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We have designed and built a data-base system for the storage of nucleic-acid sequences. The system consists of a data base ("the library") and software that manages and provides access to that data base ("the Librarian").
A computer based radiotherapy dose compensator system is presented. A plane of uniform dose (pud) is chosen which passes through the central axis at a reference depth in the patient. The pud is oriented at an arbitrary angle. Tissues thicknesses are the ray line distances from the patient surface to the pud. Relative dose estimates on the pud are derived from tissue-air ratio, tissue-maximum ratio, or tissue-phantom ratio tables interpolated for field size and tissue thickness. An inverse square law correction is also applied. Compensator thicknesses are calculated from measured effective attenuation coefficients to attenuate the beam by a factor proportional to the estimated dose on the pud. Water phantom measurements for 60Co for both oblique incidence and wedge geometries demonstrate dose uniformity to better than +/- 4%. Dose measurement with radiographic films sandwiched between the two halves of a wax phantom verify adequate compensation for neck irradiation by 60Co opposed lateral beams and 6-MV x-ray inferiorly angled lateral beams. Compensator factors used for absolute dose determination are accurate to better than +/- 3%. The dose modeling routine, QCBEAM, is found to be sufficiently accurate for routine compensator verification for these geometries.
Protein L consists of a single alpha-helix packed on a four-stranded beta-sheet formed by two symmetrically opposed beta-hairpins. We use a computer-based protein design procedure to stabilize a domain-swapped dimer of protein L in which the second beta-turn straightens and the C-terminal strand inserts into the beta-sheet of the partner. The designed obligate dimer contains three mutations (A52V, N53P, and G55A) and has a dissociation constant of approximately 700 pM, which is comparable to the dissociation constant of many naturally occurring protein dimers. The structure of the dimer has been determined by x-ray crystallography and is close to the in silico model.
Three pyrrolyl heteroaryl sulfones (ethyl 1-[(1H-benzimidazol-2(3H)one-5-yl)sulfonyl]-1H-pyrrole-2-carboxyla te, ethyl 1-[(1H-benzimidazol-5(6)-yl)sulfonyl]-1H-pyrrole-2-carboxylate and ethyl 1-[(1H-benzotriazol-5(6)-yl)sulfonyl]-1H-pyrrole-2-carboxylate) were designed as novel HIV-1 reverse transcriptase non-nucleoside inhibitors using structure-based computational methods. Although these compounds were inactive in the cell-based assay, they inhibited the target enzyme with micromolar potency (IC50s = 2 microM, 3 microM and 9 microM, respectively).
When designing wheelchairs for use as motor vehicle seats, special design criteria must be followed to assure the crash safety of the wheelchair user. Failure of seating system components under crash loading conditions could lead to serious injury or fatality. In this study, seat and seat-back loading in a frontal crash are explored using computer simulation techniques. A previously validated simulation model consisting of a powerbase wheelchair and a seated 50th-percentile male test dummy subjected to a 20g/30mph frontal impact were used for the study. Since such a wide range of seating systems are available, parametric analyses were conducted to evaluate the influence of surface stiffness and seat-back angle on wheelchair seat and back loading. Seat loading varied with stiffness, ranging from 819-3,273 lb., while seat-back loading was found to be between 1,427-2,691 lb., depending upon back stiffness and recline angle.
The effect of intravenous theophylline on the outcome of inhospital treatment of acute bronchospasm has been assessed, comparing the results achieved by computer-assisted dosing, designed to achieve and maintain a serum theophylline level of 16 micrograms.ml-1 (10 patients) with those of unaided physicians (15 control patients). The outcome measures compared were clinical improvement, peak expiratory flow rate and serum theophylline concentration. Loading doses of theophylline in the control and computer groups were: 167 and 437 mg, respectively. Initial serum theophylline concentrations, measured 20 min after the loading dose, were 13.6 and 17.0 micrograms.ml-1 in the control and computer groups, respectively. In patients who had not received theophylline prior to admission, loading doses and initial concentrations were: 200 mg and 9.4 micrograms.ml-1 in the control group (n = 5) versus 613 mg and 15.7 micrograms.ml-1 in the computer group (n = 4), respectively. During maintenance therapy, serum theophylline concentrations were kept in the therapeutic range (10-20 micrograms.ml-1) throughout 51% and 77% of the hospitalisation period, in the control and computer groups, respectively. There were no differences between the two groups in the rate or extent of clinical improvement or in change in peak expiratory flow rate. The computer assisted theophylline dosing regimen outperformed that of the unaided physicians in achieving and maintaining therapeutic serum theophylline concentrations in acute bronchospasm. There was no correlation between clinical outcome and serum theophylline concentration, but this may have been due to the small sample size and modest difference in serum theophylline between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)
This study served as a pilot to develop the methodology for a larger number of clinical trials. Ten trans-tibial amputees compared sockets made by conventional methods with sockets made using computer aided socket design (CASD). Prosthetists, paired for experience, fitted each subject with one prosthesis using each method. A preferred socket was selected by the subject on the basis of comfort without knowledge of the method by which the socket was designed. Prosthetists also evaluated the sockets. Three subjects preferred sockets built using CASD and one subject preferred the conventional socket only slightly more than the CASD socket. Six subjects clearly preferred the conventional fitting.
Three-dimensional (3D) computer modeling, simulation, and rendering techniques were used to redesign the diagnostic workstations and radiology reading rooms for a proposed hospital with particular attention given to lighting conditions, noise reduction, and optimal use of limited workspace. The results were presented to a panel of multidisciplinary experts and iteratively improved and redesigned with the development or addition of new design criteria or requirements. These 3D techniques allowed faster, more efficient design and presentation of multiple options than is possible with traditional two-dimensional drawings, thereby expediting decision making and resulting in significant savings. The current workstation designs can easily be developed and implemented with available technology at a reasonable cost. They can also accommodate anticipated advances in computer and display technology as well as new imaging paradigms (eg, changes in keyboard and control ergonomics such as adjustable virtual keys on touch-sensitive screens, digital drawing tablets for annotations and controls, direct film digitizing, personal identification devices, offline media readers such as compact disks and digital videodisks, and speech recognition and voice activation). Use of 3D techniques in designing other parts of the radiology department (eg, examination rooms, technologists' areas, physicians' offices) could greatly improve and facilitate the design and implementation of complex settings in these work areas.
Subperiosteal implants are currently fabricated by using the classic two-stage direct bone impression technique or by the use of the one-stage computer tomography/computer-assisted design-computer-assisted manufacture (CT/CAD-CAM) method. This study compares the accuracy of the two techniques by using cadaver maxillae and mandibles as the models for fabrication of casts. Seven cadaver jaw specimens were collected and subjected to direct bone impressions and to CT scans. Those derived from the direct bone impressions were poured in die stone, while the CT scans were sent for fabrication of CAD-CAM-generated casts. On each of the 14 models so produced, a cast grid was fabricated that was designed as a measuring device. The preciseness of fit of each grid was subjected to analyses that presented levels of accuracy. Statistical evaluation of these levels, reduced to numerical indices, revealed that the direct bone techniques resulted in acceptable castings in seven of seven cases, whereas the CAD-CAM method yielded adequate castings in five of seven cases.
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A computational method to determine the energetically favorable positions of functional groups with respect to the transition states of stereoselective reactions based on force field energy minimization is presented. The parameters of this functionality mapping, the characteristics of the target transition states, and the features of the probe structures are outlined. Our method was found to reproduce the positions of the stereodiscriminating fragments for some known chiral ligands including the Masamune dimethylborolane, dimenthylborane, the Corey stien reagent, the Roush allylboronate tartrates, and the secondary amine Diels-Alder catalysts described by MacMillan. Functionality mapping can be used to better understand the specific interactions in the transition states leading to the products by providing a quantitative measure of the stabilization/destabilization afforded by the different ligand components via nonbonded interactions. The method can determine if a chiral ligand imparts the observed selectivity by stabilizing one reaction pathway, by destabilizing a reaction pathway, or by a combination of both. Orientational as well as positional information about potential functional groups is readily obtained. In addition to its utility as an analytical tool, functionality mapping can be used to explore starting points for the design of new chiral ligands.
Oligonucleotide microarrays have demonstrated potential for the analysis of gene expression, genotyping, and mutational analysis. Our work focuses primarily on the detection and identification of bacteria based on known short sequences of DNA. Oligo Design, the software described here, automates several design aspects that enable the improved selection of oligonucleotides for use with microarrays for these applications. Two major features of the program are: (i) a tiling algorithm for the design of short overlapping temperature-matched oligonucleotides of variable length, which are useful for the analysis of single nucleotide polymorphisms and (ii) a set of tools for the analysis of multiple alignments of gene families and related short DNA sequences, which allow for the identification of conserved DNA sequences for PCR primer selection and variable DNA sequences for the selection of unique probes for identification. Note that the program does not address the full genome perspective but, instead, is focused on the genetic analysis of short segments of DNA. The program is Internet-enabled and includes a built-in browser and the automated ability to download sequences from GenBank by specifying the GI number. The program also includes several utilities, including audio recital of a DNA sequence (useful for verifying sequences against a written document), a random sequence generator that provides insight into the relationship between melting temperature and GC content, and a PCR calculator.
Achieving atomic-level resolution in the computational design of a protein structure remains a challenging problem despite recent progress. Rigorous experimental tests are needed to improve protein design algorithms, yet studies of the structure and dynamics of computationally designed proteins are very few. The NMR structure and backbone dynamics of a redesigned protein of 96 amino acids are compared here with the design target, human U1A protein. We demonstrate that the redesigned protein reproduces the target structure to within the uncertainty of the NMR coordinates, even as 65 out of 96 amino acids were simultaneously changed by purely computational methods. The dynamics of the backbone of the redesigned protein also mirror those of human U1A, suggesting that the protein design algorithm captures the shape of the potential energy landscape in addition to the local energy minimum.
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De novo design provides an in silico toolkit for the design of novel molecular structures to a set of specified structural constraints, and is thus ideally suited for creating molecules for chemical genomics. The design process involves manipulation of the input, modification of structural constraints, and further processing of the de novo-generated molecules using various modular toolkits. The development of a theoretical framework for each of these stages will provide novel practical solutions to the problem of creating compounds with maximal chemical diversity. This chapter describes the fundamental problems encountered in the application of novel chemical design technologies to chemical genomics by means of a formal representation. Formal representations help to outline and clarify ideas and hypotheses that can then be explored using mathematical algorithms. It is only by developing this rigorous foundation, that in silico design can progress in a rational way.
For decades the computer has been the primary tool used for optical design. Typical tasks include performing numerical calculations for ray tracing and analysis and rendering graphics for system drawings. As machines become faster with each new generation, the time needed for a particular design task has greatly reduced, allowing multiple assignments to be performed with little noticeable delay. This lets the designer modify a system and then immediately see the results rendered in graphics with a single motion. Such visual design methods are discussed here, where graphics of systems and plots relating to their performance are produced in real time, permitting the optical designer to design by pictures. Three examples are given: an educational tutorial for designing a simple microscope objective, an unobstructed reflective telescope composed of three spherical mirrors, and a modified Offner relay with an accessible pupil.
The aim of the present study was to compare sockets for below-knee (BK) prostheses made by Computer Aided Design-Computer Aided Manufacture (CAD-CAM) to those made by hand. The patients in the study were provided with two prostheses each, which apart from the sockets, were identical. One socket was made by the CAD-CAM technique developed at the Bioengineering Centre, Roehampton, University College London and one was made by hand at the OT-Centre, Stockholm, Sweden. The results were based on investigation of eight unilateral below-knee amputees evaluating their own sockets by Visual Analogous Scale with respect to comfort, pressure, and pain. The sockets were evaluated on seven occasions, at two tests, on delivery, after use every second day for six days and every second week for two weeks. All CAD-CAM sockets except one had to be changed once as compared to the hand made of which only two had to be changed. As to comfort it could not be demonstrated that there was any significant difference between the two types of sockets and both types were well accepted by all patients. Differences in pressure and pain were rarely reported. There were obvious differences between the two types of socket with respect to height, width, and inner surface configuration. The authors feel that CAD-CAM will in the near future be an excellent tool for design and manufacture of prosthetic sockets.