Resonant infrared irradiation of CO and CH3OH interstellar ices

Solid-phase photo-processes involving icy dust grains greatly affect the chemical evolution of the interstellar medium by leading to the formation of complex organic molecules and by inducing photodesorption. So far, the focus of laboratory studies has been mainly on the impact of energetic ultraviolet (UV) photons on ices, but direct vibrational excitation by infrared (IR) photons is expected to influence the morphology and content of interstellar ices as well. However, little is still known about the mechanisms through which this excess vibrational energy is dissipated, and its implications on the structure and ice photochemistry. In this work, we present a systematic investigation of the behavior of interstellar relevant CO and CH3OH ice analogues upon resonant excitation of vibrational modes using tunable infrared radiation, leading to both the quantification of infrared-induced photodesorption and insights in the impact of vibrational energy dissipation on ice morphology. We utilize an ultrahigh vacuum setup at cryogenic temperatures to grow pure CO and CH3OH ices, as well as mixtures of the two. We expose the ices to intense, near-monochromatic mid-infrared free-electron-laser radiation to selectively excite the species. The dissipation of vibrational energy is observed to be highly dependent on the excited mode and the chemical environment of the ice. All amorphous ices undergo some degree of restructuring towards a more organized configuration upon on-resonance irradiation. Moreover, IR-induced photodesorption is observed to occur for both pure CO and CH3OH ices, with interstellar photodesorption efficiencies of the order of 10 molecules cm-2 s-1 (i.e., comparable to or higher than UV-induced counterparts). Indirect photodesorption of CO upon vibrational excitation of CH3OH in ice mixtures is also observed to occur, particularly in environments rich in methanol.Comment: Accepted for publication in A&A. 19 pages, 14 figures, 2 table

Adaptations in mitochondrial function parallel, but fail to rescue, the transition to severe hyperglycemia and hyperinsulinemia: a study in Zucker diabetic fatty rats.

Cross-sectional human studies have associated mitochondrial dysfunction to type 2 diabetes. We chose Zucker diabetic fatty (ZDF) rats as a model of progressive insulin resistance to examine whether intrinsic mitochondrial defects are required for development of type 2 diabetes. Muscle mitochondrial function was examined in 6-, 12-, and 19-week-old ZDF (fa/fa) and fa/+ control rats (n = 8-10 per group) using respirometry with pyruvate, glutamate, and palmitoyl-CoA as substrates. Six-week-old normoglycemic-hyperinsulinemic fa/fa rats had reduced mitochondrial fat oxidative capacity. Adenosine diphosphate (ADP)-driven state 3 and carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP)-stimulated state uncoupled (state u) respiration on palmitoyl-CoA were lower compared to controls (62.3 ± 9.5 vs. 119.1 ± 13.8 and 87.8 ± 13.3 vs. 141.9 ± 14.3 nmol O2/mg/min.). Pyruvate oxidation in 6-week-old fa/fa rats was similar to controls. Remarkably, reduced fat oxidative capacity in 6-week-old fa/fa rats was compensated for by an adaptive increase in intrinsic mitochondrial function at week 12, which could not be maintained toward week 19 (140.9 ± 11.2 and 57.7 ± 9.8 nmol O2/mg/min, weeks 12 and 19, respectively), whereas hyperglycemia had developed (13.5 ± 0.6 and 16.1 ± 0.3 mmol/l, weeks 12 and 19, respectively). This mitochondrial adaptation failed to rescue the progressive development of insulin resistance in fa/fa rats. The transition of prediabetes state toward advanced hyperglycemia and hyperinsulinemia was accompanied by a blunted increase in uncoupling protein-3 (UCP3). Thus, in ZDF rats insulin resistance develops progressively in the absence of mitochondrial dysfunction. In fact, improved mitochondrial capacity in hyperinsulinemic hyperglycemic rats does not rescue the progression toward advanced stages of insulin resistance

About the computation of the signature of surface singularities z^N+g(x,y)=0

In this article we describe our experiences with a parallel SINGULAR-implementation of the signature of a surface singularity defined by z^N+g(x,y)=0.Comment: 6 page

Serum sex hormone-binding globulin levels are reduced and inversely associated with intrahepatic lipid content and saturated fatty acid fraction in adult patients with glycogen storage disease type 1a

PURPOSE: De novo lipogenesis has been inversely associated with serum sex hormone-binding globulin (SHBG) levels. However, the directionality of this association has remained uncertain. We, therefore, studied individuals with glycogen storage disease type 1a (GSD1a), who are characterized by a genetic defect in glucose-6-phosphatase resulting in increased rates of de novo lipogenesis, to assess the downstream effect on serum SHBG levels. METHODS: A case-control study comparing serum SHBG levels in patients with GSD1a (n = 10) and controls matched for age, sex, and BMI (n = 10). Intrahepatic lipid content and saturated fatty acid fraction were quantified by proton magnetic resonance spectroscopy. RESULTS: Serum SHBG levels were statistically significantly lower in patients with GSD1a compared to the controls (p = 0.041), while intrahepatic lipid content and intrahepatic saturated fatty acid fraction-a marker of de novo lipogenesis-were significantly higher in patients with GSD1a (p = 0.001 and p = 0.019, respectively). In addition, there was a statistically significant, inverse association of intrahepatic lipid content and saturated fatty acid fraction with serum SHBG levels in patients and controls combined (β: - 0.28, 95% CI: - 0.47;- 0.09 and β: - 0.02, 95% CI: - 0.04;- 0.01, respectively). CONCLUSION: Patients with GSD1a, who are characterized by genetically determined higher rates of de novo lipogenesis, have lower serum SHBG levels than controls

Relationship between de novo lipogenesis and serum sex hormone binding globulin in humans

Objective Obesity and liver fat are associated with decreased levels of serum sex hormone binding globulin (SHBG). Laboratory studies suggest that hepatic de novo lipogenesis (DNL) is involved in the downregulation of SHBG synthesis. The aim of the present study was to address the role of DNL on serum SHBG in humans. Design A cross-sectional study examining the association between DNL, measured by stable isotopes, and serum SHBG, stratified by sex. Participants Healthy men (n = 34) and women (n = 21) were combined from two cross-sectional studies. Forty-two per cent of participants had hepatic steatosis, and the majority were overweight (62%) or obese (27%). Results DNL was inversely associated with SHBG in women (beta: -0.015, 95% CI: -0.030; 0.000), but not in men (beta: 0.007, 95% CI: -0.005; 0.019) (p for interaction = .068). Adjustment for study population, age and body mass index did not materially change these results, although statistical significance was lost after adjustment for serum insulin. Conclusions An inverse association between DNL and SHBG may explain the decreased SHBG levels that are observed in obesity, at least in women.Peer reviewe

Hepatic saturated fatty acid fraction is associated with de novo lipogenesis and hepatic insulin resistance

Hepatic steatosis is associated with poor cardiometabolic health, with de novo lipogenesis (DNL) contributing to hepatic steatosis and subsequent insulin resistance. Hepatic saturated fatty acids (SFA) may be a marker of DNL and are suggested to be most detrimental in contributing to insulin resistance. Here, we show in a cross-sectional study design (ClinicalTrials.gov ID: NCT03211299) that we are able to distinguish the fractions of hepatic SFA, mono- and polyunsaturated fatty acids in healthy and metabolically compromised volunteers using proton magnetic resonance spectroscopy (H-1-MRS). DNL is positively associated with SFA fraction and is elevated in patients with non-alcoholic fatty liver and type 2 diabetes. Intriguingly, SFA fraction shows a strong, negative correlation with hepatic insulin sensitivity. Our results show that the hepatic lipid composition, as determined by our H-1-MRS methodology, is a measure of DNL and suggest that specifically the SFA fraction may hamper hepatic insulin sensitivity. Hepatic steatosis is associated with poor cardiometabolic health, with de novo lipogenesis (DNL) contributing to hepatic steatosis and subsequent insulin resistance. Here, the authors use H-1-MRS methodology to show hepatic SFA fraction is a measure of DNL and specifically may hamper hepatic insulin sensitivity.Peer reviewe

Four novel UCP3 gene variants associated with childhood obesity: effect on fatty acid oxidation and on prevention of triglyceride storage

The objective of the study was to look for uncoupling protein 3 (UCP3) gene variants in early-onset severe childhood obesity and to determine their effect on long-chain fatty acid oxidation and triglyceride storage

Citizenship:Contrasting Dynamics at the Interface of Integration and Constitutionalism

EUDO Citizenship ObservatoryThis paper explores the different ways in which citizenship has played a role in polity formation in the context of the European Union. It focuses on both the ‘integration’ and the ‘constitution’ dimensions. The paper thus has two substantive sections. The first addresses the role of citizenship of the Union, examining the dynamic relationship between this concept, the role of the Court of Justice, and the free movement dynamic of EU law. The second turns to citizenship in the Union, looking at some recent political developments under which concepts of citizenship, and democratic membership as a key dimension of citizenship, have been given greater prominence. One key finding of the paper is that there is a tension between citizenship of the Union, as part of the EU's ‘old’ incremental constitutionalism based on the constitutionalisation of the existing Treaties, and citizenship in the Union, where the possibilities of a ‘new’ constitutionalism based on renewed constitutional documents have yet to be fully realise

Optimized parameter search for large datasets of the regularization parameter and feature selection for ridge regression

In this paper we propose mathematical optimizations to select the optimal regularization parameter for ridge regression using cross-validation. The resulting algorithm is suited for large datasets and the computational cost does not depend on the size of the training set. We extend this algorithm to forward or backward feature selection in which the optimal regularization parameter is selected for each possible feature set. These feature selection algorithms yield solutions with a sparse weight matrix using a quadratic cost on the norm of the weights. A naive approach to optimizing the ridge regression parameter has a computational complexity of the order with the number of applied regularization parameters, the number of folds in the validation set, the number of input features and the number of data samples in the training set. Our implementation has a computational complexity of the order . This computational cost is smaller than that of regression without regularization for large datasets and is independent of the number of applied regularization parameters and the size of the training set. Combined with a feature selection algorithm the algorithm is of complexity and for forward and backward feature selection respectively, with the number of selected features and the number of removed features. This is an order faster than and for the naive implementation, with for large datasets. To show the performance and reduction in computational cost, we apply this technique to train recurrent neural networks using the reservoir computing approach, windowed ridge regression, least-squares support vector machines (LS-SVMs) in primal space using the fixed-size LS-SVM approximation and extreme learning machines

Paradoxical Increase in TAG and DAG Content Parallel the Insulin Sensitizing Effect of Unilateral DGAT1 Overexpression in Rat Skeletal Muscle

BACKGROUND: The involvement of muscle triacylglycerol (TAG) storage in the onset of insulin resistance is questioned and the attention has shifted towards inhibition of insulin signalling by the lipid intermediate diacylglycerol (DAG). The enzyme 1,2-acylCoA:diacylglyceroltransferase-1 (DGAT1) esterifies a fatty acyl-CoA on DAG to form TAG. Therefore, the aim of the present study was to investigate if unilateral overexpression of DGAT1 in adult rat Tibialis anterior (TA) muscle will increase conversion of the lipid intermediate DAG into TAG, thereby improving muscle insulin sensitivity. METHODOLOGY/PRINCIPAL FINDINGS: The DGAT1 gene construct was injected in the left TA muscle of male rats on chow or high-fat (45% kcal) diet for three weeks, followed by application of one 800 V/cm and four 80 V/cm pulses, using the contralateral leg as sham-electroporated control. Seven days after electroporation, muscle specific insulin sensitivity was assessed with a hyperinsulinemic euglycemic clamp using 2-deoxy-[3H]glucose. Here, we provide evidence that unilateral overexpression of DGAT1 in TA muscle of male rats is associated with an increased rather than decreased DAG content. Strikingly, this increase in DAG content was accompanied by improved muscle insulin sensitivity. Interestingly, markers of muscle lipolysis and mitochondrial function were also increased in DGAT1 overexpressing muscle. CONCLUSIONS/SIGNIFICANCE: We conclude that unilateral DGAT1 overexpression can rescue insulin sensitivity, possibly by increasing DAG and TAG turnover in skeletal muscle. In case of a proper balance between the supply and oxidation of fatty acids in skeletal muscle, the lipid intermediate DAG may not exert harmful effects on insulin signalling