Pegylated peptides. V. Carboxy-terminal PEGylated analogs of growth hormone-releasing factor (GRF) display enhanced duration of biological activity in vivo

In the present study, human growth hormone-releasing factor (hGRF) and analogs were successfully pegylated at the carboxy-terminus using a novel solid- and solution-phase strategy. Following synthesis, these pegylated hGRF analogs were evaluated for in vitro and in vivo biological activity. Specifically, hGRF (1-29)-NH2, [Ala15]-hGRF (1-29)-NH2, [desNH2Tyr1, D-Ala2, Ala15]-hGRF(1-29)-NH2 and [His1, Val2, Gln8, Ala15, Leu27]-hGRF(1-32)-OH were each C-terminally extended using a Gly-Gly-Cys-NH2 spacer (previously demonstrated not to alter intrinsic biological activity), and then monopegylated via coupling to an activated dithiopyridyl-PEG reagent. PEG moieties of 750, 2000, 5000 or 10,000 molecular weight (MW) were examined to determine the effect of polymer weight on activity. Initial biological evaluations in vitro revealed that all C-terminally pegylated hGRF analogs retained high growth hormone (GH)-releasing potencies, regardless of the MW of PEG polymer employed. Two of these pegylated hGRF analogs, [desNH2Tyr1, D-Ala2, Ala15]-hGRF (1-29)-Gly-Gly-Cys(NH2)-S-Nle-PEG5000 and [His1, Val2, Gln8, Ala15, Leu27]-hGRF(1-32)-Gly-Cys(NH2)-S-Nle-PEG5000, were subsequently evaluated in both pig and mouse models and found to be highly potent (in vivo potency range = 12-55-fold that of native hGRF). Relative to their non-pegylated counterparts, these two pegylated hGRF analogs exhibited enhanced duration of activity.     

Multi-input,multi-output flight control system design for the YF-16 using nonlinear QFT and pilot compensation

Nonlinear quantitative feedback theory (QFT) and pilot compensation techniques are used to design a 2 × 2 flight control system for the YF-16 aircraft over a large range of plant uncertainty. The design is based on numerical input-output time histories generated with a FORTRAN implemented nonlinear simulation of the YF-16. The first step of the design process is the generation of a set of equivalent linear time-invariant (LTI) plant models to represent the actual nonlinear plant. It has been proven that the solution to the equivalent plant problem is guaranteed to solve the original nonlinear problem. Standard QFT techniques are then used in the design synthesis based on the equivalent plant models. A detailed mathematical development of the method used to develop these equivalent LTI plant models is provided. After this inner-loop design, pilot compensation is developed to reduce the pilot's workload. This outer-loop design is also based on a set of equivalent LTI plant models. This is accomplished by modelling the pilot with parameters that result in good handling qualities ratings, and developing the necessary compensation to force the desired system responses.     

The ability of the rat to metabolize myristoyl-methionine: an acylamino acid with potentially useful antibacterial properties

Two experiments with Sprague Dawley rats tested their ability to hydrolyse myristoyl-methionine (M-M) into myristic acid and L-methionine (M). In the first experiment, lasting for 3 days. male rats were orally administered [9,10-3H]myristoyl-L-[35S]methionine. The recovery of radioactivity was approximately 90% for both isotopes; 19% of the administered 3H was recovered in the urine and 16% in the faeces, while the recovered 35S activity was 13 and 12%, respectively. The balance of the radioactivity was found among the tissues, organs and blood. In the second experiment, male and female rats received soybean-based diets which were supplemented with either 0.305% M-M or 0.2% M (both diets contained equal amounts of M) for periods up to 4 weeks. The growth rate of the rats receiving the 0.305% M-M diets was slightly slower than that for the rats on the 0.2% M diet, but the difference was not statistically significant (P > 0.05). The M-M rats had a transitory decrease in feed consumption, suggesting that palatability may have contributed to the growth difference and that a somewhat greater amount of M-M was necessary for the rat to attain the same growth rate as that produced by 0.2% M. When the amount of dietary M-M was increased to 3.05% M-M, a greater reduction in feed consumption and body weight gain was observed. This latter diet was an initial attempt to study the potential toxicity of M-M. None of the haematological, clinical chemistry or organ weight data suggested that M-M was overtly toxic per se, but longer-term feeding studies are needed to evaluate the potential toxicity of M-M more fully.     

International Working Group on Assurance Cases (for Security)

Critical systems are aptly named - from electric power to water and gas to the telephone system and the Internet, they're all critical to some aspect of our daily lives. We're a networked society and as such, it's important to both know whether critical systems are trustworthy and be able to communicate, review, and debate the level of trust achieved in them. In the safety domain, explicit safety cases are increasingly required by law, regulations, and standards. In this article, we outline what a small, international group of experts, spanning various disciplines in safety, security, reliability, and critical infrastructure, been doing with the International Working Group on Assurance Cases (for Security), what we hope to achieve, and where we go next.     

The Effect of Moisture Content in Epoxy Film Adhesives on their Performance. II. T-Peel and 105°C Lap Shear Strength

The benefits of adhesively bonded structures are well known. However, the most significant factor limiting the extensive application of metal bonding in primary aerospace structures is the prevailing lack of confidence in its long term durability under hostile environmental conditions.^1,2     

Single-Phase Permanent-Magnet Motor Analysis

A unified theoretical approach is presented for the calculation of the performance of the single-phase capacitor-start permanent-magnet (PM) ac line-start motor. The earlier work of Chang and of Finch and Lawrenson on capacitor reluctance motors is extended. As far as possible, a common set of reference frame transformations for steady-state, transient, and asynchronous performance is also provided, permitting the use of all the theory developed for the analysis of the balanced polyphase PM motor. A new approximate technique is given for estimating the average asynchronous torque/speed curve from computed acceleration curves.