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PubMed2006

A simplified method for power-law modelling of metabolic pathways from time-course data and steady-state flux profiles.

BACKGROUND: In order to improve understanding of metabolic systems there have been attempts to construct S-system models from time courses. Conventionally, non-linear curve-fitting algorithms have been used for modelling, because of the non-linear properties of parameter estimation from time series. However, the huge iterative calculations required have hindered the development of large-scale metabolic pathway models. To solve this problem we propose a novel method involving power-law modelling of metabolic pathways from the Jacobian of the targeted system and the steady-state flux profiles by linearization of S-systems. RESULTS: The results of two case studies modelling a straight and a branched pathway, respectively, showed that our method reduced the number of unknown parameters needing to be estimated. The time-courses simulated by conventional kinetic models and those described by our method behaved similarly under a wide range of perturbations of metabolite concentrations. CONCLUSION: The proposed method reduces calculation complexity and facilitates the construction of large-scale S-system models of metabolic pathways, realizing a practical application of reverse engineering of dynamic simulation models from the Jacobian of the targeted system and steady-state flux profiles.

Kinetics↗

PubMed1996

Multi-layered perceptron as a model for the pupillary pathway.

Derived from models of neural networks, a model for the pupillary pathway is introduced that can easily be handled computationally and analytically. To model the binocular pupillary reactions we use a feed-forward network, namely, a multi-layered perception. It is possible to calculate the pupillary reactions analytically as a function of the light stimuli of the retinal hemifields, on the one hand, and the set of neural couplings between the neural layers, on the other. Several lesions, e.g., lesions of the intercalated neurons between the afferent and efferent pupillary pathways, can be simulated within the model and the corresponding pupillary reactions such as anisocoria or relative afferent pupillary defects (RAPD) can be calculated analytically. Due to its neural network structure the model described herein can easily be extended to much more complex pupillary pathways while remaining calculable computationally and analytically.

Humans↗

PubMed2006

Integrated mechanistic and data-driven modelling for multivariate analysis of signalling pathways.

Mathematical models of highly interconnected and multivariate signalling networks provide useful tools to understand these complex systems. However, effective approaches to extracting multivariate regulation information from these models are still lacking. In this study, we propose a data-driven modelling framework to analyse large-scale multivariate datasets generated from mathematical models. We used an ordinary differential equation based model for the Fas apoptotic pathway as an example. The first step in our approach was to cluster simulation outputs generated from models with varied protein initial concentrations. Subsequently, decision tree analysis was applied, in which we used protein concentrations to predict the simulation outcomes. Our results suggest that no single subset of proteins can determine the pathway behaviour. Instead, different subsets of proteins with different concentrations ranges can be important. We also used the resulting decision tree to identify the minimal number of perturbations needed to change pathway behaviours. In conclusion, our framework provides a novel approach to understand the multivariate dependencies among molecules in complex networks, and can potentially be used to identify combinatorial targets for therapeutic interventions.

Apoptosis↗

PubMed2004

The impact of reinforcement contingencies on AD/HD: a review and theoretical appraisal.

One of the core deficits in attention deficit/hyperactivity disorder (AD/HD) is thought to be an aberrant sensitivity to reinforcement, such as reward and response cost. Twenty-two studies (N=1181 children) employing AD/HD and reinforcement contingencies are reviewed from vantage points: task performance, motivation, and psychophysiology. Results indicate that reinforcement contingencies have a positive impact on task performance and levels of motivation for both children with AD/HD and normal controls. There is evidence that the effect related to task performance is somewhat more prominent in AD/HD. There is some evidence that a high intensity of reinforcement is highly effective in AD/HD. Children with AD/HD prefer immediate over delayed reward. From a psychophysiological point of view, children with AD/HD seem less sensitive to reinforcement compared to controls. While comorbid disorders are suggested to be confounders of the dependent variables, many studies do not examine the effect of oppositional defiant disorder (ODD) and conduct disorder (CD). We discuss the implications of the findings for five theoretical frameworks, including the model by, the cognitive-energetic model (CEM), the dual-pathway model and the BIS/BAS model. Results show a discrepancy between the theoretical models and the behavioural findings.

Antisocial Personality Disorder↗

PubMed2002

Mechanisms underlying atrioventricular nodal conduction and the reentrant circuit of atrioventricular nodal reentrant tachycardia using optical mapping.

The findings of multiple nondiscrete AV nodal pathways and asymmetric transitional zone provide a biophysical basis for understanding normal and abnormal AV node electrophysiology. Unidirectional block occurring at the transitional zone transforms the nondiscrete pathways model into a classic dual pathways physiology for AVNRT.

Action Potentials↗

PubMedDate not supplied

Radioactive materials in biosolids: national survey, dose modeling, and publicly owned treatment works (POTW) guidance.

The Nuclear Regulatory Commission (NRC) announced the availability of three new documents concerning radioactive materials in sewage sludge and ash from publicly owned treatment works (POTW). One of the documents is a report presenting the results of a volunteer survey of sewage sludge and ash samples provided by 313 POTWs. The second document is a dose modeling document, using multiple exposure pathway modeling focused on a series of generic scenarios, to track possible exposure of POTW workers and members of the general public to radioactivity from the sewage sludge or ash. The third document is a guidance report providing recommendations on the management of radioactivity in sewage sludge and ash for POTW owners and operators. This paper explains how radioactive materials enter POTWs, provides criteria for evaluating levels of radioactive material in sludge and ash, and gives a summary of the results of the survey and dose modeling efforts.

Data Collection↗

PubMed1993

Cone pathways and the pi 0 and pi 0' rod mechanisms.

The field-adaptation properties of two scotopic (rod) mechanisms, pi 0 and pi 0', were measured to test a two-pathway model that associates the fast temporal properties of pi 0' with the processing of rod signals by early cone pathways, possibly including cone photoreceptors, and the sluggish temporal properties of pi 0 with processing of rod signals by classical rod pathways. This model predicts that cone stimulation will differentially affect the flicker sensitivity of pi 0' compared to pi 0. Both rod mechanisms are seen in double-branched flicker-threshold-vs-intensity (FTVI) curves measured with a 15-Hz, square-wave-modulated, rod-detected test stimulus. We show that the position of the upper branch (pi 0') shifts relative to the lower branch in response to changes of background wavelength, indicating that different receptor types regulate sensitivity of pi 0 and pi 0'. Field spectral sensitivity (FSS) functions for pi 0 closely match the scotopic spectral sensitivity function, indicating that only rods adapt pi 0 under these conditions. In contrast, fitting of FSS functions for pi 0' required a combination of cone and rod spectral sensitivity functions. The relative adaptational effect of cone stimulation compared to rod stimulation increases with background light level: at highest levels, cone stimulation has more influence than rod stimulation. Test additivity experiments assessed the degree of additivity between cones and rods to ensure that the pi 0' branch did not result from sub-threshold summation between receptor mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Female↗

PubMed2006

Kinetic modeling of tricarboxylic acid cycle and glyoxylate bypass in Mycobacterium tuberculosis, and its application to assessment of drug targets.

BACKGROUND: Targeting persistent tubercule bacilli has become an important challenge in the development of anti-tuberculous drugs. As the glyoxylate bypass is essential for persistent bacilli, interference with it holds the potential for designing new antibacterial drugs. We have developed kinetic models of the tricarboxylic acid cycle and glyoxylate bypass in Escherichia coli and Mycobacterium tuberculosis, and studied the effects of inhibition of various enzymes in the M. tuberculosis model. RESULTS: We used E. coli to validate the pathway-modeling protocol and showed that changes in metabolic flux can be estimated from gene expression data. The M. tuberculosis model reproduced the observation that deletion of one of the two isocitrate lyase genes has little effect on bacterial growth in macrophages, but deletion of both genes leads to the elimination of the bacilli from the lungs. It also substantiated the inhibition of isocitrate lyases by 3-nitropropionate. On the basis of our simulation studies, we propose that: (i) fractional inactivation of both isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 is required for a flux through the glyoxylate bypass in persistent mycobacteria; and (ii) increasing the amount of active isocitrate dehydrogenases can stop the flux through the glyoxylate bypass, so the kinase that inactivates isocitrate dehydrogenase 1 and/or the proposed inactivator of isocitrate dehydrogenase 2 is a potential target for drugs against persistent mycobacteria. In addition, competitive inhibition of isocitrate lyases along with a reduction in the inactivation of isocitrate dehydrogenases appears to be a feasible strategy for targeting persistent mycobacteria. CONCLUSION: We used kinetic modeling of biochemical pathways to assess various potential anti-tuberculous drug targets that interfere with the glyoxylate bypass flux, and indicated the type of inhibition needed to eliminate the pathogen. The advantage of such an approach to the assessment of drug targets is that it facilitates the study of systemic effect(s) of the modulation of the target enzyme(s) in the cellular environment.

Antitubercular Agents↗

PubMed1992

Protein folding pathways determined using disulphide bonds.

The best-characterized model pathway of protein folding, that of disulphide bond formation in the small protein BPTI, has been questioned recently. A reinvestigation of that pathway, using alternative methods, concluded that the intermediates with non-native disulphide bonds accumulated to lower levels than previously had been observed. On this basis, a revised pathway was proposed that simply omitted those intermediates. Even if totally correct, however, the new observations are not inconsistent with the important characteristics of the original pathway and even confirmed many of them. Certain crucial observations that were the experimental basis for the original pathway were ignored, and these observations invalidate the revised pathway.

Animals↗

PubMed1981

Problems in evaluating radiation dose via terrestrial and aquatic pathways.

This review is concerned with exposure risk and the environmental pathways models used for predictive assessment of radiation dose. Exposure factors, the adequacy of available data, and the model subcomponents are critically reviewed from the standpoint of absolute error propagation. Although the models are inherently capable of better absolute accuracy, a calculated dose is usually overestimated by from two to six orders of magnitude, in practice. The principal reason for so large an error lies in using "generic" concentration ratios in situations where site specific data are needed. Major opinion of the model makers suggests a number midway between these extremes, with only a small likelihood of ever underestimating the radiation dose. Detailed evaluations are made of source considerations influencing dose (i.e., physical and chemical status of released material); dispersal mechanisms (atmospheric, hydrologic and biotic vector transport); mobilization and uptake mechanisms (i.e., chemical and other factors affecting the biological availability of radioelements); and critical pathways. Examples are shown of confounding in food-chain pathways, due to uncritical application of concentration ratios. Current thoughts of replacing the critical pathways approach to calculating dose with comprehensive model calculations are also shown to be ill-advised, given present limitations in the comprehensive data base. The pathways models may also require improved parametrization, as they are not at present structured adequately to lend themselves to validation. The extremely wide errors associated with predicting exposure stand in striking contrast to the error range associated with the extrapolation of animal effects data to the human being.

Animals↗

PubMed2003

Parent-child conflict and the comorbidity among childhood externalizing disorders.

BACKGROUND: Previous research has suggested that substantial comorbidity exists among childhood externalizing disorders, specifically attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD). Moreover, parent-child conflict predicts each of these disorders. Our goals were to determine whether parent-child conflict was associated with the comorbidity among ADHD, CD, and ODD, and to explicitly examine the etiology of this association via a genetically informative design. METHODS: We compared the fit of the following 2 biometric models: the 2-factor common-pathway model, which examined genetic and environmental contributions to the relationship between conflict and the covariation among the 3 disorders, and the Cholesky model, which examined the relationship between conflict and each disorder individually. The sample consisted of 808 same-sex 11-year-old twin pairs from the Minnesota Twin Family Study, a population-based sample of Minnesota twins and their families. Main outcome measures included symptom counts for ADHD, CD, and ODD, obtained from structured interviews administered to twins and their mothers. Parent-child conflict was assessed via mother and twin reports of the Parental Environment Questionnaire. RESULTS: The 2-factor model provided a better fit to the data. These results indicated that conflict accounted for 33% of the covariation among the disorders, via genetic and environmental factors. CONCLUSIONS: Parent-child conflict appears to act as a common vulnerability that increases risk for multiple childhood disorders. Furthermore, this association is mediated via common genetic and environmental factors. These findings support the idea that the comorbidity among these disorders partially reflects core psychopathological processes in the family environment that link putatively separate psychiatric disorders.

Adult↗

PubMedDate not supplied

Potential and challenges of a human cytome project.

BACKGROUND: The elucidation of the molecular pathways from the 20-40.000 genes of the sequenced human genome via investigation of genetic networks and molecular pathways up to the cellular and organismal phenotypes is highly complex and time consuming. STRATEGY AND GOALS: The proposed upside-down research strategy of a human cytome project accesses the expressed molecular cell phenotypes by differential screening, for example of diseased versus healthy, or undifferentiated versus differentiated cells to obtain information on disease or differentiation related molecular hotspots at the single cell level. The genome serves as inventory of the biomolecular capacities of organisms while the mechanisms of genome realisation are initially entirely bypassed. Detected molecular hotspots are further investigated by backward directed systems biology, including molecular pathway modelling to elucidate disease related molecular pathways. New drug targets may be identified to specifically influence such pathways. Differential screening provides, in addition, individualized disease course predictions for everyday medicine, in form of "predictive medicine by cytomics." The early recognition of future disease complications enables an immediate application of preventive therapies. This is likely to lower disease related irreversible tissue destruction and adverse drug reactions and will allow to individually optimize patient therapy. OUTLOOK: Immediate medical use, facilitated access to the detection of new drug targets, increased research speed and the stimulation for advanced technological developments represent major driving forces for the efforts to establish a human cytome project.

Cell Biology↗

PubMed1985

Mathematical modelling of metabolic pathways affected by an enzyme deficiency. A mathematical model of glycolysis in normal and pyruvate-kinase-deficient red blood cells.

A mathematical model of glycolysis in human erythrocytes is proposed to study the influence of a pyruvate kinase deficiency on the energy metabolism. The model takes into account the main regulatory properties of the non-equilibrium enzymes and the magnesium-complex formation by the adenine nucleotides and by 2,3-bisphosphoglycerate. In the normal case (no enzyme defect) the calculated flux rates and metabolite concentrations are in a good agreement with experimental data. It is shown that a severe pyruvate kinase deficiency manifested in a tenfold diminished activity of that enzyme leads to a remarkable decrease of the glycolytic flux and the ATP concentration of about 50% of the normal values. On the other hand a lowering of the pyruvate kinase activity to half of the normal value, characteristic for the heterozygotes, gives no significant alterations of the metabolite concentrations and the flux rates compared with the normal case which is in accordance with the lack of clinical symptoms for a metabolic disease of these probands. For three patients with known alterations of their pyruvate kinase mutants the calculated metabolite concentrations and the control characteristics permit estimation of the degree of disorder of the glycolytic pathway. The resulting classification corresponds well to other independent experimental and clinical findings. In particular, the calculation demonstrates that there is no simple correlation between the lowered enzyme activity and the reduced flux rate through the affected pathway.

Adenosine Triphosphate↗

PubMed1979

Activation of human complement by liposomes: a model for membrane activation of the alternative pathway.

Liposomal model membranes were found to activate the alternative pathway of human complement. Activation was measured by C3 conversion and component consumption in serum that had been incubated with liposomes. C3 conversion did not require C1 or C2 of the classical pathway, since it was observed in serum from a C1r-deficient patient, serum from a C2-dificient patient, and normal serum in buffer containing EGTA and MgCl2. The incubation of liposomes with C2-deficient serum resulted in consumption of components C3 through C9 with no consumption of C1 or C4 in a profile typical of alternative pathwya activation. The reaction was further shown to require alternative pathway factor D, and to be independent of antibody. Activation of the alterative pathway was dependent on the membrane composition of the liposomes. A positive charge was required for liposomes to produce C3 conversion. Liposomal cholesterol concentration and phospholipid fatty acyl chain length and unsaturation all influenced activation, suggesting the importance of membrane fluidity. Positively charged liposomes containing dimyristoyl phosphatidylcholine and cholesterol required the presence of certain glycolipids for C3 conversion. The activation of the alternative complement pathway by liposomes of defined membrane composition may provide a suitable model for the study of alternative pathway activation by cellular membranes.

Agammaglobulinemia↗

PubMed2006

Algorithmic and complexity results for decompositions of biological networks into monotone subsystems.

A useful approach to the mathematical analysis of large-scale biological networks is based upon their decompositions into monotone dynamical systems. This paper deals with two computational problems associated to finding decompositions which are optimal in an appropriate sense. In graph-theoretic language, the problems can be recast in terms of maximal sign-consistent subgraphs. The theoretical results include polynomial-time approximation algorithms as well as constant-ratio inapproximability results. One of the algorithms, which has a worst-case guarantee of 87.9% from optimality, is based on the semidefinite programming relaxation approach of Goemans-Williamson [Goemans, M., Williamson, D., 1995. Improved approximation algorithms for maximum cut and satisfiability problems using semidefinite programming. J. ACM 42 (6), 1115-1145]. The algorithm was implemented and tested on a Drosophila segmentation network and an Epidermal Growth Factor Receptor pathway model, and it was found to perform close to optimally.

Algorithms↗

PubMed1988

Measurement of rapid membrane permeation in cell suspensions by application of a generalized capillary method.

An improved version of the capillary technique for the determination of diffusion coefficients has been developed as a simple method of measuring membrane permeabilities of single cells suspended at relative densities between 0.70 and 0.97. A new, generalized theoretical formulation to describe the diffusion process of a solute in a composite system was derived using a series-parallel-pathway model with explicit consideration of the diffusion pathways inside and between the cells. This renders the technique insensitive to unstirred layer effects. Any single cell population of known size distribution may be investigated. High permeabilities (above 5.10(-3) cm/s) can be measured with the greatest precision, but lower permeabilities, down to a limit of about 5.10(-4) cm/s, may also be determined by the method. Measurements in erythrocyte suspensions have been made using non-electrolytes such as hexanol, water and ethylene glycol as test solutes. The permeabilities obtained agree with the values obtained by much more sophisticated equipment. Cell shape was shown to be without significant influence on the permeability data obtained. The procedure may become of particular interest for measurement of suspensions of membrane vesicles.

Cell Membrane Permeability↗

PubMed2004

Normal performance and expression of learning in the vestibulo-ocular reflex (VOR) at high frequencies.

The rotatory vestibulo-ocular reflex (VOR) keeps the visual world stable during head movements by causing eye velocity that is equal in amplitude and opposite in direction to angular head velocity. We have studied the performance of the VOR in darkness for sinusoidal angular head oscillation at frequencies ranging from 0.5 to 50 Hz. At frequencies of > or = 25 Hz, the harmonic distortion of the stimulus and response were estimated to be <14 and 22%, respectively. We measured the gain of the VOR (eye velocity divided by head velocity) and the phase shift between eye and head velocity before and after adaptation with altered vision. Before adaptation, VOR gains were close to unity for frequencies < or = 20 Hz and increased as a function of frequency reaching values of 3 or 4 at 50 Hz. Eye velocity was almost perfectly out of phase with head velocity for frequencies < or = 12.5 Hz, and lagged perfect compensation increasingly as a function of frequency. After adaptive modification of the VOR with magnifying or miniaturizing optics, gain showed maximal changes at frequencies <12.5 Hz, smaller changes at higher frequencies, and no change at frequencies larger than 25 Hz. Between 15 and 25 Hz, the phase of eye velocity led the unmodified VOR by as much as 50 degrees when the gain of the VOR had been decreased, and lagged when the gain of the VOR had been increased. We were able to reproduce the main features of our data with a two-pathway model of the VOR, where the two pathways had different relationships between phase shift and frequency.

Adaptation, Physiological↗

PubMed2005

What have animal models taught us about the p53 pathway?

Mouse models have provided important insight into the in vivo significance of upstream and downstream signals that regulate the p53 tumour suppressor. One important lesson learned from these models is that negative regulators of p53 are critical in vivo modulators of p53 activity. Additionally, upstream regulators of p53 activity, such as p19(Arf) and Atm, are themselves critical tumour modifiers/suppressors. The presence of multiple positive regulators of p53 and numerous downstream targets indicates a redundancy that ensures activation of the p53 pathway. Importantly, p53 plays a prominent role as a tumour suppressor in vivo by virtue of its ability both to block cell cycle progression and to induce cell death. Finally, different p53 mutants have different properties in vivo. Three missense mutations have been generated at the p53 locus and all three exhibit unique differences in their ability to contribute to the tumour phenotype. Clearly, determining the levels of p53 inhibitors, and the typing of p53 mutations in human tumours should be performed to determine the best avenue for treatment.

Animals↗