Analysis of severe elevated thunderstorms using DCIN and DCAPE

A 10-year study of elevated severe thunderstorms was performed using The National Centers for Environmental Information (NCEI) Storm Report database. This research further corroborates previous studies of occurrence, frequency, and severe characteristic distributions of elevated convection with severe weather. From the aforementioned database, 55 Significant ([greater than or equal to] 5 severe storm reports) and 25 Marginally (<5 severe storm reports) severe cases occurred at least 50 statute miles away from a surface boundary within a cold sector. Previous studies have established the importance in predicting whether a downdraft has enough energy to penetrate through the subinversion layer to cause severe surface winds. This study will advance an effort in predicting severe winds from an elevated thunderstorm by implementing a tool to help measure the potential for a downdraft to penetrate through the depth of the stable surface layer by using downdraft convective available potential energy (DCAPE) and downdraft convective inhibition (DCIN). Using outputs from the RUC/RAP analyses, 2-D plan view maps of DCIN and DCAPE were created to assess elevated thunderstorms as they propagated into different environments. Additionally, point sounding analyses were used to analyze the vertical thermodynamic profile for the hour prior to, and at the location of, the first storm report. The findings of this study provide insight of a environment favoring weather with severe winds. The hypothesis is posed that if the DCIN/DCAPE ratio gets progressively smaller in the path of a thunderstorm, then one may expect a greater possibility of observing severe winds at the surface. A statistical analysis was performed to determine correlations between thermodynamic variables of cases that were Significant versus Marginal using a Mann-Whitney test due to the gamma-like distributions associated with each of the variables. The Significant case set had values of DCIN closer to zero, which is consistent with the expectation that downdrafts will be able to penetrate to the surface more easily. Also, the DCIN/DCAPE ratio of Significant cases tends to be near zero with all Significant-Wind cases having a DCIN/DCAPE ratio equal to zero. Secondly, a comparison was made between thermodynamic variables of the dominant severe-type events (hail severe-type or wind severe-type). Again, these variables exhibited a skewing of the medians closer to zero than the mean indicating a gamma-like distribution. A Mann-Whitney test was carried out again to show a comparison of the thermodynamic variables. The DCIN-Hail to DCIN-Wind comparison Mann-Whitney results show DCIN-Wind values are closer to zero indicating the downdraft is able to penetrate to the surface causing severe observed winds. Thus, comparing DCIN and DCAPE is a viable tool in determining if downdrafts will reach the surface within an elevated thunderstorm.Includes bibliographical reference

Courtly Representation Play, Singspiel, Opéra Comique. On the Reception of Antonio Sacchini’s 'L´isola d´amore'

Up to now, scholars have treated ”opera as a form of courtly representation,” a topic of great significance for cultural history, primarily with regard to opera seria as well as festa teatrale. By contrast, opera buffa has been neglected, often being given the label ”bourgeois,” although the works of this genre were also addressed to a primarily aristocratic audience and could play an important role in the context of the court. The article discusses this topic using the example of Antonio Sacchini’s 'L’isola d’amore,' an intermezzo composed for Rome that was staged in Vienna as a German singspiel, an opéra comique, and, in 1769, in its original form, albeit in two different versions, one of which served as a courtly festive opera

Analysis of severe elevated thunderstorms over frontal surfaces using DCIN and DCAPE

A 10-year study of elevated severe thunderstorms was performed using The National Centers for Environmental Information Storm Events Database. A total of 80 elevated thunderstorm cases were identified, verified, and divided into "Prolific" and "Marginal" classes. These severe cases occurred at least 80 km away from, and on the cold side of, a surface boundary. The downdraft convective available potential energy (DCAPE), downdraft convective inhibition (DCIN), and their ratio are tools to help estimate the potential for a downdraft to penetrate through the depth of a stable surface layer. The hypothesis is that as the DCIN/DCAPE ratio decreases, there exists enhanced possibility of severe surface winds. Using the initial fields from the Rapid Refresh numerical weather prediction model, datasets of DCIN, DCAPE, and their ratio were created. Mann-Whitney U tests on the Prolific versus Marginal case sets were undertaken to determine if the DCAPE and DCIN values come from different populations for the two different case sets. Results show that the Prolific cases have values of DCIN closer to zero, suggesting the downdraft is able to penetrate to the surface causing severe winds. Thus, comparing DCIN and DCAPE is a viable tool in determining if downdrafts will reach the surface from elevated thunderstorms

Quantitative PCR tissue expression profiling of the human SGLT2 gene and related family members

SGLT2 (for “Sodium GLucose coTransporter” protein 2) is the major protein responsible for glucose reabsorption in the kidney and its inhibition has been the focus of drug discovery efforts to treat type 2 diabetes. In order to better clarify the human tissue distribution of expression of SGLT2 and related members of this cotransporter class, we performed TaqMan™ (Applied Biosystems, Foster City, CA, USA) quantitative polymerase chain reaction (PCR) analysis of SGLT2 and other sodium/glucose transporter genes on RNAs from 72 normal tissues from three different individuals. We consistently observe that SGLT2 is highly kidney specific while SGLT5 is highly kidney abundant; SGLT1, sodium-dependent amino acid transporter (SAAT1), and SGLT4 are highly abundant in small intestine and skeletal muscle; SGLT6 is expressed in the central nervous system; and sodium myoinositol cotransporter is ubiquitously expressed across all human tissues

Investigation of salicylate hepatic responses in comparison with chemical analogues of the drug

AbstractAnti-hyperglycaemic effects of the hydroxybenzoic acid salicylate might stem from effects of the drug on mitochondrial uncoupling, activation of AMP-activated protein kinase, and inhibition of NF-κB signalling. Here, we have gauged the contribution of these effects to control of hepatocyte glucose production, comparing salicylate with inactive hydroxybenzoic acid analogues of the drug. In rat H4IIE hepatoma cells, salicylate was the only drug tested that activated AMPK. Salicylate also reduced mTOR signalling, but this property was observed widely among the analogues. In a sub-panel of analogues, salicylate alone reduced promoter activity of the key gluconeogenic enzyme glucose 6-phosphatase and suppressed basal glucose production in mouse primary hepatocytes. Both salicylate and 2,6 dihydroxybenzoic acid suppressed TNFα-induced IκB degradation, and in genetic knockout experiments, we found that the effect of salicylate on IκB degradation was AMPK-independent. Previous data also identified AMPK-independent regulation of glucose but we found that direct inhibition of neither NF-κB nor mTOR signalling suppressed glucose production, suggesting that other factors besides these cell signalling pathways may need to be considered to account for this response to salicylate. We found, for example, that H4IIE cells were exquisitely sensitive to uncoupling with modest doses of salicylate, which occurred on a similar time course to another anti-hyperglycaemic uncoupling agent 2,4-dinitrophenol, while there was no discernible effect at all of two salicylate analogues which are not anti-hyperglycaemic. This finding supports much earlier literature suggesting that salicylates exert anti-hyperglycaemic effects at least in part through uncoupling

Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration

Background & Aims: Excess liver iron content is common and is linked to hepatic and extrahepatic disease risk. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. Methods: First, we performed a genome-wide association study (GWAS) in 8,289 individuals in UK Biobank with MRI quantified liver iron, and validated our findings in an independent cohort (n=1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 29 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 anthropometric traits and diseases. Results: We identified three independent genetic variants (rs1800562 (C282Y) and rs1799945 (H63D) in HFE and rs855791 (V736A) in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p<5x10-8). The two HFE variants account for ~85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. Conclusion: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases

Effect of Canagliflozin on Renal Threshold for Glucose, Glycemia, and Body Weight in Normal and Diabetic Animal Models

Background: Canagliflozin is a sodium glucose co-transporter (SGLT) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus (T2DM). Methods: 14 C-alpha-methylglucoside uptake in Chinese hamster ovary-K cells expressing human, rat, or mouse SGLT2 or SGLT1; 3 H-2-deoxy-D-glucose uptake in L6 myoblasts; and 2-electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed. Graded glucose infusions were performed to determine rate of urinary glucose excretion (UGE) at different blood glucose (BG) concentrations and the renal threshold for glucose excretion (RTG) in vehicle or canagliflozin-treated Zucker diabetic fatty (ZDF) rats. This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity. Results: Treatment with canagliflozin 1 mg/kg lowered RT G from 415612 mg/dl to 94610 mg/dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RTG. Canagliflozin dose-dependently decreased BG concentrations in db/db mice treated acutely. In ZDF rats treated for 4 weeks, canagliflozin decreased glycated hemoglobin (HbA1c) and improved measures of insulin secretion. In obese animal models, canagliflozin increased UGE and decreased BG, body weight gain, epididymal fat, liver weight, and the respiratory exchange ratio

Pharmacogenomics of GLP-1 receptor agonists: a genome-wide analysis of observational data and large randomised controlled trials

Background: In the treatment of type 2 diabetes, GLP-1 receptor agonists lower blood glucose concentrations, body weight, and have cardiovascular benefits. The efficacy and side effects of GLP-1 receptor agonists vary between people. Human pharmacogenomic studies of this inter-individual variation can provide both biological insight into drug action and provide biomarkers to inform clinical decision making. We therefore aimed to identify genetic variants associated with glycaemic response to GLP-1 receptor agonist treatment. Methods: In this genome-wide analysis we included adults (aged ≥18 years) with type 2 diabetes treated with GLP-1 receptor agonists with baseline HbA1c of 7% or more (53 mmol/mol) from four prospective observational cohorts (DIRECT, PRIBA, PROMASTER, and GoDARTS) and two randomised clinical trials (HARMONY phase 3 and AWARD). The primary endpoint was HbA1c reduction at 6 months after starting GLP-1 receptor agonists. We evaluated variants in GLP1R, then did a genome-wide association study and gene-based burden tests. Findings: 4571 adults were included in our analysis, of these, 3339 (73%) were White European, 449 (10%) Hispanic, 312 (7%) American Indian or Alaskan Native, and 471 (10%) were other, and around 2140 (47%) of the participants were women. Variation in HbA1c reduction with GLP-1 receptor agonists treatment was associated with rs6923761G→A (Gly168Ser) in the GLP1R (0·08% [95% CI 0·04–0·12] or 0·9 mmol/mol lower reduction in HbA1c per serine, p=6·0 × 10−5) and low frequency variants in ARRB1 (optimal sequence kernel association test p=6·7 × 10−8), largely driven by rs140226575G→A (Thr370Met; 0·25% [SE 0·06] or 2·7 mmol/mol [SE 0·7] greater HbA1c reduction per methionine, p=5·2 × 10−6). A similar effect size for the ARRB1 Thr370Met was seen in Hispanic and American Indian or Alaska Native populations who have a higher frequency of this variant (6–11%) than in White European populations. Combining these two genes identified 4% of the population who had a 30% greater reduction in HbA1c than the 9% of the population with the worse response. Interpretation: This genome-wide pharmacogenomic study of GLP-1 receptor agonists provides novel biological and clinical insights. Clinically, when genotype is routinely available at the point of prescribing, individuals with ARRB1 variants might benefit from earlier initiation of GLP-1 receptor agonists. Funding: Innovative Medicines Initiative and the Wellcome Trus