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PubMed2004

Interactive DNA sequence and structure design for DNA nanoapplications.

DNA sequence and structure design is very important for DNA nanoapplications. A computer-aided design tool is needed for exploring DNA sequence and structure of interests before experimental synthesis, which is a time- and labor-consuming process. In this paper, an interactive DNA sequence and structure design software tool called DNA shop is proposed and implemented. The visualization tool can generate DNA structures by specifying, selecting, and moving DNA sequences around and display corresponding structures. Using the tool, DNA sequence and structure can be visually inspected in three-dimensional space before experimental studies.

Algorithms↗
PubMed2005

Computational studies and peptidomimetic design for the human p53-MDM2 complex.

The interaction between human p53 and MDM2 is a key event in controlling cell growth. Many studies have suggested that a p53 mimic would be sufficient to inhibit MDM2 to reduce cell growth in cancerous tissue. In order to design a potent p53 mimic, molecular dynamics (MD) simulations were used to examine the binding interface and the effect of mutating key residues in the human p53-MDM2 complex. The Generalized Born surface area (GBSA) method was used to estimate free energies of binding, and a computational alanine-scanning approach was used to calculate the relative effects in the free energy of binding for key mutations. Our calculations determine the free energy of binding for a model p53-MDM2 complex to be -7.4 kcal/mol, which is in very good agreement with the experimentally determined values (-6.6--8.8 kcal/mol). The alanine-scanning results are in good agreement with experimental data and calculations by other groups. We have used the information from our studies of human p53-MDM2 to design a beta-peptide mimic of p53. MD simulations of the mimic bound to MDM2 estimate a free energy of binding of -8.8 kcal/mol. We have also applied alanine scanning to the mimic-MDM2 complex and reveal which mutations are most likely to alter the binding affinity, possibly giving rise to escape mutants. The mimic was compared to nutlins, a new class of inhibitors that block the formation of the p53-MDM2 complex. There are interesting similarities between the nutlins and our mimic, and the differences point to ways that both inhibitors may be improved. Finally, an additional hydrophobic pocket is noted in the interior of MDM2. It may be possible to design new inhibitors to take advantage of that pocket.

Binding Sites↗
PubMed1995

Noninvasive tracking of coronary atherosclerosis by electron beam computed tomography: rationale and design of the Felodipine Atherosclerosis Prevention Study (FAPS).

The Felodipine Atherosclerosis Prevention Study is designed to evaluate the efficacy of the calcium antagonist felodipine ER and combined felodipine/simvastatin therapy on retarding the progression of atherosclerosis, estimated by serial changes in coronary calcium evaluated by noninvasive electron beam computed tomography. Subjects include 180 men and women aged 40 to 69 and 50 to 69 years, respectively, with moderate type IIa dyslipidemia, with either cardiovascular disease or risk factors. All subjects receive simvastatin lipid-lowering therapy, and are randomized either to felodipine or placebo for a treatment period of 2 years. Monitoring of blood chemistry, measures of lipids and apolipoproteins, blood pressure, evaluation of symptoms, and interim clinical event monitoring are done at routine follow-up visits. Baseline and 2-year follow-up electron beam computed tomography, measuring changes in total calcium score, area, and mass, evaluate the effects of intervention on the progression of calcified atherosclerosis. The results from the Felodipine Atherosclerosis Prevention Study will provide valuable information about the effect of felodipine alone and in combination with simvastatin on progression of calcified atherosclerosis evaluated noninvasively.

Aged↗
PubMed2002

The association between children's computer use and musculoskeletal discomfort.

UNLABELLED: As American children spend more time working at computers, they may be putting themselves at risk for musculoskeletal disorders and other conditions that can result from overuse. There is little research that describes the home computer use of American middle school children or that describes the prevalence of musculoskeletal discomfort in this population. This study provides a general description of the computer set-up and home use of 152 6th grade children and looks at the association between overall musculoskeletal discomfort and various ergonomic variables. METHOD: 152 6th grade children completed the Musculoskeletal Discomfort Questionnaire and a survey of home computer use. RESULTS: More than half of the children reported some musculoskeletal discomfort within the last year. This pain could be made worse by computer use. Students reported that they had three computers in their house, and that they generally did not have furniture specifically designed for computer use. There was a significant association between the number of hours on the computer and overall musculoskeletal discomfort (r = 0.19, p = 0.05). The odds ratios between having furniture designed for the computer and touch typing and musculoskeletal discomfort were borderline significant, but suggested that students without proper furniture were more likely to have musculoskeletal discomfort (OR = 1.89, 95% CI = 0.94-3.84) and that those who could touch type were less likely to have musculoskeletal discomfort (OR = 0.54, 95%, CI = 0.26-1.10), OR). CONCLUSION: American children are reporting moderate amounts of musculoskeletal discomfort and this discomfort can be associated with computer use. Risk factors associated with computer use and discomforts are similar to those reported in the adult literature. Further study is necessary to understand the similarities and differences between adult and children computer use and how to protect both from developing musculoskeletal discomfort.

Child↗
PubMed1991

Can humans think? The Ergonomics Society Lecture 1991.

For many years, computer scientists have been concerned with whether computers can think. Considerable thought, therefore, goes into designing 'thinking' computer systems and into wondering whether they really can think, or just pretend to. On the other hand, it is 'obvious' that humans can think, and therefore little thought has gone into the related question, 'Can humans think?' This paper explores the ergonomic implications of the affirmative answer. Computers get better treatment than humans, yet humans are more than machines. However, not only do designers seem to forget this, but they do not even treat users with the same respect as they would a machine.

Computer Systems↗
PubMed1999

Determination of Hounsfield value for CT-based design of custom femoral stems.

Ct and advanced computer-aided design techniques offer the means for designing customised femoral stems. Our aim was to determine the Hounsfield (HU) value of the bone at the corticocancellous interface, as part of the criteria for the design algorithm. We obtained transverse CT images from eight human cadaver femora. The proximal femoral canal was rasped until contact with dense cortical bone was achieved. The femora were cut into several sections corresponding to the slice positions of the CT images. After obtaining a computerised image of the anatomical sections using a scanner, the inner cortical contour was outlined and transferred to the corresponding CT image. The pixels beneath this contour represent the CT density of the bone remaining after surgical rasping. Contours were generated automatically at nine HU levels from 300 to 1100 and the mean distance between the transferred contour and each of the HU-generated contours was computed. The contour generated along the 600-HU pixels was closest to the inner cortical contour of the rasped femur and therefore 600 HU seem to be the CT density of the corticocancellous interface in the proximal part of cadaver femora. Generally, femoral bone with a CT density beyond 600 HU is not removable by conventional reamers. Thus, we recommend the 600 HU threshold as one of several criteria for the design of custom femoral implants from CT data.

Adult↗
PubMed2005

Rational design of dental materials using computational chemistry.

One of our primary research emphases is the rational design of biomaterials. In this effort we apply a combination of theoretical and experimental approaches, both of which contribute directly to the completion of such a project. Computational chemistry has achieved routine status in modern chemical investigations, and the state-of-the-art is briefly summarized. In such a difficult endeavor as the systematic development of biomaterials, computational chemistry is a natural partner for traditional chemists. Herein, we describe several successful applications of this synergy to the design of dental biomaterials. These include reactivity modeling, sensitization, and density. We also report preliminary progress of polymerization volume change experiments on epoxides that have been specifically designed to provide standardized results for computational analysis.

Combinatorial Chemistry Techniques↗
PubMed1997

Heuristic lipophilicity potential for computer-aided rational drug design.

In this contribution we suggest a heuristic molecular lipophilicity potential (HMLP), which is a structure-based technique requiring no empirical indices of atomic lipophilicity. The input data used in this approach are molecular geometries and molecular surfaces. The HMLP is a modified electrostatic potential, combined with the averaged influences from the molecular environment. Quantum mechanics is used to calculate the electron density function rho(r) and the electrostatic potential V(r), and from this information a lipophilicity potential L(r) is generated. The HMLP is a unified lipophilicity and hydrophilicity potential. The interactions of dipole and multipole moments, hydrogen bonds, and charged atoms in a molecule are included in the hydrophilic interactions in this model. The HMLP is used to study hydrogen bonds and water-octanol partition coefficients in several examples. The calculated results show that the HMLP gives qualitatively and quantitatively correct, as well as chemically reasonable, results in cases where comparisons are available. These comparisons indicate that the HMLP has advantages over the empirical lipophilicity potential in many aspects. The HMLP is a three-dimensional and easily visualizable representation of molecular lipophilicity, suggested as a potential tool in computer-aided three-dimensional drug design.

Drug Design↗
PubMed2006

Computational redesign of endonuclease DNA binding and cleavage specificity.

The reprogramming of DNA-binding specificity is an important challenge for computational protein design that tests current understanding of protein-DNA recognition, and has considerable practical relevance for biotechnology and medicine. Here we describe the computational redesign of the cleavage specificity of the intron-encoded homing endonuclease I-MsoI using a physically realistic atomic-level forcefield. Using an in silico screen, we identified single base-pair substitutions predicted to disrupt binding by the wild-type enzyme, and then optimized the identities and conformations of clusters of amino acids around each of these unfavourable substitutions using Monte Carlo sampling. A redesigned enzyme that was predicted to display altered target site specificity, while maintaining wild-type binding affinity, was experimentally characterized. The redesigned enzyme binds and cleaves the redesigned recognition site approximately 10,000 times more effectively than does the wild-type enzyme, with a level of target discrimination comparable to the original endonuclease. Determination of the structure of the redesigned nuclease-recognition site complex by X-ray crystallography confirms the accuracy of the computationally predicted interface. These results suggest that computational protein design methods can have an important role in the creation of novel highly specific endonucleases for gene therapy and other applications.

Base Pairing↗
PubMed2005

ProbeMaker: an extensible framework for design of sets of oligonucleotide probes.

BACKGROUND: Procedures for genetic analyses based on oligonucleotide probes are powerful tools that can allow highly parallel investigations of genetic material. Such procedures require the design of large sets of probes using application-specific design constraints. RESULTS: ProbeMaker is a software framework for computer-assisted design and analysis of sets of oligonucleotide probe sequences. The tool assists in the design of probes for sets of target sequences, incorporating sequence motifs for purposes such as amplification, visualization, or identification. An extension system allows the framework to be equipped with application-specific components for evaluation of probe sequences, and provides the possibility to include support for importing sequence data from a variety of file formats. CONCLUSION: ProbeMaker is a suitable tool for many different oligonucleotide design and analysis tasks, including the design of probe sets for various types of parallel genetic analyses, experimental validation of design parameters, and in silico testing of probe sequence evaluation algorithms.

Algorithms↗
PubMed2007

Participatory design in health sciences: Using cooperative experimental methods in developing health services and computer technology.

Participatory design (PD) is a research approach to the development of technological solutions to real-world problems, an approach that shares many concerns and some of its roots with action research. In this article, the authors discuss their experience in conducting a PD research project intended to develop a technological and a related organizational intervention to support the treatment of foot ulcers for people with diabetes at home. They provide a historical overview of the PD approach and a description of how they used it in their research study. They describe their experience in conducting the research, including the participants' responses, the outcomes of the research, and the challenges confronted in bridging the practical and disciplinary issues that arose. In the conclusion, they propose that PD holds potential as a research approach that might effectively merge computer technology and health-related interventional research.

Biomedical Research↗
PubMed1995

Prefabricated prostheses for the reconstruction of skull defects.

Cranioplasties using intraoperatively modeled prostheses may fail to create harmonic contours with long-term stability. In contrast, preoperative modeling would allow more sophisticated planning of the contour and better preparation of the implant material, if a sufficiently precise model of the defect-site was available. In this respect, computer aided design and manufacturing (CAD/CAM)-techniques based on helical computed tomography (CT) data are successfully used for the prefabrication of prostheses: An individual computer-based 3-dimensional model of the bony defect is generated after acquisition, transfer and evaluation of the CT data; from this freeform surfaces geometry an individual and "idealized" prosthesis-geometry is derived and fabricated by a numerically controlled milling machine using modern industrial CAD/CAM-systems and design software. The margins of this prosthesis-geometry are generated by the borders of the defect and the surface by considering the non-affected neighbouring contours. Cranioplasties in cases of large postsurgical skull defects are presented as the first clinical applications of this new method, which also allows the use of titanium and fabrication of integrated fixation-devices.

Computer Simulation↗
PubMed1984

Intelligent computational assistance for experiment design.

We have developed an automated system for the design of laboratory experiments in molecular biology. The system uses a planning method known as skeletal plan refinement that attempts to emulate the human cognitive task of experiment design. This paper describes the theory, history, and implementation of the design system and illustrates its function in the domain of DNA cloning experiments.

Base Sequence↗
PubMed1990

'Stereovectorcardiogram' made by stereolithography.

A method for making directly a single solid vectorcardiogram is reported. A solid vectorcardiogram was made by employing an apparatus for production of three-dimensional objects by stereolithography. Stereolithography is a computer-aided manufacturing technique that is practiced in conjunction with computer-aided design and engineering. To design the solid vectorcardiogram, voltages in the X, Y and Z axes obtained according to the Frank lead are memorized in the computer-aided design system. By use of the stereolithography apparatus, the designed solid vectorcardiogram is formed in a vat filled with liquid plastic. In the vat, the plastic changes rapidly from liquid to solid in the presence of ultraviolet light so that a solid vectorcardiogram made of solid plastic may be formed.

Equipment Design↗
PubMed2000

Role of the finite element model in dental implants.

Computer-aided design and finite element methods (FEM) have interested dental researchers because of its use in the computer simulation and design of dental implants, a process greatly facilitated by the development of new computer technology and more accurate modeling technologies. FEM allows for a better understanding of stresses along the surfaces of an implant and in surrounding bone. This will aid in the optimization of implant design and placement of the implant into the bone; it will also help when designing the final prostheses to minimize stresses. The purpose of this review is to elucidate the role of FEM and the impact of this technology in clinical dentistry in the new millennium.

Dental Implantation, Endosseous↗
PubMed2002

PoPMuSiC, rationally designing point mutations in protein structures.

PoPMuSiC is an efficient tool for rational computer-aided design of single-site mutations in proteins and peptides. Two types of queries can be submitted. The first option allows to estimate the changes in folding free energy for specific point mutations given by the user. In the second option, all possible point mutations in a given protein or protein region are performed and the most stabilizing or destabilizing mutations, or the neutral mutations with respect to thermodynamic stability, are selected. For each sequence position or secondary structure the deviation from the most stable sequence is moreover evaluated, which helps to identify the most suitable sites for the introduction of mutations.

Computer-Aided Design↗
PubMed2003

Novel collagen scaffolds with predefined internal morphology made by solid freeform fabrication.

Novel collagen scaffolds possessing predefined and reproducible internal channels with widths of 135 microm and greater have been produced. The process employed to make the collagen scaffold utilises a sacrificial mould, manufactured using solid freeform fabrication technology, and critical point drying technique. A computer aided design (CAD) file of the mould to be produced is created. This mould is manufactured using a phase change ink-jet printer. A dispersion of collagen is then cast into the mould and frozen. The mould is dissolved away with ethanol and the collagen scaffold is then critical point dried with liquid carbon dioxide. The effect of processing on the tertiary structure of collagen is assessed by monitoring the wavenumber of the N-H stretching vibration peak using Fourier transform infra-red spectroscopy and it is found that processing does not denature the collagen. Ultraviolet-visual spectroscopy was used to detect the presence of any contamination from the sacrificial mould on the collagen. The ability to use computer aided design and manufacture (CAD/CAM) provides a route to optimise scaffold designs using collagen in tissue engineering applications.

Animals↗