Atlas of plasma NMR biomarkers for health and disease in 118,461 individuals from the UK Biobank.

Blood lipids and metabolites are markers of current health and future disease risk. Here, we describe plasma nuclear magnetic resonance (NMR) biomarker data for 118,461 participants in the UK Biobank. The biomarkers cover 249 measures of lipoprotein lipids, fatty acids, and small molecules such as amino acids, ketones, and glycolysis metabolites. We provide an atlas of associations of these biomarkers to prevalence, incidence, and mortality of over 700 common diseases ( nightingalehealth.com/atlas ). The results reveal a plethora of biomarker associations, including susceptibility to infectious diseases and risk of various cancers, joint disorders, and mental health outcomes, indicating that abundant circulating lipids and metabolites are risk markers beyond cardiometabolic diseases. Clustering analyses indicate similar biomarker association patterns across different disease types, suggesting latent systemic connectivity in the susceptibility to a diverse set of diseases. This work highlights the value of NMR based metabolic biomarker profiling in large biobanks for public health research and translation.

Effects of dexmedetomidine, propofol, sevoflurane and S-ketamine on the human metabolome: A randomised trial using nuclear magnetic resonance spectroscopy.

BACKGROUND: Pharmacometabolomics uses large-scale data capturing methods to uncover drug-induced shifts in the metabolic profile. The specific effects of anaesthetics on the human metabolome are largely unknown. OBJECTIVE: We aimed to discover whether exposure to routinely used anaesthetics have an acute effect on the human metabolic profile. DESIGN: Randomised, open-label, controlled, parallel group, phase IV clinical drug trial. SETTING: The study was conducted at Turku PET Centre, University of Turku, Finland, 2016 to 2017. PARTICIPANTS: One hundred and sixty healthy male volunteers were recruited. The metabolomic data of 159 were evaluable. INTERVENTIONS: Volunteers were randomised to receive a 1-h exposure to equipotent doses (EC50 for verbal command) of dexmedetomidine (1.5 ng ml-1; n  = 40), propofol (1.7 µg ml-1; n  = 40), sevoflurane (0.9% end-tidal; n  = 39), S-ketamine (0.75 µg ml-1; n  = 20) or placebo (n = 20). MAIN OUTCOME MEASURES: Metabolite subgroups of apolipoproteins and lipoproteins, cholesterol, glycerides and phospholipids, fatty acids, glycolysis, amino acids, ketone bodies, creatinine and albumin and the inflammatory marker GlycA, were analysed with nuclear magnetic resonance spectroscopy from arterial blood samples collected at baseline, after anaesthetic administration and 70 min post-anaesthesia. RESULTS: All metabolite subgroups were affected. Statistically significant changes vs. placebo were observed in 11.0, 41.3, 0.65 and 3.9% of the 155 analytes in the dexmedetomidine, propofol, sevoflurane and S-ketamine groups, respectively. Dexmedetomidine increased glucose, decreased ketone bodies and affected lipoproteins and apolipoproteins. Propofol altered lipoproteins, fatty acids, glycerides and phospholipids and slightly increased inflammatory marker glycoprotein acetylation. Sevoflurane was relatively inert. S-ketamine increased glucose and lactate, whereasbranched chain amino acids and tyrosine decreased. CONCLUSION: A 1-h exposure to moderate doses of routinely used anaesthetics led to significant and characteristic alterations in the metabolic profile. Dexmedetomidine-induced alterations mirror a2-adrenoceptor agonism. Propofol emulsion altered the lipid profile. The inertness of sevoflurane might prove useful in vulnerable patients. S-ketamine induced amino acid alterations might be linked to its suggested antidepressive properties. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02624401.

One-year Results of Health-related and Vision-related Quality of Life After Clear Lens Extraction and Multifocal Intraocular Lens Implantation.

PURPOSE: Multifocal intraocular lenses (MIOLs) are effective in treating presbyopia before cataracts develop. This study measured health-related quality of life (HRQoL) and vision-related quality of life (VRQoL) after clear lens extraction (CLE) and MIOL implantation. DESIGN: Before-and-after study METHODS: Patients were treated in Medilaser Coronaria, CorGroup, Oulu, Finland. HRQoL was measured by a generic 15-dimension (15D) instrument. VRQoL was measured with Visual Function Index-14 (VF-14) questionnaire. RESULTS: CLE and MIOL implantation was performed in 137 patients. The patient age was 57 ± 6.2 years (mean ± standard deviation), and 58% were women. The near add was 2.1±0.3 diopters (D). The overall HRQoL 15D score increased from 0.938±0.058 to 0.955±0.057 at 6 months (P < .0001 vs baseline) and to 0.948±0.060 at 1 year (P = .02 vs baseline). The VRQoL VF14 score increased from 85.32±15.57 to 96.57±5.07 at 6 months (P < .0001 vs baseline) and to 96.61±6.48 at 1 year (P < .0001 vs baseline). The increase of HRQoL was correlated with the increase of VRQoL (P < .04). CONCLUSIONS: CLE and MIOL implantation improved HRQoL and VRQoL compared to spectacles in this 1-year follow-up study. Improvement of HRQoL was correlated with VRQoL.

Quantum mechanical reference spectrum simulation for precursors and degradation products of chemicals relevant to the Chemical Weapons Convention.

A selection of acidic, alkaline and neutral degradation products relevant to the Chemical Weapons Convention was studied in wide range of pH conditions to determine their spin systems as well as spectral parameters. The pH dependence of chemical shifts and J couplings was parameterized using Henderson-Hasselbalch-based functions using dichloromethane as additional shift reference in TSP-d4 referenced spectra. The resulting parameters allowed calculation of precise chemical shifts and J coupling constants in arbitrary pH conditions. The validity of the obtained spin system definitions and parameters as a source of quantum mechanically simulated reference data in chemical verification analysis is demonstrated.

Biosynthesis of the Bis-Prenylated Alkaloids Muscoride A and B.

Prenylation is a common step in the biosynthesis of many natural products and plays an important role in increasing their structural diversity and enhancing biological activity. Muscoride A is a linear peptide alkaloid that contain two contiguous oxazoles and unusual prenyl groups that protect the amino- and carboxy-termini. Here we identified the 12.7 kb muscoride (mus) biosynthetic gene clusters from Nostoc spp. PCC 7906 and UHCC 0398. The mus biosynthetic gene clusters encode enzymes for the heterocyclization, oxidation, and prenylation of the MusE precursor protein. The mus biosynthetic gene clusters encode two copies of the cyanobactin prenyltransferase, MusF1 and MusF2. The predicted tetrapeptide substrate of MusF1 and MusF2 was synthesized through a novel tandem cyclization route in only eight steps. Biochemical assays demonstrated that MusF1 acts on the carboxy-terminus while MusF2 acts on the amino-terminus of the tetrapeptide substrate. We show that the MusF2 enzyme catalyzes the reverse or forward prenylation of amino-termini from Nostoc spp. PCC 7906 and UHCC 0398, respectively. This finding expands the regiospecific chemical functionality of cyanobactin prenyltransferases and the chemical diversity of the cyanobactin family of natural products to include bis-prenylated polyoxazole linear peptides.

pH-Dependent Piecewise Linear Correlation of 1H,31P Chemical Shifts: Application in NMR Identification of Nerve Agent Metabolites in Urine Samples.

The NMR-observable nuclei of the acidic and basic compounds experience pH dependence in chemical shift. This phenomenon can be exploited in NMR titrations to determine p Ka values of compounds, or in pH measurement of solutions using dedicated pH reference compounds. On the other hand, this sensitivity can also cause problems in, for example, metabolomics, where slight changes in pH result in significant difficulties for peak alignment between spectra of set of samples for comparative analysis. In worst case, the pH sensitivity of chemical shifts can prevent unambiguous identification of compounds. Here, we propose an alternative approach for NMR identification of pH-sensitive analytes. The 1H and X (13C, 15N, 31P, ...) chemical shifts in close proximity to the acidic or basic functional group should, when presented as ordered pairs, express piecewise linear correlation with distinct slope, intercept, and range. We have studied the pH dependence of 1H and 31P chemical shifts of the CH3-P moiety in urinary metabolites of nerve agents sarin, soman and VX using 2D 1H-31P fast-HMQC spectroscopy. The 1H and 31P chemical shifts of these chemicals appear in very narrow range, and due to subtle changes in sample pH the identification on either 1H or 31P chemical shift alone is uncertain. However, if the observed 1H and 31P chemical shifts of the CH3-P moiety of individual compounds are presented as ordered pairs, they fall into distinct linear spaces, thus, facilitating identification with high confidence.

Liquid-State NMR Analysis of Nanocelluloses.

Recent developments in ionic liquid electrolytes for cellulose or biomass dissolution has also allowed for high-resolution 1H and 13C NMR on very high molecular weight cellulose. This permits the development of advanced liquid-state quantitative NMR methods for characterization of unsubstituted and low degree of substitution celluloses, for example, surface-modified nanocelluloses, which are insoluble in all molecular solvents. As such, we present the use of the tetrabutylphosphonium acetate ([P4444][OAc]):DMSO- d6 electrolyte in the 1D and 2D NMR characterization of poly(methyl methacrylate) (PMMA)-grafted cellulose nanocrystals (CNCs). PMMA- g-CNCs was chosen as a difficult model to study, to illustrate the potential of the technique. The chemical shift range of [P4444][OAc] is completely upfield of the cellulose backbone signals, avoiding signal overlap. In addition, application of diffusion-editing for 1H and HSQC was shown to be effective in the discrimination between PMMA polymer graft resonances and those from low molecular weight components arising from the solvent system. The bulk ratio of methyl methacrylate monomer to anhydroglucose unit was determined using a combination of HSQC and quantitative 13C NMR. After detachment and recovery of the PMMA grafts, through methanolysis, DOSY NMR was used to determine the average self-diffusion coefficient and, hence, molecular weight of the grafts compared to self-diffusion coefficients for PMMA GPC standards. This finally led to a calculation of both graft length and graft density using liquid-state NMR techniques. In addition, it was possible to discriminate between triads and tetrads, associated with PMMA tacticity, of the PMMA still attached to the CNCs (before methanolysis). CNC reducing end and sulfate half ester resonances, from sulfuric acid hydrolysis, were also assignable. Furthermore, other biopolymers, such as hemicelluloses and proteins (silk and wool), were found to be soluble in the electrolyte media, allowing for wider application of this method beyond just cellulose analytics.

NMR chemical shift and J coupling parameterization and quantum mechanical reference spectrum simulation for selected nerve agent degradation products in aqueous conditions.

The spectral parameters of selected nerve agent degradation products relevant to the Chemical Weapons Convention, namely, ethyl methylphosphonate, isopropyl methylphosphonate, pinacolyl methylphosphonate and methylphosphonic acid, were studied in wide range of pH conditions and selected temperatures. The pH and temperature dependence of chemical shifts and J couplings was parameterized using Henderson-Hasselbalch-based functions. The obtained parameters allowed calculation of precise chemical shifts and J coupling constants in arbitrary pH conditions and typical measurement temperatures, thus facilitating quantum mechanical simulation of reference spectra in the chosen magnetic field strength for chemical verification. Copyright © 2017 John Wiley & Sons, Ltd.

ME-CAGEBIRDr,X-CPMG-HSQMBC. A phase sensitive, multiplicity edited long range HSQC with absorptive line shapes.

ME-CAGEBIRDr,X-CPMG-HSMBC pulse sequence is a phase sensitive, carbon multiplicity edited 2D-experiment for detecting heteronuclear correlations originating from long-range 1H, 13C-couplings, nJCH. The presented method allows measurement of nJCH-values as well as is capable of separating different carbon types in subspectra (13C/13CH2 and 13CH/13CH3) with minimal amount of cross talk i.e. cross peaks from wrong carbon multiplicity. Pure lineshapes and clean subspectra are achieved by utilizing CPMG in polarization transfer period, CRISIS-approach in multiplicity editing period and zero-quantum filtration. The obtained spectral properties together with simple setup of the experiment make ME-CAGEBIRDr,X-CPMG-HSMBC a useful addition into synthetic organic chemistry oriented NMR-tool collection.

Identification of gymnodimine D and presence of gymnodimine variants in the dinoflagellate Alexandrium ostenfeldii from the Baltic Sea.

Gymnodimines are lipophilic toxins produced by the marine dinoflagellates Karenia selliformis and Alexandrium ostenfeldii. Currently four gymnodimine analogues are known and characterized. Here we describe a novel gymnodimine and a range of gymnodimine related compounds found in an A. ostenfeldii isolate from the northern Baltic Sea. Gymnodimine D (1) was extracted and purified from clonal cultures, and characterized by liquid chromatography-tandem mass spectrometry (LC-MS/MS), nuclear magnetic resonance (NMR) spectroscopy, and liquid chromatography-high resolution mass spectrometry (LC-HRMS) experiments. The structure of 1 is related to known gymnodimines (2-5) with a six-membered cyclic imine ring and several other fragments typical of gymnodimines. However, the carbon chain in the gymnodimine macrocyclic ring differs from the known gymnodimines in having two tetrahydrofuran rings in the macrocyclic ring.