Characterisation of magnesium ascorbyl phosphate, a raw material in cell therapy

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Cation-pi Interactions accelerate the living cationic ring-opening polymerization of unsaturated 2-alkyl-2-oxazolines

Cation-dipole interactions were previously shown to have a rate-enhancing effect on the cationic ring-opening polymerization (CROP) of 2-oxazolines bearing a side-chain ester functionality. In line with this, a similar rate enhancement-via intermolecular cation-pi interactions-was anticipated to occur when pi-bonds are introduced into the 2-oxazoline side-chains. Moreover, the incorporation of pi-bonds allows for facile postfunctionalization of the resulting poly(2-oxazoline)s with double and triple bonds in the side-chains via various click reactions. Herein, a combined molecular modeling and experimental approach was used to study the CROP reaction rates of 2-oxazolines with side-chains having varying degrees of unsaturation and side-chain length. The presence of cation-pi interactions and the influence of the degree of unsaturation were initially confirmed by means of regular molecular dynamics simulations on pentameric systems. Furthermore, a combination of enhanced molecular dynamics simulations, static calculations, and a thorough analysis of the noncovalent interactions was performed to unravel to what extent cation-pi interactions alter the reaction kinetics. Additionally, the observed trends were confirmed also in the presence of acetonitrile as solvent, in which experimentally the polymerization is performed. Most intriguingly, we found only a limited effect on the intrinsic reaction kinetics of the CROP and a preorganization effect in the reactive complex region. The latter effect was established by the unsaturated side-chains and the cationic center through a complex interplay between cation-pi, pi-pi, pi-induced dipole, and cation-dipole interactions. These findings led us to propose a two-step mechanism comprised of an equilibration step and a CROP reaction step. The influence of the degree of unsaturation, through a preorganization effect, on the equilibration step was determined with the following trend for the polymerization rates: n-ButylOx = PentynOx. The trend was experimentally confirmed by determining the polymerization rate constants

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

TAMkin : a versatile package for vibrational analysis and chemical kinetics

TAMkin is a program for the calculation and analysis of normal modes, thermochemical properties and chemical reaction rates. At present, the output from the frequently applied software programs ADF, CHARMM, CPMD, CP2K, Gaussian, Q-Chem, and VASP can be analyzed. The normal-mode analysis can be performed using a broad variety of advanced models, including the standard full Hessian, the Mobile Block Hessian, the Partial Hessian Vibrational approach, the Vibrational Subsystem Analysis with or without mass matrix correction, the Elastic Network Model, and other combinations. TAMkin is readily extensible because of its modular structure. Chemical kinetics of unimolecular and bimolecular reactions can be analyzed in a straightforward way using conventional transition state theory, including tunneling corrections and internal rotor refinements. A sensitivity analysis can also be performed, providing important insight into the theoretical error margins on the kinetic parameters. Two extensive examples demonstrate the capabilities of TAMkin: the conformational change of the biological system adenylate kinase is studied, as well as the reaction kinetics of the addition of ethene to the ethyl radical. The important feature of batch processing large amounts of data is highlighted by performing an extended level of theory study, which TAMkin can automate significantly

Opposite regiospecific ring opening of 2-(cyanomethyl)aziridines by hydrogen bromide and benzyl bromide : experimental study and theoretical rationalization

Ring opening of 1-arylmethyl-2-(cyanomethyl)aziridines with HBr afforded 3-(arylmethyl)amino-4-bromobutyronitriles via regiospecific ring opening at the unsubstituted aziridine carbon. Previous experimental and theoretical reports show treatment of the same compounds with benzyl bromide to furnish 4-amino-3-bromobutanenitriles through ring opening at the substituted aziridine carbon. To gain insights into the regioselective preference with HBr, reaction paths have been analyzed with computational methods. The effect of solvation was taken into account by the use of explicit solvent molecules. Geometries were determined at the B3LYP/6-31++G(d,p) level of theory, and a Grimme-type correction term was included for long-range dispersion interactions; relative energies were refined with the meta-hybrid MPW1B95 functional. Activation barriers confirm preference for ring opening at the unsubstituted ring carbon for HBr. HBr versus benzyl bromide ring opening was analyzed through comparison of the electronic structure of corresponding aziridinium intermediates. Although the electrostatic picture fails to explain the opposite regiospecific nature of the reaction, frontier molecular orbital analysis of LUMOs and nucleophilic Fukui functions show a clear preference of attack for the substituted aziridine carbon in the benzyl bromide case and for the unsubstituted aziridine carbon in the HBr case, successfully rationalizing the experimentally observed regioselectivity

Catalytic performance of vanadium MIL-47 and linker-substituted variants in the oxidation of cyclohexene: a combined theoretical and experimental approach

The epoxidation of cyclohexene has been investigated on a metal-organic framework MIL-47 containing saturated V+IV sites linked with functionalized terephthalate linkers (MIL-47-X, X= OH, F, Cl, Br, CH3, NH2). Experimental catalytic tests have been performed on the MIL-47-X materials to elucidate the effect of linker substitution on the conversion. Notwithstanding the fact that these substituted materials are prone to leaching in the performed catalytic tests, the initial catalytic activity of these materials correlates with the Hammett substituent constants. In general, substituents led to an increased activity relative to the parent MIL-47. To rationalize the experimental findings, first-principles kinetic calculations were performed on periodic models of MIL-47 to determine the most important active sites by creating defect structures in the interior of the crystalline material. In a next step these defect structures were used to propose extended cluster models, which are able to reproduce in an adequate way the direct environment of the active metal site. An alkylperoxo species V+VO-(OOtBu) was identified as the most abundant and therefore the most active epoxidation site. The structure of the most active site was a starting basis for the construction of extended cluster models including substituents. They were used for quantifying the effect of functionalization of the linkers on the catalytic performance of the heterogeneous catalyst MIL-47-X. Electron-withdrawing as well as electron-donating groups have been considered. The epoxidation activity of the functionalized models has been compared with the measured experimental conversion of cyclohexene. The agreement is fairly good. This combined experimental-theoretical study makes it possible to elucidate the structure of the most active site and to quantify the electronic modulating effects of linker substituents on the catalytic activity

Functionalized metal-organic frameworks: MIL-47(V)+X: a computational investigation of its properties

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