A Laser System for the Spectroscopy of Highly-Charged Bismuth Ions

We present and characterize a laser system for the spectroscopy on highly-charged ^209Bi^82+ ions at a wavelength of 243.87 nm. For absolute frequency stabilization, the laser system is locked to a near-infra-red laser stabilized to a rubidium transition line using a transfer cavity based locking scheme. Tuning of the output frequency with high precision is achieved via a tunable rf offset lock. A sample-and-hold technique gives an extended tuning range of several THz in the UV. This scheme is universally applicable to the stabilization of laser systems at wavelengths not directly accessible to atomic or molecular resonances. We determine the frequency accuracy of the laser system using Doppler-free absorption spectroscopy of Te_2 vapour at 488 nm. Scaled to the target wavelength of 244 nm, we achieve a frequency uncertainty of \sigma_{244nm} = 6.14 MHz (one standard deviation) over six days of operation.Comment: Contribution to the special issue on "Trapped Ions" in "Applied Physics B

Farnesoid X Receptor Deficiency Improves Glucose Homeostasis in Mouse Models of Obesity

International audienceOBJECTIVE Bile acids (BA) participate in the maintenance of metabolic homeostasis acting through different signaling pathways. The nuclear BA receptor farnesoid X receptor (FXR) regulates pathways in BA, lipid, glucose, and energy metabolism, which become dysregulated in obesity. However, the role of FXR in obesity and associated complications, such as dyslipidemia and insulin resistance, has not been directly assessed. RESEARCH DESIGN AND METHODS Here, we evaluate the consequences of FXR deficiency on body weight development, lipid metabolism, and insulin resistance in murine models of genetic and diet-induced obesity. RESULTS FXR deficiency attenuated body weight gain and reduced adipose tissue mass in both models. Surprisingly, glucose homeostasis improved as a result of an enhanced glucose clearance and adipose tissue insulin sensitivity. In contrast, hepatic insulin sensitivity did not change, and liver steatosis aggravated as a result of the repression of β-oxidation genes. In agreement, liver-specific FXR deficiency did not protect from diet-induced obesity and insulin resistance, indicating a role for nonhepatic FXR in the control of glucose homeostasis in obesity. Decreasing elevated plasma BA concentrations in obese FXR-deficient mice by administration of the BA sequestrant colesevelam improved glucose homeostasis in a FXR-dependent manner, indicating that the observed improvements by FXR deficiency are not a result of indirect effects of altered BA metabolism. CONCLUSIONS Overall, FXR deficiency in obesity beneficially affects body weight development and glucose homeostasis

Identifying the anti-inflammatory response to lipid lowering therapy: a position paper from the working group on atherosclerosis and vascular biology of the European Society of Cardiology

Dysregulated lipid metabolism induces an inflammatory and immune response leading to atherosclerosis. Conversely, inflammation may alter lipid metabolism. Recent treatment strategies in secondary prevention of atherosclerosis support beneficial effects of both anti-inflammatory and lipid-lowering therapies beyond current targets. There is a controversy about the possibility that anti-inflammatory effects of lipid-lowering therapy may be either independent or not of a decrease in low-density lipoprotein cholesterol. In this Position Paper, we critically interpret and integrate the results obtained in both experimental and clinical studies on anti-inflammatory actions of lipid-lowering therapy and the mechanisms involved. We highlight that: (i) besides decreasing cholesterol through different mechanisms, most lipid-lowering therapies share anti-inflammatory and immunomodulatory properties, and the anti-inflammatory response to lipid-lowering may be relevant to predict the effect of treatment, (ii) using surrogates for both lipid metabolism and inflammation as biomarkers or vascular inflammation imaging in future studies may contribute to a better understanding of the relative importance of different mechanisms of action, and (iii) comparative studies of further lipid lowering, anti-inflammation and a combination of both are crucial to identify effects that are specific or shared for each treatment strategy

Bile Acid Sequestrants for Lipid and Glucose Control

Bile acids are generated in the liver and are traditionally recognized for their regulatory role in multiple metabolic processes including bile acid homeostasis, nutrient absorption, and cholesterol homeostasis. Recently, bile acids emerged as signaling molecules that, as ligands for the bile acid receptors farnesoid X receptor (FXR) and TGR5, activate and integrate multiple complex signaling pathways involved in lipid and glucose metabolism. Bile acid sequestrants are pharmacologic molecules that bind to bile acids in the intestine resulting in the interruption of bile acid homeostasis and, consequently, reduction in low-density lipoprotein cholesterol levels in hypercholesterolemia. Bile acid sequestrants also reduce glucose levels and improve glycemic control in persons with type 2 diabetes mellitus (T2DM). This article examines the mechanisms by which bile acid–mediated activation of FXR and TGR5 signaling pathways regulate lipid and glucose metabolism and the potential implications for bile acid sequestrant–mediated regulation of lipid and glucose levels in T2DM

Characterization of Adaptable Interpreted-DSML

Abstract. One of the main goals of model-driven engineering (MDE) is the manipulation of models as exclusive software artifacts. Model ex-ecution is in particular a means to substitute models for code. More precisely, as models of a dedicated domain-specific modeling language (DSML) are interpreted through an execution engine, such a DSML is called interpreted-DSML (i-DSML for short). On another way, MDE is a promising discipline for building adaptable systems based on models at runtime. When the model is directly executed, the system becomes the model: This is the model that is adapted. In this paper, we propose a characterization of adaptable i-DSML where a single model is executed and directly adapted at runtime. If model execution only modifies the dy-namical elements of the model, we show that the adaptation can modify each part of the model and that the execution and adaptation semantics can be changed at runtime

Changes in metabolic parameters and cardiovascular risk factors after therapeutic control of acromegaly vary with the treatment modality. Data from the Bicêtre cohort, and review of the literature

CONTEXT: Untreated acromegaly is associated with increased morbidity and mortality due to malignant, cardiovascular, and cerebrovascular disorders. Effective treatment of acromegaly reduces excess mortality, but its impact on cardiovascular risk factors and metabolic parameters are poorly documented. AIM: We analyzed changes in cardiovascular risk factors and metabolic parameters in patients receiving various treatment modalities. PATIENTS AND METHODS: We retrospectively studied 96 patients with acromegaly, both at diagnosis and after IGF-I normalization following surgery alone (n = 51) or medical therapy with first generation somatostatin analogues (SSA, n = 23), or pegvisomant (n = 22). Duration of follow-up was 77 (42-161) months, 75 (42-112) months, and 62 (31-93) months, in patients treated with surgery alone, SSA, and pegvisomant, respectively. In all the cases except four, patients treated medically had underwent previous unsuccessful surgery. RESULTS: IGF-I normalization was associated with increased body weight, decreased systolic blood pressure (SBP) in hypertensive patients, decreased fasting plasma glucose (FPG) and HOMA-IR and HOMA-B levels, increased HDL cholesterol (HDLc); whereas, LDL cholesterol (LDLc) was not significantly different. Plasma PCSK9 levels were unchanged in patients with available values. Cardiovascular and metabolic changes varied with the treatment modality: surgery, but not pegvisomant, had a beneficial effect on SBP; FPG decreased after surgery but increased after SSA; the decline in HOMA-IR was only significant after surgery; pegvisomant significantly increased LDLc and total cholesterol; whereas SA increased HDLc and had no effect on LDLc levels. CONCLUSION: Treatments used to normalize IGF-I levels in patients with acromegaly could have differential effects on cardiovascular risk factors and metabolic parameters

Realistic measurement uncertainties for marine macronutrient measurements conducted using gas segmented flow and Lab-on-Chip techniques

Highlights • Accounting for systematic bias is required for a realistic analytical uncertainty • Gas segmented flow techniques achieved a combined uncertainties of 1-4 % • Lab-on-Chip nitrate + nitrite analysers achieved a combined uncertainties < 5% Abstract Accurate and precise measurements of marine macronutrient concentrations are fundamental to our understanding of biogeochemical cycles in the ocean. Quantifying the measurement uncertainty associated with macronutrient measurements remains a challenge. Large systematic biases (up to 10 %) have been identified between datasets, restricting the ability of marine biogeochemists to distinguish between the effects of environmental processes and analytical uncertainty. In this study we combine the routine analyses of certified reference materials (CRMs) with the application of a simple statistical technique to quantify the combined (random + systematic) measurement uncertainty associated with marine macronutrient measurements using gas segmented flow techniques. We demonstrate that it is realistic to achieve combined uncertainties of ~1-4 % for nitrate + nitrite (ΣNOx), phosphate (PO43-) and silicic acid (Si(OH)4) measurements. This approach requires only the routine analyses of CRMs (i.e. it does not require inter-comparison exercises). As CRMs for marine macronutrients are now commercially available, it is advocated that this simple approach can improve the comparability of marine macronutrient datasets and therefore should be adopted as ‘best practice’. Novel autonomous Lab-on-Chip (LoC) technology is currently maturing to a point where it will soon become part of the marine chemist’s standard analytical toolkit used to determine marine macronutrient concentrations. Therefore, it is critical that a complete understanding of the measurement uncertainty of data produced by LoC analysers is achieved. In this study we analysed CRMs using 7 different LoC ΣNOx analysers to estimate a combined measurement uncertainty of < 5%. This demonstrates that with high quality manufacturing and laboratory practices, LoC analysers routinely produce high quality measurements of marine macronutrient concentrations

Dynamics of air–sea CO2 fluxes in the northwestern European shelf based on voluntary observing ship and satellite observations

From January 2011 to December 2013, we constructed a comprehensive pCO2 data set based on voluntary observing ship (VOS) measurements in the western English Channel (WEC). We subsequently estimated surface pCO2 and air–sea CO2 fluxes in northwestern European continental shelf waters using multiple linear regressions (MLRs) from remotely sensed sea surface temperature (SST), chlorophyll a concentration (Chl a), wind speed (WND), photosynthetically active radiation (PAR) and modeled mixed layer depth (MLD). We developed specific MLRs for the seasonally stratified northern WEC (nWEC) and the permanently well-mixed southern WEC (sWEC) and calculated surface pCO2 with uncertainties of 17 and 16 μatm, respectively. We extrapolated the relationships obtained for the WEC based on the 2011–2013 data set (1) temporally over a decade and (2) spatially in the adjacent Celtic and Irish seas (CS and IS), two regions which exhibit hydrographical and biogeochemical characteristics similar to those of WEC waters. We validated these extrapolations with pCO2 data from the SOCAT and LDEO databases and obtained good agreement between modeled and observed data. On an annual scale, seasonally stratified systems acted as a sink of CO2 from the atmosphere of −0.6 ± 0.3, −0.9 ± 0.3 and −0.5 ± 0.3 mol C m−2 yr−1 in the northern Celtic Sea, southern Celtic sea and nWEC, respectively, whereas permanently well-mixed systems acted as source of CO2 to the atmosphere of 0.2 ± 0.2 and 0.3 ± 0.2 mol C m−2 yr−1 in the sWEC and IS, respectively. Air–sea CO2 fluxes showed important inter-annual variability resulting in significant differences in the intensity and/or direction of annual fluxes. We scaled the mean annual fluxes over these provinces for the last decade and obtained the first annual average uptake of −1.11 ± 0.32 Tg C yr−1 for this part of the northwestern European continental shelf. Our study showed that combining VOS data with satellite observations can be a powerful tool to estimate and extrapolate air–sea CO2 fluxes in sparsely sampled area

Efficacy, safety, and tolerability of oral semaglutide versus placebo added to insulin with or without metformin in patients with type 2 diabetes: The PioNEER 8 trial

OBJECTIVE To investigate the efficacy, safety, and tolerability of oral semaglutide added to insulin with or without metformin. RESEARCH DESIGN AND METHODS Patients with type 2 diabetes uncontrolled on insulin with or without metformin were randomized to oral semaglutide 3 mg (N 5 184), 7 mg (N 5 182), or 14 mg (N 5 181) or to placebo (N 5 184) in a 52-week, double-blind trial. End points were change from baseline to week 26 in HbA1c (primary) and body weight (confirmatory secondary). Two estimands were defined: treatment policy (effect regardless of trial product discontinuation or rescue medication) and trial product (effect assuming trial product continuation without rescue medication) in randomized patients. RESULTS Oral semaglutide was superior to placebo in reducing HbA1c (estimated treatment difference [ETD] –0.5% [95% CI –0.7, –0.3], –0.9% [–1.1, –0.7], and –1.2% [–1.4, –1.0] for 3, 7, and 14 mg, respectively; P &lt; 0.001) and body weight (ETD 20.9 kg [95% CI 21.8, 20.0], 22.0 kg [23.0, 21.0], and 23.3 kg [24.2, 22.3]; P 5 0.0392 for 3 mg, P £ 0.0001 for 7 and 14 mg) at week 26 (treatment policy estimand). Significantly greater dose-dependent HbA1c and body weight reductions versus placebo were achieved with oral semaglutide at weeks 26 and 52 (both estimands). The most frequent adverse event with oral semaglutide was nausea (11.4–23.2% of patients vs. 7.1% with placebo; mostly mild to moderate). CONCLUSIONS Oral semaglutide was superior to placebo in reducing HbA1c and body weight when added to insulin with or without metformin in patients with type 2 diabetes. The safety profile was consistent with other glucagon-like peptide 1 receptor agonists