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

Mid-infrared Galaxy Morphology from the Spitzer Survey of Stellar Structure in Galaxies (S^4G): The Imprint of the De Vaucouleurs Revised Hubble-Sandage Classification System at 3.6 μm

Spitzer Space Telescope Infrared Array Camera imaging provides an opportunity to study all known morphological types of galaxies in the mid-IR at a depth significantly better than ground-based near-infrared and optical images. The goal of this study is to examine the imprint of the de Vaucouleurs classification volume in the 3.6 μm band, which is the best Spitzer waveband for galactic stellar mass morphology owing to its depth and its reddening-free sensitivity mainly to older stars. For this purpose, we have prepared classification images for 207 galaxies from the Spitzer archive, most of which are formally part of the Spitzer Survey of Stellar Structure in Galaxies (S^4G), a Spitzer post-cryogenic ("warm") mission Exploration Science Legacy Program survey of 2331 galaxies closer than 40 Mpc. For the purposes of morphology, the galaxies are interpreted as if the images are blue light, the historical waveband for classical galaxy classification studies. We find that 3.6 μm classifications are well correlated with blue-light classifications, to the point where the essential features of many galaxies look very similar in the two very different wavelength regimes. Drastic differences are found only for the most dusty galaxies. Consistent with a previous study by Eskridge et al., the main difference between blue-light and mid-IR types is an ≈1 stage interval difference for S0/a to Sbc or Sc galaxies, which tend to appear "earlier" in type at 3.6 μm due to the slightly increased prominence of the bulge, the reduced effects of extinction, and the reduced (but not completely eliminated) effect of the extreme population I stellar component. We present an atlas of all of the 207 galaxies analyzed here and bring attention to special features or galaxy types, such as nuclear rings, pseudobulges, flocculent spiral galaxies, I0 galaxies, double-stage and double-variety galaxies, and outer rings, that are particularly distinctive in the mid-IR

The wide-field, multiplexed, spectroscopic facility WEAVE: Survey design, overview, and simulated implementation

WEAVE, the new wide-field, massively multiplexed spectroscopic survey facility for the William Herschel Telescope, will see first light in late 2022. WEAVE comprises a new 2-degree field-of-view prime-focus corrector system, a nearly 1000-multiplex fibre positioner, 20 individually deployable 'mini' integral field units (IFUs), and a single large IFU. These fibre systems feed a dual-beam spectrograph covering the wavelength range 366$-$959\,nm at $R\sim5000$, or two shorter ranges at $R\sim20\,000$. After summarising the design and implementation of WEAVE and its data systems, we present the organisation, science drivers and design of a five- to seven-year programme of eight individual surveys to: (i) study our Galaxy's origins by completing Gaia's phase-space information, providing metallicities to its limiting magnitude for $\sim$3 million stars and detailed abundances for $\sim1.5$ million brighter field and open-cluster stars; (ii) survey $\sim0.4$ million Galactic-plane OBA stars, young stellar objects and nearby gas to understand the evolution of young stars and their environments; (iii) perform an extensive spectral survey of white dwarfs; (iv) survey $\sim400$ neutral-hydrogen-selected galaxies with the IFUs; (v) study properties and kinematics of stellar populations and ionised gas in $z<0.5$ cluster galaxies; (vi) survey stellar populations and kinematics in $\sim25\,000$ field galaxies at $0.3\lesssim z \lesssim 0.7$; (vii) study the cosmic evolution of accretion and star formation using $>1$ million spectra of LOFAR-selected radio sources; (viii) trace structures using intergalactic/circumgalactic gas at $z>2$. Finally, we describe the WEAVE Operational Rehearsals using the WEAVE Simulator.Comment: 41 pages, 27 figures, accepted for publication by MNRA

The wide-field, multiplexed, spectroscopic facility WEAVE : survey design, overview, and simulated implementation

Funding for the WEAVE facility has been provided by UKRI STFC, the University of Oxford, NOVA, NWO, Instituto de Astrofísica de Canarias (IAC), the Isaac Newton Group partners (STFC, NWO, and Spain, led by the IAC), INAF, CNRS-INSU, the Observatoire de Paris, Région Île-de-France, CONCYT through INAOE, Konkoly Observatory (CSFK), Max-Planck-Institut für Astronomie (MPIA Heidelberg), Lund University, the Leibniz Institute for Astrophysics Potsdam (AIP), the Swedish Research Council, the European Commission, and the University of Pennsylvania.WEAVE, the new wide-field, massively multiplexed spectroscopic survey facility for the William Herschel Telescope, will see first light in late 2022. WEAVE comprises a new 2-degree field-of-view prime-focus corrector system, a nearly 1000-multiplex fibre positioner, 20 individually deployable 'mini' integral field units (IFUs), and a single large IFU. These fibre systems feed a dual-beam spectrograph covering the wavelength range 366-959 nm at R ∼ 5000, or two shorter ranges at R ∼ 20,000. After summarising the design and implementation of WEAVE and its data systems, we present the organisation, science drivers and design of a five- to seven-year programme of eight individual surveys to: (i) study our Galaxy's origins by completing Gaia's phase-space information, providing metallicities to its limiting magnitude for ∼ 3 million stars and detailed abundances for ∼ 1.5 million brighter field and open-cluster stars; (ii) survey ∼ 0.4 million Galactic-plane OBA stars, young stellar objects and nearby gas to understand the evolution of young stars and their environments; (iii) perform an extensive spectral survey of white dwarfs; (iv) survey  ∼ 400 neutral-hydrogen-selected galaxies with the IFUs; (v) study properties and kinematics of stellar populations and ionised gas in z 1 million spectra of LOFAR-selected radio sources; (viii) trace structures using intergalactic/circumgalactic gas at z > 2. Finally, we describe the WEAVE Operational Rehearsals using the WEAVE Simulator.PostprintPeer reviewe

The wide-field, multiplexed, spectroscopic facility WEAVE: Survey design, overview, and simulated implementation

WEAVE, the new wide-field, massively multiplexed spectroscopic survey facility for the William Herschel Telescope, will see first light in late 2022. WEAVE comprises a new 2-degree field-of-view prime-focus corrector system, a nearly 1000-multiplex fibre positioner, 20 individually deployable 'mini' integral field units (IFUs), and a single large IFU. These fibre systems feed a dual-beam spectrograph covering the wavelength range 366−959\,nm at R∼5000, or two shorter ranges at R∼20000. After summarising the design and implementation of WEAVE and its data systems, we present the organisation, science drivers and design of a five- to seven-year programme of eight individual surveys to: (i) study our Galaxy's origins by completing Gaia's phase-space information, providing metallicities to its limiting magnitude for ∼3 million stars and detailed abundances for ∼1.5 million brighter field and open-cluster stars; (ii) survey ∼0.4 million Galactic-plane OBA stars, young stellar objects and nearby gas to understand the evolution of young stars and their environments; (iii) perform an extensive spectral survey of white dwarfs; (iv) survey ∼400 neutral-hydrogen-selected galaxies with the IFUs; (v) study properties and kinematics of stellar populations and ionised gas in z1 million spectra of LOFAR-selected radio sources; (viii) trace structures using intergalactic/circumgalactic gas at z>2. Finally, we describe the WEAVE Operational Rehearsals using the WEAVE Simulator

Effects of Arachidonic Acid and Its Metabolites on Functional Beta-Cell Mass

Arachidonic acid (AA) is a polyunsaturated 20-carbon fatty acid present in phospholipids in the plasma membrane. The three primary pathways by which AA is metabolized are mediated by cyclooxygenase (COX) enzymes, lipoxygenase (LOX) enzymes, and cytochrome P450 (CYP) enzymes. These three pathways produce eicosanoids, lipid signaling molecules that play roles in biological processes such as inflammation, pain, and immune function. Eicosanoids have been demonstrated to play a role in inflammatory, renal, and cardiovascular diseases as well type 1 and type 2 diabetes. Alterations in AA release or AA concentrations have been shown to affect insulin secretion from the pancreatic beta cell, leading to interest in the role of AA and its metabolites in the regulation of beta-cell function and maintenance of beta-cell mass. In this review, we discuss the metabolism of AA by COX, LOX, and CYP, the roles of these enzymes and their metabolites in beta-cell mass and function, and the possibility of targeting these pathways as novel therapies for treating diabetes

Pharmacological modulation of prostaglandin E2 (PGE2) EP receptors improves cardiomyocyte function under hyperglycemic conditions

Abstract Type 2 diabetes (T2D) affects >30 million Americans and nearly 70% of individuals with T2D will die from cardiovascular disease (CVD). Circulating levels of the inflammatory signaling lipid, prostaglandin E2 (PGE2), are elevated in the setting of obesity and T2D and are associated with decreased cardiac function. The EP3 and EP4 PGE2 receptors have opposing actions in several tissues, including the heart: overexpression of EP3 in cardiomyocytes impairs function, while EP4 overexpression improves function. Here we performed complementary studies in vitro with isolated cardiomyocytes and in vivo using db/db mice, a model of T2D, to analyze the effects of EP3 inhibition or EP4 activation on cardiac function. Using echocardiography, we found that 2 weeks of systemic treatment of db/db mice with 20 mg/kg of EP3 antagonist, beginning at 6 weeks of age, improves ejection fraction and fractional shortening (with no effect on heart rate). We further show that either EP3 blockade or EP4 activation enhances contractility and calcium cycling in isolated mouse cardiomyocytes cultured in both normal and high glucose. Thus, peak [Ca2+]I transient amplitude was increased, while time to peak [Ca2+]I and [Ca2+]I decay were decreased. These data suggest that modulation of EP3 and EP4 activity has beneficial effects on cardiomyocyte contractility and overall heart function

Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU.

ObjectiveTo update and expand the 2013 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the ICU.DesignThirty-two international experts, four methodologists, and four critical illness survivors met virtually at least monthly. All section groups gathered face-to-face at annual Society of Critical Care Medicine congresses; virtual connections included those unable to attend. A formal conflict of interest policy was developed a priori and enforced throughout the process. Teleconferences and electronic discussions among subgroups and whole panel were part of the guidelines' development. A general content review was completed face-to-face by all panel members in January 2017.MethodsContent experts, methodologists, and ICU survivors were represented in each of the five sections of the guidelines: Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption). Each section created Population, Intervention, Comparison, and Outcome, and nonactionable, descriptive questions based on perceived clinical relevance. The guideline group then voted their ranking, and patients prioritized their importance. For each Population, Intervention, Comparison, and Outcome question, sections searched the best available evidence, determined its quality, and formulated recommendations as "strong," "conditional," or "good" practice statements based on Grading of Recommendations Assessment, Development and Evaluation principles. In addition, evidence gaps and clinical caveats were explicitly identified.ResultsThe Pain, Agitation/Sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) panel issued 37 recommendations (three strong and 34 conditional), two good practice statements, and 32 ungraded, nonactionable statements. Three questions from the patient-centered prioritized question list remained without recommendation.ConclusionsWe found substantial agreement among a large, interdisciplinary cohort of international experts regarding evidence supporting recommendations, and the remaining literature gaps in the assessment, prevention, and treatment of Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) in critically ill adults. Highlighting this evidence and the research needs will improve Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) management and provide the foundation for improved outcomes and science in this vulnerable population