Preventing the next generation of extensively drug-resistant tuberculosis.

Multidrug-resistant and extremely drug-resistant tuberculosis strains threaten to become an intractable problem. Misuse of antibiotics and inadequacy of diagnostic tools have fostered drug resistance. Effective diagnostic technology would eliminate this problem, but it remains unavailable in high-burden areas. New drugs with novel targets may help combat drug resistance. However, if added singly to existing combination regimens, resistance will increase. To protect the efficacy of a new drug, it should first be used only as a second-line drug, in cases that have undergone drug susceptibility testing. Widespread use of new drugs as first-line agents would follow with the dawn of a new rapid diagnostic era.

Numerical simulation of a laboratory-scale turbulent V-flame.

We present a three-dimensional, time-dependent simulation of a laboratory-scale rod-stabilized premixed turbulent V-flame. The experimental parameters correspond to a turbulent Reynolds number, Re(t) = 40, and to a Damköhler number, D(a) = 6. The simulations are performed using an adaptive time-dependent low-Mach-number model with detailed chemical kinetics and a mixture model for differential species diffusion. The algorithm is based on a second-order projection formulation and does not require an explicit subgrid model for turbulence or turbulence/chemistry interaction. Adaptive mesh refinement is used to dynamically resolve the flame and turbulent structures. Here, we briefly discuss the numerical procedure and present detailed comparisons with experimental measurements showing that the computation is able to accurately capture the basic flame morphology and associated mean velocity field. Finally, we discuss key issues that arise in performing these types of simulations and the implications of these issues for using computation to form a bridge between turbulent flame experiments and basic combustion chemistry.

Syntheses and beta-adrenergic binding affinities of (R)- and (S)-fluoronaphthyloxypropanolamines.

The beta-adrenergic receptors mediate several physiological processes including heart rate (beta 1), bronchodilation (beta 2), and lipolysis (beta 3). Therefore, selectivity is important for a possible therapeutic agent acting via these receptors. Aryloxypropanolamines are beta-receptor agonists or antagonists, depending on the aryl group and its substituents. We therefore hypothesized that fluorine substitution on the aromatic ring in this class could lead to significant biological effects because of the unique chemical characteristics of fluorine. Because the target compound has a chiral center, we set out to synthesize the two enantiomers so that effects of stereochemistry on biological activity could be evaluated. Syntheses of the enantiomers were performed starting with commercially available fluoronaphthalene and subsequent use of the chiral synthon (2R)- or (2S)-glycidyl 3-nitrobenzenesulfonate, depending on the desired enantiomer. High-pressure liquid chromatography (HPLC) methods were used to characterize %ee. Each enantiomer was synthesized. They exhibited nanomolar binding activities on beta-adrenergic receptors. The (S)-enantiomer was found to be up to 310 times more potent than the (R). It was also found to be about five-fold more selective for beta 2- than for beta 1-receptors. The current report demonstrates the importance of stereochemistry for the fluoroaromatic beta-receptor ligands.