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PubMed2002

De novo designed peptide-based amyloid fibrils.

Identification of therapeutic strategies to prevent or cure diseases associated with amyloid fibril deposition in tissue (Alzheimer's disease, spongiform encephalopathies, etc.) requires a rational understanding of the driving forces involved in the formation of these organized assemblies rich in beta-sheet structure. To this end, we used a computer-designed algorithm to search for hexapeptide sequences with a high propensity to form homopolymeric beta-sheets. Sequences predicted to be highly favorable on this basis were found experimentally to self-associate efficiently into beta-sheets, whereas point mutations predicted to be unfavorable for this structure inhibited polymerization. However, the property to form polymeric beta-sheets is not a sufficient requirement for fibril formation because, under the conditions used here, preformed beta-sheets from these peptides with charged residues form well defined fibrils only if the total net charge of the molecule is +/-1. This finding illustrates the delicate balance of interactions involved in the formation of fibrils relative to more disordered aggregates. The present results, in conjunction with x-ray fiber diffraction, electron microscopy, and Fourier transform infrared measurements, have allowed us to propose a detailed structural model of the fibrils.

Algorithms↗
PubMed1996

Overhead transparency skills for perioperative nurse educators.

Successful design of creative overhead transparencies should be part of the instructional repertoire of perioperative educators. Personal computers and user-friendly software have revolutionized overhead transparencies' dynamic, imaginative production. This article reviews the advantages and disadvantages of overhead projection, presents practical suggestions for generating and using transparencies, and displays computer designed examples.

Audiovisual Aids↗
PubMed2004

A molecularly imprinted catalyst designed by a computational approach in catalysing a transesterification process.

A computational approach was developed to optimize the monomer formulation of molecularly imprinted catalysts. A virtual library of the intermediates of a lipase-catalysed transesterification process was constructed using Chem3D software with p-nitrophenyl acetate as substrate. The energies of the intermediates were minimized using the semi-empirical MOPAC method with the most stable intermediate expected to lead to a higher turn over rate. According to the optimization results, a MIC was prepared by co-polymerising 4(5)-vinylimidazole and itaconic acid with trimethylpropanol trimethacrylate micro spheres in the presence of p-nitrophenyl acetate. The MIC achieved of the transesterification process between p-nitrophenyl acetate and hexanol with a turn over rate of 26.2 min(-1), and showed substrate specificity towards its template with a 6.5-fold preference for p-nitrophenyl acetate over p-nitrophenyl salicylate.

Acetates↗
PubMed2004

Medicine without drugs--a new direction for application of nanotechnology.

A working model of direct computer-organism interaction is described. The model is based on the understanding of the ways/modes, by which information is transmitted in the living organism. Information is transmitted in an organism by different ways. Communication between (among) the streams of different modes of information is provided by particular natural mechanisms--transformers and interconnectors. The model suggests that the functions of the cells, organs and systems of an organism can be monitored, controlled and governed directly by means of nano-computers. The application of a computer enables one to provide early diagnostics and successful treatment using specifically designed computer programs instead of, or in conjunction with, medications or surgery. The computer-organism interaction is being achieved through an effective engagement and interaction of the streams of computer generated information with the streams of information naturally transmitted in the organism.

Biotechnology↗
PubMed1992

The ergonomic analysis of a trauma resuscitation room.

Ergonomics is the practical and scientific study of people in relation to their working environment. We describe its application to the operation of a trauma resuscitation room. We used specifically designed computer software. This methodology enables a unique and objective assessment of the design and operation of a clinical system. It may be particularly applicable to other hospital areas where the efficient interaction of staff, patients and equipment is crucial to the optimal clinical outcome.

Equipment and Supplies, Hospital↗
PubMed1989

Cognitive performance deficits in a simulated climb of Mount Everest: Operation Everest II.

Cognitive function at simulated altitude was investigated in a repeated-measures, within-subject study of performance by seven volunteers in a hypobaric chamber, in which atmospheric pressure was systematically lowered over a period of 40 d to finally reach a pressure equivalent to 8,845 m, the approximate height of Mount Everest. The portable cognitive test battery used, Automated Performance Test System (APTS), was specifically designed for field research under adverse environmental conditions as evidenced by compact computer design; automated test administrations, data storage, and retrieval; psychometric properties of stability and reliability; and factorial richness. Significant impairments of cognitive function were seen for three of the five tests in the battery; on two tests, grammatical reasoning and pattern comparison, every subject showed a substantial decrement. The results are discussed in terms of the impact of altitude on specific aspects of cognitive function and the importance of having sensitive and reliable instruments to monitor such effects.

Adult↗
PubMed2004

Periplasmic binding proteins: a versatile superfamily for protein engineering.

The diversity of biological function, ligand binding, conformational changes and structural adaptability of the periplasmic binding protein superfamily have been exploited to engineer biosensors, allosteric control elements, biologically active receptors and enzymes using a combination of techniques, including computational design. Extensively redesigned periplasmic binding proteins have been re-introduced into bacteria to function in synthetic signal transduction pathways that respond to extracellular ligands and as biologically active enzymes.

Computer-Aided Design↗
PubMed2001

Optimizing free fibular grafting in femoral head osteonecrosis: the Ioannina aiming device.

The extracapsular placement of a vascularized fibular graft in the subchondral region of the femoral head now is a widely accepted method for treating patients with osteonecrosis of the femoral head. The effectiveness of the fibular graft seems to be dependent on precise placement in a biologically and anatomically relevant site within the femoral head. The current authors present the Ioannina technique for application of a new computer-aided design and computer-aided manufacturing process in the treatment of osteonecrosis of the femoral head using free vascularized fibular transplantation. The objective was to develop a computer-assisted design and manufacturing system for an accurate and easier approach to the necrotic area in the femoral head. The Ioannina technique uses serial computed tomography scans of the proximal femur to identify the configuration of the proximal femur, and the size, location, and configuration of the lesion using a computer-aided design and computer-aided manufacturing process. Optimal graft placement is determined and a guide wire canal is drilled into an patient-specific aiming device. In this process, identification of the optimal graft location is related to achieving that location surgically. The more arbitrary placement of the graft during conventional fibular graft surgery leads to accurate graft placement in only 55% of the patients, whereas the use of the patient-specific Ioannina aiming device resulted in optimal graft placement in 89% of the patients.

Bone Transplantation↗
PubMed2003

Neurocranial suture autotransplantation and periosteal dura stripping to provide a passive growth site in craniosynostosis--a case report.

AIM: The behaviour of a neurocranial suture autograft in a plagiocephalic infant is described. PATIENT AND METHODS: In a 7-month-old girl, born with right-sided unicoronal synostosis, part of the left-sided unicoronal suture was transplanted to the right-sided synostosectomy site. Also, in the pathological area, the periosteal 'layer' of the dura was surgically removed. The suture autotransplantation was integrated into the classical concept of radical remodelling, planned in a computer design environment. Growth of the suture was monitored by CT. RESULTS: Suture patency and osseous growth within the autograft could be demonstrated over a 1-year period. CONCLUSION: Neurocranial suture autotransplantation together with the prohibition of fusion-inducing dural signals seems to be a promising technique in the treatment of certain premature synostoses. This warrants a prospective clinical trial.

Bone Transplantation↗
PubMed2003

Natural gas flow computer with open architecture using intelligent instrumentation and field bus.

A new approach to natural gas flow computer design is presented in this paper. The developed system runs on a personal computer and employs the state-of-the-art mathematical models for corrections of some aspects of fluid flow dynamics, as well as for compressible behavior of gaseous fluid considerations. Orifice plates were used as primary elements. Measurements were performed through intelligent sensors. Results of the system metrological tests are also presented.

Journal Article↗
PubMed2004

Characterization of the folding energy landscapes of computer generated proteins suggests high folding free energy barriers and cooperativity may be consequences of natural selection.

To determine the extent to which protein folding rates and free energy landscapes have been shaped by natural selection, we have examined the folding kinetics of five proteins generated using computational design methods and, hence, never exposed to natural selection. Four of these proteins are complete computer-generated redesigns of naturally occurring structures and the fifth protein, called Top7, has a computer-generated fold not yet observed in nature. We find that three of the four redesigned proteins fold much faster than their naturally occurring counterparts. While natural selection thus does not appear to operate on protein folding rates, the majority of the designed proteins unfold considerably faster than their naturally occurring counterparts, suggesting possible selection for a high free energy barrier to unfolding. In contrast to almost all naturally occurring proteins of less than 100 residues but consistent with simple computational models, the folding energy landscape for Top7 appears to be quite complex, suggesting the smooth energy landscapes and highly cooperative folding transitions observed for small naturally occurring proteins may also reflect the workings of natural selection.

Computational Biology↗
PubMed2006

Advanced surgical guidance technology: a review.

To maximize the outcome of implant placement, the use of advanced radiographic procedures such as computerized tomography, along with fabrication of surgical guides, has been advocated to inform surgeons of ideal implant location. More recently, simulation computer software has been introduced to view radiographic images and test potential implant locations. Yet, surgical guides are processed based on ideal tooth position, with little consideration for underlying anatomical limitations, which creates a disconnection between diagnostic planning and surgical restrictions. In response to this "missing link," computer-assisted design and computer-assisted manufacturing, as well as real-time surgical navigation were recently developed to obtain fully integrated surgical and prosthetic planning. Today, there are several technologies available, but, to our knowledge, a systematic assessment of surgical guidance has not yet been performed. Therefore, the aims of this review are to introduce advanced radiographic and software modalities, and present a detailed assessment of computer-assisted design and computer-assisted manufacturing methods and surgical navigation.

Computer-Aided Design↗
PubMed2006

Use of CAD/CAM technology to fabricate a removable partial denture framework.

This article reports on the first patient-fitted chromium cobalt removable partial denture framework produced by computer-assisted design, computer-assisted manufacture and rapid prototype technologies. Once the dental cast was scanned, virtual surveying and design of the framework on a 3-dimensional computer model was accomplished. A rapid prototype machine was used for direct fabrication of the alloy framework. Traditional finishing techniques were applied, the framework was assessed by a clinician in a conventional manner, fitted to the patient, and judged to be satisfactory by both the patient and clinician.

Aged↗
PubMed1996

Computational combinatorial ligand design: application to human alpha-thrombin.

A new method is presented for computer-aided ligand design by combinatorial selection of fragments that bind favorably to a macromolecular target of known three-dimensional structure. Firstly, the multiple-copy simultaneous-search procedure (MCSS) is used to exhaustively search for optimal positions and orientations of functional groups on the surface of the macromolecule (enzyme or receptor fragment). The MCSS minima are then sorted according to an approximated binding free energy, whose solvation component is expressed as a sum of separate electrostatic and nonpolar contributions. The electrostatic solvation energy is calculated by the numerical solution of the linearized Poisson-Boltzmann equation, while the nonpolar contribution to the binding free energy is assumed to be proportional to the loss in solvent-accessible surface area. The program developed for computational combinatorial ligand design (CCLD) allows the fast and automatic generation of a multitude of highly diverse compounds, by connecting in a combinatorial fashion the functional groups in their minimized positions. The fragments are linked as two atoms may be either fused, or connected by a covalent bond or a small linker unit. To avoid the combinatorial explosion problem, pruning of the growing ligand is performed according to the average value of the approximated binding free energy of its fragments. The method is illustrated here by constructing candidate ligands for the active site of human alpha-thrombin. The MCSS minima with favorable binding free energy reproduce the interaction patterns of known inhibitors. Starting from these fragments, CCLD generates a set of compounds that are closely related to high-affinity thrombin inhibitors. In addition, putative ligands with novel binding motifs are suggested. Probable implications of the MCSS-CCLD approach for the evolving scenario of drug discovery are discussed.

Binding Sites↗
PubMed2004

Contributions of amino acid side chains to the kinetics and thermodynamics of the bivalent binding of protein L to Ig kappa light chain.

Protein L is a bacterial surface protein with 4-5 immunoglobulin (Ig)-binding domains (B1-B5), each of which appears to have two binding sites for Ig, corresponding to the two edges of its beta-sheet. To verify these sites biochemically and to probe their relative contributions to the protein L-Ig kappa light chain (kappa) interaction, we compared the binding of PLW (the Y47W mutant of the B1 domain) to that of mutants designed to disrupt binding to sites 1 and 2, using gel filtration, BIAcore surface plasmon resonance, fluorescence titration, and solid-phase radioimmunoassays. Gel filtration experiments show that PLW binds kappa both in 1:1 complexes and multivalently, consistent with two binding sites. Covalent dimers of the A20C and V51C mutants of PLW were prepared to eliminate site 1 and site 2 binding, respectively; both the A20C and V51C dimers bind kappa in 1:1 complexes and multivalently, indicating that neither site 1 nor site 2 is solely responsible for kappa binding. The A20R mutant was designed computationally to eliminate site 1 binding while preserving site 2 binding; consistent with this design, the A20R mutant binds kappa in 1:1 complexes but not multivalently. To probe the contributions of amino acid side chains to binding, we prepared 75 point mutants spanning nearly every residue of PLW; BIAcore studies of these mutants revealed two binding-energy "hot spots" consistent with sites 1 and 2. These data indicate that PLW binds kappa at both sites with similar affinities (high nanomolar), with the strongest contributions to the binding energy from Tyr34 (site 2) and Tyr36 (site 1). Compared to other protein-protein complexes, the binding is insensitive to amino acid substitutions at these sites, consistent with the large number of main chain interactions relative to side chain interactions. The strong binding of protein L to Ig kappa light chains of various species may result from the ambidextrous binding of the B1-B5 domains and the unimportance of specific side chain interactions.

Alanine↗