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PubMed2005

Extraction, interpretation and validation of information for comparing samples in metabolic LC/MS data sets.

LC/MS is an analytical technique that, due to its high sensitivity, has become increasingly popular for the generation of metabolic signatures in biological samples and for the building of metabolic data bases. However, to be able to create robust and interpretable (transparent) multivariate models for the comparison of many samples, the data must fulfil certain specific criteria: (i) that each sample is characterized by the same number of variables, (ii) that each of these variables is represented across all observations, and (iii) that a variable in one sample has the same biological meaning or represents the same metabolite in all other samples. In addition, the obtained models must have the ability to make predictions of, e.g. related and independent samples characterized accordingly to the model samples. This method involves the construction of a representative data set, including automatic peak detection, alignment, setting of retention time windows, summing in the chromatographic dimension and data compression by means of alternating regression, where the relevant metabolic variation is retained for further modelling using multivariate analysis. This approach has the advantage of allowing the comparison of large numbers of samples based on their LC/MS metabolic profiles, but also of creating a means for the interpretation of the investigated biological system. This includes finding relevant systematic patterns among samples, identifying influential variables, verifying the findings in the raw data, and finally using the models for predictions. The presented strategy was here applied to a population study using urine samples from two cohorts, Shanxi (People's Republic of China) and Honolulu (USA). The results showed that the evaluation of the extracted information data using partial least square discriminant analysis (PLS-DA) provided a robust, predictive and transparent model for the metabolic differences between the two populations. The presented findings suggest that this is a general approach for data handling, analysis, and evaluation of large metabolic LC/MS data sets.

Chromatography, Liquid↗

PubMed1993

Similarities between dynamic elastance of left ventricular chamber and papillary muscle of rabbit heart.

The frequency-dependent dynamic elastance of the left ventricle (LV) of isolated rabbit heart was determined and compared with dynamic stiffness of excised rabbit papillary muscle. Comparison was made in three states: 1) relaxed, 2) BaCl2 contracture, and 3) rigor. Dynamic chamber elastance was determined by pressure-to-volume ratio at 12 frequencies of sinusoidal volume variation between 0.1 and 30 Hz. Dynamic elastance during BaCl2 contracture was distinctly different from that during either relaxed or rigor states. Characteristics of BaCl2 contracture were 1) as frequency increased, polar plot of real and imaginary elastance showed a progressively opening clockwise spiral that tended eventually to become tangent to the apogee of a semi-circle by 30 Hz; 2) modulus spectrum exhibited asymptotes at low and high frequencies with an intervening dip to a minimum at 1.25 Hz; and 3) phase showed a sharp transition at dip frequency from small negative values at lower frequencies to large positive values at intermediate frequencies and then declined at highest frequencies. There was little dependence of dynamic elastance on frequency in both relaxed and rigor states. Dynamic muscle stiffness exhibited all features of dynamic chamber elastance in all three states. We concluded that dynamic elements responsible for myofiber stiffness were also responsible for LV chamber elastance. Furthermore, it was possible to describe and interpret dynamic chamber elastance and muscle stiffness with a common model based on muscle cross-bridge theory. This model did a reasonable job of reproducing all important features of experimentally observed LV chamber elastance and muscle stiffness. Thus dynamic homologies between chamber and muscle were established in experimental data and in the fact that a single interpretive model served equally well for both chamber elastance and muscle stiffness.

Animals↗

PubMed2000

A physical model for dual-energy X-ray absorptiometry--derived bone mineral density.

RATIONALE AND OBJECTIVES: Dual-energy X-ray absorptiometry (DXA)-derived areal bone mineral density (BMD) is an established predictor of osteoporotic fractures and reflects bone strength as well. The goal of this study was to develop and validate a physical model for appropriate interpretation of BMD. METHODS: DXA and peripheral quantitative computed tomography investigations of the distal tibia (n = 45), proximal tibia (n = 12), distal femur (n = 26), and distal radius (n = 34) were carried out. The DXA-derived BMD was analytically modeled as a nonlinear function of volumetric bone mineral apparent density and the cross-sectional area (eCSA) of given bone; ie, BMD(mod) = apparent BMD x square root of eCSA. RESULTS: At every measured skeletal site, the relationship between BMD and BMD(mod) was systematically stronger than that observed separately between BMD and apparent BMD or cross-sectional area. The models (r2) explained 85%, 94%, 87%, and 74% of the variability in BMD at the distal tibia, proximal tibia, distal femur, and distal radius, respectively. CONCLUSIONS: The mutual contributions of bone density and size to BMD can vary to some extent in a site-dependent fashion. This dual nature of BMD on one hand provides a reasonable mechanical explanation for why BMD is a good surrogate of bone strength and a predictor of osteoporotic fractures but on the other hand, complicates its detailed interpretation.

Absorptiometry, Photon↗

PubMed1994

Measurement of long-range2 13C-1H coupling constants of 95% uniformly 13C-labeled polysaccharide from Streptococcus mitis J22.

The coaggregation of Streptococcus mitis strain J22 in the early stages of dental plaque formation has been shown to result from interaction of cell wall polysaccharides with lectins on the surface of other oral bacterial species. This bacterium was grown in a medium containing 13C as the sole carbon source. We have isolated the lectin receptor polysaccharide from this strain with full enrichment in 13C and have determined a number of two-bond and three-bond 13C-1H coupling constants from measurements of the offsets in two-dimensional homonuclear nmr spectra [exclusive correlated spectroscopy (E-COSY) method]. A scheme for reliable extraction of these coupling constants from homonuclear Hartmann-Hahn and nuclear Overhauser effect spectroscopy spectra is tested in model compounds. We interpret the three-bond coupling across the glycosidic linkage in terms of dihedral angles in order to provide conformational information to supplement molecular modeling and nuclear Overhauser effect data. We show that the E-COSY method works well even for coupling constants smaller than the nmr line width and that a number of the 3JCH across the glycosidic linkage are in the range of 1-2 Hz, which is much smaller than many previously reported values.

Carbohydrate Conformation↗

PubMed2004

Modelling in vitro hepatotoxicity using molecular interaction fields and SIMCA.

There is currently a great deal of interest in creating computational tools for predicting the pharmacological properties of drug development candidates, ranging from physicochemical properties such as pK(a) and solubility to more complex biological properties such as oral bioavailability and toxicity. The limiting factor in many cases is a shortage of good data from which to construct training sets. In other cases, large amounts of data are available, but they use surrogate end-points or are comprised of compounds very different from those usually encountered in drug discovery and development. In such cases large training sets and global models are not necessarily better than local models based on smaller data sets. Such considerations make it as important to examine the available data carefully so as to avoid over-interpretation of the models obtained as it is to minimise errors in prediction per se. The kinds of complications likely to be encountered for in vitro hepatotoxicity modelling are discussed in general terms and illustrated in particular by SIMCA analysis of data obtained from assays of cultured hepatocytes for a large, structurally diverse data set and a smaller, much more focussed one.

Adenosine Triphosphate↗

PubMed1985

Equilibrium muscle cross-bridge behavior. Theoretical considerations.

We have developed a model for the equilibrium attachment and detachment of myosin cross-bridges to actin that takes into account the possibility that a given cross-bridge can bind to one of a number of actin monomers, as seems likely, rather than to a site on only a single actin monomer, as is often assumed. The behavior of this multiple site model in response to constant velocity, as well as instantaneous stretches, was studied and the influence of system parameters on the force response explored. It was found that in the multiple site model the detachment rate constant has considerably greater influence on the mechanical response than the attachment rate constant. It is shown that one can obtain information about the detachment rate constants either by examining the relationship between the apparent stiffness and duration of stretch for constant velocity stretches or by examining the force-decay rate constants following an instantaneous stretch. The main effect of the attachment rate constant is to scale the mechanical response by influencing the number of attached cross-bridges. The significance of the modeling for the interpretation of experimental results is discussed.

Actins↗

PubMedDate not supplied

Modeling robust QSAR. 1. Coding molecules in 3D-QSAR--from a point to surface sectors and molecular volumes.

Shape analysis is a powerful tool in chemistry and drug design. In the current work, we compare the results of CoMFA and Comparative Molecular Surface Analysis (CoMSA), the 3D-QSAR method, for a series of hypolipidemic and antiplatelet asarones and antifungal N-myristoyltransferase inhibitors. In this publication we show that a sector CoMSA formalism enables an analysis of the biological activity that is more directly related to the molecular shape and individual molecular functionalities than the traditional uniform and directionless CoMFA field. Iterative Variable Elimination allowed us to identify the potential pharmacophoric sites. We modeled QSARs for both series and demonstrate that sector-based molecular descriptors give very predictive models and allow one to generate a spatial interpretation of the QSAR models. In particular, we identified the central aromatic ring and carbonyl functions as the moieties determining the activity of the asarones series, while the pattern of substitution of the aromatic ring determines the activity of N-myristoyltransferase inhibitors.

Acyltransferases↗

PubMed2005

A functional-structural model of elongation of the grass leaf and its relationships with the phyllochron.

The emergence of a regular phyllochron from the dynamic processes of leaf initiation, leaf elongation and whorl construction suggests causal relationships between leaf elongation and leaf emergence. This paper presents a hypothesis as to how the ontogeny of the growth zone of leaves is triggered by emergence events, and implements it in a dynamic model of leaf elongation. Two different experiments, presenting two contrasted cases of relationships between leaf emergence and kinetics of leaf elongation, were analysed and interpreted with the model in terms of the functioning of the growth zone. Analysis of elongation kinetics revealed that the hypothesis allows for several contrasted elongation patterns that were observed, and for a regular phyllochron emerging from the variable dynamic of elongation. The model was able to simulate these patterns, and helped to identify the mechanisms underlying the key points of the analysis. The hypothesis is not demonstrated, but its coherence and robustness are established, which should inform a renewal of the modelling of leaf elongation in architectural models.

Models, Biological↗

PubMed2000

Differential maintenance and frequency-dependent tuning of LTP at hippocampal synapses of specific strains of inbred mice.

Transgenic and knockout mice are used extensively to elucidate the molecular mechanisms of hippocampal synaptic plasticity. However, genetic and phenotypic variations between inbred mouse strains that are used to construct genetic models may confound the interpretation of cellular neurophysiological data derived from these models. Using in vitro slice stimulation and recording methods, we compared the membrane biophysical, cellular electrophysiological, and synaptoplastic properties of hippocampal CA1 neurons in four specific strains of inbred mice: C57BL/6J, CBA/J, DBA/2J, and 129/SvEms/J. Hippocampal long-term potentiation (LTP) induced by theta-pattern stimulation, and by repeated multi-burst 100-Hz stimulation at various interburst intervals, was better maintained in area CA1 of slices from BL/6J mice than in slices from CBA and DBA mice. At an interburst interval of 20 s, maintenance of LTP was impaired in CBA and DBA slices, as compared with BL/6J slices. When the interburst interval was reduced to 3 s, induction of LTP was significantly enhanced in129/SvEms slices, but not in DBA and CBA slices. Long-term depression (LTD) was not significantly different between slices from these four strains. For the four strains examined, CA1 pyramidal neurons showed no significant differences in spike-frequency accommodation, membrane input resistance, and number of spikes elicited by current injection. Synaptically-evoked glutamatergic postsynaptic currents did not significantly differ among CA1 pyramidal neurons in these four strains. Since the observed LTP deficits resembled those previously seen in transgenic mice with reduced hippocampal cAMP-dependent protein kinase (PKA) activity, we searched for possible strain-dependent differences in cAMP-dependent synaptic facilitation induced by forskolin (an activator of adenylate cyclase) and IBMX (a phosphodiesterase inhibitor). We found that forskolin/IBMX-induced synaptic facilitation was deficient in area CA1 of DBA/2J and CBA/J slices, but not in BL/6J and 129/SvEms/J slices. These defects in cAMP-induced synaptic facilitation may underlie the deficits in memory, observed in CBA/J and DBA/2J mice, that have been previously reported. We conclude that hippocampal LTP is influenced by genetic background and by the temporal characteristics of the stimulation protocol. The plasticity of hippocampal synapses in some inbred mouse strains may be "tuned" to particular temporal patterns of synaptic activity. From a broader perspective, our data support the notion that strain-dependent variation in genetic background is an important factor that can influence the synaptoplastic phenotypes observed in studies that use genetically modified mice to explore the molecular bases of synaptic plasticity.

Action Potentials↗

PubMed2003

The InterMed approach to sharable computer-interpretable guidelines: a review.

InterMed is a collaboration among research groups from Stanford, Harvard, and Columbia Universities. The primary goal of InterMed has been to develop a sharable language that could serve as a standard for modeling computer-interpretable guidelines (CIGs). This language, called GuideLine Interchange Format (GLIF), has been developed in a collaborative manner and in an open process that has welcomed input from the larger community. The goals and experiences of the InterMed project and lessons that the authors have learned may contribute to the work of other researchers who are developing medical knowledge-based tools. The lessons described include (1) a work process for multi-institutional research and development that considers different viewpoints, (2) an evolutionary lifecycle process for developing medical knowledge representation formats, (3) the role of cognitive methodology to evaluate and assist in the evolutionary development process, (4) development of an architecture and (5) design principles for sharable medical knowledge representation formats, and (6) a process for standardization of a CIG modeling language.

Computer Systems↗

PubMed2004

Analysis of longitudinal metabolomics data.

MOTIVATION: Metabolomics datasets are generally large and complex. Using principal component analysis (PCA), a simplified view of the variation in the data is obtained. The PCA model can be interpreted and the processes underlying the variation in the data can be analysed. In metabolomics, often a priori information is present about the data. Various forms of this information can be used in an unsupervised data analysis with weighted PCA (WPCA). A WPCA model will give a view on the data that is different from the view obtained using PCA, and it will add to the interpretation of the information in a metabolomics dataset. RESULTS: A method is presented to translate spectra of repeated measurements into weights describing the experimental error. These weights are used in the data analysis with WPCA. The WPCA model will give a view on the data where the non-uniform experimental error is accounted for. Therefore, the WPCA model will focus more on the natural variation in the data. AVAILABILITY: M-files for MATLAB for the algorithm used in this research are available at http://www-its.chem.uva.nl/research/pac/Software/pcaw.zip.

Algorithms↗

PubMed1998

Application of the Spherical Harmonic Model to the Study of the Terminal nu(CO) Spectra of Transition Metal Carbonyl Clusters.

The application of the spherical harmonic model to the interpretation of the terminal nu(CO) spectra of transition metal carbonyl clusters is explored. Unless there is strong spectral evidence to the contrary (when the tensor harmonic model is applicable), the coupling between CO vibrators at each metal atom is to be ignored when these vibrators are symmetry-related. The overwhelming majority of carbonyl clusters conform to the spherical harmonic model, either in its simplest form-in which only a single infrared band is observed in the solution infrared spectrum-or in its more elaborate form. In the latter, bands of lower intensity are observed on the low-frequency side of the intense band. The greater the separation from the intense band, the weaker the additional band, indicating an intensity stealing mechanism. The observations have been interpreted in terms of a "cluster selection rule" analogous to the "surface selection rule" of metal surface spectroscopy and the implications of this rule are discussed.

Journal Article↗

PubMed2000

Dynamics and ordering in a spin-labeled oligonucleotide observed by 220 GHz electron paramagnetic resonance.

The dynamics of a newly synthesized cytosine spin-label and the spin-labeled pentamer TTC*TT have been observed by high-frequency (220 GHz) electron paramagnetic resonance (EPR) in aqueous solution at ambient temperature using only nanomolar amounts of spin-label. Temperature studies were carried out for both labeled species in buffer containing glycerol. The motion of the spin-labeled monomer could be fitted using a model of fully anisotropic rotation (FAR) over the entire temperature range studied. In the single-stranded pentamer, the high-field spectra are best interpreted using a model of microscopic ordering with macroscopic disorder (MOMD) with the probe in a highly nonpolar environment. The observed local order parameters of 0.60-0.70 suggest a micelle-like structure in which the label is tightly packed with the hydrophobic bases. These preliminary studies illustrate how the excellent orientation selectivity of high-field EPR provides new dynamic information about local base motions in DNA, and also how high-field EPR of spin-labels allows one to discriminate accurately between the effects of local versus global motions in spin-labeled macromolecules.

Base Sequence↗

PubMed1997

Simulation of the clonal growth of Bostrychia radicans (Ceramiales-Rhodophyta) using Lindenmayer systems.

A mathematical model for the clonal growth of the alga Bostrychia radicans was constructed based on architectural growth rules and Lindenmayer systems. The sequence of theoretical growth and invasive strategy of space is shown in several graphical schemes which represent different steps of the model. We postulate that Bostrychia radicans has a 'phalanx' strategy of colonization (Lovett Doust, L. 1981. J. Ecol. 69, 743-755.) based on the biological interpretation of the model and field observations.

Eukaryota↗

PubMed1999

An attribution-emotion model of helping behavior.

To investigate the help-giving judgment of the attribution-emotion model further, data from five manifest variables of controllability, responsibility, anger, sympathy, and help-giving, were subjected to path analysis, which provided an easy interpretation of the model. Participants were 90 men and 81 women in an introductory psychology course.

Adult↗

PubMed1990

Two equally valid interpretations of the linear multicompartment mammillary pharmacokinetic model.

In pharmacokinetic modeling it is common to use compartmental structures to describe the disposition of a drug in the blood or plasma. Typically, a linear multicompartment mammillary model is equated with the multiexponential equation derived from observing the decay of the plasma drug concentration following an intravascular injection. Classically, the mammillary models are constructed so that the concentrations in each of the compartments are equal at steady state, the apparent volume of distribution at steady state is equal to the sum of the individual compartment volumes, and the apparent volume of each peripheral compartment is equal to the ratio of its intercompartmental rate constants times the central compartment volume. On the basis of what can be measured in the plasma, however, it is equally valid to assume that the sizes of the peripheral compartment volumes are equal to the central compartment volume and that the steady-state concentration in each peripheral compartment is equal to the ratio of its intercompartmental rate constants times the concentration in the central compartment. In fact, these are but two of an infinite number of interpretations of the peripheral compartment volumes.

Infusions, Intravenous↗

PubMed1993

Automated interpretation of cardiac arrhythmias. Design and evaluation of a computerized model.

Historically, the development of computerized models that utilize the deductive methods used by clinicians for the interpretation of cardiac arrhythmias have been limited by the absence of a consistently reliable means of detecting atrial activation. In this study, a theoretical model was developed with a hierarchical organization of problem-solving strategies utilizing automated analysis of atrial activation from a commercially available esophageal pill electrode and ventricular activation from a simultaneously recorded surface electrocardiographic lead. The theoretical model was then tested in 21 patients with 1 or more of 28 distinct supraventricular and ventricular arrhythmias. Of the 641 individual cardiac cycles analyzed, 636 (99.2%) were correctly identified. The accuracy of a contextual, that is, more comprehensive, interpretation of consecutive cardiac cycles was 638/641 (99.5%). The following cardiac arrhythmias were identified: sinus rhythm, sinus bradycardia, atrial premature depolarizations, atrial flutter, and supraventricular tachycardias with normal and aberrant ventricular conduction, first-degree and second-degree heart block; junctional escape, junctional rhythm, idioventricular rhythm, ventricular premature depolarization, and ventricular tachycardia with and without retrograde activation; atrial bigeminy, atrial trigeminy, atrial couplets, ventricular bigeminy, ventricular trigeminy, and ventricular couplets. This study represents the first computerized model ever developed to incorporate the morphology and timing of atrial activation with the morphology and timing of ventricular activation for arrhythmia diagnosis. Such modeling appears to be capable of achieving accurate interpretation of spontaneous, complex clinical cardiac arrhythmias and atrioventricular relationships.

Arrhythmias, Cardiac↗

PubMed2004

The feasibility of replacing animal testing for assessing consumer safety: a suggested future direction.

At present, we are unable to use much of the data derived from alternative (non-animal) tests for human health risk assessment. This brief Comment outlines why it is plausible that new paradigms could be developed to enable risk assessment to support consumer safety decisions, without the need to generate data in animal tests. The availability of technologies that did not exist 10 years ago makes this new approach possible. The approach is based on the concept that data and information derived from applying existing and new technologies to non-animal models can be interpreted in terms of harm and disease in man. A prerequisite is that similar data and information generated in a clinical setting are available to permit this "translation". The incorporation of this additional translation step should make it possible to use data and information generated in non-animal models as inputs to risk assessment. The new technologies include genomics, transcriptomics, proteomics and metabonomics. Their application to in vitro and human "models" enables large amounts of data to be generated very quickly. The processing, interpretation and translation of these data need to be supported by powerful informatics capabilities and statistical tools. The use of integrated "systems biology" approaches will further support the interpretation by providing better understanding of the underlying biological complexity and mechanisms of toxicity. Clinical medicine is using the opportunities offered by the new "omics" technologies to advance the understanding of disease. The application of these technologies in clinical medicine will generate massive amounts of data that will need processing and interpretation to allow clinicians to better diagnose disease and understand the patients' responses to therapeutic interventions. Support from clinical epidemiology will be essential. If these data and information can be made generally accessible in an ethical and legal way, they should also permit the "translation" of experimental non-animal data, so that they can then be used in risk assessment.

Animal Testing Alternatives↗