Structural plasticity of the cyclic-cystine-knot framework: implications for biological activity and drug design

The cyclotide family of plant proteins is of interest because of their unique topology, which combines a head-to-tail cyclic backbone with an embedded cystine knot, and because their-remarkable chemical and biological properties make them ideal candidates as grafting templates for biologically active peptide epitopes. The present Study describes the first steps towards exploiting the cyclotide framework by synthesizing and structurally characterizing two grafted analogues of the cyclotide kalata B1. The modified peptides have polar or charged residues substituted for residues that form part of a surface-exposed hydrophobic patch that plays a significant role in the folding and biological activity of kalata B1. Both analogues retain the native cyclotide fold, but lack the undesired haemolytic activity of their parent molecule, kalata B1. This finding confirms the tolerance of the cyclotide framework to residue Substitutions and opens up possibilities for the Substitution of biologically active peptide epitopes into the framework.

The impact of computer display height and desk design on 3D posture during information technology work by young adults

Computer display height and desk design to allow forearm support are two critical design features of workstations for information technology tasks. However there is currently no 3D description of head and neck posture with different computer display heights and no direct comparison to paper based information technology tasks. There is also inconsistent evidence on the effect of forearm support on posture and no evidence on whether these features interact. This study compared the 3D head, neck and upper limb postures of 18 male and 18 female young adults whilst working with different display and desk design conditions. There was no substantial interaction between display height and desk design. Lower display heights increased head and neck flexion with more spinal asymmetry when working with paper. The curved desk, designed to provide forearm support, increased scapula elevation/protraction and shoulder flexion/abduction.

Effect of anode material and cavity design on the performance of microcavity OLEDs

We report on the effect of the replacement of the conventional ITO anode with the semitransparent metallic material on the performance of microcavity OLEDs. We performed comprehensive simulations of the emission from microcavity OLEDs consisting of widely used organic materials, N,N′-di(naphthalene-1- yl)-N,N′-diphenylbenzidine (NPB) as a hole transport layer and tris (8-hydroxyquinoline) (Alq3) as emitting and electron transporting layer. Silver and LiF/Al were considered as a cathode, while metallic (Au and Ag) anode was used and simulations were performed on devices with both the metallic and conventional ITO anode. The electroluminescence emission spectra, electric field distribution inside the device, carrier density, recombination rate and exciton density were calculated as a function of the position of the emission layer. The results show that the metallic anode enhances light output and that optimum emission from a microcavity OLED is achieved when the position of the recombination region is aligned with the antinode of the standing wave inside the cavity. The microcavity OLED devices with Ag/Ag and Ag/Au mirrors were fabricated and characterized. The experimental results have been compared to the simulations and the influence of the different anode, emission region width and position on the performance of microcavity OLEDs was discussed.

Hybrid knowledge representation in a blackboard KBS for liquid retaining structure design

This paper highlights the importance of design expertise, for designing liquid retaining structures, including subjective judgments and professional experience. Design of liquid retaining structures has special features different from the others. Being more vulnerable to corrosion problem, they have stringent requirements against serviceability limit state of crack. It is the premise of the study to transferring expert knowledge in a computerized blackboard system. Hybrid knowledge representation schemes, including production rules, object-oriented programming, and procedural methods, are employed to express engineering heuristics and standard design knowledge during the development of the knowledge-based system (KBS) for design of liquid retaining structures. This approach renders it possible to take advantages of the characteristics of each method. The system can provide the user with advice on preliminary design, loading specification, optimized configuration selection and detailed design analysis of liquid retaining structure. It would be beneficial to the field of retaining structure design by focusing on the acquisition and organization of expert knowledge through the development of recent artificial intelligence technology. (C) 2003 Elsevier Ltd. All rights reserved.

Design, Synthesis, Potency and Cytoselectivity of Anticancer Agents Derived by Parallel Synthesis from alpha-Aminosuberic Acid

Chemotherapy in the last century was characterized by cytotoxic drugs that did not discriminate between cancerous and normal cell types and were consequently accompanied by toxic side effects that were often dose limiting. The ability of differentiating agents to selectively kill cancer cells or transform them to a nonproliferating or normal phenotype could lead to cell- and tissue-specific drugs without the side effects of current cancer chemotherapeutics. This may be possible for a new generation of histone deacetylase inhibitors derived from amino acids. Structure-activity relationships are now reported for 43 compounds derived from 2-aminosuberic acid that kill a range of cancer cells, 26 being potent cytotoxins against MM96L melanoma cells (IC50 20 nM-1 mu M), while 17 were between 5- and 60-fold more selective in killing MM96L melanoma cells versus normal (neonatal foreskin fibroblasts, NFF) cells. This represents a 10- to 100-fold increase in potency and up to a 10-fold higher selectivity over previously reported compounds derived from cysteine (J. Med. Chem. 2004, 47, 2984). Selectivity is also an underestimate, because the normal cells, NFF, are rarely all killed by the drugs that also induce selective blockade of the cell cycle for normal but not cancer cells. Selected compounds were tested against a panel of human cancer cell lines (melanomas, prostate, breast, ovarian, cervical, lung, and colon) and found to be both selective and potent cytotoxins (IC50 20 nM-1 mu M). Compounds in this class typically inhibit human histone deacetylases, as evidenced by hyperacetylation of histones in both normal and cancer cells, induce expression of p21, and differentiate surviving cancer cells to a nonproliferating phenotype. These compounds may be valuable leads for the development of new chemotherapeutic agents.