Rational design of an enzyme mutant for anti-cocaine therapeutics

(-)-Cocaine is a widely abused drug and there is no available anti-cocaine therapeutic. The disastrous medical and social consequences of cocaine addiction have made the development of an effective pharmacological treatment a high priority. An ideal anti-cocaine medication would be to accelerate (-)-cocaine metabolism producing biologically inactive metabolites. The main metabolic pathway of cocaine in body is the hydrolysis at its benzoyl ester group. Reviewed in this article is the state-of-the-art computational design of high-activity mutants of human butyrylcholinesterase (BChE) against (-)-cocaine. The computational design of BChE mutants have been based on not only the structure of the enzyme, but also the detailed catalytic mechanisms for BChE-catalyzed hydrolysis of (-)-cocaine and (+)-cocaine. Computational studies of the detailed catalytic mechanisms and the structure-and-mechanism-based computational design have been carried out through the combined use of a variety of state-of-the-art techniques of molecular modeling. By using the computational insights into the catalytic mechanisms, a recently developed unique computational design strategy based on the simulation of the rate-determining transition state has been employed to design high-activity mutants of human BChE for hydrolysis of (-)-cocaine, leading to the exciting discovery of BChE mutants with a considerably improved catalytic efficiency against (-)-cocaine. One of the discovered BChE mutants (i.e., A199S/S287G/A328W/Y332G) has a approximately 456-fold improved catalytic efficiency against (-)-cocaine. The encouraging outcome of the computational design and discovery effort demonstrates that the unique computational design approach based on the transition-state simulation is promising for rational enzyme redesign and drug discovery.     

Effects of vocal training on the acoustic parameters of the singing voice

Vocal training (VT) has, in part, been associated with the distinctions in the physiological, acoustic, and perceptual parameters found in singers' voices versus the voices of nonsingers. This study provides information on the changes in the singing voice as a function of VT over time. Fourteen college voice majors (12 females and 2 males; age range, 17–20 years) were recorded while singing, once a semester, for four consecutive semesters. Acoustic measures included fundamental frequency (F₀) and sound pressure level (SPL) of the 10% and 90% levels of the maximum phonational frequency range (MPFR), vibrato pulses per second, vibrato amplitude variation, and the presence of the singer's formant. Results indicated that VT had a significant effect on the MPFR. F₀ and SPL of the 90% level of the MPFR and the 90–10% range increased significantly as VT progressed. However, no vibrato or singers' formant differences were detected as a function of training. This longitudinal study not only validates previous cross-sectional research, ie, that VT has a significant effect on the singing voice, but also it demonstrates that these effects can be acoustically detected by the fourth semester of college vocal training.     

Laryngeal Herpes: A Case Report

Herpetic laryngitis is a rare inflammatory disease caused by herpes simplex or herpes zoster virus. The propensity for spreading along peripheral nerves and within the central nervous system, with frank herpetic meningoencephalitis, is a rare complication. We present one case of herpetic laryngitis by reactivation of varicella zoster, with central nervous system spreading, and discuss the relevant literature on the pathophysiology, diagnosis, evaluation, and management of this disease.     

“笑气”:让人欢喜让人忧*——“笑气”的功过及其滥用问题的思考

我国青少年“笑气”滥用问题日趋严峻,引发社会关注。介绍了“笑气”的简要历史、制备方法、结构与性质、重要应用、滥用原因及危害等,期望引导青少年全面了解“笑气”,科学使用“笑气”,提早构筑起心理防线,自觉抵制“笑气”滥用。     

Voltammetric Oxidation of Drugs of Abuse II. Codeine and Metabolites

The oxidation of codeine on glassy carbon electrodes has been studied in detail using differential pulse voltammetry. The results obtained using a glassy carbon electrode clearly show a much more complex oxidation mechanism than that previously reported when platinum and gold electrodes were used. To clarify the codeine oxidative profile, several metabolites and analogues of this alkaloid, codeine N‐oxide, norcodeine, dihydrocodeine, acetylcodeine and 6‐chlorodesoxycodeine, were synthesized and studied. It was deduced that the anodic waves observed in codeine oxidation are related to the presence of methoxy, hydroxy and tertiary amine groups. Due to the similarity of potentials at which these oxidative processes take place, at some pHs an overlap of peaks occurs and only one anodic wave is observed.