Display Platforms Research Articles

Examination of halogen substituent effects on HIV-1 integrase inhibitors derived from 2,3-dihydro-6,7-dihydroxy-1 H-isoindol-1-ones and 4,5-dihydroxy-1 H-isoindole-1,3(2 H)-diones

Using 2,3-dihydro-6,7-dihydroxy-1 H-isoindol-1-one and 4,5-dihydroxy-1 H-isoindole-1,3(2 H)-dione based HIV-1 integrase inhibitors as display platforms, we undertook a thorough examination of the effects of modifying the halogen substituents on a key benzyl ring that is hypothesized to bind in a hydrophobic pocket of the integrase·DNA complex. Data from this study suggest that in general dihalo-substituted analogues have higher potency than monohalo-substituted compounds, but that further addition of halogens is not beneficial.

Human antibody libraries: A race to engineer and explore a larger diversity

Several recombinant antibody libraries associated with different screening technologies have been generated since the first steps of antibody engineering 15 years ago, in order to isolate human monoclonal antibodies. In this race to isolate antibody with virtually any specificity, innovative strategies have been developed to clone natural antibody repertoires or to increase library diversity beyond the scope of the immune system. After the in vitro transfer of the natural diversity, the second generation of partly or completely man-designed libraries was based on the available structural data of the antibody binding. Efficient selection strategies have proven critical in exploiting the potential of a library's diversity. The development and improvement of screening methods such as phage display, yeast display, ribosome display and robotic platforms have provided innovative tools to efficiently screen and sort out the desired binding specificities of billions of antibodies. Efforts to improve diversity exploration have been mainly focused on screening conditions of display techniques and the new emerging techniques. Here we review some of these prominent approaches in the field of human recombinant antibody libraries.

Roundtable: Design and CAD Challenges for Leading-Edge Multimedia Designs

Multimedia, game, and entertainment devices have pushed the leading edge of performance, complexity, power, form factor, design cycle time, and other key aspects of ASIC design for the past several technology nodes. This roundtable brings together experts who are defining the next generation of gaming, mobile-TV, digital-home, display, and multimedia-processing platforms. The discussion spans the underlying chip architectures and roadmaps, as well as the key design, technology, and market challenges for next-generation products.

Technologies and Solutions for Data Display in the Operating Room

Recent advances in technology have led to the introduction of a variety of innovative devices, each with their own platform for data display, into the operating room (OR). While these innovative applications are expanding the traditional boundaries of the surgical space and enhancing treatment capabilities, the introduction of additional screens and displays is placing an ever-increasing load on the OR team. This review describes the main data display platforms currently available in ORs: computer monitors with CRT (cathode ray tube) or LCD (liquid crystal display) screens, suspended imaging displays, wearable computers (WC), auditory displays and tactile (haptic) displays. The different display platforms are evaluated according to their compatibility with the characteristics of the working environment (OR), the monitoring task, and the users (the surgical team). No single display configuration provides an ultimate solution for presenting patient data in the OR. A multi-sensory data display including visual, acoustic and haptic manipulation is suggested as a promising configuration for data display in the OR.

Axes of differentiation in the bower‐building cichlids of Lake Malawi

The 500-1000 cichlid species endemic to Lake Malawi constitute one of the most rapid and extensive radiations of vertebrates known. There is a growing debate over the role natural and sexual selection have played in creating this remarkable assemblage of species. Phylogenetic analysis of the Lake Malawi species flock has been confounded by the lack of appropriate morphological characters and an exceptional rate of speciation, which has allowed ancestral molecular polymorphisms to persist within species. To overcome this problem we used amplified fragment length polymorphism (AFLP) to reconstruct the evolution of species within three genera of Lake Malawi sand-dwelling cichlids that construct elaborate male display platforms, or bowers. Sister taxa with distinct bower morphologies, and that exist in discrete leks separated by only 1-2 m of depth, are divergent in both sexually selected and ecological traits. Our phylogeny suggests that the forces of sexual and ecological selection are intertwined during the speciation of this group and that specific bower characteristics and trophic morphologies have evolved repeatedly. These results suggest that trophic morphology and bower form may be inappropriate characters for delineating taxonomic lineages. Specifically the morphological characters used to describe the genera Lethrinops and Tramitichromis do not define monophyletic clades. Using a combination of behavioural and genetic characters, we were able to identify several cryptic cichlid species on a single beach, which suggests that sand dweller species richness has been severely underestimated.

Optimizing the affinity and specificity of proteins with molecular display

Affinity maturation of receptor-ligand interactions represents an important area of academic and pharmaceutical research. Improving affinity and specificity of proteins can tailor potency for both in vivo and in vitro applications. A number of different display platforms including phage display, bacterial and yeast display, ribosome display, and mRNA display can optimize protein affinity and specificity. Here, we will review the advantages and disadvantages of these molecular display methods with a focus on their suitability for protein affinity maturation.

Icosahedral virus particles as polyvalent carbohydrate display platforms.

Sugar-coated viruses behave as large dendrimeric poly(carbohydrates). Readily prepared from the icosahedral cowpea mosaic virus (one-twelfth of the structure of this scaffold is shown here, with attachment points in yellow) and electrophilic sugar derivatives, the resulting particles bind strongly to the lectin concanavalin-A, forming cross-linked networks. Measurements of binding strength demonstrate effective polyvalencies comparable to the most potent dendrimer- and polymer-based systems reported to date, with the added advantage of near atomic-resolution control over structure.

Engineering M13 for phage display

Phage display is achieved by fusing polypeptide libraries to phage coat proteins. The resulting phage particles display the polypeptides on their surfaces and they also contain the encoding DNA. Library members with particular functions can be isolated with simple selections and polypeptide sequences can be decoded from the encapsulated DNA. The technology's success depends on the efficiency with which polypeptides can be displayed on the phage surface, and significant progress has been made in engineering M13 bacteriophage coat proteins as improved phage display platforms. Functional display has been achieved with all five M13 coat proteins, with both N- and C-terminal fusions. Also, coat protein mutants have been designed and selected to improve the efficiency of heterologous protein display, and in the extreme case, completely artificial coat proteins have been evolved specifically as display platforms. These studies demonstrate that the M13 phage coat is extremely malleable, and this property can be used to engineer the phage particle specifically for phage display. These improvements expand the utility of phage display as a powerful tool in modern biotechnology.

Phosphoryltyrosyl mimetics in the design of peptide-based signal transduction inhibitors.

The central roles played by protein-tyrosine kinase (PTK)-dependent signal transduction in normal cellular regulation and homeostasis have made inappropriate or aberrant functions of certain of these pathways contributing factors to a variety of diseases, including several cancers. For this reason, development of PTK signaling inhibitors has evolved into an important approach toward new therapeutics. Since in these pathways phosphotyrosyl (pTyr) residues provide unique and defining functions either by their creation under the catalysis of PTKs, their recognition and binding by protein modules such as SH2 and phosphotyrosyl binding (PTB) domains, or their destruction by protein-tyrosine phosphatases, pTyr mimetics provide useful general starting points for inhibitor design. Important considerations in the development of such pTyr mimetics include enzymatic stability (particularly toward PTPs), high affinity recognition by target pTyr binding proteins, and good cellular bioavailability. Although small molecule, nonpeptide inhibitors may be ultimate objectives of inhibitor development, peptides frequently serve as display platforms for pTyr mimetics, which afford useful and conceptually straightforward starting points in the development process. Reported herein is a limited overview of pTyr mimetic development as it relates to peptide-based agents. Of particular interest are recent findings that highlight potential limitations of peptides as display platforms for the identification of small molecule leads. One conclusion that results from this work is that while peptide-based approaches toward small molecule inhibitor design are often intellectually satisfying from a structure-based perspective, extrapolation of negative findings to small molecule, nonpeptide contexts should be undertaken with extreme caution.

Molecular Architecture of Bacteriophage T4 Capsid: Vertex Structure and Bimodal Binding of the Stabilizing Accessory Protein, Soc

T4 encodes two dispensable proteins that bind to the outer surface of the mature capsid. Soc (9 kDa) stabilizes the capsid against extremes of alkaline pH and temperature, but Hoc (40 kDa) has no perceptible effect. Both proteins have been developed as display platforms. Their positions on the hexagonal surface lattice of gp23*, the major capsid protein, were previously defined by two-dimensional image averaging of negatively stained electron micrographs of elongated variant capsids. We have extended these observations by reconstructing cryo-electron micrographs of isometric capsids produced by a point mutant in gene 23, for both Hoc+.Soc+ and Hoc+.Soc− phages. The expected T = 13 lattice was observed, with a single Hoc molecule at the center of each gp23* hexamer. The vertices are occupied by pentamers of gp24*: despite limited sequence similarity with gp23*, the respective monomers are similar in size and shape, suggesting they may have the same fold. However, gp24* binds neither Hoc nor Soc; in situ, Soc is visualized as trimers at the trigonal points of the gp23* lattice and as monomers at the sites closest to the vertices. In solution, Soc is a folded protein (∼10% α-helix and 50–60% β sheet) that is monomeric as determined by analytic ultracentrifugation. Thus its trimerization on the capsid surface is imposed by a template of three symmetry-related binding sites. The observed mode of Soc binding suggests that it stabilizes the capsid by a clamping mechanism and offers a possible explanation for the phenotype of osmotic shock resistance.