exclusion of 11% of randomized patients with sub-threshold parasitemias on confirmatory microscopy and direct observation of only morning artemether-lumefantrine dosing.Artemisinin-naphthoquine is non-inferior to artemether-lumefantrine in PNG children with falciparum malaria but has greater efficacy against vivax malaria, findings with implications in similar geo-epidemiologic settings within and beyond Oceania.Australian New Zealand Clinical Trials Registry ACTRN12610000913077.Please see later in the article for the Editors' Summary