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Background: The rupture of atherosclerotic plaque contributes significantly to cardiovascular disease. Plasma concentrations of bilirubin—a byproduct of heme catabolism—inversely associate with risk of cardiovascular disease, although the link between bilirubin and atherosclerosis remains unclear. Methods: To assess the role of bilirubin in atherosclerotic plaque stability, we crossed Bvra −/− with Apoe −/− mice and used the tandem stenosis model of plaque instability. Human coronary arteries were obtained from heart transplant recipients. Analysis of bile pigments, heme metabolism, and proteomics were performed by liquid chromatography tandem mass spectrometry. MPO (myeloperoxidase) activity was determined by in vivo molecular magnetic resonance imaging, liquid chromatography tandem mass spectrometry analysis, and immunohistochemical determination of chlorotyrosine. Systemic oxidative stress was evaluated by plasma concentrations of lipid hydroperoxides and the redox status of circulating Prx2 (peroxiredoxin 2), whereas arterial function was assessed by wire myography. Atherosclerosis and arterial remodeling were quantified by morphometry and plaque stability by fibrous cap thickness, lipid accumulation, infiltration of inflammatory cells, and the presence of intraplaque hemorrhage. Results: Compared with Bvra +/+ Apoe −/− tandem stenosis littermates, Bvra −/− Apoe −/− tandem stenosis mice were deficient in bilirubin, showed signs of increased systemic oxidative stress, endothelial dysfunction, as well as hyperlipidemia, and had a higher atherosclerotic plaque burden. Heme metabolism was increased in unstable compared with stable plaque of both Bvra +/+ Apoe −/− and Bvra −/− Apoe −/− tandem stenosis mice and in human coronary plaques. In mice, Bvra deletion selectively destabilized unstable plaque, characterized by positive arterial remodeling and increased cap thinning, intraplaque hemorrhage, infiltration of neutrophils, and MPO activity. Proteomic analysis confirmed Bvra deletion enhanced extracellular matrix degradation, recruitment and activation of neutrophils, and associated oxidative stress in unstable plaque. Conclusions: Bilirubin deficiency, resulting from global Bvra deletion, generates a proatherogenic phenotype and selectively enhances neutrophil-mediated inflammation and destabilization of unstable plaque, thereby providing a link between bilirubin and cardiovascular disease risk.

Conversion of the redox probe hydroethidine (HE) to 2-chloroethidium (2-Cl-E

Near-infrared autofluorescence (NIRAF) in unstable atherosclerotic plaque has been suggested as a novel imaging technology for high-risk atherosclerosis. Intraplaque hemorrhage (IPH) and bilirubin, derived from the subsequent degradation of heme, have been proposed as the source of NIRAF, although their roles and the underlying mechanism responsible for NIRAF remain unclear. To test the proposed role of bilirubin as the source of NIRAF in high-risk atherosclerosis, Biliverdin reductase a gene and apolipoprotein E gene double-knockout (Bvra−/−Apoe−/−) mice were subjected to the Western diet and tandem stenosis (TS) surgery, as a model of both bilirubin deficiency and plaque instability. Human coronary arteries containing atherosclerotic plaques were obtained from heart transplant recipients. The NIRAF was determined by in vivo fluorescence emission computed tomography, and ex vivo infrared imaging. The cholesterol content was quantified by HPLC with UV detection. In Bvra+/+Apoe−/− TS mice, the NIRAF intensity was significantly higher in unstable plaque than in stable plaque, yet the NIRAF in unstable plaque was undistinguishable in Bvra+/+Apoe−/− and littermate Bvra−/−Apoe−/− TS mice. Moreover, the unstable plaque in TS mice exhibited a lower NIRAF compared with highly cellular plaque that lacked most of the features of unstable plaque. In human coronary arteries, the NIRAF associated with cholesterol-rich, calcified lesions, rather than just cholesterol-rich lesions. The NIRAF in atherosclerotic plaque can be dissociated from IPH and bilirubin, such that the compositional meaning of an elevated NIRAF remains obscure.

The completeness of the system of eigenfunctions of the complex Schrodinger operator L c = − d 2 / d x 2 + c x 2 / 3 on the semi-axis in L 2 ( R + ) with Dirichlet boundary conditions is proved for all c: | arg ⁡ c | π / 2 + θ 0 , where π / 10 θ 0 π / 2 is determined as the only solution of a certain transcendental equation.

AGPATs (1-acylglycerol-3-phosphate O-acyltransferases) catalyze the acylation of lysophosphatidic acid to form phosphatidic acid (PA), a key step in the glycerol-3-phosphate pathway for the synthesis of phospholipids and triacylglycerols. AGPAT2 is the only AGPAT isoform whose loss-of-function mutations cause a severe form of human congenital generalized lipodystrophy. Paradoxically, AGPAT2 deficiency is known to dramatically increase the level of its product, PA. Here, we find that AGPAT2 deficiency impairs the biogenesis and growth of lipid droplets. We show that AGPAT2 deficiency compromises the stability of CDP-diacylglycerol (DAG) synthases (CDSs) and decreases CDS activity in both cell lines and mouse liver. Moreover, AGPAT2 and CDS1/2 can directly interact and form functional complexes, which promote the metabolism of PA along the CDP-DAG pathway of phospholipid synthesis. Our results provide key insights into the regulation of metabolic flux during lipid synthesis and suggest substrate channelling at a major branch point of the glycerol-3-phosphate pathway., AGPATs (1-acylglycerol-3-phosphate O-acyltransferases) catalyze the acylation of lysophosphatidic acid to form phosphatidic acid (PA), a key step in the synthesis of all glycerolipids. Here, the authors show that AGPAT2 and CDP-DAG synthases (CDS1 and CDS2) form functional complexes that promote further conversion of PA along the CDP-DAG pathway of phospholipid synthesis.

Atherosclerosis is a complex, multifactorial disease characterized by the buildup of plaque in the arterial wall. Apolipoprotein E gene deficient (Apoe-/-) mice serve as a commonly used tool to elucidate the pathophysiology of atherosclerosis because of their propensity to spontaneously develop arterial lesions. To date, however, an integrated omics assessment of atherosclerotic lesions in individual Apoe-/- mice has been challenging because of the small amount of diseased and nondiseased tissue available. To address this current limitation, we developed a multiomics method (Multi-ABLE) based on the proteomic method called accelerated Barocycler lysis and extraction (ABLE) to assess the depth of information that can be obtained from arterial tissue derived from a single mouse by splitting ABLE to allow for a combined proteomics-metabolomics-lipidomics analysis (Multi-ABLE). The new method includes tissue lysis via pressure cycling technology (PCT) in a Barocycler, followed by proteomic analysis of half the sample by nanoLC-MS and sequential extraction of lipids (organic extract) and metabolites (aqueous extract) combined with HILIC and reversed phase chromatography and time-of-flight mass spectrometry on the other half. Proteomic analysis identified 845 proteins, 93 of which were significantly altered in lesion-containing arteries. Lipidomic and metabolomic analyses detected 851 lipid and 362 metabolite features, which included 215 and 65 identified lipids and metabolites, respectively. The Multi-ABLE method is the first to apply a concurrent multiomics pipeline to cardiovascular disease using small (

Background and Aims The volatile thiols, such as 3‐mercaptohexanol, 3‐mercaptohexyl acetate and 4‐mercapto‐4‐methylpentan‐2‐one, are major aroma compounds responsible for the distinctive tropical notes (passionfruit and grapefruit) in New Zealand Sauvignon Blanc wines. Previously, it was observed that traces of linoleic acid in grape juice can significantly affect the development of these volatile thiols and other aroma compounds in wine. Here, we examined the effect of the fatty acids commonly found in Sauvignon Blanc grape juice as well as juice lipid lipolysis on the development of aroma compounds in the resulting wines. Methods and Results Experiments were performed to increase the total free fatty acid concentration in grape juice through juice treatment with acidic lipase from Aspergillus niger and through co‐cultured fermentations with non‐Saccharomyces lipase‐secreting yeasts. We observed a significant reduction in the production of 3‐mercaptohexyl acetate in fermented wines upon supplementation with linoleic acid and lipase. Supplementation with lipase increased the concentration of 3‐mercaptohexanol and all ethyl esters detected, while reducing the development of acetate esters. Co‐cultured fermentations also affected the development of many classes of aroma compounds. Conclusions This study demonstrated that the aroma profile of wines could be effectively manipulated by altering the amount of free unsaturated fatty acids in grape juice through lipolytic enzyme supplementation or co‐fermentation with non‐Saccharomyces lipolytic yeast species. Significance of the Study The key findings of this study may lead to new winemaking strategies through the manipulation of the lipid component of grape juice.

This study presents a comprehensive lipidome analysis of Sauvignon blanc grape juice by combining GC-MS based fatty acid profiling with shotgun lipidomics strategy. We observed that despite grape juice being a water based matrix it contains a diverse range of lipid species, including common saturated and unsaturated free and intact fatty acids as well as odd-numbered and hydroxy fatty acids. Based on GC-MS quantitative data, we found that the total lipid content of grape juice could be as high as 2.80 g/L. The majority of lipids were present in the form of complex lipids with relatively small amount of free fatty acids (15%). Therefore we concluded that the lipidome should be considered an important component of grape juice with the potential to impact on fermentation processes as well as on the sensorial properties of fermented products. This work serves as a hypothesis generating tool, the results of which justify follow-up studies to explore the influence of the grape juice lipidome and lipid metabolism in yeast on the aroma profile of wine.

Succinate dehydrogenase (SDH) is a hetero-tetrameric nuclear-encoded complex responsible for the oxidation of succinate to fumarate in the tricarboxylic acid (TCA) cycle. Loss-of-function mutations in any of the SDH genes are associated with cancer formation. However, the impact of SDH loss on cell metabolism and the mechanisms enabling growth of SDH-defective cells are largely unknown. Here, we generated Sdhb-ablated kidney mouse cells and employed comparative metabolomics and stable isotope-labelling approaches to identify nutritional requirements and metabolic adaptations to SDH loss. We found that lack of SDH activity commits cells to consume extracellular pyruvate, which sustains Warburg-like bioenergetic features. We further demonstrated that pyruvate carboxylation diverts glucose-derived carbons into aspartate biosynthesis, thus sustaining cell growth. By identifying pyruvate carboxylase as an essential gene for the proliferation and tumorigenic capacity of SDH-deficient cells, this study revealed a metabolic vulnerability for potential future treatment of SDH-associated malignancies.

Cultures of dissociated hippocampal neurons are often used to study neuronal cell biology. We report that the development of these neurons is strongly affected by chemicals leaching from commonly used disposable medical-grade syringes and syringe filters. Contamination of culture medium by bioactive substance(s) from syringes and filters occurred with multiple manufacturing lots and filter types under normal use conditions and resulted in changes to neurite growth, axon formation and the neuronal microtubule cytoskeleton. The effects on neuronal morphology were concentration dependent and significant effects were detected even after substantial dilution of the contaminated medium. Gas chromatography-mass spectrometry analyses revealed many chemicals eluting from the syringes and filters. Three of these chemicals (stearic acid, palmitic acid and 1,2-ethanediol monoacetate) were tested but showed no effects on neurite growth. Similar changes in neuronal morphology were seen with high concentrations of bisphenol A and dibutyl phthalate, two hormonally active plasticisers. Although no such compounds were detected by gas chromatography–mass spectrometry, unknown plasticisers in leachates may affect neurites. This is the first study to show that leachates from laboratory consumables can alter the growth of cultured hippocampal neurons. We highlight important considerations to ensure leachate contamination does not compromise cell biology experiments.

The recent history and the current state of relations between Russia and the European Union (EU) reflect the geopolitical competition between the two powers over their contested neighbourhood – Ukraine, Belarus and Moldova. Although prioritizing the EU as its major trade and political partner, Russia is also conscious of its strategic interests in the ‘near abroad’. While there is little discrimination in the political discourse of Russian elites in relation to the European Neighbourhood Policy (ENP), in reality, as popular opinion indicates, those neighbours who openly show their allegiances to the EU – Ukraine, Georgia and Moldova – have been increasingly categorized as hostile and unfriendly towards Russia. Public opinion remains strikingly congruent with and reflective of government foreign policy preferences.

We evaluated the quality and content of fish oil supplements in New Zealand. All encapsulated fish oil supplements marketed in New Zealand were eligible for inclusion. Fatty acid content was measured by gas chromatography. Peroxide values (PV) and anisidine values (AV) were measured and total oxidation values (Totox) calculated. Only 3 of 32 fish oil supplements contained quantities of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) that were equal or higher than labelled content, with most products tested (69%) containing

Oxygen and oxidative stress have become relevant components in clarifying the mechanism that weakens bacterial cells in parallel to the mode of action of bactericidal antibiotics. Given the importance of oxidative stress in the overall defense mechanism of bacteria and their apparent role in the antimicrobial mode of action, it is important to understand how bacteria respond to this stress at a metabolic level. The aim of this study was to determine the impact of oxygen on the metabolism of the facultative anaerobe Enterococcus faecalis using continuous culture, metabolomics and 13C-enrichment of metabolic intermediates. When E. faecalis was rapidly transitioned from anaerobic to aerobic growth, cellular metabolism was directed towards intracellular glutathione production and glycolysis was upregulated two-fold, which increased the supply of critical metabolite precursors (e.g. glycine and glutamate) for sulfur metabolism and glutathione biosynthesis as well as reducing power for cellular respiration in the presence of haemin. The ultimate metabolic response of E. faecalis to an aerobic environment was the upregulation of fatty acid metabolism and benzoate degradation, which was linked to important changes in the bacterial membrane composition as evidenced by changes in membrane fatty acid composition and the reduction of membrane-associated demethylmenaquinone. These key metabolic pathways associated with the response of E. faecalis to oxygen may represent potential new targets to increase the susceptibility of this bacterium to bactericidal drugs., This work was funded by the HRC (Health and Research Council of New Zealand) and the FCT (Portuguese Foundation for Science and Technology), with grant reference SFRH/BD/47016/2008.

Research in the United States and Europe has focused on the prejudice of majority groups towards minority groups, the implication somehow being that majority groups were more prejudiced than minority groups. In the former Soviet Union, ethnic environments were more complex; the same ethnic group could be a majority in one region but a minority in others. Using a sample of 1,459 first‐ and fourth‐year university students from eight regions of the former USSR, this study focuses on Russian, Tatar and Ukrainian respondents (n = 821) to test the hypothesis that the status of an ethnic group (majority/minority) or in‐group bias explains members’ prejudice. According to in‐group bias, all ethnic groups are equally prejudiced, minority and majority alike, whereas group status posits that groups in a majority position are more prejudiced. Findings show that group status has greater impact on prejudice than does in‐group bias. This applies, however, only to Russians. Interpretations of the findings rest o...