Properties of lipoic acid analogs

Two chain-shortened analogs of lipoic (1,2-dithiolane-3-pentanoic) acid, viz. bisnor-lipoic (1,2-dithiolane-3-propanoic) and tetranorlipoic (1,2-dithiolane-3-carboxylic) acids, have been chemically synthesized. The ir, uv, pmr, and mass spectroscopic properties and paper, thin-layer, and column chromatographic mobilities of lipoic acid and its analogs were investigated and are given.     

The electronic structure of ArF and Ar2F

Calculations have been performed on the electronic structure, potential energy curves and radiative transition probabilities of ArF and Ar₂F. Our predicted emission spectra for ArF indicates that only the B²Σ⁺_{$\text{1}\text{2}$} → X²Σ⁺_{$\text{1}\text{2}$} transition exhibits a large transition moment and hence a short (≈5 ns) radiative lifetime. Calculations for Ar₂F indicate that the bound upper ionic state has ²B₂ symmetry with ArAr and ArF bond lengths similar to those in the corresponding diatomic species. The terminating state also has ²B₂ symmetry and this polyatomic system should exhibit a relatively long radiative lifetime (≈200 ns)     

An analysis of the thermal characteristics of magnetic field modulation method of magneto-optical recording

The thermal characteristics of magnetic field modulation (MFM) recording are analyzed. It is found that the heat accumulation in MFM recording can greatly reduce the temperature gradient at the recording edge, resulting in a reduction of bit boundary regularity. A specially considered dual modulation method is thus proposed and discussed which shows a greatly improved thermal situation.     

Resolution of discordant HIV-1 protease resistance rankings using molecular dynamics simulations

The emergence of drug resistance is a major challenge for the effective treatment of HIV. In this article, we explore the application of atomistic molecular dynamics simulations to quantify the level of resistance of a patient-derived HIV-1 protease sequence to the inhibitor lopinavir. A comparative drug ranking methodology was developed to compare drug resistance rankings produced by the Stanford HIVdb, ANRS, and RegaDB clinical decision support systems. The methodology was used to identify a patient sequence for which the three rival online tools produced differing resistance rankings. Mutations at only three positions ( L10I , A71IV, and L90M ) influenced the resistance level assigned to the sequence. We use ensemble molecular dynamics simulations to elucidate the origin of these discrepancies and the mechanism of resistance. By simulating not only the full patient sequences but also systems containing the constituent mutations, we gain insight into why resistance estimates vary and the interactions between the various mutations. In the same way, we also gain valuable knowledge of the mechanistic causes of resistance. In particular, we identify changes in the relative conformation of the two beta sheets that form the protease dimer interface which suggest an explanation of the relative frequency of different amino acids observed in patients at residue 71.     

Inhibition of <em>Burkholderia multivorans</em> Adhesion to Lung Epithelial Cells by Bivalent Lactosides

Burkholderia cepacia complex (Bcc) is an opportunistic pathogen in cystic fibrosis patients which is inherently resistant to antimicrobial agents. The mechanisms of attachment and pathogenesis of Bcc, a group of 17 species, are poorly understood. The most commonly identified Bcc species in newly colonised patients, Burkholderia multivorans, continues to be acquired from the environment. Development of therapies which can prevent or reduce the risk of colonization on exposure to Bcc in the environment would be a better alternative to antimicrobial agents. Previously, it has been shown that Bcc strains bound to many glycolipid receptors on lung epithelia. Using a real-time PCR method to quantify the levels of binding of B. multivorans to the lung epithelial cells, we have examined glycoconjugate derivatives for their potential to inhibit host cell attachment. Bivalent lactosides previously shown to inhibit galectin binding significantly reduced the attachment of B. multivorans to CF lung epithelial cells at micromolar concentrations. This was in contrast to monosaccharides and lactose, which were only effective in the millimolar range. Development of glycoconjugate therapies such as these, which inhibit attachment to lung epithelial cells, represent an alternative means of preventing infection with inherently antimicrobially resistant pathogens such as B. multivorans.     

A structural and magnetic study of organolanthanide(III) amides

The syntheses, structures and magnetic properties of the series of dimeric organolanthanide(III) amides [Cp2Ln{2-NH-4,6-Me2pm}]2 [Ln = Nd (1), Gd (2), Dy (3), Yb (4) and pm = pyrimidine], which are formed from the deprotonation of 2-amino-4,6-dimethylpyrimidine by the corresponding lanthanide tris-cyclopentadienide, are reported. The synthesis and structure of [{Cp2Yb(2-NH-4-MeO-6-MeOpm)(2)(mu3-O)(YbCp)] (5), formed in a similar deprotonation reaction but in the presence of adventitious water, is also reported.     

Measurement of gastric emptying in man using deuterated octanoic acid.

Gamma scintigraphy is considered the gold standard for the measurement of gastric emptying in humans. Recently, it has been proposed that a [(13)C]octanoate breath test can be used as an alternative technique for measuring gastric emptying of the solid phase, but the results from the two methods are not directly equivalent since in the breath test the label is subject to post-absorptive processing and consequently the emptying functions cannot be observed directly. This work investigates an alternative stable isotope method using deuterated octanoate where the kinetics of redistribution between and elimination from the various body pools are much more easily modelled. Gastric emptying was studied in healthy human volunteers by simultaneous measurement using both [(13)C]octanoate and [(2)H]octanoate as well as gamma scintigraphy. Comparison of the gastric emptying functions from the deuterium method and scintigraphy indicated that the two methods gave equivalent results. The new method can therefore be used in populations considered too vulnerable to ionising radiation to allow gamma scintigraphy to be performed, or as a proxy gold standard in laboratories where scintigraphic methods are unavailable, allowing further comparisons with the breath test method to be made to validate the latter in different population groups.     

Singlet oxygen-mediated protein oxidation: evidence for the formation of reactive side chain peroxides on tyrosine residues

Singlet oxygen (1O2) is generated by a number of enzymes as well as by UV or visible light in the presence of a sensitizer and has been proposed as a damaging agent in a number of pathologies including cataract, sunburn, and skin cancers. Proteins, and Cys, Met, Trp, Tyr and His side chains in particular, are major targets for 1O2 as a result of their abundance and high rate constants for reaction. In this study it is shown that long-lived peroxides are formed on free Tyr, Tyr residues in peptides and proteins, and model compounds on exposure to 1O2 generated by both photochemical and chemical methods. The yield of these species is significantly enhanced in D2O and decreased by azide. Nuclear magnetic resonance and mass spectroscopic analysis of reaction mixtures, or materials separated by high-performance liquid chromatography, are consistent with the initial formation of an (undetected) endoperoxide that undergoes rapid ring-opening to give a hydroperoxide situated at the C1 ring-position (i.e. para to the phenolic group). In the presence of a free alpha-amino group (e.g. with free Tyr), rapid ring-closure occurs to give an indolic hydroperoxide that decays into the corresponding alcohol, 3a-hydroxy-6-oxo-2,3,3a,6,7,7a-hexahydro-1H-indole-2-carboxylic acid. Hydroperoxides that lack a free alpha-amino group (e.g. those formed on 3-(4-hydroxyphenyl)propionic acid, N-Ac-Tyr and Tyr-containing peptides) are longer-lived, with half-lives of hours to days. These species undergo slow decay at low temperatures to give the corresponding alcohol. Their rate of decay is enhanced at 37 degrees C, or on exposure to UV light or metal ions, and gives rise to reactive radicals, via cleavage of the peroxide bond. These radicals have been characterized by electron paramagnetic resonance spin trapping. These studies demonstrate that long-lived Tyr-derived peroxides are formed on proteins exposed to 1O2 and that these may promote damage to other targets via further radical generation.