Metabolism of Zidovudine

1. The anti-HIV drug zidovudine (3'-azido-2',3'-dideoxythymidine; ZDV) has three important pathways of metabolism. ZDV is a prodrug and must be phosphorylated in lymphocytes in order to exert its antiviral action. However, in quantitative terms this is a minor pathway probably accounting for less than 1% of the overall metabolic profile. The predominant pathway of metabolism is glucuronidation to GZDV and the metabolite is renally excreted. A further metabolite, derived by reduction of the azido moiety is 3'-amino-3'-deoxythymidine (AMT). 2. Zidovudine glucuronidation has been characterised in human liver microsomes. A number of drugs (e.g., naproxen, indomethacin and probenecid) have been shown to inhibit the in vitro conjugation of ZDV. Some of these drugs have also been co-administered with ZDV in HIV-positive patients. Significant pharmacokinetic interactions have been demonstrated with probenecid, naproxen and fluconazole. 3. 3'-amino-3'-deoxythymidine formation is probably mediated by both cytochrome P450 isozymes and NADPH-cytochrome P450 reductase. Peak plasma concentrations of AMT are approximately 10-15% of ZDV in patients. This is a potentially important metabolite because of its alleged cytotoxicity. 4. Measurement of intracellular ZDV phosphates in patients provides the key to our understanding of both the efficacy and toxicity of ZDV. Important recent work has demonstrated that as patients deteriorate (i.e., CD4 counts decrease below 100 x 10(6)/L), there is a corresponding increase in intracellular ZDV-monophosphate. This could have toxicological implications.     

Cdc34 and the F-box protein Met30 are required for degradation of the Cdk-inhibitory kinase Swe1

Ubiquitin-mediated proteolysis controls the abundance of many cell cycle regulatory proteins. Recent work in Saccharomyces cerevisiae suggests that a complex consisting of Cdc53, Skp1, and a third component known as an F-box protein (termed SCF) in combination with Cdc34 specifically targets regulatory proteins for degradation, and that substrate specificity is likely to be mediated by the F-box subunit. A screen for genetic interactions with a cdc34 mutation yielded MET30, which encodes an F-box protein. MET30 is an essential gene required for cell cycle progression and met30 mutations interact genetically with mutations in SCF components. Furthermore, physical interactions between Met30, Cdc53, Cdc34, and Skp1 in vivo provide evidence for an SCFMet30 complex. We demonstrate the involvement of Met30 in the degradation of the Cdk-inhibitory kinase Swe1. Swe1 is stabilized in met30 mutants and GST-Met30 pull-down experiments reveal that Met30 specifically binds Swe1 in vivo. Furthermore, extracts prepared from cdc34 or met30 mutants are defective in polyubiquitination of Swe1. Taken together, these data suggest that SCF-mediated proteolysis may contribute to the regulation of entry into mitosis. Our data, in combination with previously published results, also provide evidence for distinct SCF complexes in vivo and support the idea that their F-box subunits mediate SCF substrate specificity.     

Cyclosporin A in patients receiving renal allografts from cadaver donors. 1978

A psychrotrophic yeast, Rhodotorula glutinis KUJ 2731, isolated from soil, effectively produced an extracellular endo-beta-glucanase (EC 3.2.1.4). The enzyme was monomeric, and the molecular mass was about 40,000 Da. The N-terminal amino acid sequence was H-Ser-Leu-Pro- Lys-Leu-Gly-Gly-Val-Asp-Leu-Ala-Gly-Leu-Asp-Ile-Gly-Lys-Asp-Lys-Asn-. alpha-Helix content was calculated to be about 32.6%. The isoelectric point was 8.57. The activation energy was 20.9 kJ/mol, which was much smaller than that of mesophilic enzymes. The enzyme was active at temperatures from 0 to 70 degrees C, with a highest initial velocity at 50 degrees C similar to other psychrotrophic enzymes. The enzyme was inhibited by Hg2+. The enzyme catalyzed hydrolysis of carboxymethyl cellulose with an apparent K(m) of 1.1% and Vmax of 556 mumol/min/mg. Products from the enzymatic hydrolysis of carboxymethyl cellulose by the enzyme were glucose, cellobiose, and cellotriose. The enzyme also catalyzed the transglycosylation of p-nitrophenyl-beta-cellotrioside to cellotetraose.     

Induced magnetic fields as evidence for subsurface oceans in Europa and Callisto

The Galileo spacecraft has been orbiting Jupiter since 7 December 1995, and encounters one of the four galilean satellites-Io, Europa, Ganymede and Callisto-on each orbit. Initial results from the spacecraft's magnetometer have indicated that neither Europa nor Callisto have an appreciable internal magnetic field, in contrast to Ganymede and possibly Io. Here we report perturbations of the external magnetic fields (associated with Jupiter's inner magnetosphere) in the vicinity of both Europa and Callisto. We interpret these perturbations as arising from induced magnetic fields, generated by the moons in response to the periodically varying plasma environment. Electromagnetic induction requires eddy currents to flow within the moons, and our calculations show that the most probable explanation is that there are layers of significant electrical conductivity just beneath the surfaces of both moons. We argue that these conducting layers may best be explained by the presence of salty liquid-water oceans, for which there is already indirect geological evidence in the case of Europa.     

Esophageal cyst--a rare cause of backache

BACKGROUND: The duration of action of muscle relaxants is poorly correlated to the rate of decay of their plasma concentration. The plasma concentration of mivacurium may rapidly decrease below its active concentration because of the extensive hydrolysis of mivacurium. By inflating a tourniquet on one upper limb for 3 min after the administration of atracurium, mivacurium or vecuronium, we studied the influence of the initial decline of their plasma concentration on their effect. METHODS: In 50 patients anaesthetised with thiopental, isoflurane and fentanyl, the effect of bolus doses of 0.15 or 0.25 mg.kg-1 mivacurium (MIV 15, MIV 25), 0.3 or 0.5 mg.kg-1 atracurium (ATR 30, ATR 50) and 0.06 or 0.1 mg.kg-1 vecuronium (VEC 06, VEC 10) were measured on both arms (evoked response of the adductor pollicis to train-of-four stimulation every 12 s), a tourniquet being applied on one arm just before and during 3 min after the muscle relaxant bolus. RESULTS: Tourniquet inflation of 3 min almost abolished the neuromuscular effect of mivacurium. In the vecuronium groups and in the ATR 50 group, tourniquet inflation did not modify the maximum degree of depression of the twitch response. Also, the duration of action of vecuronium was unaffected by the tourniquet. In the ATR 30 group, times to return of the twitch response to 25% (duration 25%) and 75% (duration 75%) of control response were significantly shorter in the cuffed arm, 23 min vs 27 min, and 41 min vs 45 min, respectively. In the ATR 50 group, only duration 25% was significantly shorter in the cuffed arm (41 min vs 45 min). CONCLUSION: The results suggest that the rate of decline of the plasma concentration of mivacurium is so rapid, that a very low and almost clinically ineffective concentration is present as soon as 3 min after its administration. The results also indicate that the recovery from a mivacurium-induced neuromuscular blockade is not influenced by the rate of decay of its plasma concentration in patients with genotypically normal plasma cholinesterase.     

Catalytic oxidation of methanol over molybdenum oxide–tungsten oxide

The vapour phase oxidation of methanol to formaldehyde over molybdenum oxide, tungsten oxide and their mixtures has been investigated in an integral flow reactor at atmospheric pressure. The effect of several process variables on the conversion and yield were determined. A high conversion of 95.6% methanol with nearly 95% selectivity was obtained at 430°C. A rate expression has been derived from the kinetics of the reaction.     

In-Plane Cracking Behavior and Ultimate Strength for 2D Woven and Braided Melt-Infiltrated SiC/SiC Composites Tensile Loaded in Off-Axis Fiber Directions

The tensile mechanical properties of ceramic matrix composites (CMC) in directions off the primary axes of the reinforcing fibers are important for the architectural design of CMC components that are subjected to multiaxial stress states. In this study, two-dimensional (2D)-woven melt-infiltrated (MI) SiC/SiC composite panels with balanced fiber content in the 0° and 90° directions were tensile loaded in-plane in the 0° direction and at 45° to this direction. In addition, a 2D triaxially braided MI SiC/SiC composite panel with a higher fiber content in the ±67° bias directions compared with the axial direction was tensile loaded perpendicular to the axial direction tows (i.e., 23° from the bias fibers). Stress–strain behavior, acoustic emission, and optical microscopy were used to quantify stress-dependent matrix cracking and ultimate strength in the panels. It was observed that both off-axis-loaded panels displayed higher composite onset stresses for through-thickness matrix cracking than the 2D-woven 0/90 panels loaded in the primary 0° direction. These improvements for off-axis cracking strength can in part be attributed to higher effective fiber fractions in the loading direction, which in turn reduces internal stresses on weak regions in the architecture, e.g., minicomposite tows oriented normal to the loading direction and/or critical flaws in the matrix for a given composite stress. Both off-axis-oriented panels also showed relatively good ultimate tensile strength when compared with other off-axis-oriented composites in the literature, both on an absolute strength basis as well as when normalized by the average fiber strength within the composites. Initial implications are discussed for constituent and architecture design to improve the directional cracking of SiC/SiC CMC components with MI matrices.     

Dynamic gas disengagement: A new technique for assessing the behaviour of bubble columns

A precise measure of the liquid motion and distribution of bubble sizes is essential for designing gas-liquid reactors for complex reactions in which product distribution may be a function of bubble size. A theoretical approach is presented which shows how the interaction of bubble size distribution and bubble rise velocity functions leads to predictions of the overall steady state hold-up in a bubble column within which the liquid flow is understood. Since this approach is based on a physical understanding of how bubble flow at a given superficial velocity must relate to the static hold-up, the theory can be immediately extended to describe the disengagement of gas bubbles if the gas feed is cut off. Thus the dynamic gas hold-up during gas disengagement can be used to provide new insights into the fundamentals of bubble column behaviour. In this way it becomes possible in principle to inter-relate macroscopic properties such as surface area, gas phase residence time distribution and intensity of mixing in the liquid phase.A new experimental technique is described which measures the dynamic gas hold-up during gas disengagement Experimental results at a nominal 20 mm/s gas superficial velocity are compared with various approaches based upon the theory. The effects of the accompanying induced liquid movements are represented by a simplified core-annulus circulation model. Bubble size distributions and liquid circulation can then be related to both the static and dynamic hold-up behaviour. It is shown that ambiguity due to uncertainty about the relative differences in bubble size distribution in upflow and downflow regions can be resolved from a knowledge of the surface area.     

Antireflection coatings for UV radiation obtained by molecular-beam deposition

We have developed fluoride antireflection (AR) coatings on MgF(2) substrates for a wavelength of 248 nm by molecular-beam deposition. Transmission and laser-induced damage threshold of the samples were measured and atomic force microscope (AFM) investigations were carried out. We compare a 14-layer design for AR coatings with sublayer thicknesses of 12 nm with a conventional two-layer design with quarter-wavelength thicknesses. The laser-induced damage threshold of the 14-layer coating is slightly higher than that of the two-layer coating. The AFM surface images show that the 14-layer coating has a smoother surface than the two-layer coating.