Selective chemical functional probes of granzymes A and B reveal granzyme B is a major effector of natural killer cell-mediated lysis of target cells

The mechanism of target cell lysis in cytotoxic lymphocyte-mediated death is not well understood, and the role of granzymes in this process is unclear. Chemical functional probes were thus prepared for the major granzymes A and B to deconvolute their role in natural killer cell-mediated lysis of target cells. These biotinylated and substrate specificity-based diphenyl phosphonates allowed facile evaluation of selectivity through activity-based profiling in cell lysates and intact cells. Both inhibitors were found to be extremely selective in vitro and in cells. Use of these inhibitors in cell-based assays revealed granzyme A to be a minor effector and granzyme B to be a major effector of target cell lysis by natural killer cells. These studies indicate that the proapoptotic granzyme B functions also as a pronecrotic effector of target cell death.     

The relationship between 19F and 13C substituent chemical shifts and electron densities. 2—p-phenylacetyl fluorides

The ¹⁹F substituent chemical shifts (SCS) of a series of para-phenylacetyl fluorides (X? Ph? CH₂? COF) are reported and compared with the related benzoyl fluoride series (X? Ph? COF). A dual substituent parameter analysis of the results for the new series shows that both inductive and resonance effects are reduced by one third when compared with the benzoyl fluorides. ¹³C shifts for the side chain carbonyl were also measured and found to follow a reversed trend in substituent effects, consistent with a pi polarization mechanism. SCS values for the fluorine and its adjacent carbon are not directly related. Ab initio (STO-3G) calculations of the carbon and fluorine electron density for this series have been compared with the appropriate SCS values. From the electron densities and the observation that the fluorine SCS values follow a normal direction, whilst those for electron densities and the observation that the fluorine SCS values follow a normal direction, whilst those for the adjacent carbon are reversed, it is concluded that fluorine SCS values (and Δqπ values) result from polarization of the C? F pi bond and do not merely monitor changes in electron density of the adjacent carbon.     

The effect of random errors on a large statistical energy analysis model

The framework of analysis known as Statistical Energy Analysis has many important applications particularly in systems where detailed information is not available. As a result of the approximations made, to simplify the calculations, random error can be introduced into the SEA model. For large systems this gives rise to uncertainty in the energy levels. It is shown that the effect of these errors on the model depends on the “shape” of the model. A compact model dominated by short paths is less affected than a model controlled by long paths. In either case the ratio of the average error in the resultant energy level to the average error in the coupling loss factor decreases as the errors increase. This means that large models may be used with confidence even when based on data that is known to be approximate.     

The prediction of sound transmission through buildings using statistical energy analysis

Measurements were carried out on a building to evaluate the uses of statistical energy analysis for determining sound transmission performance. Coupling loss factors were measured and compared with predicted values. It was found that, in general, good agreement was obtained. The coupling loss factors were also used to calculate the sound pressure level, or surface velocity, of each subsystem in the building for a number of different sources. Comparison with the measured results gave an average error of 4 dB. Some large errors were obtained but these were due mainly to the omission of airborne flanking paths from the SEA model or due to the breakdown of the theory for specific coupling loss factors.     

The measurement of structure-borne sound transmission using impulsive sources

A simple method to measure structure-borne sound transmission is described. Measurement is made of the level difference in the acceleration between two structural elements using a plastic headed hammer as a noise source. The method is at least as accurate as conventional measurements made under steady-state conditions using continuous noise sources and can be carried out with less instrumentation on site and in about a tenth of the time.The portability of the source greatly simplifies the measurements as a hammer can be used to hit structures in a wide variety of positions whereas shakers can only be used in limited situations. In addition, attaching a shaker to a wall can damage the wall surface whereas, with care, a hammer hit will not.     

Improving on Nature: Making a Cyclic Heptapeptide Orally Bioavailable

The use of peptides in medicine is limited by low membrane permeability, metabolic instability, high clearance, and negligible oral bioavailability. The prediction of oral bioavailability of drugs relies on physicochemical properties that favor passive permeability and oxidative metabolic stability, but these may not be useful for peptides. Here we investigate effects of heterocyclic constraints, intramolecular hydrogen bonds, and side chains on the oral bioavailability of cyclic heptapeptides. NMR‐derived structures, amide H–D exchange rates, and temperature‐dependent chemical shifts showed that the combination of rigidification, stronger hydrogen bonds, and solvent shielding by branched side chains enhances the oral bioavailability of cyclic heptapeptides in rats without the need for N‐methylation.