Evaluation of ENTLN Performance Characteristics Based on the Ground Truth Natural and Rocket-Triggered Lightning Data Acquired in Florida

The performance characteristics of the Earth Networks Total Lightning Network (ENTLN) were evaluated by using as ground truth natural cloud-to-ground (CG) lightning data acquired at the Lightning Observatory in Gainesville (LOG) and rocket-triggered lightning data obtained at Camp Blanding (CB), Florida, in 2014 and 2015. Two ENTLN processors (data processing algorithms) were evaluated. The old processor (P2014) was put into use in June 2014 and the new one (P2015) has been operational since August 2015. Based on the natural-CG-lightning data set (219 flashes containing 608 strokes), the flash detection efficiency (DE), flash classification accuracy (CA), stroke DE, and stroke CA for the new processor were found to be 99%, 97%, 96%, and 91%, respectively, and the corresponding values for the old processor were 99%, 91%, 97%, and 68%. The stroke DE and stroke CA for first strokes are higher than those for subsequent strokes. Based on the rocket-triggered lightning data set (36 CG flashes containing 175 strokes), the flash DE, flash CA, stroke DE, and stroke CA for the new processor were found to be 100%, 97%, 97%, and 86%, respectively, while the corresponding values for the old processor were 100%, 92%, 97%, and 42%. The median values of location error and absolute peak current estimation error were 215 m and 15% for the new processor, and 205 m and 15% for the old processor. For both natural and triggered CG lightning, strokes with higher peak currents were more likely to be both detected and correctly classified by the ENTLN

Assessing fossil fuel CO_2 emissions in California using atmospheric observations and models

Analysis systems incorporating atmospheric observations could provide a powerful tool for validating fossil fuel CO_2 (ffCO_2) emissions reported for individual regions, provided that fossil fuel sources can be separated from other CO_2 sources or sinks and atmospheric transport can be accurately accounted for. We quantified ffCO_2 by measuring radiocarbon (^(14)C) in CO_2, an accurate fossil-carbon tracer, at nine observation sites in California for three months in 2014–15. There is strong agreement between the measurements and ffCO_2 simulated using a high-resolution atmospheric model and a spatiotemporally-resolved fossil fuel flux estimate. Inverse estimates of total in-state ffCO_2 emissions are consistent with the California Air Resources Board's reported ffCO_2 emissions, providing tentative validation of California's reported ffCO_2 emissions in 2014–15. Continuing this prototype analysis system could provide critical independent evaluation of reported ffCO_2 emissions and emissions reductions in California, and the system could be expanded to other, more data-poor regions

Polyomic profiling reveals significant hepatic metabolic alterations in glucagon-receptor (GCGR) knockout mice: implications on anti-glucagon therapies for diabetes

<p>Abstract</p> <p>Background</p> <p>Glucagon is an important hormone in the regulation of glucose homeostasis, particularly in the maintenance of euglycemia and prevention of hypoglycemia. In type 2 Diabetes Mellitus (T2DM), glucagon levels are elevated in both the fasted and postprandial states, which contributes to inappropriate hyperglycemia through excessive hepatic glucose production. Efforts to discover and evaluate glucagon receptor antagonists for the treatment of T2DM have been ongoing for approximately two decades, with the challenge being to identify an agent with appropriate pharmaceutical properties and efficacy relative to potential side effects. We sought to determine the hepatic & systemic consequence of full glucagon receptor antagonism through the study of the glucagon receptor knock-out mouse (Gcgr^-/-) compared to wild-type littermates.</p> <p>Results</p> <p>Liver transcriptomics was performed using Affymetric expression array profiling, and liver proteomics was performed by iTRAQ global protein analysis. To complement the transcriptomic and proteomic analyses, we also conducted metabolite profiling (~200 analytes) using mass spectrometry in plasma. Overall, there was excellent concordance (R = 0.88) for changes associated with receptor knock-out between the transcript and protein analysis. Pathway analysis tools were used to map the metabolic processes in liver altered by glucagon receptor ablation, the most notable being significant down-regulation of gluconeogenesis, amino acid catabolism, and fatty acid oxidation processes, with significant up-regulation of glycolysis, fatty acid synthesis, and cholesterol biosynthetic processes. These changes at the level of the liver were manifested through an altered plasma metabolite profile in the receptor knock-out mice, e.g. decreased glucose and glucose-derived metabolites, and increased amino acids, cholesterol, and bile acid levels.</p> <p>Conclusions</p> <p>In sum, the results of this study suggest that the complete ablation of hepatic glucagon receptor function results in major metabolic alterations in the liver, which, while promoting improved glycemic control, may be associated with adverse lipid changes.</p

Inactivation of Staphylococcal Phenol Soluble Modulins by Serum Lipoprotein Particles

Staphylococcus aureus virulence has been associated with the production of phenol soluble modulins (PSM). PSM are known to activate, attract and lyse neutrophils. However, the functional characterizations were generally performed in the absence of human serum. Here, we demonstrate that human serum can inhibit all the previously-described activities of PSM. We observed that serum can fully block both the cell lysis and FPR2 activation of neutrophils. We show a direct interaction between PSM and serum lipoproteins in human serum and whole blood. Subsequent analysis using purified high, low, and very low density lipoproteins (HDL, LDL, and VLDL) revealed that they indeed neutralize PSM. The lipoprotein HDL showed highest binding and antagonizing capacity for PSM. Furthermore, we show potential intracellular production of PSM by S. aureus upon phagocytosis by neutrophils, which opens a new area for exploration of the intracellular lytic capacity of PSM. Collectively, our data show that in a serum environment the function of PSM as important extracellular toxins should be reconsidered

Molecular Characterisation of Small Molecule Agonists Effect on the Human Glucagon Like Peptide-1 Receptor Internalisation

The glucagon-like peptide receptor (GLP-1R), which is a G-protein coupled receptor (GPCR), signals through both Gαs and Gαq coupled pathways and ERK phosphorylation to stimulate insulin secretion. The aim of this study was to determine molecular details of the effect of small molecule agonists, compounds 2 and B, on GLP-1R mediated cAMP production, intracellular Ca2+ accumulation, ERK phosphorylation and its internalisation. In human GLP-1R (hGLP-1R) expressing cells, compounds 2 and B induced cAMP production but caused no intracellular Ca2+ accumulation, ERK phosphorylation or hGLP-1R internalisation. GLP-1 antagonists Ex(9-39) and JANT-4 and the orthosteric binding site mutation (V36A) in hGLP-1R failed to inhibit compounds 2 and B induced cAMP production, confirming that their binding site distinct from the GLP-1 binding site on GLP-1R. However, K334A mutation of hGLP-1R, which affects Gαs coupling, inhibited GLP-1 as well as compounds 2 and B induced cAMP production, indicating that GLP-1, compounds 2 and B binding induce similar conformational changes in the GLP-1R for Gαs coupling. Additionally, compound 2 or B binding to the hGLP-1R had significantly reduced GLP-1 induced intracellular Ca2+ accumulation, ERK phosphorylation and hGLP-1R internalisation. This study illustrates pharmacology of differential activation of GLP-1R by GLP-1 and compounds 2 and B

Nanosecond time-resolved characterization of a pentacene-based room-temperature MASER

The United Kingdom Engineering and Physical Sciences Research Council (EPSRC) supported this work through grants EP/K011987/1 and EP/K011804/1 (Room Temperature, Earth’s Field MASER), and M.O.’s Manufacturing Research Fellowship EP/K037390

Assessing fossil fuel CO_2 emissions in California using atmospheric observations and models

Analysis systems incorporating atmospheric observations could provide a powerful tool for validating fossil fuel CO_2 (ffCO_2) emissions reported for individual regions, provided that fossil fuel sources can be separated from other CO_2 sources or sinks and atmospheric transport can be accurately accounted for. We quantified ffCO_2 by measuring radiocarbon (^(14)C) in CO_2, an accurate fossil-carbon tracer, at nine observation sites in California for three months in 2014–15. There is strong agreement between the measurements and ffCO_2 simulated using a high-resolution atmospheric model and a spatiotemporally-resolved fossil fuel flux estimate. Inverse estimates of total in-state ffCO_2 emissions are consistent with the California Air Resources Board's reported ffCO_2 emissions, providing tentative validation of California's reported ffCO_2 emissions in 2014–15. Continuing this prototype analysis system could provide critical independent evaluation of reported ffCO_2 emissions and emissions reductions in California, and the system could be expanded to other, more data-poor regions

A Naturally Occurring Polymorphism at Drosophila melanogaster Lim3 Locus, a Homolog of Human LHX3/4, Affects Lim3 Transcription and Fly Lifespan

Lim3 encodes an RNA polymerase II transcription factor with a key role in neuron specification. It was also identified as a candidate gene that affects lifespan. These pleiotropic effects indicate the fundamental significance of the potential interplay between neural development and lifespan control. The goal of this study was to analyze the causal relationships between Lim3 structural variations, and gene expression and lifespan changes, and to provide insights into regulatory pathways controlling lifespan. Fifty substitution lines containing second chromosomes from a Drosophila natural population were used to analyze the association between lifespan and sequence variation in the 5′-regulatory region, and first exon and intron of Lim3A, in which we discovered multiple transcription start sites (TSS). The core and proximal promoter organization for Lim3A and a previously unknown mRNA named Lim3C were described. A haplotype of two markers in the Lim3A regulatory region was significantly associated with variation in lifespan. We propose that polymorphisms in the regulatory region affect gene transcription, and consequently lifespan. Indeed, five polymorphic markers located within 380 to 680 bp of the Lim3A major TSS, including two markers associated with lifespan variation, were significantly associated with the level of Lim3A transcript, as evaluated by real time RT-PCR in embryos, adult heads, and testes. A naturally occurring polymorphism caused a six-fold change in gene transcription and a 25% change in lifespan. Markers associated with long lifespan and intermediate Lim3A transcription were present in the population at high frequencies. We hypothesize that polymorphic markers associated with Lim3A expression are located within the binding sites for proteins that regulate gene function, and provide general rather than tissue-specific regulation of transcription, and that intermediate levels of Lim3A expression confer a selective advantage and longer lifespan

Recent Progress in the Use of Glucagon and Glucagon Receptor Antagonists in the Treatment of Diabetes Mellitus

Glucagon is an important pancreatic hormone, released into blood circulation by alpha cells of the islet of Langerhans. Glucagon induces gluconeogenesis and glycogenolysis in hepatocytes, leading to an increase in hepatic glucose production and subsequently hyperglycemia in susceptible individuals. Hyperglucagonemia is a constant feature in patients with T2DM. A number of bioactive agents that can block glucagon receptor have been identified. These glucagon receptor antagonists can reduce the hyperglycemia associated with exogenous glucagon administration in normal as well as diabetic subjects. Glucagon receptor antagonists include isoserine and beta-alanine derivatives, bicyclic 19-residue peptide BI-32169, Des-His1-[Glu9] glucagon amide and related compounds, 5-hydroxyalkyl-4-phenylpyridines, N-[3-cano-6- (1,1 dimethylpropyl)-4,5,6,7-tetrahydro-1-benzothien-2-yl]-2-ethylbutamide, Skyrin and NNC 250926. The absorption, dosage, catabolism, excretion and medicinal chemistry of these agents are the subject of this review. It emphasizes the role of glucagon in glucose homeostasis and how it could be applied as a novel tool for the management of diabetes mellitus by blocking its receptors with either monoclonal antibodies, peptide and non-peptide antagonists or gene knockout techniques