Deceptively Simple NMR Spectra of Contiguously 13C-enriched Compounds

Contiguously 13C-enriched compounds are widely used in biosynthetic studies, since they effectively label a bonded pair of carbon atoms, rather than an individual atom. Such compounds are referred to as »bond labeled« compounds. With such substrates, the course of biosynthesis can be followed using 13C-NMR spectroscopy. When the enriched carbon atoms are chemically but not magnetically equivalent, the 13C-NMR spectra are unusual, and such spectra have been labeled "deceptively simple«. Furthermore, the use of standard NMR experiments such as DEPT (Distortionless Enhancement by Polarization Transfer) is complicated by the presence of homonuclear coupling between 13C nuclei. At natural abundance, the 13C nucleus is magnetically dilute and shows no homonuclear coupling. This paper analyzes the 13C-NMR spectra of a series of molecules derived from fully 13C-enriched acetylene, and explores some of the complications that arise in applying pulse NMR methods

Stereochemical rearrangements in tricarbonylrhenium(I) halide complexes of the non-racemic chiral ligand 2-[(4R),(5R)-dimethyl-1,3-dioxan-2-yl]pyridine (L): a dynamic NMR study

Tricarbonylrhenium(I) halide complexes of the non-racemic chiral ligand 2-[(4R),(5R)-dimethyl-1,3-dioxan-2-yl]pyridine (L), namely fac-[ReX(CO)3L] (X = Cl, Br or I), have been prepared and their latent fluxionality studied by dynamic NMR techniques in the slow and intermediate exchange regimes. In solution, these complexes give rise to four diastereoisomers, depending on the configuration at the metal and at the acetal-carbon atom, respectively; the relative populations are in the order SR > RR >> RS > SS. At moderate temperatures, a reversible ‘acetal ring flip’ leads to formal inversion of configuration at the acetal-carbon atom; the free energies of activation are in the range 84 - 88 kJ mol-1 at 298 K. Above ca. 370 K, reversible ligand dissociation also occurs, leading to an exchange of all four diastereoisomers on the NMR chemical shift time-scale

A detailed NMR study of the solution stereodynamics in tricarbonylrhenium(I) halide complexes of the non-racemic chiral ligand 2,6-bis[(4R,5R)-4,5-dimethyl-1,3-dioxolan-2-yl]pyridine (L¹) and the molecular structure of fac-[ReBr(CO)₃(L¹)]

1 Tricarbonylrhenium(I) halide complexes of the non-racemic chiral ligand 2,6-bis[(4R, 5R)-dimethyl-1,3-dioxan-2-yl]pyridine (L¹), namely fac-[ReX(CO)₃(L¹)] (X = Cl, Br or I), have been prepared. In these complexes the ligand is bound in a bidentate fashion, with the N atom of the pyridine ring and an O atom of one of the acetal rings co-ordinated to the octahedral metal centre. The bidentate mode is confirmed by the X-ray structure of fac-[ReBr(CO)₃(L¹)]. There are four possible diastereoisomers, depending on the configuration at the metal centre and at the acetal-carbon atom of the co-ordinated ring; the X-ray structure of fac-[ReBr(CO)₃(L¹)] shows that the SR diastereoisomer is present in the solid state. In solution, three of the four possible diastereoisomers are observed, namely SR, RR and RS; their relative populations are in the order SR > RR > SS. Above ambient temperature the complexes are stereochemically non-rigid. The fluxional kinetics have been measured by a combination of standard band shape analysis and selective inversion experiments. Two distinct processes are present: an acetal ring flip and exchange of the pendant and co-ordinated acetal rings. The latter process occurs via two independent mechanisms, namely tick-tock and rotation pathways. The activation energies for the stereodynamics are in the ranges 72 – 73 kJ mol⁻¹ (tick-tock), 77 – 78 kJ mol⁻¹ (acetal ring flip) and 83 – 90 kJ mol⁻¹ (rotation) at 298 K

Effectiveness and meaningful use of paediatric surgical safety checklists and their implementation strategies: a systematic review with narrative synthesis

Objective: To examine the effectiveness and meaningful use of paediatric surgical safety checklists (SSCs) and their implementation strategies through a systematic review with narrative synthesis. Summary background data Since the launch of the WHO SSC, checklists have been integrated into surgical systems worldwide. Information is sparse on how SSCs have been integrated into the paediatric surgical environment. Methods: A broad search strategy was created using Pubmed, Embase, CINAHL, Cochrane Central, Web of Science, Science Citation Index and Conference Proceedings Citation Index. Abstracts and full texts were screened independently, in duplicate for inclusion. Extracted study characteristic and outcomes generated themes explored through subgroup analyses and idea webbing. Results: 1826 of 1921 studies were excluded after title and abstract review (kappa 0.77) and 47 after full-text review (kappa 0.86). 20 studies were of sufficient quality for narrative synthesis. Clinical outcomes were not affected by SSC introduction in studies without implementation strategies. A comprehensive SSC implementation strategy in developing countries demonstrated improved outcomes in high-risk surgeries. Narrative synthesis suggests that meaningful compliance is inconsistently measured and rarely achieved. Strategies involving feedback improved compliance. Stakeholder-developed implementation strategies, including team-based education, achieved greater acceptance. Three studies suggest that parental involvement in the SSC is valued by parents, nurses and physicians and may improve patient safety. Conclusions: A SSC implementation strategy focused on paediatric patients and their families can achieve high acceptability and good compliance. SSCs’ role in improving measures of paediatric surgical outcome is not well established, but they may be effective when used within a comprehensive implementation strategy especially for high-risk patients in low-resource settings

Effects of anharmonic strain on phase stability of epitaxial films and superlattices: applications to noble metals

Epitaxial strain energies of epitaxial films and bulk superlattices are studied via first-principles total energy calculations using the local-density approximation. Anharmonic effects due to large lattice mismatch, beyond the reach of the harmonic elasticity theory, are found to be very important in Cu/Au (lattice mismatch 12%), Cu/Ag (12%) and Ni/Au (15%). We find that is the elastically soft direction for biaxial expansion of Cu and Ni, but it is for large biaxial compression of Cu, Ag, and Au. The stability of superlattices is discussed in terms of the coherency strain and interfacial energies. We find that in phase-separating systems such as Cu-Ag the superlattice formation energies decrease with superlattice period, and the interfacial energy is positive. Superlattices are formed easiest on (001) and hardest on (111) substrates. For ordering systems, such as Cu-Au and Ag-Au, the formation energy of superlattices increases with period, and interfacial energies are negative. These superlattices are formed easiest on (001) or (110) and hardest on (111) substrates. For Ni-Au we find a hybrid behavior: superlattices along and like in phase-separating systems, while for they behave like in ordering systems. Finally, recent experimental results on epitaxial stabilization of disordered Ni-Au and Cu-Ag alloys, immiscible in the bulk form, are explained in terms of destabilization of the phase separated state due to lattice mismatch between the substrate and constituents.Comment: RevTeX galley format, 16 pages, includes 9 EPS figures, to appear in Physical Review

Metabolomic Profiling Reveals Mitochondrial-Derived Lipid Biomarkers That Drive Obesity-Associated Inflammation

Obesity has reached epidemic proportions worldwide. Several animal models of obesity exist, but studies are lacking that compare traditional lard-based high fat diets (HFD) to “Cafeteria diets" (CAF) consisting of nutrient poor human junk food. Our previous work demonstrated the rapid and severe obesogenic and inflammatory consequences of CAF compared to HFD including rapid weight gain, markers of Metabolic Syndrome, multi-tissue lipid accumulation, and dramatic inflammation. To identify potential mediators of CAF-induced obesity and Metabolic Syndrome, we used metabolomic analysis to profile serum, muscle, and white adipose from rats fed CAF, HFD, or standard control diets. Principle component analysis identified elevations in clusters of fatty acids and acylcarnitines. These increases in metabolites were associated with systemic mitochondrial dysfunction that paralleled weight gain, physiologic measures of Metabolic Syndrome, and tissue inflammation in CAF-fed rats. Spearman pairwise correlations between metabolites, physiologic, and histologic findings revealed strong correlations between elevated markers of inflammation in CAF-fed animals, measured as crown like structures in adipose, and specifically the pro-inflammatory saturated fatty acids and oxidation intermediates laurate and lauroyl carnitine. Treatment of bone marrow-derived macrophages with lauroyl carnitine polarized macrophages towards the M1 pro-inflammatory phenotype through downregulation of AMPK and secretion of pro-inflammatory cytokines. Results presented herein demonstrate that compared to a traditional HFD model, the CAF diet provides a robust model for diet-induced human obesity, which models Metabolic Syndrome-related mitochondrial dysfunction in serum, muscle, and adipose, along with pro-inflammatory metabolite alterations. These data also suggest that modifying the availability or metabolism of saturated fatty acids may limit the inflammation associated with obesity leading to Metabolic Syndrome

A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial

Background Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. Methods This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. Findings Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48–0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78–2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. Interpretation This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation