Exploring the Effect of G6PC2 Single Nucleotide Polymorphisms on Enzyme Activity and Human Health

G6PC2 encodes a glucose-6-phosphatase catalytic subunit that is highly expressed in pancreatic islet beta cells. Genome wide association studies (GWAS) have shown that single nucleotide polymorphisms (SNPs) in the G6PC2 gene are associated with variations in fasting blood glucose (FBG), a parameter linked with risk for type 2 diabetes (T2D). Studies in mice have complemented these GWAS data by showing that deletion of G6pc2 abolishes islet glucose-6-phosphatase activity and lowers FBG. We hypothesize that G6pc2 forms a substrate cycle with glucokinase that determines the sensitivity of glucose-stimulated insulin secretion (GSIS) to glucose. In support of this hypothesis we have previously shown that deletion of G6pc2 enhances GSIS at sub-maximal glucose concentrations and abolishes glucose cycling in isolated islets. More recently we have demonstrated that deletion of G6pc2 enhances glycolysis in isolated mouse islets, and that high rates of glucose cycling are also detected in human islets. Our broad hypothesis is that the results of these studies will strongly suggest that G6PC2 inhibition should be considered as a novel therapeutic strategy for lowering FBG and thereby preventing T2D. To extend these observations we have developed a novel intact cell assay for G6PC2 activity. This assay relies on the observation that CREB and ChREBP bound to the rat G6PC1 promoter are highly glucose responsive in the rat islet-derived 832/13 cell line and the fact that endogenous G6PC2 is absent. In the presence of catalytically-dead G6PC2, glucose stimulates G6PC1-luciferase fusion gene expression. However, this induction is blunted in the presence of wild type G6PC2. We are using this assay to determine the effect of non-synonymous G6PC2 SNPs on G6PC2 activity and then examining the association between SNPs that markedly affect G6PC2 activity with their effects on human health as assessed using Vanderbilt’s BioVU biobank. These data will reveal whether SNPs in G6PC2 are associated with only altered FBG or whether G6PC2 affects other aspects of human health

Understanding Shape and Centroid Deviations in 39 Strong Lensing Galaxy Clusters in Various Dynamical States

Through observational tests of strong lensing galaxy clusters, we can test simulation derived structure predictions that follow from $\Lambda$ Cold Dark Matter ($\Lambda$CDM) cosmology. The shape and centroid deviations between the total matter distribution, stellar matter distributions, and hot intracluster gas distribution serve as an observational test of these theoretical structure predictions. We measure the position angles, ellipticities, and locations/centroids of the brightest cluster galaxy (BCG), intracluster light (ICL), the hot intracluster medium (ICM), and the core lensing mass for a sample of strong lensing galaxy clusters from the SDSS Giant Arcs Survey (SGAS). We utilize HST WFC3/IR imaging data to measure the shapes/centroids of the ICL and BCG distributions and use Chandra ACIS-I X-ray data to measure the shapes/centroids of ICM. Additionally, we measure the concentration parameter c and asymmetry parameter A to incorporate cluster dynamical state into our analysis. Using this multicomponent approach, we attempt to constrain the astrophysics of our strong lensing cluster sample and evaluate the different components in terms of their ability to trace out the DM halo of clusters in various dynamical states.Comment: 6 pages, 4 figures, to appear in Proc. of the mm Universe 2023 conference, Grenoble (France), June 2023, published by F. Mayet et al. (Eds), EPJ Web of conferences, EDP Science

K2-19b and c are in a 3:2 Commensurability but out of Resonance: A Challenge to Planet Assembly by Convergent Migration

K2-19b and c were among the first planets discovered by NASA's K2 mission and together stand in stark contrast with the physical and orbital properties of the solar system planets. The planets are between the size of Uranus and Saturn at 7.0 ± 0.2 R⊕ and 4.1 ± 0.2 R⊕, respectively, and reside a mere 0.1% outside the nominal 3:2 mean-motion resonance. They represent a different outcome of the planet formation process than the solar system, as well as the vast majority of known exoplanets. We measured the physical and orbital properties of these planets using photometry from K2, Spitzer, and ground-based telescopes, along with radial velocities from Keck/HIRES. Through a joint photodynamical model, we found that the planets have moderate eccentricities of e ≈ 0.20 and well-aligned apsides Δϖ ≈ 0°. The planets occupy a strictly nonresonant configuration: the resonant angles circulate rather than librate. This defies the predictions of standard formation pathways that invoke convergent or divergent migration, both of which predict Δ ≈ 180° and eccentricities of a few percent or less. We measured masses of M_(p,b) = 32.4 ± 1.7 M⊕ and M_(p,c) = 10.8 ± 0.6 M⊕. Our measurements, with 5% fractional uncertainties, are among the most precise of any sub-Jovian exoplanet. Mass and size reflect a planet's core/envelope structure. Despite having a relatively massive core of M_(core) ≈ 15 M⊕, K2-19b is envelope-rich, with an envelope mass fraction of roughly 50%. This planet poses a challenge to standard models of core-nucleated accretion, which predict that cores ≳10 M⊕ will quickly accrete gas and trigger runaway accretion when the envelope mass exceeds that of the core

TEMPLATES: A Robust Outlier Rejection Method for JWST/NIRSpec Integral Field Spectroscopy

We describe a custom outlier rejection algorithm for JWST/NIRSpec integral field spectroscopy. This method uses a layered sigma clipping approach that adapts clipping thresholds based upon the spatial profile of the science target. We find that this algorithm produces a robust outlier rejection while simultaneously preserving the signal of the science target. Originally developed as a response to unsatisfactory initial performance of the jwst pipeline outlier detection step, this method works either as a standalone solution, or as a supplement to the current pipeline software. Comparing leftover (i.e., not flagged) artifacts with the current pipeline's outlier detection step, we find that our method results in one fifth as many residual artifacts as the jwst pipeline. However, we find a combination of both methods removes nearly all artifacts -- an approach that takes advantage of both our algorithm's robust outlier rejection and the pipeline's use of individual dithers. This combined approach is what the TEMPLATES Early Release Science team has converged upon for our NIRSpec observations. Finally, we publicly release the code and Jupyter notebooks for the custom outlier rejection algorithm.Comment: 10 pages, including 5 figures. Submitted to the Publications of the Astronomical Society of the Pacific (PASP). Code associated with paper released at https://github.com/aibhleog/baryon-swee

WASP-131 b with ESPRESSO I : a bloated sub-Saturn on a polar orbit around a differentially rotating solar-type star

In this paper, we present observations of two high-resolution transit datasets obtained with ESPRESSO of the bloated sub-Saturn planet WASP-131 b. We have simultaneous photometric observations with NGTS and EulerCam. In addition, we utilised photometric lightcurves from TESS, WASP, EulerCam and TRAPPIST of multiple transits to fit for the planetary parameters and update the ephemeris. We spatially resolve the stellar surface of WASP-131 utilising the Reloaded Rossiter McLaughlin technique to search for centre-to-limb convective variations, stellar differential rotation, and to determine the star-planet obliquity for the first time. We find WASP-131 is misaligned on a nearly retrograde orbit with a projected obliquity of $\lambda = 162.4\substack{+1.3 \\-1.2}^{\circ }$. In addition, we determined a stellar differential rotation shear of α = 0.61 ± 0.06 and disentangled the stellar inclination ($i_* = 40.9\substack{+13.3 \\-8.5}^{\circ }$) from the projected rotational velocity, resulting in an equatorial velocity of $v_{\rm {eq}} = 7.7\substack{+1.5 \\-1.3}$ km s−1. In turn, we determined the true 3D obliquity of $\psi = 123.7\substack{+12.8 \\-8.0}^{\circ }$, meaning the planet is on a perpendicular/polar orbit. Therefore, we explored possible mechanisms for the planetary system’s formation and evolution. Finally, we searched for centre-to-limb convective variations where there was a null detection, indicating that centre-to-limb convective variations are not prominent in this star or are hidden within red noise

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Characterizing and Tuning Perfusion Parameters Within an Innovative, Versatile Oxygenating Perfusion System

The advantages of oxygenated perfusion are continuing to be demonstrated by many groups focused on improving the efficacy of tissue preservation for transplant, bioreactors for studies of basic tissue physiology, and closed-loop resuscitation. This work presents a novel and portable device that supplies oxygenated and pulsatile perfusion, both of which are regulated by a single pump-oxygenator component comprised of silicone tubes that are cyclically inflated/deflated with compressed oxygen. In this study, pump variables (oxygen supply pressure and length of a silicone tube) were evaluated against hydraulic elements that mimicked the vascular resistance of kidneys, livers, and hearts. The perfusion pressures, flow rates, and oxygenation rates produced by the device were characterized for all configurations of pump variables, and the pulse rates were tuned to improve performance. The device supplied perfusion pressures ranging from 3.5 to 109 mmHg, flow rates ranging from 1.4 to 71.8 mL min−1, and oxygenation rates up to 316.6 µmol min−1. From those results, it was determined that the device was capable of achieving perfusion parameters used in previous kidney, liver, and heart preservation studies. Ultimately, this research demonstrated the efficacy of a novel device that is designed to supply oxygenated perfusion across a range of applications