Surface Cathepsin B Protects Cytotoxic Lymphocytes from Self-destruction after Degranulation

The granule exocytosis cytotoxicity pathway is the major molecular mechanism for cytotoxic T lymphocyte (CTL) and natural killer (NK) cytotoxicity, but the question of how these cytotoxic lymphocytes avoid self-destruction after secreting perforin has remained unresolved. We show that CTL and NK cells die within a few hours if they are triggered to degranulate in the presence of nontoxic thiol cathepsin protease inhibitors. The potent activity of the impermeant, highly cathepsin B–specific membrane inhibitors CA074 and NS-196 strongly implicates extracellular cathepsin B. CTL suicide in the presence of cathepsin inhibitors requires the granule exocytosis cytotoxicity pathway, as it is normal with CTLs from gld mice, but does not occur in CTLs from perforin knockout mice. Flow cytometry shows that CTLs express low to undetectable levels of cathepsin B on their surface before degranulation, with a substantial rapid increase after T cell receptor triggering. Surface cathepsin B eluted from live CTL after degranulation by calcium chelation is the single chain processed form of active cathepsin B. Degranulated CTLs are surface biotinylated by the cathepsin B–specific affinity reagent NS-196, which exclusively labels immunoreactive cathepsin B. These experiments support a model in which granule-derived surface cathepsin B provides self-protection for degranulating cytotoxic lymphocytes

Measurement of adsorption of a single component from the liquid phase : modelling investigation and sensitivity analysis

In this work, we consider an alternative approach for the measurement of adsorption from the liquid phase. Consider a mixture consisting of a non-adsorbed component (B) and an adsorbed component (A) present at some low concentration. Initially, a feed of component B only flows through a column packed with an adsorbent. Then, the feed is switched to the mixture of A and B. As soon as the mixture enters the column, there will be a reduction in the outlet flow rate as component A leaves the liquid phase and passes into the adsorbed phase. There are three stages to this work. The first is to develop overall and component balances to show how the amount adsorbed of component A can be determined from the variation in the column outlet flow rate. The second is to determine the actual variation in the column outlet flow rate for both plug flow and axial-dispersed plug flow. The final stage is to consider the suitability of a gravity-fed system to deliver the feed to the column. An analysis of the results shows that the experimental arrangement should be able to accurately monitor adsorption from the liquid phase where the mass fraction of the solute is of the order of 1%: the limiting experimental factor is how constant the volumetric flow rate of the liquid feed can be maintained

Improved model for the analysis of the Heat Release Rate (HRR) in Compression Ignition (CI) engines

The accuracy of the Heat Release Rate (HRR) model of Internal Combustion Engines (ICEs) is highly depended on the ratio of specific heats, gamma (γ). Previous γ models were largely expressed as functions of temperature only. The effects of the excess air ratio (λ) and the Exhaust Gas Recirculation (EGR) rate on γ were neglected in most of the existing γ functions. Furthermore, previous HRR models were developed for stoichiometric or near – stoichiometric air - fuel mixtures in an engine condition. However, Compression Ignition (CI) engines operate over a wide range of λ. No work has been done to model the HRR of CI engines under non – stoichiometric conditions. Also, no work has been done to investigate the accuracy of existing γ functions specifically with respect to the modelling of the HRR of CI engines for non – stoichiometric conditions. The aim of this work was to develop an improved HRR model for the analysis of the HRR of CI engines for non – stoichiometric conditions (λ>1). In this work, a modified γ(T,λ), was used to model the HRR of a 96 kW, multiple fuel injection, Euro V, Direct Injection (DI) engine. The modified HRR model (Leeds HRR model) predicted the fuel consumption of the engine with an average error of 1.41% confirming that the accuracy of the HRR model of CI engines is improved by using γ(T,λ). The typical average error in the prediction of the other models was 16%. The much improved HRR model leads to more accurate prediction of fuel consumption, which enables the development of and enhances better fuel consumption management strategies for engines and fuels. It was also ascertained in this work that EGR has insignificant effect on the HRR of CI engines at low and medium loads

Bioorg. Med. Chem. Lett.

Based on bifunctional diketopiperazines as templates and m- aminomethyl-phenylalanine as arginine mimetic, we have synthesized a new class of structurally related dibasic tryptase inhibitors with systematically increasing spacer length. These compounds were used to scan the distance between the active sites of two neighboring subunits of the beta- tryptase tetramer. The K-i-values obtained are a function of the distance between the terminal amino groups and indicate optimal binding of inhibitors with 29-31 bonds between the amino groups. These experimental data are in full agreement with predictions derived from a novel modeling program that allows the docking of bivalent ligands. (C) 2002 Elsevier Science Ltd. All rights reserved