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Development of computer assisted orthosis design and manufacturing system for malformed ears.

Most cases of malformed ears in neonates can be treated by mounting a suitably shaped orthosis. Our objective was to develop a computer-assisted orthosis design and manufacturing system for the treatment of malformed ears. Also, we aimed to manufacture a first experimental orthosis made of nitinol shape-memory alloy wire. First, the target posttherapeutic auricular shape is input from computed tomography scans, and characteristic points and contours are extracted. The shape of the orthosis is then created by tracing the necessary contours automatically. Finally, the orthosis shape data are projected onto one or more approximate planes and autoconverted into numerical control (NC) data for plate groove processing. The nitinol shape-memory alloy wires are inserted in the groove and the shape is memorized by heat treatment. The shape of the manufactured orthosis can be memorized from the generated NC data within 1.0 mm of error. Stahl's ear in a 9-month-old baby was treated 7 months ago by mounting the orthosis manufactured by the system. The developed system allows the design and manufacture of orthoses made of nitinol shape-memory alloy wire for the treatment of malformed ears.

Alloys↗

Computer search algorithms in protein modification and design.

The computer-aided design of protein sequences requires efficient search algorithms to handle the enormous combinatorial complexity involved. A variety of different algorithms have now been applied with some success. The choice of algorithm can influence the representation of the problem in several important ways--the discreteness of the configuration, the types of energy terms that can be used and the ability to find the global minimum energy configuration. The use of dead end elimination to design the complete sequence for a small protein motif and the use of genetic and mean-field algorithms to design hydrophobic cores for proteins represent the major themes of the past year.

Algorithms↗

A Macintosh computer program for designing DNA sequences that code for specific peptides and proteins.

A computer program (PINCERS) is described for use in the design of synthetic genes and mixed-probe DNA sequences. A protein sequence is reverse translated with generation of synonymous codons at each position producing a degenerate sequence. In order to locate potential restriction enzyme sites, the degenerate sequence is searched with a library of restriction enzymes for sites that utilize any combination of synonymous codons. These sites are indicated in a map so that they may be incorporated into the synthetic gene sequence. The program allows the user to select the appropriate codon usage table for the organism of interest and then to set a threshold usage frequency below which codons are not generated. PINCERS may also be used to assist in planning the synthesis of mixed-probe DNA sequences for cross-hybridization experiments. It can identify regions of specified length with the protein sequence that have the least overall degeneracy, thereby minimizing the number of probes to be synthesized and, therefore, maximizing the concentration of a given probe sequence.

DNA↗

ALADDIN: an integrated tool for computer-assisted molecular design and pharmacophore recognition from geometric, steric, and substructure searching of three-dimensional molecular structures.

ALADDIN is a computer program for the design or recognition of compounds that meet geometric, steric, and substructural criteria. ALADDIN searches a database of three-dimensional structures, marks atoms that meet substructural criteria, evaluates geometric criteria, and prepares a number of files that are input for molecular modification and coordinate generation as well as for molecular graphics. Properties calculated from the three-dimensional structure are described by either properties calculated from the molecule itself or from the molecule as compared to a reference molecule and associated surfaces. ALADDIN was used to design analogues to probe a bioactive conformation of a small molecule and a peptide, to test alternative superposition rules for receptor mapping of the D2 dopamine receptor, to recognize unexpected D2 dopamine agonist activity of existing compounds, and to design compounds to fit a binding site on a protein of known structure. We have found that series designed by ALADDIN show much more subtle variation in shape than do those designed by traditional methods and that compounds can be designed to be very close matches to the objective.

Binding Sites↗

TOMOCOMD-CARDD, a novel approach for computer-aided 'rational' drug design: I. Theoretical and experimental assessment of a promising method for computational screening and in silico design of new anthelmintic compounds.

In this work, the TOMOCOMD-CARDD approach has been applied to estimate the anthelmintic activity. Total and local (both atom and atom-type) quadratic indices and linear discriminant analysis were used to obtain a quantitative model that discriminates between anthelmintic and non-anthelmintic drug-like compounds. The obtained model correctly classified 90.37% of compounds in the training set. External validation processes to assess the robustness and predictive power of the obtained model were carried out. The QSAR model correctly classified 88.18% of compounds in this external prediction set. A second model was performed to outline some conclusions about the possible modes of action of anthelmintic drugs. This model permits the correct classification of 94.52% of compounds in the training set, and 80.00% of good global classification in the external prediction set. After that, the developed model was used in virtual in silico screening and several compounds from the Merck Index, Negwer's handbook and Goodman and Gilman were identified by models as anthelmintic. Finally, the experimental assay of one organic chemical (G-1) by an in vivo test coincides fairly well (100%) with model predictions. These results suggest that the proposed method will be a good tool for studying the biological properties of drug candidates during the early state of the drug-development process.

Animals↗

Evolutionary algorithms in computer-aided molecular design.

In recent years, search and optimisation algorithms inspired by evolutionary processes have been applied with marked success to a wide variety of problems in diverse fields of study. In this review, we survey the growing application of these 'evolutionary algorithms' in one such area: computer-aided molecular design. In the course of the review, we seek to summarise the work to date and to indicate where evolutionary algorithms have met with success and where they have not fared so well. In addition to this, we also attempt to discern some future trends in both the basic research concerning these algorithms and their application to the elucidation, design and modelling of chemical and biochemical structures.

Algorithms↗

Artificial neural networks for computer-based molecular design.

The theory of artificial neural networks is briefly reviewed focusing on supervised and unsupervised techniques which have great impact on current chemical applications. An introduction to molecular descriptors and representation schemes is given. In addition, worked examples of recent advances in this field are highlighted and pioneering publications are discussed. Applications of several types of artificial neural networks to compound classification, modelling of structure-activity relationships, biological target identification, and feature extraction from biopolymers are presented and compared to other techniques. Advantages and limitations of neural networks for computer-aided molecular design and sequence analysis are discussed.

Computer-Aided Design↗

Thrombin inhibitors identified by computer-assisted multiparameter design.

Here, we present a series of thrombin inhibitors that were generated by using powerful computer-assisted multiparameter optimization process. The process was organized in design cycles, starting with a set of randomly chosen molecules. Each cycle combined combinatorial synthesis, multiparameter characterization of compounds in a variety of bioassays, and algorithmic processing of the data to devise a set of compounds to be synthesized in the next cycle. The identified lead compounds exhibited thrombin inhibitory constants in the lower nanomolar range. They are by far the most selective synthetic thrombin inhibitors, with selectivities of >100,000-fold toward other proteases such as Factor Xa, Factor XIIa, urokinase, plasmin, and Plasma kallikrein. Furthermore, these compounds exhibit a favorable profile, comprising nontoxicity, high metabolic stability, low serum protein binding, good solubility, high anticoagulant activity, and a slow and exclusively renal elimination from the circulation in a rat model. Finally, x-ray crystallographic analysis of a thrombin-inhibitor complex revealed a binding mode with a neutral moiety in the S1 pocket of thrombin.

Antithrombins↗

Computer models for designing hypertension experiments and studying concepts.

This paper demonstrates how computer models along with animal experiments have been used to work out the conceptual bases of hypertensive mechanisms, especially the following: (1) The renal-fluid volume pressure control mechanism has a feed-back gain for pressure control of infinity. Therefore, the chronic level to which the arterial pressure is controlled can be changed only by altering this pressure control mechanism. (2) An increase in total peripheral resistance is not sufficient by itself to cause hypertension. The only resistances in the circulatory system that, when increased, will cause hypertension are those along a restricted axis from the root of the aorta to Bowman's capsule in the kidneys. (3) Autoregulation in the peripheral vascular beds does not increase the arterial pressure in hypertension. However, autoregulation can convert high cardiac output hypertension into high peripheral resistance hypertension. (4) In a computer simulation that cannot yet be performed in animals, a simulated hypertension caused by a combination of increased renal afferent and efferent arteriolar resistances has characteristics that match almost exactly those of essential hypertension.

Animals↗

Design features of alternative computer keyboards: a review of experimental data.

Design of computer keyboards no longer is limited to the flat keyboards that are typically shipped with personal computers. Keyboards now exist that are split into halves and these halves can be slanted away from each other (creating a triangle between the halves), sloped downward toward the visual display terminal, tilted upward like a tent, or simply separated. These design features are intended to alleviate discomfort and possible musculoskeletal disorders that have been suggested to be associated with the extensive use of conventional computer keyboards. The geometry of conventional keyboards requires the wrists to be in 10 degrees to 15 degrees of ulnar deviation and 20 degrees of extension and the forearms to be nearly fully pronated while typing. A review of the available experimental data collected on 10-digit touch typists indicates that (1) keyboards with a slant angle (half of the opening angle) of 10 degrees to 12.5 degrees or keyboards with halves separated to approximately shoulder width are both effective in placing the wrist in near neutral (0 degree) ulnar/radial deviation when typing, (2) wrist extension can be reduced to near neutral (0 degrees) when a keyboard with a negative slope of 7.5 degrees is used, contingent on the wrist rest also sloping with the keyboard, and (3) tilting the keyboard halves 20 degrees to 30 degrees is effective in reducing forearm pronation to approximately 45 degrees. These studies also indicate that experienced 10-digit touch typists readily adapt (within 10 minutes) to these individual alternative keyboard features, and can type with approximately the same speed and accuracy as with the conventional keyboard. While placing the wrist and forearm in a more neutral position could, in theory, reduce the incidence of musculoskeletal disorders, randomized controlled trials are necessary before strong recommendations can be made on the effectiveness of alternative keyboards for the prevention and/or treatment of musculoskeletal disorders. In the absence of these randomized controlled trials, the information in this article provides preliminary guidance to clinicians in their evaluation of computer keyboards and workstations and their recommendations to patients.

Computer Peripherals↗

From electric patterns to drugs: perspectives of computational neuroscience in drug design.

A novel way of computational modeling by integrating compartmental neural techniques and detailed kinetic description of pharmacological modulation of transmitter-receptor interaction is offered as a method to test the electro-physiological and behavioral effects of potential drugs. Even more, an inverse method is suggested as a method for controlling a neural system to realize a prescribed temporal pattern. Generation and pharamcological modulation of theta rhythm in area CA1 of the hippocampus related to anxiety is analyzed. Integrative modeling might help to find positive allosteric modulators of alpha1 subunits as potential candidates for being selective anxyolitics.

Computer-Aided Design↗

Classifier design for computer-aided diagnosis: effects of finite sample size on the mean performance of classical and neural network classifiers.

Classifier design is one of the key steps in the development of computer-aided diagnosis (CAD) algorithms. A classifier is designed with case samples drawn from the patient population. Generally, the sample size available for classifier design is limited, which introduces variance and bias into the performance of the trained classifier, relative to that obtained with an infinite sample size. For CAD applications, a commonly used performance index for a classifier is the area, Az, under the receiver operating characteristic (ROC) curve. We have conducted a computer simulation study to investigate the dependence of the mean performance, in terms of Az, on design sample size for a linear discriminant and two nonlinear classifiers, the quadratic discriminant and the backpropagation neural network (ANN). The performances of the classifiers were compared for four types of class distributions that have specific properties: multivariate normal distributions with equal covariance matrices and unequal means, unequal covariance matrices and unequal means, and unequal covariance matrices and equal means, and a feature space where the two classes were uniformly distributed in disjoint checkerboard regions. We evaluated the performances of the classifiers in feature spaces of dimensionality ranging from 3 to 15, and design sample sizes from 20 to 800 per class. The dependence of the resubstitution and hold-out performance on design (training) sample size (Nt) was investigated. For multivariate normal class distributions with equal covariance matrices, the linear discriminant is the optimal classifier. It was found that its Az-versus-1/Nt curves can be closely approximated by linear dependences over the range of sample sizes studied. In the feature spaces with unequal covariance matrices where the quadratic discriminant is optimal, the linear discriminant is inferior to the quadratic discriminant or the ANN when the design sample size is large. However, when the design sample is small, a relatively simple classifier, such as the linear discriminant or an ANN with very few hidden nodes, may be preferred because performance bias increases with the complexity of the classifier. In the regime where the classifier performance is dominated by the 1/Nt term, the performance in the limit of infinite sample size can be estimated as the intercept (1/Nt= 0) of a linear regression of Az versus 1/Nt. The understanding of the performance of the classifiers under the constraint of a finite design sample size is expected to facilitate the selection of a proper classifier for a given classification task and the design of an efficient resampling scheme.

Computer Simulation↗

Combinatorial protein design strategies using computational methods.

Computational methods continue to facilitate efforts in protein design. Most of this work has focused on searching sequence space to identify one or a few sequences compatible with a given structure and functionality. Probabilistic computational methods provide information regarding the range of amino acid variability permitted by desired functional and structural constraints. Such methods may be used to guide the construction of both individual sequences and combinatorial libraries of proteins.

Amino Acid Sequence↗

Simultaneous liquid chromatographic determination of seventeen of the major monoamine neurotransmitters, precursors and metabolites. I. Optimization of the mobile phase using factorial designs and a computer program to predict chromatograms.

Utilizing reversed-phase high-performance liquid chromatography (HPLC) with electrochemical detection and optimization of the mobile phase using factorial designs and a constructed computer program to predict chromatograms, it has been possible to obtain a satisfactory resolution of seventeen of the major monoamine neurotransmitters, precursors and metabolites. A rapid (less than 25 min) isocratic system for the simultaneous determination of 3,4-dihydroxyphenylalanine, dopamine, dihydroxyphenylacetic acid, 3-methoxytyramine, homovanillic acid, norepinephrine, normetanephrine, 3,4-dihydroxyphenylethylene glycol, 3-methoxy-4-hydroxyphenylethylene glycol, epinephrine, metanephrine, vanillylmandelic acid, 5-hydroxytryptophan, serotonin, 5-hydroxytryptophol and 5-hydroxyindoleacetic acid in addition to the internal standard isoproterenol is presented. The optimization strategy included selection of variables to optimize by a reduced factorial design a detailed study of these variables by a complete factorial design, theoretical predictions of chromatograms by a constructed computer program and test on the HPLC system. This optimization strategy can easily be applied to any problem of solute separation by liquid chromatography.

Chromatography, High Pressure Liquid↗