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At least 1,027 records · Page 57Linked to original sources
PubMed2006

Computational neurogenetic modelling: a pathway to new discoveries in genetic neuroscience.

The paper presents a methodology for using computational neurogenetic modelling (CNGM) to bring new original insights into how genes influence the dynamics of brain neural networks. CNGM is a novel computational approach to brain neural network modelling that integrates dynamic gene networks with artificial neural network model (ANN). Interaction of genes in neurons affects the dynamics of the whole ANN model through neuronal parameters, which are no longer constant but change as a function of gene expression. Through optimization of interactions within the internal gene regulatory network (GRN), initial gene/protein expression values and ANN parameters, particular target states of the neural network behaviour can be achieved, and statistics about gene interactions can be extracted. In such a way, we have obtained an abstract GRN that contains predictions about particular gene interactions in neurons for subunit genes of AMPA, GABAA and NMDA neuro-receptors. The extent of sequence conservation for 20 subunit proteins of all these receptors was analysed using standard bioinformatics multiple alignment procedures. We have observed abundance of conserved residues but the most interesting observation has been the consistent conservation of phenylalanine (F at position 269) and leucine (L at position 353) in all 20 proteins with no mutations. We hypothesise that these regions can be the basis for mutual interactions. Existing knowledge on evolutionary linkage of their protein families and analysis at molecular level indicate that the expression of these individual subunits should be coordinated, which provides the biological justification for our optimized GRN.

Algorithms↗
PubMed1993

Multivariate assessment of computer-analyzed corneal topographers.

Methodological aspects of multivariate statistical models to describe and to assess data from computer-analyzed corneal topographers (CACT) are considered. The data generated by repeated curvature mappings of calibrated steel balls are discussed in detail with the objective of formulating the basic questions and suggesting directions to assess data from clinical applications of CACT. The interpretation of seemingly straightforward concepts such as accuracy and precision is revisited with the objective of understanding its meaning in future clinical and experimental applications of CACT. Some of the statistical problems related to the analysis of corneal astigmatism based on CACT data are also discussed.

Astigmatism↗
PubMed2004

Testing computational hypotheses of brain systems function: a case study with the basal ganglia.

We develop a methodology for testing computational hypotheses about neural functionality articulated in models at the systems level of description. In this approach, the first step is to attempt the construction of a model of the underlying brain system which is consistent with the known anatomy and physiology, but which is also able to exhibit functional properties consistent with a putative computational hypothesis. If this is successful, the second step consists of including additional known pathways into the model and testing the new models to see whether they show an improvement in functional performance (using appropriate performance metrics). A positive outcome is taken as evidence in support of the hypothesis. A final step is to construct 'control' models by including pathways that are not consistent with biological data. In this case a performance detriment is taken as support for the hypothesis. The methodology is applied to the basal ganglia, and builds on a previously published model of this system (Gurney et al 2001 Biol. Cybern. 84 401-23) which was based on the hypothesis that the basal ganglia perform action selection. The realistically constrained models show a selection benefit, while control models show a decrement in selection ability. These results, taken together, provide further validation of our selection hypothesis of basal ganglia function.

Animals↗
PubMed1984

Quantitative assessment of the glandular activity of endocrine cells of gastrointestinal mucosae by computer-assisted analysis of ultrastructural images: methodology.

A method is described for studying the morphological features of endocrine cells of gastrointestinal mucosae in man and some animal species by semi-automatic analysis of ultrastructural images. The method enables possible ultrastructural variations in gastrointestinal endocrine glandular cells of different types to be determined with an acceptable margin of error. Various causes of error are investigated. It is found that the main cause is the choice of microscope magnification, despite the corrections made. The factor of inconsistency in the reproducibility of measurements performed by several operators is also calculated.

Animals↗
PubMed1996

Mathematical modeling of AVM physiology using compartmental network analysis: theoretical considerations and preliminary in vivo validation using a previously developed animal model.

The development of computer modeling technique of cerebral arteriovenous malformations using circuit network analysis, validated with a previously developed animal model is presented. Such a malformation and its vascular connections are rendered into a complex system of interconnecting tubes, which is then simulated by an analogous electrical circuit using commercially available computer software. This methodology was tested using a swine model, of which a detailed computer model was constructed from anatomic and angiographic measurements of the cranial vessels. Flow conditions, before and after creation of the in vivo model, were predicted from the computer model and compared with previously reported in vivo measurements. Detailed analysis of flow within the CAVM nidus was also performed. There was a good correlation between the computer and in vivo models regarding changes in flow and pressure drop across the rete. Flow mapping within the nidus showed localized directional flow that was determined by global inputs, consistent with functional compartmentalization. This method of computer modeling appears promising for studying clinically relevant aspects of cerebral arteriovenous malformation pathophysiology. To our knowledge it is the first computer model to demonstrate functional compartmentalization.

Animals↗
PubMed1995

Molecular biology experimental strategies for craniofacial-oral-dental dysmorphology.

This paper is a minireview of molecular biology experimental strategies for problems within craniofacial-oral-dental biology. Many of these strategies have already made remarkable contributions towards understanding the complex developmental processes associated with craniofacial biology. For example, the utilization of these strategies has resulted in the successful mapping of approximately 70 genes related to craniofacial anomalies (e.g., Pax, retinoic acid receptors, cadhedrins, aggrecan, cell adhesion molecules, substrate adhesion molecules, etc.), 30 genes related to dental tissue disorders (e.g., BMPs, bone morphogenetic proteins; dentin phosphoproteins, dentin sialoglycoproteins, enamelins, amelogenins), 20 genes related to facial clefting defects (e.g., Hox genes, transforming growth factor alpha), and 3 genes related to craniosynostosis (e.g., Msx-2). This minireview highlights selected examples of scientific progress derived from the following experimental strategies: (i) molecular approaches to the organization of the mouse and human chromosomes, with the mapping of specific gene sequences linked to human diseases (e.g., amelogenesis imperfecta, Boston type craniosynostosis, Rieger's syndrome, Treacher Collins syndrome); (ii) reverse genetic approaches for studies of gene function; (iii) homologous recombinations and the advances from "knock-out" transgenic mouse models for human craniofacial-oral-dental diseases; (iv) mutational analyses of congenital craniofacial-oral-dental dysmorphogenesis; (v) structural biology studies using computer-assisted molecular modeling for protein-protein, protein-nucleic acid and protein-inorganic interactions; (vi) computer modeling of genetic paradigms; and (vii) a cluster of newer methodologies including computer-assisted morphometry, new microinjection techniques, new cell membrane and intracellular dyes, and a number of new RNA and DNA viral constructs for the delivery of genes to enhance the resolution of cell fate maps, cell lineage studies and gene therapy approaches to human diseases.

Animals↗
PubMed2000

Internal dosimetry of plutonium using the late urinary excretion.

An attempt has been made to standardize the methodology of internal dose computation from the late urinary excretion data. The methodology was selected keeping in mind the most recent ICRP publications and the results of internal dosimetry intercomparison studies reported in literature. The key element of this methodology is the PC-based computational software LUDEP 2.05, which implements the new model of the human respiratory tract. Late urinary excretion data of three male subjects involved in accidental intakes of plutonium aerosols more than 25 years ago were interpreted in terms of intakes and internal doses with the aid of the standardized methodology. An important implication of this work is that late urinary excretion data of the occupational workers of any plutonium handling facility could be used to show the compliance with the life-time dose limit.

Aerosols↗
PubMed1979

Conceptual and methodological considerations towards the development of computer-controlled research on the electro-physiology of sleep.

A critical discussion of the visual scoring approach to the measurement of sleep electrophysiology details some theoretical shortcomings of that procedural model. An alternative approach employing high-speed, general purpose digital computers is then presented. It is argued that the measurement potential of computers is barely tapped by using computers to score sleep stages and the advantages of collecting data which are suitable for parametric and multivariate statistical analysis are described. Researchers are urged to include detailed reports on their procedural choices along with a discussion of the methodological implications of these procedures. Examples of computer collected data are presented along with a description of some simple data reduction strategies.

Computers↗
PubMed2006

Evaluation of three-dimensional image registration methodologies for in vivo micro-computed tomography.

The advent of in vivo micro-computed tomography (micro-CT) provides a novel approach to measure the temporal adaptation of bone micro-architecture within an individual. Spatial alignment in the scanner between serial scans is challenging, but three-dimensional image registration can be used to superimpose the resulting image data, thus ensuring consistent regions of interest (ROI) for analysis. There have been several approaches to image registration developed, yet little is known about their application to high resolution micro-CT data. The purpose of this study was to explore combinations of three image registration similarity measures and three image interpolators, in addition to multi-resolution registration configurations, for assessment of computational efficiency and accuracy on both in vitro and in vivo micro-CT data. Accuracy measures were assessed by comparison with a gold-standard reference transform based on attached fiducial markers. It was concluded that a mutual information registration similarity measure with a linear image interpolator, applied at steps of increasing image resolution, provided the best compromise between accurate and efficient results. In vivo registration of tibial bone microstructure measured in an ovariectomized rat model provided consistent ROI thus demonstrating the usefulness of three-dimensional image registration for in vivo experimental and clinical micro-CT research. It is a technique that is poised to become commonly utilized for analysis of micro-CT data to diagnose and monitor efficacy of therapy in bone diseases.

Animals↗
PubMed2005

Evaluation of a modified TCLP methodology for RCRA toxicity characterization of computer CPUs.

A leaching method similar to the toxicity characteristic leaching procedure (TCLP) was designed and evaluated for testing of bulky wastes, such as discarded electronic devices. The objective was to meet the intent of the TCLP (same leaching solution, liquid-to-solid ratio and same leaching time) but to allow more representative and rapid testing. The procedure was evaluated by examining lead leaching from computer CPUs as a test case; disassembled CPUs were leached in their entirety (or close to entirety) in a large vessel using a drum rotator. The difference in rotation speed between the large-scale test and the TCLP was found to have no statistical impact on lead leaching. The lack of size reduction resulted in less reducing conditions than the standard TCLP (because of increased iron and zinc leaching), and this resulted in greater lead leaching. For electronic wastes with large amounts of steel, the large-scale procedure provides a more conservative estimate of TCLP lead leaching. The large-scale procedure greatly reduces sample processing effort but does increase the cost of analysis. Evaluation of this approach by the regulatory community is important as the CPUs tested here tended to leach lead at greater than the toxicity characteristic (TC) limit (5 mg/L) using the large-scale test, but less than the TC limit using the standard TCLP.

Computers↗
PubMed2003

Model selection methodology in supervised learning with evolutionary computation.

The expressive power, powerful search capability, and the explicit nature of the resulting models make evolutionary methods very attractive for supervised learning applications in bioinformatics. However, their characteristics also make them highly susceptible to overtraining or to discovering chance relationships in the data. Identification of appropriate criteria for terminating evolution and for selecting an appropriately validated model is vital. Some approaches that are commonly applied to other modelling methods are not necessarily applicable in a straightforward manner to evolutionary methods. An approach to model selection is presented that is not unduly computationally intensive. To illustrate the issues and the technique two bioinformatic datasets are used, one relating to metabolite determination and the other to disease prediction from gene expression data.

Algorithms↗
PubMed2005

Improvement in protein functional site prediction by distinguishing structural and functional constraints on protein family evolution using computational design.

The prediction of functional sites in newly solved protein structures is a challenge for computational structural biology. Most methods for approaching this problem use evolutionary conservation as the primary indicator of the location of functional sites. However, sequence conservation reflects not only evolutionary selection at functional sites to maintain protein function, but also selection throughout the protein to maintain the stability of the folded state. To disentangle sequence conservation due to protein functional constraints from sequence conservation due to protein structural constraints, we use all atom computational protein design methodology to predict sequence profiles expected under solely structural constraints, and to compute the free energy difference between the naturally occurring amino acid and the lowest free energy amino acid at each position. We show that functional sites are more likely than non-functional sites to have computed sequence profiles which differ significantly from the naturally occurring sequence profiles and to have residues with sub-optimal free energies, and that incorporation of these two measures improves sequence based prediction of protein functional sites. The combined sequence and structure based functional site prediction method has been implemented in a publicly available web server.

Algorithms↗
PubMed2004

On the evolution of statistical methods as applied to clinical trials.

This paper describes how statistical methods have evolved in parallel with activities associated with randomized control trials. In particular we emphasize the pivotal role of two papers published in British Journal of Cancer, and the paper describing the Cox proportional hazards model. In addition, the importance of early papers on estimating the sample size required for trials is highlighted. Later developments including the increasing roles for competing risks, multilevel modelling and Bayesian methodologies are described. The interplay between computer software and statistical methodological developments is stressed. Finally some future directions are indicated.

Humans↗
PubMed1993

Antifungal triazole alcohols: a comparative analysis of structure-activity, structure-teratogenicity and structure-therapeutic index relationships using the Multiple Computer-Automated Structure Evaluation (Multi-CASE) methodology.

An increase in the opportunistic fungal infections necessitates a design of new more effective and safer antifungal agents. Triazole alcohols are effective antifungals, but have a risk of teratogenicity associated with them. Therefore, successful design of drugs from this class depends on understanding the structure-activity and structure-teratogenicity relationships in conjunction. To this end, we applied the Multiple Computer-Automated Structure Evaluation (Multi-CASE) methodology to a study of the relationships between the structures of 71 triazole alcohols and their in vitro antifungal activity, teratogenicity, and therapeutic index. For each end point, several relevant structural descriptors were identified. A comparative analysis of the Multi-CASE results indicates that cyano, methoxy groups, and ortho-difluorination on the aromatic ring decrease antifungal activity, but not the therapeutic index because of the concomitant negative contribution to teratogenicity. Metabolically deactivating para-substitution in the benzene ring is beneficial for the therapeutic index in agreement with the idea of metabolically induced teratogenicity. Fluorinated para-alkyl substituents are most preferable. The pattern of ortho-substitution in the benzene ring affects both antifungal and teratogenic activity. This suggests that the relative orientation of the benzene ring with respect to the rest of the molecule may play a modulating role. The Multi-CASE model could correctly predict, a priori, the teratogenicity and antifungal potency of SCH 39304 and ICI 156,066 and be used to optimize the structure and therapeutic index of the latter.

Animals↗
PubMed2004

Methodology for improved detection of coronary stenoses with computed tomographic angiography.

BACKGROUND: Noninvasive angiography is a promising technique for visualization of the coronary lumen; however, current methodologies lead to limited accuracy. We assessed the accuracy of electron beam computed tomographic angiography (EBA) for detection of coronary stenoses, using improved triggering techniques and thinner slice collimation. METHODS: Eighty-six patients with suspected coronary disease were studied with EBA and conventional invasive coronary angiography. Electrocardiographic triggering was performed at a fixed time in end systole to reduce cardiac motion. Thin (1.5 mm) slices were obtained with 1.5 mm table incrementation. In axial (2-dimensional) EBA images and 3-dimensional reconstructions, all coronary arteries and side branches with a diameter of >or=1.5 mm were assessed for the presence of stenoses with >50% diameter reduction. Both EBA and invasive angiographic images were assessed in a blinded manner. RESULTS: In comparison to invasive coronary angiography, EBA correctly classified 49 of 53 patients (92%) as having at least 1 coronary stenosis. Overall, 103 stenoses with >50% diameter reduction were present, and 93 of these lesions were correctly detected by EBA (sensitivity 90%, specificity 93%, positive predictive value 84%, and negative predictive value 96%). Only 5% of vessels could not be assessed, predominantly due to significant calcification. CONCLUSIONS: Thinner slice collimation and end-systolic electrocardiographic triggering improves accuracy and assessment of coronary EBA for the detection of obstructive coronary artery disease, making this study clinically useful in the evaluation of obstructive coronary artery disease.

Coronary Angiography↗