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PubMed2005

Computer-aided drug design strategies used in the discovery of fructose 1, 6-bisphosphatase inhibitors.

Computational assessment of the binding affinity of enzyme inhibitors prior to synthesis is an important component of computer-aided drug design (CADD) paradigms. The free energy perturbation (FEP) methodology is the most accurate means of estimating relative binding affinities between two inhibitors. However, due to its complexity and computation-intensive nature, practical applications are restricted to analysis of structurally-related inhibitors. Accordingly, there is a need for methods that enable rapid assessment of a large number of structurally-unrelated molecules in a suitably accurate manner. In this review, the FEP method is compared with molecular mechanics (MM) methods to assess the advantages of each in the estimation of relative binding affinities of inhibitors to an enzyme. Qualitative predictions of relative binding free energies of fructose 1, 6-bisphosphatase inhibitors using MM methods are discussed and compared with the corresponding FEP results. The results indicate that the MM based methods and the FEP method are useful in the qualitative and quantitative assessment of relative binding affinities of enzyme inhibitors, respectively, prior to synthesis.

Computer-Aided Design↗
PubMed1988

Artificial intelligence research in anesthesia and intensive care.

This article describes several research directions exploring the application of artificial intelligence techniques in anesthesia and intensive care. Artificial intelligence can be loosely defined as the discipline of designing computer systems that exhibit "intelligent" behavior. This article first introduces artificial intelligence and computer science research and discusses why medicine has proved to be a challenging domain for applying artificial intelligence techniques. A discussion of the central research themes that arise in medical artificial intelligence, many of which are common to different projects and to different medical settings, is followed by a description of specific research projects that apply artificial intelligence techniques in anesthesiology, ventilatory management, and cardiovascular management. Finally, further comments are made on the current state of the field.

Anesthesia↗
PubMed2005

Analysis of polarity in the expression from a multifactorial bidirectional promoter designed for high-level expression of transgenes in plants.

A synthetic bidirectional expression module was constructed by placing a computationally designed minimal promoter sequence on the 5' and 3' sides of a transcription activation module. The activation of transcription from the unidirectional and bidirectional promoters constructed from the same sequence elements was evaluated by using the reporter genes gusA and gfp. The analysis based on transient and stable transformation of tobacco showed that the artificially designed multifactorial activation module activated transcription simultaneously to comparable levels in both the directions. The transcription activation module responded to elicitors like salicylic acid, NaCl and IAA in the forward as well as reverse directions. The concentration of the elicitor required for highest gene activation was similar for the two directions in case of the three activators. The kinetics of time of induction was similar in the two directions for salicylic acid and NaCl. In the case of IAA, the transcription activation was faster in the reverse direction. The results show that constitutive and chemically inducible bidirectional promoters can be deployed for predictable simultaneous regulation of two genes for genetic engineering in plants.

Factor Analysis, Statistical↗
PubMed1998

Examination of wear in Duraloc acetabular components: two- to five-year evaluation of Hylamer and Enduron liners.

To help increase the longevity of polyethylene components used in total joint arthroplasty, new forms of ultrahigh molecular weight polyethylene (UHMWPE) have been developed. This study reports on the in vivo performance of Hylamer (DePuy DuPont Orthopaedics, Newark, DE), a high crystalline form of UHMWPE, and on the performance of conventional Enduron polyethylene (DePuy, Warsaw, IN). With the use of a specially designed computer system, the time course of two-dimensional femoral head penetration into 80 Hylamer and 140 Enduron acetabular liners in situ from two to five years was compared. At the most recent follow-up (mean, 3.6 years), the rate of femoral head penetration into the Hylamer liners was lower than the rate of head penetration into the Enduron liners (0.15 mm/year versus 0.20 mm/year, P = . 10). Temporal analysis revealed that the Hylamer liners had lower penetration rates than those of the conventional polyethylene liners in the first three postoperative years, but that head-penetration rates between the two groups became similar with increased time in situ. Continued examination of both types of polyethylene components is imperative before conclusions on long-term performance can be drawn.

Acetabulum↗
PubMed2004

Stabilization of TRAIL, an all-beta-sheet multimeric protein, using computational redesign.

Protein thermal stability is important for therapeutic proteins, both influencing the pharmacokinetic and pharmacodynamic properties and for stability during production and shelf-life of the final product. In this paper we show the redesign of a therapeutically interesting trimeric all-beta-sheet protein, the cytokine TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), yielding variants with improved thermal stability. A combination of tumor necrosis factor (TNF) ligand family alignment information and the computational design algorithm PERLA was used to propose several mutants with improved thermal stability. The design was focused on non-conserved residues only, thus reducing the use of computational resources. Several of the proposed mutants showed a significant increase in thermal stability as experimentally monitored by far-UV circular dichroism thermal denaturation. Stabilization of the biologically active trimer was achieved by monomer subunit or monomer-monomer interface modifications. A double mutant showed an increase in apparent T(m) of 8 degrees C in comparison with wild-type TRAIL and remained biologically active after incubation at 73 degrees C for 1 h. To our knowledge, this is the first study that improves the stability of a large multimeric beta-sheet protein structure by computational redesign. A similar approach can be used to alter the characteristics of other multimeric proteins, including other TNF ligand family members.

Algorithms↗
PubMed1992

SCUT: clinical data organization for physicians using pen computers.

The role of computers in assisting physicians with patient care is rapidly advancing. One of the significant obstacles to efficient use of computers in patient care has been the unavailability of reasonably configured portable computers. Lightweight portable computers are becoming more attractive as physician data-management devices, but still pose a significant problem with bedside use. The advent of computers designed to accept input from a pen and having no keyboard present a usable computer platform to enable physicians to perform clinical computing at the bedside. This paper describes a prototype system to maintain an electronic "scut" sheet. SCUT makes use of pen-input and background rule checking to enhance patient care. GO Corporation's PenPoint Operating System is used to implement the SCUT project.

Handwriting↗
PubMed2006

Design and evaluation of single-stranded DNA carrier molecules for DNA-directed assembly.

Due to the exceptional molecular recognition properties of nucleic acids, the computational design of DNA sequence motifs is of paramount interest for a wide variety of applications, ranging from DNA-based nanotechnology and DNA computing to the broad field of DNA microarray technologies. These applications rely on the specificity of Watson-Crick base-pairing, and thus, are highly sensitive to non-specific interactions and the formation of any undesired secondary structures, which contradict an efficient intermolecular hybridization. Here we report on the in silico design and in vitro evaluation of single-stranded DNA (ssDNA) carrier strands for the directional DNA-based positioning of streptavidin (STV) conjugates covalently tagged with short ssDNA oligonucleotides. Each such carrier strand consists of four hybridization sites complementary to the conjugate DNA strands. The high and homogeneous hybridization efficiency measured in vitro by microarray hybridization assays confirms the quality of our in silico sequence design method. Hybridization efficiency of DNA-STV-conjugates depends on the position of the hybridization site in the carrier sequence, where the positions nearest to and farthest from the microarray surface proved to be most favorable.

Carrier Proteins↗
PubMed1992

Automated fabrication of mobility aids (AFMA): below-knee CASD/CAM testing and evaluation program results.

In 1988 the Department of Veterans Affairs Rehabilitation Research and Development Service, under the directorship of Margaret J. Giannini, M.D., began a nationally directed computer-aided design and computer-aided manufacturing (CAD/CAM) research program for the Automated Fabrication of Mobility Aids (AFMA). Under this program CAD/CAM research and development centers were established at the Prosthetics Research Study in Seattle, WA; at Northwestern University and the VA Lakeside Medical Center in Chicago, IL; and at the VA Medical Center and New York University Medical Center in New York, NY. These three centers conducted a collaborative program: (a) to introduce CAD/CAM technologies to prosthetists, physicians, therapists, and rehabilitation health care professionals in the United States; (b) to evaluate the feasibility of using CAD/CAM systems in clinical prosthetics settings; (c) to test and evaluate the University College London-Bioengineering Center's and the University of British Columbia-Medical Engineering Resource Unit's respective systems for the computer-aided design and computer-aided manufacture of prosthetic sockets (CASD/CAM) for below-knee amputees; and, (d) to obtain quantitative data for refinement of the CASD/CAM systems tested, and for the development of new, enhanced, more efficacious, and expedient systems.

Adult↗
PubMed1994

Antiestrogenic piperidinediones designed prospectively using computer graphics and energy calculations of DNA-ligand complexes.

Drug design technology based upon DNA stereochemistry and now supplemented by computer modeling was used to design a novel compound to inhibit estrogen-induced tumor cell growth. A known compound 3-phenylacetylamino-2,6-piperidinedione (PP) was accommodated in partially unwound DNA in a manner consistent with criteria for antiestrogens. Examination of the PP-DNA complex revealed that substitution of a hydroxyl group at the para position (p-OH-PP) would provide a stereospecific hydrogen bond and a substantial increase in fit as assessed by energy calculations. The antiestrogen tamoxifen could also be accomodated within the site; analogous substitution of a hydroxyl at the 4 position resulted in a better fitting molecule. 4-Hydroxytamoxifen is a more potent antiestrogen than tamoxifen. Synthesis and subsequent evaluation of p-OH-PP as an inhibitor of estrogen stimulated MCF-7 (E3) human breast cancer cell growth demonstrated that p-OH-PP was more active than both PP and its hydrolysis product phenylacetylglutamine. As predicted, the order of fit into DNA correlated with the relative ability to inhibit estrogen-induced growth of tumor cells suggesting that the evolving drug design technology will be valuable in developing new drugs for breast cancer.

Benzeneacetamides↗
PubMed2001

Nighttime bracing with the Providence brace in adolescent girls with idiopathic scoliosis.

STUDY DESIGN: A prospective study was conducted of 102 consecutive female patients with adolescent idiopathic scoliosis. Those patients with Risser 0, 1, and 2 met the criteria for inclusion and were treated only with the Providence brace. OBJECTIVES: To report the authors' experience with a hypercorrective nighttime brace and to evaluate the results with respect to risk factors for progression. Second, the study compares results with expectations from the natural history as reported by others. SUMMARY OF BACKGROUND DATA: Compliance with full-time brace treatment for adolescent idiopathic scoliosis has been a problem. Since the introduction of the Milwaukee brace, alternatives such as low-profile braces, reduced wearing schedules, and nighttime only bracing have been tried. However, many factors influence the success or failure besides compliance. These include in-brace correction, brace design, and the orthotist's skills. This is the first report of the results of treatment with a new nighttime brace that is made with CAD/CAM technology that can achieve higher initial in-brace corrections than other reported methods. METHODS: Results were analyzed with respect to curve size, curve pattern, maturity, and level of the primary curve apex. Both compliant and noncompliant patients were included in the analysis. A univariate analysis was done on those factors thought to influence success with bracing using the Pearson chi2 test. RESULTS: The average initial in-brace correction with a supine radiograph was 96% for major curves and 98% for minor curves. Seventy-five patients (74%) did not progress >5 degrees and 27 patients (26%) progressed > or =6 degrees or went on to surgery. Twenty-nine percent of Risser 0 or 1 patients progressed and 17% of patients Risser 2 progressed. The risk of progression anticipated by natural history data, which included all curve patterns, was 68% for Risser 0 and 1 and 23% for Risser 2. Risser 3 and 4 patients were excluded from the study. Seventy-six percent of patients with curve apexes between T8 and L1 had successful outcomes using the Providence brace. This is compared with a 74% success rate in the prospective Scoliosis Research Society study of patients wearing a thoraco lumbar sacral orthosis for 16 hours per day with curve apexes between T8 and L1. With the Providence brace, 63% of thoracic curves and 65% of double curves were successful. Ninety-four percent of lumbar curves and 93% of thoracolumbar curves were successful. CONCLUSION: Excellent initial in-brace correction of adolescent idiopathic scoliosis was observed with this computer-designed and manufactured recumbent brace. Patients with high apex curves cephalad to T8 (n = 31) had a success rate of 61% compared with a success rate of 79% (n = 71) if the apex was at or below T9. Compared with previous natural history and the prospective study data, the Providence brace is effective in preventing progression of adolescent idiopathic scoliosis for curves <35 degrees. It was effective for larger curves with a low apex. The authors' experience with patients with curves >35 degrees (n = 8) is too small to validate its effectiveness for larger curves with a higher apex.

Adolescent↗
PubMed1980

The amino acid requirements of chicks: experimental validation of model-calculated requirements.

The amino acid requirements of broiler chicks, on a weekly or biweekly basis, were calculated according to a model presented previously (Hurwitz et al., 1978). Based on the present results, the model has been somewhat modified. The model requirements provided the basis for computer-designed diets which were fed to chicks of different ages and were composed to others computed on the basis of NRC (1971, 1977) requirements. In all cases the model-based diets, which were considerably lower in protein, supported weight gains equivalent to those obtained on NRC-based diets. The relatively poorer feed efficiency observed in the first trial with chicks fed the model-based diets, could be alleviated by equalizing both energy and lipid concentrations in the experimental diets. Thus, equal growth and feed efficiency were obtained with the model and NRC (1971)-based diets, for 2- to 10-week-old chicks. The possible reasons for the slightly higher abdominal fat content of the chicks fed the model-based diets are discussed.

Amino Acids↗
PubMed1994

[Development of quantitative structure-activity relationships and computer-aided drug design].

Recent development of quantitative structure-activity relationships (QSARs) and computer-aided drug design contributed by the author and his coworkers was briefly reviewed. Fuzzy adaptive least-squares (FALS), a pattern recognition method for analysing structure-activity rating data to generate QSAR models was developed. A novel feature of FALS is that the degree to which each sample belongs to its activity class is given by a fuzzy membership function. Using FALS, non-congeneric QSAR analyses of carcinogenicity, mutagenicity, and six kinds of pharmacokinetic properties of miscellaneous organic chemicals were performed to construct predictive models for drug design. In these QSAR analyses, the values of log P (partition coefficient in octanol/water) calculated by the simple method of Moriguchi et al. were used as the descriptor for hydrophobicity. The method of Moriguchi et al. is not only simple and convenient but also reliable in the application to 22 drugs selected by Rekker et al. compared to the Rekker method and the Hansch-Leo method. Lastly, a heulistic search method for active conformers using molecular mechanical conformational analysis and principal component analysis was proposed.

Animals↗
PubMed1992

Computer-aided radiopharmaceutical design.

The ultimate goal of a QSAR analysis is prediction, which depends on the elaboration of the most appropriate set of molecular descriptors. As such, molecular description is the nucleus of QSAR and in the absence of exhaustive molecular description, rational drug design may be greatly impeded. As previously discussed, computational methods such as quantum mechanics and molecular mechanics provide molecular description at a fundamental level which then enhances the descriptive capability and predictive power of a QSAR analysis. In recognition of these capabilities, semi-empirical molecular orbital methods and molecular mechanics now have been incorporated into or interphased with QSAR programs. Such integrated packages are being successfully used in computer-aided molecular modeling. Computer-aided molecular modeling can provide the three-dimensional structure of a molecule, its chemical and physical characteristics, comparisons of structures of different molecules, and visualization of complexes formed between them. From the foregoing, predictions may be made about how related new molecules may function. Thus, the combination of quantum and/or molecular mechanics and QSAR provides a formidable weapon in the chemist's armamentarium. The molecular modeling approaches are certainly more practical to use than physicochemical methods. They also provide electronic and thermodynamic data that are not available from x-ray crystallographic data. Of course, these techniques are not confined to radiopharmaceutical development and they also could aid in the development of contrast agents for radiography or magnetic resonance imaging. We believe that as computational resources and capabilities increase over the next decade, computer-aided drug design will become a standard procedure in all drug development laboratories.

Binding Sites↗
PubMed2002

A designed phenylalanyl-tRNA synthetase variant allows efficient in vivo incorporation of aryl ketone functionality into proteins.

Incorporation of non-natural amino acids into proteins in vivo expands the scope of protein synthesis and design. p-Acetylphenylalanine was incorporated into recombinant dihydrofolate reductase (DHFR) in Escherichia coli via a computationally designed mutant form of the phenylalanyl-tRNA synthetase of the host. DHFR outfitted with ketone functionality can be chemoselectively ligated with hydrazide reagents under mild conditions.

Escherichia coli↗
PubMed2005

Clinical marginal and internal gaps of In-Ceram crowns fabricated using the GN-I system.

The marginal and internal gaps of ceramic crowns with alumina copings fabricated using a computer-aided design, computer-aided manufacturing system, were evaluated in vivo using silicone materials. Black and white silicone materials were used to record the marginal and internal gaps of 82 In-Ceram crowns before final cementation. The silicone materials were sectioned bucco-lingually and mesio-distally and viewed under a microscope to measure the thickness of the white silicone layer. Sixteen reference points were measured on each specimen. The mean marginal gaps were compared among the anterior, premolar and molar teeth, and the mean gaps at the reference points within the groups were compared by analysis of variance and the Dunnett T3 test. The mean marginal gap was 66.8 mum. There were no differences in marginal gaps among the three groups. In all the groups, the marginal gaps were the smallest, whereas the occlusal gaps were the largest. The mean marginal gaps of the In-Ceram crowns with the alumina copings fabricated using the GN-I system were within the range of clinically acceptable values.

Aluminum Oxide↗
PubMed2001

Fabrication of a functionally graded dental composite resin post and core by laser lithography and finite element analysis of its stress relaxation effect on tooth root.

Laser lithography was applied for Computer Aided Design and Computer Aided Manufacturing (CAD/CAM) fabrication of dental prostheses made of composite resin. First, the conditions to obtain the optimum resolution for photo-curing were determined, and then a composite resin full crown was fabricated by laser lithography. Second, a functionally graded composite resin post and core which had gradient elasticity in the post, was manufactured by the gradual change in the filler contents of the composite resin. Finally, stress analysis of the functionally graded post and core was performed by a two-dimensional finite element method. This demonstrated the effects of reducing the stress concentration around the apex of the post.

Composite Resins↗
PubMed2006

Press-to-zirconia: a case study utilizing cad/cam technology and the wax injection method.

Computer technology is increasingly becoming an effective tool in restorative dentistry. Whether chairside or laboratory-fabricated, computer-aided design/ computer-aided manufacturing (CAD/CAM) engineering has become widely accepted in the fabrication of dental restorations. Zirconia has been successfully used in medical therapy and is now considered a viable alternative to metal as a substrate in single- and multiple-unit fixed restorations. Proper tooth preparation and handling of this material is essential for a successful outcome. This presentation will discuss how CAD/CAM systems can utilize zirconia frameworks to provide treatment of a maxillary anterior restoration.

Computer-Aided Design↗
PubMed2000

Cross-sectional geometry of the sacral ala for safe insertion of iliosacral lag screws: a computed tomography model.

OBJECTIVE: To measure the dimensions of the narrowest portion of the sacral ala for safe insertion of iliosacral lag screws. DESIGN: Computed tomography (CT) model. SETTING: Level One trauma center. PATIENTS: Thirteen adult patients underwent pelvic CT imaging. MAIN OUTCOME MEASURE: Axial CT scans of intact pelves were reformatted in the sagittal plane at three-millimeter intervals from the first sacral body (S1 body) to the sacroiliac (SI) joint. Computer analysis and measurements of sacral geometry were used to determine the narrowest portion of the bony sacral ala. The maximum height, maximum width, and slope of the sacral ala through its geometric center in cross-section were measured. RESULTS: The narrowest portion of the sacral ala in all patients was consistently located at the junction between the sacral body and the alar wings, termed the sacral pedicle, directly cephalad to the first sacral foramen. The average slope of the sacral ala at the sacral pedicle was 45.08 degrees (range 25 to 65 degrees). The average maximum height at the geometric center in cross-section was 27.76 millimeters, and the average width was 28.05 millimeters. However, outside the geometric center there was a sharp decrease in height and width of the sacral ala that was in large part determined by its relative slope. CONCLUSION: Although the cross-sectional geometry of the sacral ala is highly variable among patients, there is ample space for iliosacral screws. To ensure safe insertion, iliosacral lag screws must be positioned in the geometric center of the sacral ala to avoid extraosseous placement.

Adult↗