Observation of intense low energy autoionization lines in the wings of the forward peak from fast ion-atom collisions

In the ejected electron spectra from collisions of C²⁺, O⁴⁺ and Si^10,11,12+ with argon toms at energies of 2–4 MeV/amu, a series of intense lines has been observed, which originates from doubly excited autoionizing states of Belike projectiles. These lines correspond to electron energies between 2 and 20 eV in the projectile frame. For kinematic reasons these lines can only be detected near the forward direction.     

Selective oxidation of glycerol to glyceric acid using a gold catalyst in aqueous sodium hydroxide

Glycerol is oxidised to glyceric acid with 100% selectivity using either 1% Au/charcoal or 1% Au/graphite catalyst under mild reaction conditions (60 degrees C, 3 h, water as solvent).     

Dynamic nuclear polarization at 9T using a novel 250GHz gyrotron microwave source

In this communication, we report enhancements of nuclear spin polarization by dynamic nuclear polarization (DNP) in static and spinning solids at a magnetic field strength of 9T (250 GHz for g=2 electrons, 380 MHz for 1H). In these experiments, 1H enhancements of up to 170+/-50 have been observed in 1-13C-glycine dispersed in a 60:40 glycerol/water matrix at temperatures of 20K; in addition, we have observed significant enhancements in 15N spectra of unoriented pf1-bacteriophage. Finally, enhancements of approximately 17 have been obtained in two-dimensional 13C-13C chemical shift correlation spectra of the amino acid U-13C, 15N-proline during magic angle spinning (MAS), demonstrating the stability of the DNP experiment for sustained acquisition and for quantitative experiments incorporating dipolar recoupling. In all cases, we have exploited the thermal mixing DNP mechanism with the nitroxide radical 4-amino-TEMPO as the paramagnetic dopant. These are the highest frequency DNP experiments performed to date and indicate that significant signal enhancements can be realized using the thermal mixing mechanism even at elevated magnetic fields. In large measure, this is due to the high microwave power output of the 250 GHz gyrotron oscillator used in these experiments.     

Application of multivariate outlier detection to fluid velocity measurements

A statistical-based approach to detect outliers in fluid-based velocity measurements is proposed. Outliers are effectively detected from experimental unimodal distributions with the application of an existing multivariate outlier detection algorithm for asymmetric distributions (Hubert and Van der Veeken, J Chemom 22:235–246, 2008). This approach is an extension of previous methods that only apply to symmetric distributions. For fluid velocity measurements, rejection of statistical outliers, meaning erroneous as well as low probability data, via multivariate outlier rejection is compared to a traditional method based on univariate statistics. For particle image velocimetry data, both tests are conducted after application of the current de facto standard spatial filter, the universal outlier detection test (Westerweel and Scarano, Exp Fluids 39:1096–1100, 2005). By doing so, the utility of statistical outlier detection in addition to spatial filters is demonstrated, and further, the differences between multivariate and univariate outlier detection are discussed. Since the proposed technique for outlier detection is an independent process, statistical outlier detection is complementary to spatial outlier detection and can be used as an additional validation tool.     

Multivalent drug design. Synthesis and in vitro analysis of an array of vancomycin dimers

The design, synthesis, and in vitro microbiological analysis of an array of forty covalently linked vancomycin dimers are reported. This work was undertaken to systematically probe the impact of linkage orientation and linker length on biological activity against susceptible and drug-resistant Gram-positive pathogens. To prepare the array, monomeric vancomycin synthons were linked through four distinct positions of the glycopeptide (C-terminus (C), N-terminus (N), vancosamine residue (V), and resorcinol ring (R)) in 10 unique pairwise combinations. Amphiphilic, peptide-based linkers of four different lengths (11, 19, 27, and 43 total atoms) were employed. Both linkage orientation and linker length were found to affect in vitro antibacterial potency. The V-V series displayed the greatest potency against vancomycin-susceptible organisms and vancomycin-resistant Enterococcus faecalis (VRE) of VanB phenotype, while the C-C, C-V, and V-R series displayed the most promising broad-spectrum activity that included VRE of VanA phenotype. Dimers bearing the shortest linkers were in all cases preferred for activity against VRE. The effects of linkage orientation and linker length on in vitro potency were not uniform; for example, (1) no single compound displayed activity that was superior against all test organisms to that of vancomycin or the other dimers, (2) linker length effects varied with test organism, and (3) whereas one-half of the dimers were more potent than vancomycin against methicillin-susceptible Staphylococcus aureus (MSSA), only one dimer was more potent against methicillin-resistant S. aureus (MRSA) and glycopeptide-intermediate susceptible S. aureus (GISA). In interpreting the results, we have considered the potential roles of multivalency and of other phenomena.     

Judicious application of allyl protecting groups for the synthesis of 2-morpholin-4-yl-4-oxo-4H-chromen-8-yl triflate, a key precursor of DNA-dependent protein kinase inhibitors

[Structure: see text] 2-morpholin-4-yl-4-oxo-4H-chromen-8-yl 2,2,2-trifluoromethanesulfonate is a key intermediate for the synthesis of the DNA-dependent protein kinase (DNA-PK) inhibitor 8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one (NU7441). Two improved methods for the synthesis of this triflate have been developed: (A) in 35% overall yield, through modification of the published route, and (B) in 15% overall yield, by a new route employing a Baker-Venkataraman rearrangement to enable generation of the chromenone scaffold. Both syntheses depend on the judicious use of allyl protecting groups.     

3D TEDOR NMR experiments for the simultaneous measurement of multiple carbon-nitrogen distances in uniformly (13)C,(15)N-labeled solids

We describe three-dimensional magic-angle-spinning NMR experiments for the simultaneous measurement of multiple carbon-nitrogen distances in uniformly (13)C,(15)N-labeled solids. The approaches employ transferred echo double resonance (TEDOR) for (13)C-(15)N coherence transfer and (15)N and (13)C frequency labeling for site-specific resolution, and build on several previous 3D TEDOR techniques. The novel feature of the 3D TEDOR pulse sequences presented here is that they are specifically designed to circumvent the detrimental effects of homonuclear (13)C-(13)C J-couplings on the measurement of weak (13)C-(15)N dipolar couplings. In particular, homonuclear J-couplings lead to two undesirable effects: (i) they generate anti-phase and multiple-quantum (MQ) spin coherences, which lead to spurious cross-peaks and phase-twisted lines in the 2D (15)N-(13)C correlation spectra, and thus degrade the spectral resolution and prohibit the extraction of reliable cross-peak intensities, and (ii) they significantly reduce cross-peak intensities for strongly J-coupled (13)C sites (e.g., CO and C(alpha)). The first experiment employs z-filter periods to suppress the anti-phase and MQ coherences and generates 2D spectra with purely absorptive peaks for all TEDOR mixing times. The second approach uses band-selective (13)C pulses to refocus J-couplings between (13)C spins within the selective pulse bandwidth and (13)C spins outside the bandwidth. The internuclear distances are extracted by using a simple analytical model, which accounts explicitly for multiple spin-spin couplings contributing to cross-peak buildup. The experiments are demonstrated in two U-(13)C,(15)N-labeled peptides, N-acetyl-L-Val-L-Leu (N-ac-VL) and N-formyl-L-Met-L-Leu-L-Phe (N-f-MLF), where 20 and 26 (13)C-(15)N distances up to approximately 5-6 A were measured, respectively. Of the measured distances, 10 in N-ac-VL and 13 in N-f-MLF are greater than 3 A and provide valuable structural constraints.     

Effects of mutation on the amyloidogenic propensity of apolipoprotein C-II(60-70) peptide

Using experimental and computational methods we identified the effects of mutation on the structure and dynamics of the amyloidogenic peptide apoC-II(60-70), in monomeric and oligomeric states. Methionine (Met60) substitutions to hydrophilic Gln, hydrophobic Val, and methionine sulfoxide residues were investigated and the results compared with observations of fibril formation by the wild-type, Met60Gln, Met60Val, and oxidised Met60 (oxi-Met) apoC-II(60-70) peptides. ThT fluorescence measurements showed fibril formation by all peptides, however with different kinetics. The wild-type and Met60Val peptides formed fibrils fastest, while oxi-Met and Met60Gln peptides exhibited significantly longer lag phases. Molecular dynamics simulations showed that the mutated monomers exhibited structural features consistent with fibril-forming propensity, such as β-hairpin conformation and a hydrophobic core. However, important differences to the wild-type were also noted, such as increased structural flexibility (oxi-Met and Met60Gln systems) and a broader distribution of the aromatic angle orientation, which could contribute to the different fibrillation kinetics observed in these peptides. Our results also showed that the critical nucleus size for fibril formation by apoC-II(60-70) may not be very large, since tetrameric oligomers in anti-parallel configuration were very stable within the 100 ns of simulations. The single-point mutations Met60Val and Met60Gln had no significant effect on the structural stability of the tetramer. The rate of fibril formation by apoC-II(60-70) peptides was generally much faster compared to longer apoC-II(56-76) peptides. Also, the effects of amino acid modifications on the kinetics of peptide fibril formation differ from the effects observed for apoC-II(56-76) and full-length apoC-II, suggesting that additional mechanisms are involved in fibril formation by mature apoC-II.