Paracoccidioides brasiliensis, paracoccidioidomycosis, and antifungal antibiotics.

Paracoccidioides brasiliensis is the causative agent of paracoccidioidomycosis (PCM), a human systemic, chronic and progressive mycosis. Preferred antifungals are sulfamethoxazol-trimethoprim, itraconazole, amphotericin B. Treatment is lengthy, the drugs may have undesirable side effects, and some are costly. Occasional resistant strains have been reported. Therefore, the search for more selective and efficient antifungals to treat this and other mycoses continues. Ajoene, chemically derived from garlic, behaves as an antifungal agent against P. brasiliensis and other fungi. Its antiproliferative effects in P. brasiliensis are associated with a reduction of phosphatidyl choline, a concomitant increase in its precursor phosphatidyl ethanolamine, and a large increase in unsaturated fatty acids in the pathogenic yeast phase. The sterol biosynthetic pathway has been largely studied for the search of antifungals. Azoles and allilamines act on differents steps of this pathway. However, they may interfere with similar steps in the host. Hence, the search for drugs that may act on more specific steps is ongoing. One such step focuses on the sterol C-methylations catalyzed by the enzyme (S)-adenosyl-L-methionine: Delta(24) - sterol methyl transferase (SMT). SMT inhibitors such as azasterols and derivatives (AZA1, AZA2, AZA3) have proven highly effective as antiproliferative agents against protozoa and some fungi, among them, P. brasiliensis. Their chemical synthesis and structure, and their molecular electrostatic potential are discussed in order to understand their mechanism of action, and derive rationally designed improvements on these molecules, that would favour a higher efficacy and selectivity.

Towards an atomic model of the thick filaments of muscle.

The thick filaments of muscle and non-muscle cells are polymers of myosin molecules whose energy-transducing heads lie on the filament surface, where they interact with actin to generate force. A key structural question is how the myosin heads are arranged in the relaxed state, and how this arrangement changes on activation of contraction. We have fitted the atomic structure of the myosin head to the three-dimensional structure of myosin filaments of tarantula muscle determined by electron microscopy to produce a near-atomic model of the head arrangement. A good fit is obtained only when the two heads from a myosin molecule run along the helical tracks antiparallel to each other. Oppositely oriented heads from axially adjacent molecules in a helix interact with each other, with their nucleotide-binding pockets opposed. This arrangement, supported also by crosslinking evidence, suggests a simple mechanism for the stabilization of myosin head helices in relaxed muscle via the formation of intermolecular "dimers" of heads from axially adjacent myosin molecules.

Diffusion and spatially resolved NMR in Berea and Venezuelan oil reservoir rocks.

Conventional and spatially resolved proton NMR and relaxation measurements are used in order to study the molecular motions and the equilibrium and nonequilibrium diffusion of oils in Berea sandstone and Venezuelan reservoir rocks. In the water-saturated Berea a single line with T*2 congruent to 150 microseconds is observed, while the relaxation recovery is multiexponential. In an oil reservoir rock (Ful 13) a single narrow line is present while a distribution of relaxation rates is evidenced from the recovery plots. On the contrary, in the Ful 7 sample (extracted at a deeper depth in a different zone) two NMR components are present, with 3.5 and 30 KHz linewidths, and the recovery plot exhibits biexponential law. No echo signal could be reconstructed in the oil reservoir rocks. These findings can be related to the effects in the micropores, where motions at very low frequency can occur in a thin layer. From a comparison of the diffusion constant in water-saturated Berea, D congruent to 5*10(-6) cm2/sec, with the ones in model systems, the average size of the pores is estimated around 40 A. The density profiles at the equilibrium show uniform distribution of oils or of water, and the relaxation rates appear independent from the selected slice. The nonequilibrium diffusion was studied as a function of time in a Berea cylinder with z axis along H0, starting from a thin layer of oil at the base, and detecting the spin density profiles d(z,t) with slice-selection techniques. Simultaneously, the values of T1's were measured locally, and the distribution of the relaxation rates was observed to be present in any slice.(ABSTRACT TRUNCATED AT 250 WORDS)

Automatic continous frequency calibration for super-regenerative oscillators used in nuclear quadrupole resonance.

A new and improved method for continuous frequency calibration of the super-regenerative oscillator spectrum is described. The arrangement employs a Hewlett-Packard Model HP5345A reciprocal frequency counter capable of measuring the carrier frequency of rf pulses. The counter gate time is externally controlled via the quench pulses. High-resolution measurements are obtained through the use of the frequency-averaging mode provided by the counter. Three successive digits are displayed on a two-channel recorder using a digital-to-analog converter along with the lock-in output. This method provides automatic and continous high-accuracy frequency calibration of the spectrum which is independent of the rf level, quench frequency, and FM amplitude.