Divergent Synthesis of Novel Cylindrocyclophanes that Inhibit Methicillin-Resistant Staphylococcus aureus (MRSA)

The cylindrocyclophanes are a family of macrocyclic natural products reported to exhibit antibacterial activity. Little is known about the structural basis of this activity due to the challenges associated with their synthesis or isolation. We hypothesised that structural modification of the cylindrocyclophane scaffold could streamline their synthesis without significant loss of activity. Herein, we report a divergent synthesis of the cylindrocyclophane core enabling access to symmetrical macrocycles by means of a catalytic, domino cross-metathesis-ring-closing metathesis cascade, followed by late-stage diversification. Phenotypic screening identified several novel inhibitors of methicillin-resistant Staphylococcus aureus. The most potent inhibitor has a unique tetrabrominated [7,7]paracyclophane core with no known counterpart in nature. Together these illustrate the potential of divergent synthesis using catalysis and unbiased screening methods in modern antibacterial discovery.     

Book reviews

A Fourth Way? Privatization, Property and the Emergence of New Market Economies. Gregory S. Alexander & Grazyna Skapska (Eds). London, Routledge, 1994, xxiii + 336 pp., ISBN 0415906970 (HB), 0415906989 (PB)

From Public Housing to the Social Market. Rental Policy Strategies in Comparative Perspective. Jim Kemeny. London and New York, Routledge, 1995, 194 pp., £40.00

European Housing Finance. Single Market or Mosaic?. Will Bartlett & Glen Bramley (Eds). Oxford, The Alden Press, School for Advanced Urban Studies (SAUS) publication 12 (Bristol) 1994, 282 pp., £19.95, paperback, ISBN 1 873575 63 7

Housing, Financial Markets and the Wider Economy. David Miles. Chichester, John Wiley & Sons, 1994, 228 pp., £35.00

Women in the Housing Service. Marion Brion. London, Routledge, 1994, ISBN 0 415 08094 £45.00 Hardback

Slippery Customers: Estate Agents, The Public and Regulation. Michael Clarke, David Smith & Michael McConville. London, Blackstone Press, 1994, 295 pp., £19.95     

Precision of in-place concrete strenghts predicted using core strength correction factors obtained by weighted regression analysis

A two-step method for converting a concrete core compression test result to the in-place strength of the corresponding volume of concrete is presented. The strength of a non-standard core is first converted to the equivalent strength of a standard core, and then the standard core strength is converted to the equivalent in-place strength. Strength correction factors required for these conversions, obtained from weighted linear and nonlinear regression analyses presented elsewhere, are summarized. The accuracy of the predicted in-place strength is affected by the inherent error of the core strength measurement itself, and by the uncertainty of the various strength correction factors. It is shown that confidence intervals on the estimates of the strength correction factors obtained by regression analysis underestimate the true model error because the underlying models are imperfect. Instead, the accuracy of the strength correction factors is determined by a weighted regression analysis of ratios of observed-to-predicted values which accounts for the non-uniform variances of the dependent and independent variables. The coefficient of variation of the in-place strength predicted from a test of a 100 or 150 mm diameter core is between 4 and 5.5.%. If the in-place strength is predicted from a test of a 50 mm diameter core, the coefficient of variation of the predicted in-place strength is approximately 12.5%. These error estimates do not account for possible variation of in-place strength throughout the volume of the element being cored.     

Thermal characterisation of a tungsten magnetoresistive heat switch

A magnetoresistive heat switch has been developed to improve the performance of our flight-worthy cryogen-free ADR. We have characterised the switch’s thermal conductivity in the temperature range 0.3-4 K under an applied magnetic field of 1.8 T for two tungsten samples of different purity. The results are discussed relating to the key aspects of semi-classical magnetoresistance theory. We show that crystal purity has a strong effect on switch performance and magnetoresistive effect. Our findings are verified by comparison to results obtained by other authors. The measured switching ratio for our best sample is 1.75 × 10⁴ at 1.5 K and 1.51 × 10⁴ at 4.26 K. The lattice conductivity remains dominated by the electronic conductivity in the investigated range of temperatures under an applied magnetic field of 1.8 T. In order for the lattice conductivity to dominate a purity of >99.999% would be required.     

Assessing the Impacts of Nutrient Load Uncertainties on Predicted Truckee River Water Quality

This study examined the effects of uncertain model boundary conditions on dissolved oxygen (DO) predictions for the lower Truckee River, Nevada using an augmented version of the EPA’s Water Quality Analysis Simulation Program Version 5 (WASP5) that included periphyton, or attached algae, in eutrophication kinetics. Uncertainty analyses were performed on selected organic nitrogen (ON) and carbonaceous biochemical oxygen demand boundary conditions using Monte Carlo techniques. The stochastic model was run using boundary concentrations assigned from observed probability distributions. Ranges of simulated values were used to construct confidence intervals, the magnitudes of which indicated the uncertainty associated with model predictions. Uncertainty in agricultural ditch return concentrations had minimal effects on in-stream model predictions, as predicted values of daily minimum and maximum DOs, daily average ON, and periphyton biomass all failed to show significant variability as a result of ditch concentration uncertainty. This result indicates that while ditch return nutrient loads are not trivial, their exact concentrations are not needed to make relatively accurate predictions of in-stream DO. However, uncertainty in the upstream ON boundary did result in significant uncertainty during summer months with regard to in-stream model predictions of ON, periphyton biomass, and DO. The model is clearly more sensitive to changes in this boundary than to changes in agricultural ditch concentrations.     

Transduction properties of tracheal stretch receptors

1. Using single fibre vagal afferent recording, we have studied the behavior of slowly adapting stretch receptors located in an isolated, in situ, segment of the trachea in dogs. Responses to positive and negative steady and oscillating transmural pressures were investigated. 2. Seventy-eight per cent of the receptors studied were tonically active at resting tracheal volume. Ninety per cent showed a more pronounced response to positive than to negative transmural pressures. 3. During pressure oscillations the majority of the receptors had a higher discharge frequency at any given pressure during the ascending phase of the pressure wave than at the same pressure under static conditions. During most of the ensuing descent of pressure toward zero the discharge frequency led transmural pressure. 4. With increasing frequency of oscillation the differences from the static responses increased (dP/dt sensitivity), especially during the ascending limb of the pressure oscillation (rectifying behavior). 5. In a small number of receptors, discharge frequency lagged behind transmural pressure or was in phase with it ("no loop" pattern). 6. In three cases the same receptor exhibited dP/dt sensitivity during positive pressure oscillations, whereas discharge frequency lagged behind pressure during negative pressure oscillations. This indicates that the lack of dP/dt sensitivity exhibited under negative pressure conditions does not represent an intrinsic property of these receptors, but reflects some aspect of their mechanical arrangement within the airway wall. 7. THESE PATTERNS OF RESPONSE ARE DISCUSSed in terms of intrinsic and extrinsic characteristics of the receptors. 8. The physiological implications of stretch receptor behaviour are also considered.     

Association between bovine leukemia virus, production, and population age in Michigan dairy herds

The objective of this study was to determine the herd-level effect of bovine leukemia virus (BLV) infection on dairy production, culling, and cow longevity. During routine herd testing, Dairy Herd Improvement Association technicians collected milk samples from about 40 cows from each of 104 randomly selected Michigan dairy herds averaging ≥120 milking cows and 11,686 kg of milk/yr. Milk samples were analyzed for the presence of anti-BLV antibodies by ELISA, and herd- and lactation-specific estimates of BLV prevalence were computed to determine which were the most predictive of herd milk production, culling rate, and cow longevity (proportion of cows in their third or greater lactation). On this basis, the herd BLV index (an unweighted mean BLV prevalence rate for lactation number 1, 2, 3, and ≥4) was selected as the measure of BLV prevalence that was the most highly associated with BLV economic impact. Step-down multivariate analysis was used to determine the extent to which any of 19 herd-level management variables may have confounded the association of BLV index and measures of herd economic impact (milk production and cow longevity). The BLV index was not associated with the 12-mo culling rate, but was negatively associated in the final multivariable model with the proportion of cows that were ≥third lactation, and was negatively associated with herd milk production. In summary, increased prevalence of BLV within Michigan dairy herds was found to be associated with decreased herd milk production and decreased cow longevity. Our results provide evidence that BLV infection is associated with herd-level economic impacts in high-performing dairy herds.     

Radiation protection concepts and quantities for the occupational exposure to cosmic radiation.

For the purposes of dose limitation and dose control, the harm, or detriment, of exposure to radiation is assessed by the quantity effective dose. Effective dose is evaluated by the application of factors to the averaged absorbed dose in the organs and tissues of the body. Radiation monitoring instruments are generally calibrated in terms of the quantity ambient dose equivalent which is defined in a simple spherical phantom. The relationship of these quantities is described. Requirements for the radiation protection of aircraft crew are given in the European Union Council Directive 96/29/EURATOM. There are requirements to assess the exposure of aircraft crew, to inform them of health risks, to reduce higher doses, and to control the dose to the fetus. There are no explicit dose limits, other than a dose objective to be applied to the exposure of the fetus, and no requirements for designation of areas or classification of workers. There are significant differences between the exposure condition of aircraft crew and workers in most other industries where there is occupational exposure to radiation. There are greater ranges of radiation types and energy, and there are different dose distributions and characteristics of the working populations. However, the field intensity is predictable and, with the exception of rare solar events, there is no risk of significant unexpected exposures. Dose assessment is anticipated to be by folding staff roster information with estimates of route doses, since there is little variability of dose rate within an aircraft. Route doses, which may be either an agreed average value for a given airport pairing and aircraft type, or be flight specific, will be closely linked to measured values. Requirements as to the accuracy of dose assessment should be applied which are broadly similar to those used in individual monitoring generally.