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Acyl-CoA-thioesterases, which hydrolyze acyl-CoA-esters and thereby release the respective acid, have essential functions in cellular metabolism and have also been used to produce valuable compounds in biotechnological processes. Thioesterase YciA originating from Haemophilus influenzae has been previously used to produce specific dicarboxylic acids from CoA-bound intermediates of the ethylmalonyl CoA pathway (EMCP) in Methylorubrum extorquens. In order to identify variants of the YciA enzyme with the capability to hydrolyze so far inaccessible CoA-esters of the EMCP or with improved productivity, we engineered the substrate-binding region of the enzyme. Screening a small semi-rational mutant library directly in M. extorquens yielded the F35L variant which showed a drastic product level increase for mesaconic acid (6.4-fold) and 2-methylsuccinic acid (4.4-fold) compared to the unaltered YciA enzyme. Unexpectedly, in vitro enzyme assays using respective M. extorquens cell extracts or recombinantly produced thioesterases could not deliver congruent data, as the F35L variant showed strongly reduced activity in these experiments. However, applied in an Escherichia coli production strain, the protein variant again outperformed the wild-type enzyme by allowing threefold increased 3-hydroxybutyric acid product titers. Saturation mutagenesis of the codon for position 35 led to the identification of another highly efficient YciA variant and enabled structure-function interpretations. Our work describes an important module for dicarboxylic acid production with M. extorquens and can guide future thioesterase improvement approaches. Key points: • Substitutions at position F35 of YciAHI changed the productivity of YciA-based release of carboxylic acid products in M. extorquens AM1 and E. coli. • YciAHI F35N and F35L are improved variants for dicarboxylic production of 2-methylsuccinic acid and mesaconic acid with M. extorquens AM1. • In vitro enzyme assays did not reve, QC 20231114

Background: The microbial production of succinic acid (SA) from renewable carbon sources via the reverse TCA (rTCA) pathway is a process potentially accompanied by net-fixation of carbon dioxide (CO2). Among reduced carbon sources, glycerol is particularly attractive since it allows a nearly twofold higher CO2-fixation yield compared to sugars. Recently, we described an engineered Saccharomyces cerevisiae strain which allowed SA production in synthetic glycerol medium with a maximum yield of 0.23 Cmol Cmol−1. The results of that previous study suggested that the glyoxylate cycle considerably contributed to SA accumulation in the respective strain. The current study aimed at improving the flux into the rTCA pathway accompanied by a higher CO2-fixation and SA yield. Results: By changing the design of the expression cassettes for the rTCA pathway, overexpressing PYC2, and adding CaCO3 to the batch fermentations, an SA yield on glycerol of 0.63 Cmol Cmol−1 was achieved (i.e. 47.1% of the theoretical maximum). The modifications in this 2nd-generation SA producer improved the maximum biomass-specific glycerol consumption rate by a factor of nearly four compared to the isogenic baseline strain solely equipped with the dihydroxyacetone (DHA) pathway for glycerol catabolism. The data also suggest that the glyoxylate cycle did not contribute to the SA production in the new strain. Cultivation conditions which directly or indirectly increased the concentration of bicarbonate, led to an accumulation of malate in addition to the predominant product SA (ca. 0.1 Cmol Cmol−1 at the time point when SA yield was highest). Off-gas analysis in controlled bioreactors with CO2-enriched gas-phase indicated that CO2 was fixed during the SA production phase. Conclusions: The data strongly suggest that a major part of dicarboxylic acids in our 2nd-generation SA-producer was formed via the rT, Funding Information: Open Access funding enabled and organized by Projekt DEAL. We thank the German Research Foundation (NE 697/7–1) and the Marie Skłodowska-Curie Innovative Training Network YEASTDOC (grant agreement ID: 764927) for funding of our research. Publisher Copyright: © 2022, The Author(s)., BT/Industrial Microbiology

Background: Lignosulfonates are significant wood chemicals with a $700 million market, produced by sulfite pulping of wood. During the pulping process, spent sulfite liquor (SSL) is generated, which in addition to lignosulfonates contains hemicellulose-derived sugars—in case of hardwoods primarily the pentose sugar xylose. The pentoses are currently underutilized. If they could be converted into value-added chemicals, overall economic profitability of the process would increase. SSLs are typically very inhibitory to microorganisms, which presents a challenge for a biotechnological process. The aim of the present work was to develop a robust yeast strain able to convert xylose in SSL to carboxylic acids. Results: The industrial strain Ethanol Red of the yeast Saccharomyces cerevisiae was engineered for efficient utilization of xylose in a Eucalyptus globulus lignosulfonate stream at low pH using CRISPR/Cas genome editing and adaptive laboratory evolution. The engineered strain grew in synthetic medium with xylose as sole carbon source with maximum specific growth rate (µmax) of 0.28 1/h. Selected evolved strains utilized all carbon sources in the SSL at pH 3.5 and grew with µmax between 0.05 and 0.1 1/h depending on a nitrogen source supplement. Putative genetic determinants of the increased tolerance to the SSL were revealed by whole genome sequencing of the evolved strains. In particular, four top-candidate genes (SNG1, FIT3, FZF1 and CBP3) were identified along with other gene candidates with predicted important roles, based on the type and distribution of the mutations across different strains and especially the best performing ones. The developed strains were further engineered for production of dicarboxylic acids (succinic and malic acid) via overexpression of the reductive branch of the tricarboxylic acid cycle (TCA). The production strain produced 0.2 mol and 0.12 mol of malic acid and succinic acid

Background: The microbial production of succinic acid (SA) from renewable carbon sources via the reverse TCA (rTCA) pathway is a process potentially accompanied by net-fixation of carbon dioxide (CO2). Among reduced carbon sources, glycerol is particularly attractive since it allows a nearly twofold higher CO2-fixation yield compared to sugars. Recently, we described an engineered Saccharomyces cerevisiae strain which allowed SA production in synthetic glycerol medium with a maximum yield of 0.23 Cmol Cmol−1. The results of that previous study suggested that the glyoxylate cycle considerably contributed to SA accumulation in the respective strain. The current study aimed at improving the flux into the rTCA pathway accompanied by a higher CO2-fixation and SA yield. Results: By changing the design of the expression cassettes for the rTCA pathway, overexpressing PYC2, and adding CaCO3 to the batch fermentations, an SA yield on glycerol of 0.63 Cmol Cmol−1 was achieved (i.e. 47.1% of the theoretical maximum). The modifications in this 2nd-generation SA producer improved the maximum biomass-specific glycerol consumption rate by a factor of nearly four compared to the isogenic baseline strain solely equipped with the dihydroxyacetone (DHA) pathway for glycerol catabolism. The data also suggest that the glyoxylate cycle did not contribute to the SA production in the new strain. Cultivation conditions which directly or indirectly increased the concentration of bicarbonate, led to an accumulation of malate in addition to the predominant product SA (ca. 0.1 Cmol Cmol−1 at the time point when SA yield was highest). Off-gas analysis in controlled bioreactors with CO2-enriched gas-phase indicated that CO2 was fixed during the SA production phase. Conclusions: The data strongly suggest that a major part of dicarboxylic acids in our 2nd-generation SA-producer was formed via the rT, BT/Industriele Microbiologie

Temporal variations and correlation statistics of major inorganic and organic species and carbonaceous components of the total suspended particulate matter (TSPM) at Alert were concurrently studied. Organic carbon (OC) and water-soluble organic carbon (WSOC) declined from February to mid-March together with elemental carbon (EC), but OC and WSOC increased in April while EC stayed low, suggesting photochemical production of organic aerosols. WSOC/OC ratios peaked in mid-April (89%). The ammonium availability index (AAI) increases from 31% (before sunrise) to 58% (after sunrise). Strong correlations of NH4+ with WSOC and dicarboxylic acids (DCAs) were found, implying the formation of organic salts at polar sunrise. K+ is substantially correlated (R2 = 0.96; p = 0.03) with levoglucosan before sunrise; however, the correlation decreases after. Significant correlations were found for 5 cations (NH4+, Na+, K+, Mg2+, and Ca2+), 2-alkaline earth metals (Ca and Mg), and 3 transition metals (Fe, Cu, and Mn) with DCAs and WSOC during both periods. Fe and Cu are strongly correlated (up to R2 = 0.80; p < 0.05) with DCAs before and after polar sunrise, implying the Fenton reaction both in dark and light periods. On the basis of the significant correlation, we found the plausibility of Fenton chemistry of Fe and Cu with oxalic acid. In the multiple linear regression model, Mn is the most significant predictor of WSOC followed by Cu and Fe after sunrise. This study demonstrates the importance of the photochemical processing of Arctic aerosols that are carried by long-range transport to the Arctic at Alert, and bridges and answers the research gap and some questions raised in our previous study (regarding, for example, the impacts of inorganic species, primarily NH4+ and transition metals on organic aerosols).

Mitochondrial complex II, also known as succinate dehydrogenase (SDH), is an integral-membrane heterotetramer (SDHABCD) that links two essential energy-producing processes, the tricarboxylic acid (TCA) cycle and oxidative phosphorylation. A significant amount of information is available on the structure and function of mature complex II from a range of organisms. However, there is a gap in our understanding of how the enzyme assembles into a functional complex, and disease-associated complex II insufficiency may result from incorrect function of the mature enzyme or from assembly defects. Here, we investigate the assembly of human complex II by combining a biochemical reconstructionist approach with structural studies. We report an X-ray structure of human SDHA and its dedicated assembly factor SDHAF2. Importantly, we also identify a small molecule dicarboxylate that acts as an essential cofactor in this process and works in synergy with SDHAF2 to properly orient the flavin and capping domains of SDHA. This reorganizes the active site, which is located at the interface of these domains, and adjusts the pKa of SDHAR451 so that covalent attachment of the flavin adenine dinucleotide (FAD) cofactor is supported. We analyze the impact of disease-associated SDHA mutations on assembly and identify four distinct conformational forms of the complex II flavoprotein that we assign to roles in assembly and catalysis.

BackgroundBempedoic acid is a first-in-class lipid-lowering drug recommended by guidelines for the treatment of hypercholesterolemia. Our objective was to estimate its average effect on plasma lipids in humans and its safety profile.Methods and findingsWe carried out a systematic review and meta-analysis of phase II and III randomized controlled trials on bempedoic acid (PROSPERO: CRD42019129687). PubMed (Medline), Scopus, Google Scholar, and Web of Science databases were searched, with no language restriction, from inception to 5 August 2019. We included 10 RCTs (n = 3,788) comprising 26 arms (active arm [n = 2,460]; control arm [n = 1,328]). Effect sizes for changes in lipids and high-sensitivity C-reactive protein (hsCRP) serum concentration were expressed as mean differences (MDs) and 95% confidence intervals (CIs). For safety analyses, odds ratios (ORs) and 95% CIs were calculated using the Mantel-Haenszel method. Bempedoic acid significantly reduced total cholesterol (MD -14.94%; 95% CI -17.31%, -12.57%; p < 0.001), non-high-density lipoprotein cholesterol (MD -18.17%; 95% CI -21.14%, -15.19%; p < 0.001), low-density lipoprotein cholesterol (MD -22.94%; 95% CI -26.63%, -19.25%; p < 0.001), low-density lipoprotein particle number (MD -20.67%; 95% CI -23.84%, -17.48%; p < 0.001), apolipoprotein B (MD -15.18%; 95% CI -17.41%, -12.95%; p < 0.001), high-density lipoprotein cholesterol (MD -5.83%; 95% CI -6.14%, -5.52%; p < 0.001), high-density lipoprotein particle number (MD -3.21%; 95% CI -6.40%, -0.02%; p = 0.049), and hsCRP (MD -27.03%; 95% CI -31.42%, -22.64%; p < 0.001). Bempedoic acid did not significantly modify triglyceride level (MD -1.51%; 95% CI -3.75%, 0.74%; p = 0.189), very-low-density lipoprotein particle number (MD 3.79%; 95% CI -9.81%, 17.39%; p = 0.585), and apolipoprotein A-1 (MD -1.83%; 95% CI -5.23%, 1.56%; p = 0.290). Treatment with bempedoic acid was positively associated with an increased risk of discontinuation of treat

Biobased C4-dicarboxylic acids are attractive sustainable precursors for polymers and other materials. Commercial scale production of these acids at high titers requires efficient secretion by cell factories. In this study, we characterized 7 dicarboxylic acid transporters in Xenopus oocytes and in Saccharomyces cerevisiae engineered for dicarboxylic acid production. Among the tested transporters, the Mae1(p) from Schizosaccharomyces pombe had the highest activity toward succinic, malic, and fumaric acids and resulted in 3-, 8-, and 5-fold titer increases, respectively, in S. cerevisiae, while not affecting growth, which was in contrast to the tested transporters from the tellurite-resistance/dicarboxylate transporter (TDT) family or the Na+ coupled divalent anion-sodium symporter family. Similar to SpMae1(p), its homolog in Aspergillus carbonarius, AcDct(p), increased the malate titer 12-fold without affecting the growth. Phylogenetic and protein motif analyses mapped SpMae1(p) and AcDct(p) into the voltage-dependent slow-anion channel transporter (SLAC1) clade of transporters, which also include plant Slac1(p) transporters involved in stomata closure. The conserved phenylalanine residue F329 closing the transport pore of SpMae1(p) is essential for the transporter activity. The voltage-dependent SLAC1 transporters do not use proton or Na+ motive force and are, thus, less energetically expensive than the majority of other dicarboxylic acid transporters. Such transporters present a tremendous advantage for organic acid production via fermentation allowing a higher overall product yield.

Metal-organic frameworks are promising materials for energy-efficient gas separations, but little is known about the diffusion of adsorbates in materials featuring one-dimensional porosity at the nanoscale. An understanding of the interplay between framework structure and gas diffusion is crucial for the practical application of these materials as adsorbents or in mixed-matrix membranes, since the rate of gas diffusion within the adsorbent pores impacts the required size (and therefore cost) of the adsorbent column or membrane. Here, we investigate the diffusion of CO2 within the pores of Zn2(dobpdc) (dobpdc4- = 4,4'-dioxidobiphenyl-3,3'-dicarboxylate) using pulsed field gradient (PFG) nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics (MD) simulations. The residual chemical shift anisotropy for pore-confined CO2 allows PFG NMR measurements of self-diffusion in different crystallographic directions, and our analysis of the entire NMR line shape as a function of the applied field gradient provides a precise determination of the self-diffusion coefficients. In addition to observing CO2 diffusion through the channels parallel to the crystallographic c axis (self-diffusion coefficient D∥ = (5.8 ± 0.1) × 10-9 m2 s-1 at a pressure of 625 mbar CO2), we unexpectedly find that CO2 is also able to diffuse between the hexagonal channels in the crystallographic ab plane (D⊥ = (1.9 ± 0.2) × 10-10 m2 s-1), despite the walls of these channels appearing impermeable by single-crystal X-ray crystallography and flexible lattice MD simulations. Observation of such unexpected diffusion in the ab plane suggests the presence of defects that enable effective multidimensional CO2 transport in a metal-organic framework with nominally one-dimensional porosity.

In the last decades, there has been increasing demand by society for non-toxic renewable products that could be used to replace fossil-based building blocks. Lignin is a major component of nonedible biomass, and is the most abundant renewable source of aromatics in nature. The research work investigated the breakdown of lignin using a novel thermochemical approach. It resulted in the production of organic acids, which can be formulated to produce green pesticides and herbicides. The study also resulted in the production of low molecular weight aromatics, which can be used for the production of bio-based polymers, including biodegradable packaging materials.

Metal-organic frameworks are promising materials for energy-efficient gas separations, but little is known about the diffusion of adsorbates in materials featuring one-dimensional porosity at the nanoscale. An understanding of the interplay between framework structure and gas diffusion is crucial for the practical application of these materials as adsorbents or in mixed-matrix membranes, since the rate of gas diffusion within the adsorbent pores impacts the required size (and therefore cost) of the adsorbent column or membrane. Here, we investigate the diffusion of CO2 within the pores of Zn2(dobpdc) (dobpdc4- = 4,4'-dioxidobiphenyl-3,3'-dicarboxylate) using pulsed field gradient (PFG) nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics (MD) simulations. The residual chemical shift anisotropy for pore-confined CO2 allows PFG NMR measurements of self-diffusion in different crystallographic directions, and our analysis of the entire NMR line shape as a function of the applied field gradient provides a precise determination of the self-diffusion coefficients. In addition to observing CO2 diffusion through the channels parallel to the crystallographic c axis (self-diffusion coefficient D∥ = (5.8 ± 0.1) × 10-9 m2 s-1 at a pressure of 625 mbar CO2), we unexpectedly find that CO2 is also able to diffuse between the hexagonal channels in the crystallographic ab plane (D⊥ = (1.9 ± 0.2) × 10-10 m2 s-1), despite the walls of these channels appearing impermeable by single-crystal X-ray crystallography and flexible lattice MD simulations. Observation of such unexpected diffusion in the ab plane suggests the presence of defects that enable effective multidimensional CO2 transport in a metal-organic framework with nominally one-dimensional porosity.

Because of the abundance of dicarboxylic acids in the atmosphere, they are commonly studied in the aerosol field, specifically investigating their hygroscopic and cloud condensation nuclei activity. Glutaric acid, being a water-soluble dicarboxylic acid is commonly used to model water activity in dicarboxylic acid aerosols. Variability associated with glutaric acid aerosols, specifically DRH and hygroscopic data, has been reported by several groups. We hypothesize that this variability is caused by its polymorphism. Glutaric acid exhibits dimorphism, meaning the molecule can form into two different types of crystal structures, an alpha and a beta polymorph. Glutaric acid naturally forms the beta polymorph, which is more stable. The alpha polymorph is the metastable phase. These polymorphs manifest themselves as a bimodal aerosol size distribution when analyzed by Scanning Mobility Particle Sizer or other aerosol mobility sizing methods. In this paper, we discuss the formation of the nanoscale alpha glutaric acid polymorph generated from an aqueous glutaric acid solution. The formation of both polymorphs from an aqueous solution has not been documented elsewhere. We have found that the alpha polymorph forms at faster crystallization speeds, with a lower aqueous solution concentration and a lower solution flowrate into the atomizer. This identification of the presence of polymorphism in glutaric acid aerosols under common laboratory generation conditions explains the variability present in studies associated with glutaric acid aerosols. Understanding of the conditions at which the alpha polymorph is present will allow others to avoid it when using glutaric acid as a dicarboxylic acid standard.

Imaging tumoral pH may help to characterize aggressiveness, metastasis, and therapeutic response. We report the development of hyperpolarized [2-13C,D10]diethylmalonic acid, which exhibits a large pH-dependent 13C chemical shift over the physiological range. We demonstrate that co-polarization with [1-13C,D9]tert-butanol accurately measures pH via13C NMR and magnetic resonance spectroscopic imaging in phantoms.

Dicarboxylic acids are commodity chemicals used in the production of plastics, polyesters, nylons, fragrances, and medications. Bio-based routes to dicarboxylic acids are gaining attention due to environmental concerns about petroleum-based production of these compounds. Some industrial applications require dicarboxylic acids with specific carbon chain lengths, including odd-carbon species. Biosynthetic pathways involving cytochrome P450-catalyzed oxidation of fatty acids in yeast and bacteria have been reported, but these systems produce almost exclusively even-carbon species. Here we report a novel pathway to odd-carbon dicarboxylic acids directly from glucose in Escherichia coli by employing an engineered pathway combining enzymes from biotin and fatty acid synthesis. Optimization of the pathway will lead to industrial strains for the production of valuable odd-carbon diacids.

Lignin depolymerization to dicarboxylic acids (DCAs) by the one-step Fenton oxidation process results in poor yield and significant amounts of residual solids. A process based on the use of sodium percarbonate on bagasse lignin depolymerization was conducted at 60–300 °C, for 1–6 h. This approach resulted in significantly higher DCA yields (predominantly oxalic, malonic, and succinic acids), without the formation of char, when compared to the acidic H2O2/chalcopyrite process. This was in part due to the effectiveness of the alkaline reaction medium in suppressing the thermal degradation of DCAs during processing. It was determined that increasing the alkaline content of the reaction mixture further significantly improved DCA yield. When applying this process at 200 °C for 3 h, using 1 M NaOH (in addition to 0.6 M sodium percarbonate) increased DCA yield by 85%. The process developed was applied to the lignin model compounds; guaiacol, vanillic acid, and p-hydroxybenzoic acid. It was demonstrated that the degradation pathways and product ratios of these compounds differed, implying an influence of lignin monomer ratio on the DCA product range. DCAs produced from this process have the potential to be used in the industrial production of green insecticides, fungicides, and disinfectants.

Imaging tumoral pH may help to characterize aggressiveness, metastasis, and therapeutic response. We report the development of hyperpolarized [2-13C,D10]diethylmalonic acid, which exhibits a large pH-dependent 13C chemical shift over the physiological range. We demonstrate that co-polarization with [1-13C,D9]tert-butanol accurately measures pH via13C NMR and magnetic resonance spectroscopic imaging in phantoms.

Dicarboxylic acids are commodity chemicals used in the production of plastics, polyesters, nylons, fragrances, and medications. Bio-based routes to dicarboxylic acids are gaining attention due to environmental concerns about petroleum-based production of these compounds. Some industrial applications require dicarboxylic acids with specific carbon chain lengths, including odd-carbon species. Biosynthetic pathways involving cytochrome P450-catalyzed oxidation of fatty acids in yeast and bacteria have been reported, but these systems produce almost exclusively even-carbon species. Here we report a novel pathway to odd-carbon dicarboxylic acids directly from glucose in Escherichia coli by employing an engineered pathway combining enzymes from biotin and fatty acid synthesis. Optimization of the pathway will lead to industrial strains for the production of valuable odd-carbon diacids.

Chemical building blocks for plastics can be produced from renewable biomass feedstocks using microbial production organisms, such as yeast or bacteria, in a biorefinery. One class of chemical building blocks that are suitable for production of biobased and biodegradable plastics are dicarboxylic acids, e.g. succinic acid. In order to avoid competition with food and feed production it is desirable to use hydrolysates of lignocellulosic feedstocks which often not only contain hexose sugars but also pentoses, out of which xylose is the most common. One example of such a feedstock is spent sulphite liquor (SSL), a side stream from sulphite pulping of Eucalyptus, which is rich in xylose. In this thesis, microbial production of dicarboxylic acids from xylose-rich feedstocks has been studied using different host organisms. The natural succinic acid producing bacterium Actinobacillus succinogenes was found able to produce succinate from a xylose rich synthetic model medium mimicking sugar com- position in SSL, at a titer of 31 g L-1 and yield of 0.71 g g-1. In addition, A. succinogenes was tested for tolerance towards inhibiting by-products along with a related succinate producer, Basfia succiniciproducens. Of the by-products, both organisms were found to be most sensitive to formate (18-22 g L-1), while high concentration of acetate (38 g L-1) and succinate (55 g L-1) were tolerated. Succinate production with A. succinogenes was also tested in SSL, and titers above 22 g L-1 of succinate were obtained in fed-batch cultivations. A strain of Saccharomyces cerevisiae engineered for xylose utilization and formation of dicarboxylic acids was assessed and found rather tolerant to SSL even at acidic condi- tions. The relative distribution between malate and succinate was affected by cultivation conditions, with succinate strongly favoured at carboxylating conditions at high pH. Genes encoding enzymes of the Weimberg pathway, an orthogonal xylose degradation pathway, were introduced

Transporter-mediated drug-drug interactions (DDIs) are a major cause of drug toxicities. Using published genome-wide association studies (GWAS) of the human metabolome, we identified 20 metabolites associated with genetic variants in organic anion transporter, OATP1B1 (P < 5 × 10-8 ). Of these, 12 metabolites were significantly higher in plasma samples from volunteers dosed with the OATP1B1 inhibitor, cyclosporine (CSA) vs. placebo (q-value < 0.2). Conjugated bile acids and fatty acid dicarboxylates were among the metabolites discovered using both GWAS and CSA administration. In vitro studies confirmed tetradecanedioate (TDA) and hexadecanedioate (HDA) were novel substrates of OATP1B1 as well as OAT1 and OAT3. This study highlights the use of multiple datasets for the discovery of endogenous metabolites that represent potential in vivo biomarkers for transporter-mediated DDIs. Future studies are needed to determine whether these metabolites can serve as qualified biomarkers for organic anion transporters. Quantitative relationships between metabolite levels and modulation of transporters should be established.

Transporter-mediated drug-drug interactions (DDIs) are a major cause of drug toxicities. Using published genome-wide association studies (GWAS) of the human metabolome, we identified 20 metabolites associated with genetic variants in organic anion transporter, OATP1B1 (P < 5 × 10-8 ). Of these, 12 metabolites were significantly higher in plasma samples from volunteers dosed with the OATP1B1 inhibitor, cyclosporine (CSA) vs. placebo (q-value < 0.2). Conjugated bile acids and fatty acid dicarboxylates were among the metabolites discovered using both GWAS and CSA administration. In vitro studies confirmed tetradecanedioate (TDA) and hexadecanedioate (HDA) were novel substrates of OATP1B1 as well as OAT1 and OAT3. This study highlights the use of multiple datasets for the discovery of endogenous metabolites that represent potential in vivo biomarkers for transporter-mediated DDIs. Future studies are needed to determine whether these metabolites can serve as qualified biomarkers for organic anion transporters. Quantitative relationships between metabolite levels and modulation of transporters should be established.

Dicarboxylic acids and their derivatives (esters and anhydrides) have been used as acylating agents in lipase-catalyzed reactions in organic solvents. The synthetic outcomes have been dimeric or hybrid derivatives of bioactive natural compounds as well as functionalized polyesters., QC 20151009

Daytime and nighttime fine aerosol (PM2.5) samples were collected during a haze episode in January 2013 within the urban area of Chengdu, southwest China. Aerosol samples were analyzed for low-molecular-weight homologous dicarboxylic acids, oxocarboxylic acids and alpha-dicarbonyls, as well as organic carbon and elemental carbon. Concentration ranges of diacids, oxoacids, and alpha-dicarbonyls were 1,400-5,250, 272-1,380, and 88-220 ng m(-3), respectively. Molecular distributions of diacids (mean 3,388 +/- 943 ng m(-3)) were characterized by a predominance of oxalic acid (C-2; 1,373 +/- 427 ng m(-3)), followed by succinic (C-4), terephthalic (tPh), and phthalic (Ph) acids. Such high levels of tPh and Ph were different from those in other Asian cities where malonic acid (C-3) is the second or third highest species, mostly owing to significant emissions from coal combustion and uncontrolled waste incineration. High contents of diacids, oxoacids, and alpha-dicarbonyls were detected on hazy days, suggesting an enhanced emission and/or formation of these organics during such a weather condition. Concentrations of unsaturated aliphatic diacids (e.g., maleic acid) and phthalic acids were higher in nighttime than in daytime. Good positive correlations of C-2 with C-3, C-4, ketomalonic (kC(3)), pyruvic (Pyr), and glyoxylic (E center dot C-2) acids in daytime suggest secondary production of C-2 via the photooxidation of longer chain diacids and E center dot C-2. This study demonstrated that both primary emissions and secondary production are important sources of dicarboxylic acids and related compounds in atmospheric aerosols in the Sichuan Basin.

Daytime and nighttime fine aerosol (PM2.5) samples were collected during a haze episode in January 2013 within the urban area of Chengdu, southwest China. Aerosol samples were analyzed for low-molecular-weight homologous dicarboxylic acids, oxocarboxylic acids and alpha-dicarbonyls, as well as organic carbon and elemental carbon. Concentration ranges of diacids, oxoacids, and alpha-dicarbonyls were 1,400-5,250, 272-1,380, and 88-220 ng m(-3), respectively. Molecular distributions of diacids (mean 3,388 +/- 943 ng m(-3)) were characterized by a predominance of oxalic acid (C-2; 1,373 +/- 427 ng m(-3)), followed by succinic (C-4), terephthalic (tPh), and phthalic (Ph) acids. Such high levels of tPh and Ph were different from those in other Asian cities where malonic acid (C-3) is the second or third highest species, mostly owing to significant emissions from coal combustion and uncontrolled waste incineration. High contents of diacids, oxoacids, and alpha-dicarbonyls were detected on hazy days, suggesting an enhanced emission and/or formation of these organics during such a weather condition. Concentrations of unsaturated aliphatic diacids (e.g., maleic acid) and phthalic acids were higher in nighttime than in daytime. Good positive correlations of C-2 with C-3, C-4, ketomalonic (kC(3)), pyruvic (Pyr), and glyoxylic (E center dot C-2) acids in daytime suggest secondary production of C-2 via the photooxidation of longer chain diacids and E center dot C-2. This study demonstrated that both primary emissions and secondary production are important sources of dicarboxylic acids and related compounds in atmospheric aerosols in the Sichuan Basin.

Daytime and nighttime fine aerosol (PM2.5) samples were collected during a haze episode in January 2013 within the urban area of Chengdu, southwest China. Aerosol samples were analyzed for low-molecular-weight homologous dicarboxylic acids, oxocarboxylic acids and alpha-dicarbonyls, as well as organic carbon and elemental carbon. Concentration ranges of diacids, oxoacids, and alpha-dicarbonyls were 1,400-5,250, 272-1,380, and 88-220 ng m(-3), respectively. Molecular distributions of diacids (mean 3,388 +/- 943 ng m(-3)) were characterized by a predominance of oxalic acid (C-2; 1,373 +/- 427 ng m(-3)), followed by succinic (C-4), terephthalic (tPh), and phthalic (Ph) acids. Such high levels of tPh and Ph were different from those in other Asian cities where malonic acid (C-3) is the second or third highest species, mostly owing to significant emissions from coal combustion and uncontrolled waste incineration. High contents of diacids, oxoacids, and alpha-dicarbonyls were detected on hazy days, suggesting an enhanced emission and/or formation of these organics during such a weather condition. Concentrations of unsaturated aliphatic diacids (e.g., maleic acid) and phthalic acids were higher in nighttime than in daytime. Good positive correlations of C-2 with C-3, C-4, ketomalonic (kC(3)), pyruvic (Pyr), and glyoxylic (E center dot C-2) acids in daytime suggest secondary production of C-2 via the photooxidation of longer chain diacids and E center dot C-2. This study demonstrated that both primary emissions and secondary production are important sources of dicarboxylic acids and related compounds in atmospheric aerosols in the Sichuan Basin.

Aerosol samples were collected in autumn 2007 on day- and nighttime basis in the northern receptor site of Beijing, China. The samples were analyzed for total carbon (TC) and water-soluble dicarboxylic acids (C-2-C-12), oxocarboxylic adds (C-2-C-9), glyoxal and methylglyoxal to better understand the photochemical aging of organic aerosols in the vicinity of Beijing. Concentrations of TC are 50% greater in daytime when winds come from Beijing than in nighttime when winds come from the northern forest areas. Most diacids showed higher concentrations in daytime, suggesting that the organics emitted from the urban Beijing and delivered to the northern vicinity in daytime are subjected to photo-oxidation to result in diacids. However, oxalic acid (C-2), which is the most abundant diacid followed by C-3 or C-4, became on average 30% more abundant in nighttime together with azelaic, omega-oxooctanoic and omega-oxononanoic acids, which are specific oxidation products of biogenic unsaturated fatty acids. Methylglyoxal, an oxidation product of isoprene and a precursor of oxalic acid, also became 29% more abundant in nighttime. Based on a positive correlation between C-2 and glyoxylic acid (omega C-2) in nighttime when relative humidity significantly enhanced, we propose a nighttime aqueous phase production of C-2 via the oxidation of omega C-2. We found an increase in the contribution of diacids to TC by 3 folds during consecutive clear days. This study demonstrates that diacids and related compounds are largely produced in the northern vicinity of Beijing via photochemical processing of organic precursors emitted from urban center and forest areas. (C) 2014 Elsevier B.V. All rights reserved.

Aerosol samples were collected in autumn 2007 on day- and nighttime basis in the northern receptor site of Beijing, China. The samples were analyzed for total carbon (TC) and water-soluble dicarboxylic acids (C-2-C-12), oxocarboxylic adds (C-2-C-9), glyoxal and methylglyoxal to better understand the photochemical aging of organic aerosols in the vicinity of Beijing. Concentrations of TC are 50% greater in daytime when winds come from Beijing than in nighttime when winds come from the northern forest areas. Most diacids showed higher concentrations in daytime, suggesting that the organics emitted from the urban Beijing and delivered to the northern vicinity in daytime are subjected to photo-oxidation to result in diacids. However, oxalic acid (C-2), which is the most abundant diacid followed by C-3 or C-4, became on average 30% more abundant in nighttime together with azelaic, omega-oxooctanoic and omega-oxononanoic acids, which are specific oxidation products of biogenic unsaturated fatty acids. Methylglyoxal, an oxidation product of isoprene and a precursor of oxalic acid, also became 29% more abundant in nighttime. Based on a positive correlation between C-2 and glyoxylic acid (omega C-2) in nighttime when relative humidity significantly enhanced, we propose a nighttime aqueous phase production of C-2 via the oxidation of omega C-2. We found an increase in the contribution of diacids to TC by 3 folds during consecutive clear days. This study demonstrates that diacids and related compounds are largely produced in the northern vicinity of Beijing via photochemical processing of organic precursors emitted from urban center and forest areas. (C) 2014 Elsevier B.V. All rights reserved.

Aerosol samples were collected in autumn 2007 on day- and nighttime basis in the northern receptor site of Beijing, China. The samples were analyzed for total carbon (TC) and water-soluble dicarboxylic acids (C-2-C-12), oxocarboxylic adds (C-2-C-9), glyoxal and methylglyoxal to better understand the photochemical aging of organic aerosols in the vicinity of Beijing. Concentrations of TC are 50% greater in daytime when winds come from Beijing than in nighttime when winds come from the northern forest areas. Most diacids showed higher concentrations in daytime, suggesting that the organics emitted from the urban Beijing and delivered to the northern vicinity in daytime are subjected to photo-oxidation to result in diacids. However, oxalic acid (C-2), which is the most abundant diacid followed by C-3 or C-4, became on average 30% more abundant in nighttime together with azelaic, omega-oxooctanoic and omega-oxononanoic acids, which are specific oxidation products of biogenic unsaturated fatty acids. Methylglyoxal, an oxidation product of isoprene and a precursor of oxalic acid, also became 29% more abundant in nighttime. Based on a positive correlation between C-2 and glyoxylic acid (omega C-2) in nighttime when relative humidity significantly enhanced, we propose a nighttime aqueous phase production of C-2 via the oxidation of omega C-2. We found an increase in the contribution of diacids to TC by 3 folds during consecutive clear days. This study demonstrates that diacids and related compounds are largely produced in the northern vicinity of Beijing via photochemical processing of organic precursors emitted from urban center and forest areas. (C) 2014 Elsevier B.V. All rights reserved.

This study investigated spatial distributions of water-soluble dicarboxylic acids and related compounds in the marine aerosols collected at low- to mid-latitudes in the Northern Hemisphere for a better understanding of the photochemical aging of organic aerosols during long-range transport. Their molecular distributions were characterized by the predominance of oxalic acid (C2) followed by malonic (C3) and succinic (C4) acids, except for one sample (QFF114, C2>C4>C3) that was collected in the western North Pacific with a heavy influence of biomass burning. Concentration ranges of diacids, ketoacids (including glyoxylic acid and pyruvic acid), and glyoxal were 17-718 ng m^[-3] (average 218 ng m^[-3]), 0.40-72 ng m^[-3] (23 ng m^[-3]), and 0.16-19 ng m^[-3] (33 ng m^[-3]), which account for 3.6-23% (14%), 0.09-23% (1.3%), and 0.04-0.45% (0.19%) of organic carbon (OC) in the marine aerosols, respectively. Positive correlations were observed between OC and diacids/ketoacids. Positive correlations were also found between biogenic secondary organic aerosol (SOA) tracers (e.g., 2-methylglyceric acid) and diacids/ketoacids, suggesting a significant contribution of biogenic secondary source. The spatial distributions of diacids exhibited higher loadings over the coastal/tropical regions than the open oceans, which are similar to those of the concentration ratios of malonic/succinic (C3/C4) and adipic/azelaic (C6/C9), indicating a more significant influence of anthropogenic sources over the coastal regions than the remote oceans. However, the concentration ratios of oxalic acid to levoglucosan, a biomass-burning tracer, and to C29 n-alkane, a tracer for terrestrial biogenic emission showed higher values over the open oceans than the coastal regions, suggesting a continuous production of oxalic acid during long-range atmospheric transport. This study indicates that the long-range transport of primary and secondary aerosols of continental origin and photooxidation/aerosol aging

This study investigated spatial distributions of water-soluble dicarboxylic acids and related compounds in the marine aerosols collected at low- to mid-latitudes in the Northern Hemisphere for a better understanding of the photochemical aging of organic aerosols during long-range transport. Their molecular distributions were characterized by the predominance of oxalic acid (C2) followed by malonic (C3) and succinic (C4) acids, except for one sample (QFF114, C2>C4>C3) that was collected in the western North Pacific with a heavy influence of biomass burning. Concentration ranges of diacids, ketoacids (including glyoxylic acid and pyruvic acid), and glyoxal were 17-718 ng m^[-3] (average 218 ng m^[-3]), 0.40-72 ng m^[-3] (23 ng m^[-3]), and 0.16-19 ng m^[-3] (33 ng m^[-3]), which account for 3.6-23% (14%), 0.09-23% (1.3%), and 0.04-0.45% (0.19%) of organic carbon (OC) in the marine aerosols, respectively. Positive correlations were observed between OC and diacids/ketoacids. Positive correlations were also found between biogenic secondary organic aerosol (SOA) tracers (e.g., 2-methylglyceric acid) and diacids/ketoacids, suggesting a significant contribution of biogenic secondary source. The spatial distributions of diacids exhibited higher loadings over the coastal/tropical regions than the open oceans, which are similar to those of the concentration ratios of malonic/succinic (C3/C4) and adipic/azelaic (C6/C9), indicating a more significant influence of anthropogenic sources over the coastal regions than the remote oceans. However, the concentration ratios of oxalic acid to levoglucosan, a biomass-burning tracer, and to C29 n-alkane, a tracer for terrestrial biogenic emission showed higher values over the open oceans than the coastal regions, suggesting a continuous production of oxalic acid during long-range atmospheric transport. This study indicates that the long-range transport of primary and secondary aerosols of continental origin and photooxidation/aerosol

This study investigated spatial distributions of water-soluble dicarboxylic acids and related compounds in the marine aerosols collected at low- to mid-latitudes in the Northern Hemisphere for a better understanding of the photochemical aging of organic aerosols during long-range transport. Their molecular distributions were characterized by the predominance of oxalic acid (C2) followed by malonic (C3) and succinic (C4) acids, except for one sample (QFF114, C2>C4>C3) that was collected in the western North Pacific with a heavy influence of biomass burning. Concentration ranges of diacids, ketoacids (including glyoxylic acid and pyruvic acid), and glyoxal were 17-718 ng m^[-3] (average 218 ng m^[-3]), 0.40-72 ng m^[-3] (23 ng m^[-3]), and 0.16-19 ng m^[-3] (33 ng m^[-3]), which account for 3.6-23% (14%), 0.09-23% (1.3%), and 0.04-0.45% (0.19%) of organic carbon (OC) in the marine aerosols, respectively. Positive correlations were observed between OC and diacids/ketoacids. Positive correlations were also found between biogenic secondary organic aerosol (SOA) tracers (e.g., 2-methylglyceric acid) and diacids/ketoacids, suggesting a significant contribution of biogenic secondary source. The spatial distributions of diacids exhibited higher loadings over the coastal/tropical regions than the open oceans, which are similar to those of the concentration ratios of malonic/succinic (C3/C4) and adipic/azelaic (C6/C9), indicating a more significant influence of anthropogenic sources over the coastal regions than the remote oceans. However, the concentration ratios of oxalic acid to levoglucosan, a biomass-burning tracer, and to C29 n-alkane, a tracer for terrestrial biogenic emission showed higher values over the open oceans than the coastal regions, suggesting a continuous production of oxalic acid during long-range atmospheric transport. This study indicates that the long-range transport of primary and secondary aerosols of continental origin and photooxidation/aerosol aging

Isomers of muconic acid were used to investigate the effect of molecular structure and solubility on the bulk properties of alumina dispersions and the nanoscale interactions between alumina surfaces. Both the trans, trans and cis, cis isomers increased the yield stress of the slurries at low pH compared with that of pure alumina. The solubility of muconic acid fell at low pH, leading to the formation of an oily layer between the interacting surfaces. This layer was the source of a capillary force that accounted for the large increase in yield stress at low pH and high concentrations of muconic acid. The work showed that the molecular structure played a part in increasing the inter-particle strength of metal oxide surfaces, and that their concentration and solubility are linked to an attraction between the surfaces., Isomers of muconic acid were used to investigate the effect of molecular structure and solubility on the bulk properties of alumina dispersions and the nanoscale interactions between alumina surfaces. Both the trans, trans and cis, cis isomers increased the yield stress of the slurries at low pH compared with that of pure alumina. The solubility of muconic acid fell at low pH, leading to the formation of an oily layer between the interacting surfaces. This layer was the source of a capillary force that accounted for the large increase in yield stress at low pH and high concentrations of muconic acid. The work showed that the molecular structure played a part in increasing the inter-particle strength of metal oxide surfaces, and that their concentration and solubility are linked to an attraction between the surfaces.

To investigate the impact of chronic ingestion of sebacic acid (SA), a 10-carbon medium-chain dicarboxylic acid, on glycaemic control in a mouse model of type 2 diabetes (T2D).

Dicarboxylic acids are natural products with the potential of being an alternate dietary source of energy. We aimed to evaluate the effect of sebacic acid (a 10-carbon dicarboxylic acid; C10) ingestion on postprandial glycemia and glucose rate of appearance (Ra) in healthy and type 2 diabetic subjects. Furthermore, the effect of C10 on insulin-mediated glucose uptake and on GLUT4 expression was assessed in L6 muscle cells in vitro.

The natural product kainic acid is used as template for the rational design of a novel conformationally restricted (S)-glutamic acid (Glu) analogue, (1R,4S,5R,6S)-3-azabicyclo[3.3.0]octane-4,6-dicarboxylic acid (1a). The target structure 1a was synthesized from commercially available (S)-pyroglutaminol, in an enantioselective fashion, in 14 steps. Pharmacological characterization of 1a at human glutamate transporter subtypes 1, 2, and 3 yielded K(i) values of 127, 52, and 46 microM, respectively. Furthermore, binding studies at native ionotropic Glu (iGlu) receptors revealed low affinity for alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-preferring iGlu receptors (IC(50) > 100 microM), whereas affinities for the KAIN-preferring iGlu receptors and the N-methyl-d-aspartate (NMDA)-preferring group of iGlu receptors were in the low micromolar range (IC(50) = 14 and 2.9 microM, respectively). At metabotropic Glu receptors (mGluR), EC(50) values for 1a were >1000 microM for mGluR1 and 4, representing group I and III, respectively, and approximately 1000 microM (agonist) for mGluR2, representing group II.

The natural product kainic acid is used as template for the rational design of a novel conformationally restricted (S)-glutamic acid (Glu) analogue, (1R,4S,5R,6S)-3-azabicyclo[3.3.0]octane-4,6-dicarboxylic acid (1a). The target structure 1a was synthesized from commercially available (S)-pyroglutaminol, in an enantioselective fashion, in 14 steps. Pharmacological characterization of 1a at human glutamate transporter subtypes 1, 2, and 3 yielded K(i) values of 127, 52, and 46 microM, respectively. Furthermore, binding studies at native ionotropic Glu (iGlu) receptors revealed low affinity for alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-preferring iGlu receptors (IC(50) > 100 microM), whereas affinities for the KAIN-preferring iGlu receptors and the N-methyl-d-aspartate (NMDA)-preferring group of iGlu receptors were in the low micromolar range (IC(50) = 14 and 2.9 microM, respectively). At metabotropic Glu receptors (mGluR), EC(50) values for 1a were >1000 microM for mGluR1 and 4, representing group I and III, respectively, and approximately 1000 microM (agonist) for mGluR2, representing group II.

The natural product kainic acid is used as template for the rational design of a novel conformationally restricted (S)-glutamic acid (Glu) analogue, (1R,4S,5R,6S)-3-azabicyclo[3.3.0]octane-4,6-dicarboxylic acid (1a). The target structure 1a was synthesized from commercially available (S)-pyroglutaminol, in an enantioselective fashion, in 14 steps. Pharmacological characterization of 1a at human glutamate transporter subtypes 1, 2, and 3 yielded K(i) values of 127, 52, and 46 microM, respectively. Furthermore, binding studies at native ionotropic Glu (iGlu) receptors revealed low affinity for alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-preferring iGlu receptors (IC(50) > 100 microM), whereas affinities for the KAIN-preferring iGlu receptors and the N-methyl-d-aspartate (NMDA)-preferring group of iGlu receptors were in the low micromolar range (IC(50) = 14 and 2.9 microM, respectively). At metabotropic Glu receptors (mGluR), EC(50) values for 1a were >1000 microM for mGluR1 and 4, representing group I and III, respectively, and approximately 1000 microM (agonist) for mGluR2, representing group II.

In the presence of Ba2+ ions, (benzothiazolyl)ethenylbenzocrown ether forms the stable sandwich complex 2L center dot Ba2+ with an unusual structure, in which the benzothiazole fragments are arranged one above the other. Irradiation of the sandwich complex with visible light induces stereoselective [2+2] cycloaddition giving rise to two "head-to-head" isomers of biscrown-cyclobutane. The addition of dibasic dicarboxylic acids that additionally stabilize the sandwich complex in a favorable conformation affects the isomer ratio of the cyclobutanes formed. The conformational equilibria for the sandwich complex and cyclobutanes were studied by H-1 N MR spectroscopy.

Water-soluble organic acids are important components in atmospheric aerosols and can act as cloud condensation nuclei to potentially affect the climate. In this study, a total of 25 PM2.5 samples were collected from summer to winter in 2002-2003 at an urban area in Beijing. C 2-C5 dicarboxylic acids and malic, glyoxylic and pyruvic acids were determined using a capillary electrophoresis. Oxalic acid dominated in these acids with seasonal average concentrations of 107-412 ng m -3. Malonic and succinic acids were comparable in different seasons, with seasonal average concentrations ranging from 20 to 60 ng m-3. Glutaric acid was much less abundant with an average of 10 ng m-3. The sum of these seven detected acids accounted for 3-15% of organic carbon content in PM2.5. Seasonal differences of these acids were discussed in terms of their corresponding sources. Correlations of these acids with sulfate and MSA were also investigated to interpret their possible secondary formation pathways. © 2005 Elsevier Ltd. All rights reserved.

Water-soluble organic acids are important components in atmospheric aerosols and can act as cloud condensation nuclei to potentially affect the climate. In this study, a total of 25 PM2.5 samples were collected from summer to winter in 2002-2003 at an urban area in Beijing. C 2-C5 dicarboxylic acids and malic, glyoxylic and pyruvic acids were determined using a capillary electrophoresis. Oxalic acid dominated in these acids with seasonal average concentrations of 107-412 ng m -3. Malonic and succinic acids were comparable in different seasons, with seasonal average concentrations ranging from 20 to 60 ng m-3. Glutaric acid was much less abundant with an average of 10 ng m-3. The sum of these seven detected acids accounted for 3-15% of organic carbon content in PM2.5. Seasonal differences of these acids were discussed in terms of their corresponding sources. Correlations of these acids with sulfate and MSA were also investigated to interpret their possible secondary formation pathways. © 2005 Elsevier Ltd. All rights reserved.

Water-soluble organic acids are important components in atmospheric aerosols and can act as cloud condensation nuclei to potentially affect the climate. In this study, a total of 25 PM2.5 samples were collected from summer to winter in 2002-2003 at an urban area in Beijing. C 2-C5 dicarboxylic acids and malic, glyoxylic and pyruvic acids were determined using a capillary electrophoresis. Oxalic acid dominated in these acids with seasonal average concentrations of 107-412 ng m -3. Malonic and succinic acids were comparable in different seasons, with seasonal average concentrations ranging from 20 to 60 ng m-3. Glutaric acid was much less abundant with an average of 10 ng m-3. The sum of these seven detected acids accounted for 3-15% of organic carbon content in PM2.5. Seasonal differences of these acids were discussed in terms of their corresponding sources. Correlations of these acids with sulfate and MSA were also investigated to interpret their possible secondary formation pathways. © 2005 Elsevier Ltd. All rights reserved.

[1] During the Asian Pacific Regional Aerosol Characterization Experiment (ACE-Asia), samples of carbonaceous aerosols were collected on board the Center for Interdisciplinary Remotely Piloted Aircraft Studies (CIRPAS) De Havilland DHC-6 Twin Otter aircraft. The samples were analyzed to determine their total carbon (TC) and water-soluble organic compound (WSOC) contents as well as to identify the individual compounds comprising the WSOC fraction of the aerosol. The TC concentrations varied from 3.5 to 14.3 mug C m(-3); the highest TC levels were observed for samples collected in pollution layers that originated over mainland China. WSOC concentrations ranged from 0.54 to 7.2 mug C m(-3), with the WSOC fraction contributing from 10 to 50\% of the carbon mass. About 50\% of the carbonaceous aerosol mass in pollution layers could be attributed to WSOC. For samples collected in dust layers the WSOC fraction of TC was much lower than that observed in pollution layers. The sum of all the detected organic ions accounted for 6.9 - 19\% of the WSOC. In the six samples collected by the Twin Otter during ACE-Asia, of the organic ions identified in the WSOC fraction, oxalate had the highest concentration. Samples collected from pollution layers exhibited a slightly higher ratio of formate to oxalate as compared to the other samples. Two samples had a relatively high ratio of lactate to oxalate, which might be a signature of some currently unidentified source of carbonaceous aerosol. The sum of the masses of sulfate and nitrate ions exceeded the sum of the masses of the identified organic ions by a factor of 9 to 17. The chemical levoglucosan, a tracer for biomass burning, comprised from 0.1 to 0.4\% of TC mass. Comparing this ratio to the ratio measured directly in wood-burning studies it was determined that biomass burning may have represented from approximate to2 to 10\% of the carbonaceous aerosol collected during ACE-Asia.

[1] During the Asian Pacific Regional Aerosol Characterization Experiment (ACE-Asia), samples of carbonaceous aerosols were collected on board the Center for Interdisciplinary Remotely Piloted Aircraft Studies (CIRPAS) De Havilland DHC-6 Twin Otter aircraft. The samples were analyzed to determine their total carbon (TC) and water-soluble organic compound (WSOC) contents as well as to identify the individual compounds comprising the WSOC fraction of the aerosol. The TC concentrations varied from 3.5 to 14.3 mug C m(-3); the highest TC levels were observed for samples collected in pollution layers that originated over mainland China. WSOC concentrations ranged from 0.54 to 7.2 mug C m(-3), with the WSOC fraction contributing from 10 to 50\% of the carbon mass. About 50\% of the carbonaceous aerosol mass in pollution layers could be attributed to WSOC. For samples collected in dust layers the WSOC fraction of TC was much lower than that observed in pollution layers. The sum of all the detected organic ions accounted for 6.9 - 19\% of the WSOC. In the six samples collected by the Twin Otter during ACE-Asia, of the organic ions identified in the WSOC fraction, oxalate had the highest concentration. Samples collected from pollution layers exhibited a slightly higher ratio of formate to oxalate as compared to the other samples. Two samples had a relatively high ratio of lactate to oxalate, which might be a signature of some currently unidentified source of carbonaceous aerosol. The sum of the masses of sulfate and nitrate ions exceeded the sum of the masses of the identified organic ions by a factor of 9 to 17. The chemical levoglucosan, a tracer for biomass burning, comprised from 0.1 to 0.4\% of TC mass. Comparing this ratio to the ratio measured directly in wood-burning studies it was determined that biomass burning may have represented from approximate to2 to 10\% of the carbonaceous aerosol collected during ACE-Asia.

The organic compound tracers of atmospheric particulate matter, as well as organic carbon (OC) and elemental carbon (EC), have been characterized for samples acquired during the ACEAsia campaign from Gosan, Jeju Island, Korea; Sapporo, Japan, and Chichi-jima Island in the western North Pacific, as well as on the NOAA R/V Ronald H. Brown. Total extracts were analyzed by GC-MS to determine both polar and aliphatic compounds. Total particles, organic matter and lipid and saccharide compounds were high during the Asian dust episode (early April 2001) compared to levels at other times. The organic matter can be apportioned to seven emission sources and to significant oxidation producing secondary products during long-range transport. Terrestrial natural background compounds are vascular plant wax lipids derived from direct emission and as part of desert sand dust. Fossil fuel utilization is obvious and derives from petroleum product and coal combustion emissions. Saccharides are a major polar (water-soluble) carbonaceous fraction derived from soil resuspension (agricultural activities). Biomass burning smoke is evident in all samples and seasons. It contributes up to 13% of the total compound mass as water-soluble constituents. Burning of refuse is another source of organic particles. Varying levels of marine-derived lipids are superimposed during aerosol transport over the ocean. Secondary oxidation products increase with increasing transport distance and time. The ACEAsia aerosols are comprised not only of desert dust, but also of soil dust, smoke from biomass and refuse burning, and emissions from fossil fuels use in urban areas.

Atmospheric particulate matter, collected over the polluted east Asia/Pacific region in spring 2001 during research flights with the National Center for Atmospheric Research (NCAR) C-130 aircraft, was analyzed for different types of organic compounds using capillary gas chromatography–mass spectrometry. More than 70 organic species were detected in the aerosols and grouped into different compound classes on the basis of functional groups, including n-alkanes, polycyclic aromatic hydrocarbons, fatty acids, dehydroabietic acid, alkanols, water-soluble sugars (including glucose, sucrose, mycose, and levoglucosan), monocarboxylic and dicarboxylic acids, urea, and phthalates. Interestingly, the water-soluble compounds (72–133 ng m−3) were found to account for 16–50% (average 34%) of the total identified compound mass (TCM). Organic compounds were further categorized into several groups to suggest their sources. Fossil fuel combustion was recognized as the most significant source for the TCM (contributing 33–80% of TCM, average 50%), followed by soil resuspension (5–25%, average 19%) and secondary oxidation products (4–15%, average 9%). In contrast, the contribution of natural sources such as terrestrial plant wax and marine lipids (fatty acids and alkanols) was relatively small (3.4% and 9.4% on average, respectively). Biomass burning was suggested to contribute only a minor portion to the TCM of the Asian aerosols during the spring season (1.4% on average based on levoglucosan). However, levoglucosan may have been hydrolyzed and/or oxidized in part during long-range transport, and therefore this value represents a lower limit. The organic compound compositions of these samples are very different from those reported for aerosol particles of the Atlantic Ocean and from the earlier data for the mid-Pacific in terms of the abundant presence of water-soluble compounds consisting of saccharides, anhydrosaccharides, and the secondary dicarboxylic acids. This study demonstrated, ‘An edited version of this paper was published by AGU.’Copyright 2004, American Geophysical Union, Journal of Geophysical Research,109

The organic compound tracers of atmospheric particulate matter, as well as organic carbon (OC) and elemental carbon (EC), have been characterized for samples acquired during the ACEAsia campaign from Gosan, Jeju Island, Korea; Sapporo, Japan, and Chichi-jima Island in the western North Pacific, as well as on the NOAA R/V Ronald H. Brown. Total extracts were analyzed by GC-MS to determine both polar and aliphatic compounds. Total particles, organic matter and lipid and saccharide compounds were high during the Asian dust episode (early April 2001) compared to levels at other times. The organic matter can be apportioned to seven emission sources and to significant oxidation producing secondary products during long-range transport. Terrestrial natural background compounds are vascular plant wax lipids derived from direct emission and as part of desert sand dust. Fossil fuel utilization is obvious and derives from petroleum product and coal combustion emissions. Saccharides are a major polar (water-soluble) carbonaceous fraction derived from soil resuspension (agricultural activities). Biomass burning smoke is evident in all samples and seasons. It contributes up to 13% of the total compound mass as water-soluble constituents. Burning of refuse is another source of organic particles. Varying levels of marine-derived lipids are superimposed during aerosol transport over the ocean. Secondary oxidation products increase with increasing transport distance and time. The ACEAsia aerosols are comprised not only of desert dust, but also of soil dust, smoke from biomass and refuse burning, and emissions from fossil fuels use in urban areas.

The organic compound tracers of atmospheric particulate matter, as well as organic carbon (OC) and elemental carbon (EC), have been characterized for samples acquired during the ACEAsia campaign from Gosan, Jeju Island, Korea; Sapporo, Japan, and Chichi-jima Island in the western North Pacific, as well as on the NOAA R/V Ronald H. Brown. Total extracts were analyzed by GC-MS to determine both polar and aliphatic compounds. Total particles, organic matter and lipid and saccharide compounds were high during the Asian dust episode (early April 2001) compared to levels at other times. The organic matter can be apportioned to seven emission sources and to significant oxidation producing secondary products during long-range transport. Terrestrial natural background compounds are vascular plant wax lipids derived from direct emission and as part of desert sand dust. Fossil fuel utilization is obvious and derives from petroleum product and coal combustion emissions. Saccharides are a major polar (water-soluble) carbonaceous fraction derived from soil resuspension (agricultural activities). Biomass burning smoke is evident in all samples and seasons. It contributes up to 13% of the total compound mass as water-soluble constituents. Burning of refuse is another source of organic particles. Varying levels of marine-derived lipids are superimposed during aerosol transport over the ocean. Secondary oxidation products increase with increasing transport distance and time. The ACEAsia aerosols are comprised not only of desert dust, but also of soil dust, smoke from biomass and refuse burning, and emissions from fossil fuels use in urban areas.

Atmospheric particulate matter, collected over the polluted east Asia/Pacific region in spring 2001 during research flights with the National Center for Atmospheric Research (NCAR) C-130 aircraft, was analyzed for different types of organic compounds using capillary gas chromatography–mass spectrometry. More than 70 organic species were detected in the aerosols and grouped into different compound classes on the basis of functional groups, including n-alkanes, polycyclic aromatic hydrocarbons, fatty acids, dehydroabietic acid, alkanols, water-soluble sugars (including glucose, sucrose, mycose, and levoglucosan), monocarboxylic and dicarboxylic acids, urea, and phthalates. Interestingly, the water-soluble compounds (72–133 ng m−3) were found to account for 16–50% (average 34%) of the total identified compound mass (TCM). Organic compounds were further categorized into several groups to suggest their sources. Fossil fuel combustion was recognized as the most significant source for the TCM (contributing 33–80% of TCM, average 50%), followed by soil resuspension (5–25%, average 19%) and secondary oxidation products (4–15%, average 9%). In contrast, the contribution of natural sources such as terrestrial plant wax and marine lipids (fatty acids and alkanols) was relatively small (3.4% and 9.4% on average, respectively). Biomass burning was suggested to contribute only a minor portion to the TCM of the Asian aerosols during the spring season (1.4% on average based on levoglucosan). However, levoglucosan may have been hydrolyzed and/or oxidized in part during long-range transport, and therefore this value represents a lower limit. The organic compound compositions of these samples are very different from those reported for aerosol particles of the Atlantic Ocean and from the earlier data for the mid-Pacific in terms of the abundant presence of water-soluble compounds consisting of saccharides, anhydrosaccharides, and the secondary dicarboxylic acids. This study demonstrated, ‘An edited version of this paper was published by AGU.’Copyright 2004, American Geophysical Union, Journal of Geophysical Research,109

[1] During the Asian Pacific Regional Aerosol Characterization Experiment (ACE-Asia), samples of carbonaceous aerosols were collected on board the Center for Interdisciplinary Remotely Piloted Aircraft Studies (CIRPAS) De Havilland DHC-6 Twin Otter aircraft. The samples were analyzed to determine their total carbon (TC) and water-soluble organic compound (WSOC) contents as well as to identify the individual compounds comprising the WSOC fraction of the aerosol. The TC concentrations varied from 3.5 to 14.3 mug C m(-3); the highest TC levels were observed for samples collected in pollution layers that originated over mainland China. WSOC concentrations ranged from 0.54 to 7.2 mug C m(-3), with the WSOC fraction contributing from 10 to 50\% of the carbon mass. About 50\% of the carbonaceous aerosol mass in pollution layers could be attributed to WSOC. For samples collected in dust layers the WSOC fraction of TC was much lower than that observed in pollution layers. The sum of all the detected organic ions accounted for 6.9 - 19\% of the WSOC. In the six samples collected by the Twin Otter during ACE-Asia, of the organic ions identified in the WSOC fraction, oxalate had the highest concentration. Samples collected from pollution layers exhibited a slightly higher ratio of formate to oxalate as compared to the other samples. Two samples had a relatively high ratio of lactate to oxalate, which might be a signature of some currently unidentified source of carbonaceous aerosol. The sum of the masses of sulfate and nitrate ions exceeded the sum of the masses of the identified organic ions by a factor of 9 to 17. The chemical levoglucosan, a tracer for biomass burning, comprised from 0.1 to 0.4\% of TC mass. Comparing this ratio to the ratio measured directly in wood-burning studies it was determined that biomass burning may have represented from approximate to2 to 10\% of the carbonaceous aerosol collected during ACE-Asia.

Bicyclic acidic amino acids (+/-)-6 and (+/-)-7, which are conformationally constrained homologues of glutamic acid, were prepared via a strategy based on a 1,3-dipolar cycloaddition. The new amino acids were tested toward ionotropic and metabotropic glutamate receptor subtypes; both of them behaved as antagonists at mGluR1,5 and as agonists at mGluR2. Furthermore, whereas (+/-)-6 was inactive at all ionotropic glutamate receptors, (+/-)-7 displayed a quite potent antagonism at the NMDA receptors. In the in vivo tests on DBA/2 mice, the compounds displayed an anticonvulsant activity. The interesting pharmacological profile of (+/-)-7 qualifies it as a lead of novel neuroprotective agents.