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Nature Apr 2024Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism. This detailed knowledge of...
Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases. Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases.
Topics: Female; Humans; Pregnancy; Acetone; Biomarkers; Cholestasis, Intrahepatic; Cohort Studies; Genome-Wide Association Study; Hypertension; Lipoproteins; Magnetic Resonance Spectroscopy; Mendelian Randomization Analysis; Metabolic Networks and Pathways; Metabolomics; Phenotype; Polymorphism, Single Nucleotide; Pregnancy Complications
PubMed: 38448586
DOI: 10.1038/s41586-024-07148-y -
Spectrochimica Acta. Part A, Molecular... Mar 2024Conformational space of methoxyacetone (MA) was studied at the MP2/6-311++G(d,p) and DFT(B3LYP)/6-311++G(d,p) levels of theory. Computations predict MA to adopt four...
Conformational space of methoxyacetone (MA) was studied at the MP2/6-311++G(d,p) and DFT(B3LYP)/6-311++G(d,p) levels of theory. Computations predict MA to adopt four conformations, resulting from internal rotations around the O=C-C-O (Trans, Cis) and C-C-O-C (trans, gauche) dihedral angles. The Tt (Trans-trans) conformer is the most stable. The computed energies of two gauche (Tg and Cg) conformers fall in the 3-8 kJ mol range above Tt and should account for 1/3 of the room-temperature gas-phase equilibrium. The energy of Ct form is 11 kJ mol above Tt, and its expected population is negligible (below 1 %). In our earlier work, MA monomers were isolated in cryogenic argon matrices and characterized by infrared spectroscopy. In the experiment, only the most stable Tt conformer was detected in the sample. Signatures of the other conformers were not detected, either in freshly deposited samples, or in samples subjected to different UV irradiations. We rationalize those observations in terms of computed barriers for intramolecular torsions, indicating occurrence of conformational cooling during deposition. The experimental infrared spectrum of the Tt form is now assigned with the aid of anharmonic DFT computations. Exposure of MA to UV irradiation in the 300-260 nm range led to photolysis, according to the Norrish type II mechanism, resulting in dimer between enol acetone and formaldehyde observed as a cage-confined intermediate photoproduct. The subsequent photolysis resulted in the formation of carbon monoxide as the dominating photoproduct, formed in the Norrish type I photoreaction. Mechanistic interpretation of this photo decarbonylation reaction is presented.
PubMed: 38056186
DOI: 10.1016/j.saa.2023.123651 -
Nutrients Aug 2023The ketogenic diet (KD) restricts carbohydrate consumption, leading to an increase in ketone bodies, such as acetoacetate, β-hydroxybutyrate, and acetone, which are... (Review)
Review
The ketogenic diet (KD) restricts carbohydrate consumption, leading to an increase in ketone bodies, such as acetoacetate, β-hydroxybutyrate, and acetone, which are utilized as energy substrates. This dietary approach impacts several biochemical processes, resulting in improved clinical management of various disorders, particularly in childhood. However, the exact mechanisms underlying the efficacy of KD remain unclear. Interestingly, KD may also impact the gut microbiota, which plays a pivotal role in metabolism, nutrition, and the development of the immune and nervous systems. KD has gained popularity for its potential benefits in weight loss, blood sugar control, and certain neurological conditions. This narrative review sums up KD-related studies published over 30 years. While short-term studies have provided valuable insights into the effects of KD on the gut microbiota, persistent uncertainties surround its long-term efficacy and potential for inducing dysbiosis. The significant influence of KD on epigenetic mechanisms, intracellular pathways, and gut microbial composition underscores its potential as a therapeutic choice. However, a judicious consideration of the potential risks associated with the strict adherence to a low-carbohydrate, high-fat, and high-protein regimen over prolonged periods is imperative. As KDs gain popularity among the adolescent and young adult demographic for weight management, it becomes imperative to undertake additional research to comprehensively assess their impact on nutritional status and gut microbiota, ensuring a holistic and sustainable approach to medical nutrition.
Topics: Adolescent; Young Adult; Humans; Diet, Ketogenic; Gastrointestinal Microbiome; 3-Hydroxybutyric Acid; Acetone; Carbohydrates
PubMed: 37686712
DOI: 10.3390/nu15173680 -
Microorganisms Sep 2023The review provides an overview of the current status of the solvent-producing clostridia. The origin and development of industrial clostridial species, as well as the... (Review)
Review
The review provides an overview of the current status of the solvent-producing clostridia. The origin and development of industrial clostridial species, as well as the history of the industrial Acetone Butanol Ethanol fermentation process, is reexamined, and the recent resurgence of interest in the production of biobutanol is reviewed. Over 300 fully sequenced genomes for solvent-producing and closely related clostridial species are currently available in public databases. These include 270 genomes sourced from the David Jones culture collection. These genomes were allocated arbitrary DJ codes, and a conversion table to identify the species and strains has now been provided. The expanded genomic database facilitated new comparative genomic and phylogenetic analysis. A synopsis of the common features, molecular taxonomy, and phylogeny of solvent-producing clostridia and the application of comparative phylogenomics are evaluated. A survey and analysis of resident prophages in solvent-producing clostridia are discussed, and the discovery, occurrence, and role of novel R-type tailocins are reported. Prophage genomes with R-type tailocin-like features were detected in all 12 species investigated. The widespread occurrence of tailocins in Gram-negative species is well documented; this survey has indicated that they may also be widespread in clostridia.
PubMed: 37764097
DOI: 10.3390/microorganisms11092253 -
IUCrData Jul 2023The title compound, CHNO, was obtained by the reaction of 2-chloro-4-methyl-benzoic acid and -toluidine using 2-eth-oxy-ethanol as solvent. Crystals of the title...
The title compound, CHNO, was obtained by the reaction of 2-chloro-4-methyl-benzoic acid and -toluidine using 2-eth-oxy-ethanol as solvent. Crystals of the title compounds were obtained from crystallization in acetone. The mol-ecule in the crystal is twisted with a dihedral angle between the aromatic rings of 50.86 (5)°. In the crystal structure, the mol-ecules associate to form acid-acid hydrogen-bonded dimers linked by pairwise O-H⋯O hydrogen bonds.
PubMed: 37937126
DOI: 10.1107/S2414314623005990