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Results for “Computing Methodologies”

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At least 91 records · Page 5Linked to original sources

PubMed1990

Three-dimensional autoradiographic localization of quench-corrected glycine receptor specific activity in the mouse brain using 3H-strychnine as the ligand.

The autoradiographic analysis of neurotransmitter receptor distribution is a powerful technique that provides extensive information on the localization of neurotransmitter systems. Computer methodologies are described for the analysis of autoradiographic material which include quench correction, 3-dimensional display, and quantification based on anatomical boundaries determined from the tissue sections. These methodologies are applied to the problem of the distribution of glycine receptors measured by 3H-strychnine binding in the mouse CNS. The most distinctive feature of this distribution is its marked caudorostral gradient. The highest densities of binding sites within this gradient were seen in somatic motor and sensory areas; high densities of binding were seen in branchial efferent and special sensory areas. Moderate levels were seen in nuclei related to visceral function. Densities within the reticular formation paralleled the overall gradient with high to moderate levels of binding. The colliculi had low and the diencephalon had very low levels of binding. No binding was seen in the cerebellum or the telencephalon with the exception of the amygdala, which had very low levels of specific binding. This distribution of glycine receptors correlates well with the known functional distribution of glycine synaptic function. These data are illustrated in 3 dimensions and discussed in terms of the significance of the analysis techniques on this type of data as well as the functional significance of the distribution of glycine receptors.

Animals↗

PubMedDate not supplied

[Application of multifactorial statistical calculation in research for a correlation between lipid soluble vitamins and cancer].

The aim of this work was to combine computer methodology applied to multi-factorial statistical calculations with liquid chromatography results on the analysis of serum levels of retinol, bêta-carotene and tocopherols in healthy subjects and in patients with various cancers associated with certain tumor markers. Our results show that the serum levels of the vitamins studied differed in cancer patients in comparison to healthy controls. These results also confirm published data showing that serum variations are generally not characteristic of a specific tumor localization, without indicating if these variations are a cause or an effect of tumor development. Computerized multifactorial analysis taking into account the levels of all vitamins and tumor markers chosen, however, enabled us to classify the different tumors in five groups: cancers of the nervous system, urogenital tract cancers, laryngo-pulmonary cancers and two groups of digestive system cancers. This new approach may lead to the constitution of a data bank on the localization of tumors, as well as a reference system for all analyses of serum levels of vitamins associated with tumor markers.

Adult↗

PubMed2002

A novel scoring function for predicting the conformations of tightly packed pairs of transmembrane alpha-helices.

Pairs of helices in transmembrane (TM) proteins are often tightly packed. We present a scoring function and a computational methodology for predicting the tertiary fold of a pair of alpha-helices such that its chances of being tightly packed are maximized. Since the number of TM protein structures solved to date is small, it seems unlikely that a reliable scoring function derived statistically from the known set of TM protein structures will be available in the near future. We therefore constructed a scoring function based on the qualitative insights gained in the past two decades from the solved structures of TM and soluble proteins. In brief, we reward the formation of contacts between small amino acid residues such as Gly, Cys, and Ser, that are known to promote dimerization of helices, and penalize the burial of large amino acid residues such as Arg and Trp. As a case study, we show that our method predicts the native structure of the TM homodimer glycophorin A (GpA) to be, in essence, at the global score optimum. In addition, by correlating our results with empirical point mutations on this homodimer, we demonstrate that our method can be a helpful adjunct to mutation analysis. We present a data set of canonical alpha-helices from the solved structures of TM proteins and provide a set of programs for analyzing it (http://ashtoret.tau.ac.il/~sarel). From this data set we derived 11 helix pairs, and conducted searches around their native states as a further test of our method. Approximately 73% of our predictions showed a reasonable fit (RMS deviation <2A) with the native structures compared to the success rate of 8% expected by chance. The search method we employ is less effective for helix pairs that are connected via short loops (<20 amino acid residues), indicating that short loops may play an important role in determining the conformation of alpha-helices in TM proteins.

Cell Membrane↗

PubMed1995

Methodologic aspects of computed microtomography to monitor the development of osteoporosis in gastrectomized rats.

RATIONALE AND OBJECTIVES: We investigated the methodologic development of computed microtomography (CMT) for monitoring the development of osteoporosis in male Sprague-Dawley rats. METHODS: Eight rats were gastrectomized and eight rats were sham operated. Femurs, tibias, and tails were prepared, and CMT scans with spatial resolutions of 5-500 microns were made. Bone diameters, bone areas, and moments of inertia were determined from the CMT scans. Optimal slice position and the need for spatial resolution and energy optimization for future in vivo applications were investigated. RESULTS: Gastrectomy caused dramatic changes in the bone architecture of the tibia and the femur. The main features were vacuolization of the bone and reduced amounts of compact bone. Although the outer diameters of tubular bones (femur and tibia) were largely unaffected, their inner diameters were greatly increased following gastrectomy. Relative bone area and moment of inertia were greatly reduced. The optimal photon energy was 12 keV. CONCLUSION: It is possible to monitor gastrectomy-evoked changes in bone morphology at various sites in rats using CMT scanning. The changes are suggestive of osteoporosis. By optimizing the energy spectrum and spatial resolution, as well as choosing the proper slice position, it should be possible to keep absorbed doses low enough to avoid acute radiation injury in repeated in vivo measurements.

Animals↗

PubMed1998

Deconstructing (and reconstructing) cell migration.

An overriding objective in cell biology is to be able to relate properties of particular molecular components to cell behavioral functions and even physiology. In the "traditional" mode of molecular cell biology, this objective has been tackled on a molecule-by-molecule basis, and in the "future" mode sometimes termed "functional genomics," it might be attacked in a high-throughput, parallel manner. Regardless of the manner of approach, the relationship between molecular-level properties and cell-level function is exceedingly difficult to elucidate because of the large number of relevant components involved, their high degree of interconnectedness, and the inescapable fact that they operate as physico-chemical entities-according to the laws of kinetics and mechanics-in space and time within the cell. Cell migration is a prominent representative example of such a cell behavioral function that requires increased understanding for both scientific and technological advance. This article presents a framework, derived from an engineering perspective regarding complex systems, intended to aid in developing improved understanding of how properties of molecular components influence the function of cell migration. That is, cell population migration behavior can be deconstructed as follows: first in terms of a mathematical model comprising cell population parameters (random motility, chemotaxis/haptotaxis, and chemokinesis/haptokinesis coefficients), which in turn depend on characteristics of individual cell paths that can be analyzed in terms of a mathematical model comprising individual cell parameters (translocation speed, directional persistence time, chemotactic/haptotactic index), which in turn depend on cell-level physical processes underlying motility (membrane extension and retraction, cell/substratum adhesion, cell contractile force, front-vs.-rear asymmetry), which in turn depend on molecular-level properties of the plethora of components involved in governance and regulation of these processes. Hence, the influence of any molecular component on cell population migration can be understood by reconstructing these relationships from the molecular level to the physical process level to the individual cell path level to the cell population distribution level. This approach requires combining experimental, theoretical, and computational methodologies from molecular biology, biochemistry, biophysics, and bioengineering.

Cell Count↗

PubMed2003

The relaxed complex method: Accommodating receptor flexibility for drug design with an improved scoring scheme.

An extension of the new computational methodology for drug design, the "relaxed complex" method (J.-H. Lin, A. L. Perryman, J. R. Schames, and J. A. McCammon, Journal of the American Chemical Society, 2002, vol. 24, pp. 5632-5633), which accommodates receptor flexibility, is described. This relaxed complex method recognizes that ligand may bind to conformations that occur only rarely in the dynamics of the receptor. We have shown that the ligand-enzyme binding modes are very sensitive to the enzyme conformations, and our approach is capable of finding the best ligand enzyme complexes. Rapid docking serves as an efficient initial filtering method to screen a myriad of docking modes to a limited set, and it is then followed by more accurate scoring with the MM/PBSA (Molecular Mechanics/Poisson Boltzmann Surface Area) approach to find the best ligand-receptor complexes. The MM/PBSA scorings consistently indicate that the calculated binding modes that are most similar to those observed in the x-ray crystallographic complexes are the ones with the lowest free energies.

Algorithms↗

PubMed1993

A microsatellite-based multipoint index map of human chromosome 22.

Utilizing the CEPH (Centre d'Etude du Polymorphism Humain) reference panel and genotyping data for 24 simple tandem repeat polymorphism (STRP) markers, we have constructed a 15-locus multipoint genetic framework map of human chromosome 22. The markers form a continuous linkage group of 51 cM in males and 81 cM in females. Likely genetic locations are provided for 9 additional STRP sequences. The map was constructed employing the CRIMAP computational methodology to build the multipoint map via a stepwise algorithm. The quality of the framework map was evaluated using a battery of statistical diagnostics that suggest a typing error frequency of 0.1% for markers within the map.

Base Sequence↗

PubMed1991

Separation of o-phthalaldehyde-mercaptoethanol derivatives of amino acids from blood plasma on reversed-phase Nova-Pak C18 cartridges.

A separation of 25 o-phthalaldehyde-mercaptoethanol derivatives of primary amino acids in plasma prepared from human blood has been developed for Waters 10 cm x 0.8 cm I.D., 4-microns Nova-Pak C18 Radial-Pak cartridges. A binary gradient system with solvent-switching capability for the A pump is required. Computer methodologies have been utilized to develop mobile phase mixtures of phosphate buffer (pH 6.9), water, methanol and tetrahydrofuran. Advantages of the method include simple sample preparation, fast turnover time (67 min including the pre-column Autotag derivatization procedure) and exceptional column durability (several hundred analyses).

Amino Acids↗

PubMed1990

A detailed multipoint gene map of chromosome 1q.

Utilizing genotyping data for 23 markers, we have constructed a 21-locus multipoint genetic map of the long arm of chromosome 1. Five new RFLPs are reported. The map integrates anonymous loci from previous primary linkage maps and incorporates markers for 10 coding sequences. These markers form a continuous linkage group of 85 cM in males and 141 cM in females. The map was constructed employing the LINKAGE and CRIMAP computational methodologies via a stepwise algorithm.

Algorithms↗

PubMed1994

Combining rule-based reasoning and mathematical modelling in diabetes care.

A prototype computer system utilising a model of carbohydrate metabolism linked to an expert system is described. The prototype which integrates quantitative and qualitative computational methodologies can be used to predict blood glucose profiles and adjust insulin doses in insulin-dependent (type I) diabetic subjects. A feedback loop insulin-dosage optimisation procedure which allows quantitative advice to be generated is also described. Possible clinical applications for the system, which is intended for educational use and clinically as a research tool to try and attain normoglycaemia, are discussed.

Algorithms↗

PubMed2003

Multifocal versus monofocal intraocular lenses in cataract surgery: a systematic review.

OBJECTIVE: To assess the visual effects of multifocal intraocular lenses (IOLs) compared with the current standard treatment of monofocal IOL implantation. DESIGN: Systematic literature review and meta-analysis of randomized controlled trials. METHODS: The study was performed according to the Cochrane Collaboration methodology. Computer database and manual searches were made to identify all randomized trials comparing multifocal IOL implantation with a monofocal control group. Data were extracted using a standardized form and analyzed using Review Manager software. When study reporting allowed meaningful comparison, meta-analysis was performed. The chi-square test was used to examine heterogeneity between studies. Odds ratios were calculated for dichotomous outcomes and standardized mean differences for continuous variables. MAIN OUTCOME MEASURES: There is no single outcome measure that can be thought of as summarizing the efficacy of an IOL. A number of different outcomes had to be examined. The primary outcomes for this review were distance and near visual acuity (unaided and corrected) and spectacle dependence. The secondary outcomes for this review included depth of field, contrast sensitivity, glare, subjective assessment of quality of life or visual function, and surgical complications. RESULTS: Eight trials were identified. There was significant variability among the trials in the outcomes reported. Distance acuity was similar in multifocal and monofocal IOLs. Unaided near vision tended to improve with the multifocal IOL. This resulted in decreased spectacle dependence with use of the multifocal IOL. Adverse effects included reduced contrast sensitivity and the subjective experience of halos around lights. CONCLUSIONS: Multifocal IOLs are effective at improving near vision relative to monofocal IOLs. Whether that improvement outweighs the adverse effects of multifocal IOLs will vary between patients, with motivation to achieve spectacle independence likely to be the deciding factor.

Cataract Extraction↗

PubMed2001

Recent developments in computational proteomics.

The mapping of the human genome was completed earlier this year and efforts are underway to understand the role of gene products (i.e. proteins) in biological pathways and human disease and to exploit their functional roles to derive protein therapeutics and protein-based drugs. A key component to the next revolution in the 'post-genomic' era will be the increasingly widespread use of protein structure in rational experimental design. Improvements in quality, availability and utility of large-scale three- and four-dimensional protein structural information are enabling a revolution in rational design, having particular impact on drug discovery and optimization. New computational methodologies now yield modeled structures that are, in many cases, quantitatively comparable with crystal structures, at a fraction of the cost.

Journal Article↗

PubMed1997

The Hofmeister series: salt and solvent effects on interfacial phenomena.

Advances in experimental and computational methodologies have led to a recent renewed interest in the Hofmeister series and its molecular origins. New results are surveyed and assessed. Insights into the underlying mechanisms have been gained, although deeper molecular understanding still seems to be elusive. The principal reason appears to be that the Hofmeister series emerges from a combination of a general effect of cosolutes (salts, etc.) on solvent structure, and of specific interactions between the cosolutes and the solute (protein or other biopolymer). Hence every system needs to be studied individually in detail, a state of affairs which is likely to continue for some time. A deeper understanding of the Hofmeister series can be an extraordinarily valuable guide to designing experiments, including not only those probing the series per se, but also those designed to elucidate the adsorption, aggregation and stabilization phenomena which underlie so many biological events. The aim of this review is to provide an up-to-date framework to guide such understanding, consolidating recent advances in the many fields on which the Hofmeister series impinges.

Biophysical Phenomena↗

PubMed2001

Use of MCSS to design small targeted libraries: application to picornavirus ligands.

Computational methods were used to design structure-based combinatorial libraries of antipicornaviral capsid-binding ligands. The multiple copy simultaneous search (MCSS) program was employed to calculate functionality maps for many diverse functional groups for both the poliovirus and rhinovirus capsid structures in the region of the known drug binding pocket. Based on the results of the MCSS calculations, small combinatorial libraries consisting of 10s or 100s of three-monomer compounds were designed and synthesized. Ligand binding was demonstrated by a noncell-based mass spectrometric assay, a functional immuno-precipitation assay, and crystallographic analysis of the complexes of the virus with two of the candidate ligands. The P1/Mahoney poliovirus strain was used in the experimental studies. A comparison showed that the MCSS calculations had correctly identified the observed binding site for all three monomer units in one ligand and for two out of three in the other ligand. The correct central monomer position in the second ligand was reproduced in calculations in which the several key residues lining the pocket were allowed to move. This study validates the computational methodology. It also illustrates that subtle changes in protein structure can lead to differences in docking results and points to the importance of including target flexibility, as well as ligand flexibility, in the design process.

Benzimidazoles↗

PubMed1999

Probing the topological arrangement of the N- and C-terminal residues of bradykinin for agonist activity at the B1 receptor.

The conformational features of H-Lys-Arg-Ado-Ser-Pro-Phe-OH (Ado = 12-aminododecanoic acid), a des-Arg(9) analogue of Lys-bradykinin, have been determined by high-resolution NMR in the presence of a zwitterionic lipid environment. The analogue is the most active member of a series of analogues designed to probe the topological arrangement of the N- and C-termini required for agonistic activity at the B1 kinin receptor. A novel computational procedure for the utilization of NOE constraints from cis and trans configurational isomers is illustrated. Only with this computational methodology could the structural features of the N-terminus of the peptide be determined. Using radical-induced relaxation of the (1)H NMR signals, we measured the topological orientation of the peptide with respect to the zwitterionic lipid interface. The results indicate that the long, alkyl chain of the Ado amino acid imbeds into the lipid surface. The structural features of the C-terminus of the B1-selective analogue consist of a well-defined turn. Although removed from a standard beta-turn, required for activity at the B2 kinin receptor, the topological orientation of the side chains of the des-Arg(9) compound are surprisingly similar to those previously observed for beta-turn-containing bradykinin analogues. Therefore, we attribute the high B1 receptor selectivity, observed upon removal of Arg(9) from bradykinin, solely to the loss of a charged amino acid and not to altered structural features.

Kallidin↗

PubMed1991

Computation of ionic distributions around charged biomolecular structures: results for right-handed and left-handed DNA.

We introduce an efficient computational methodology employing the potentials of mean force approach for estimating the detailed three-dimensional ionic distributions around arbitrarily complex charged biomolecular structures for all monovalent salt concentrations of practical interest (e.g., 0.1-5.0 M NaCl). Such distributions are required for specifying thermodynamic and structure-specific features of ion-mediated interactions of charged proteins, DNA and RNA, membranes, and macromolecular assemblies. As a first application, we present results for distributions around the B and ZI conformers of the DNA oligomer d(C-G)18.d(C-G)18. The ionic microenvironment depends strongly on the DNA conformation, sequence, and bulk salt concentrations.

DNA↗

PubMed2002

Persistent organic pollutants exposure assessment using the US Total Diet Study.

The assessment presented in the core paper of this debate by Schafer and Kegley does not adequately describe the computational methodology or sources of data that were used to estimate exposures. While it is difficult to determine from the article, the exposure estimates seem to be very dependent on action levels, rather than on empirically derived data. There is no adequate presentation of analytical methods, limits of detection, or the significance of non-detects in deriving estimates of exposure.

Diet Surveys↗

PubMed2003

Flow and pressure distributions in vascular networks consisting of distensible vessels.

We examine the influence of vessel distensibility on the fraction of the total network flow passing through each vessel of a model vascular network. An exact computational methodology is developed yielding an analytic proof. For a class of structurally heterogeneous asymmetric vascular networks, if all the individual vessels share a common distensibility relation when the total network flow is changed, this methodology proves that each vessel will continue to receive the same fraction of the total network flow. This constant flow partitioning occurs despite a redistribution of pressures, which may result in a decrease in the diameter of one and an increase in the diameter of the other of two vessels having a common diameter at a common pressure. This theoretical observation, taken along with published experimental observations on pulmonary vessel distensibilities, suggests that vessel diameter-independent distensibility in the pulmonary vasculature may be an evolutionary adaptation for preserving the spatial distribution of pulmonary blood flow in the face of large variations in cardiac output.

Algorithms↗