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Results for “Pathway modelling”

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PubMed1989

Estimation of additive maternal and cytoplasmic genetic variances in animal models.

Two pathways for maternal genetic effects to act on production traits are additive maternal and cytoplasmic. Estimation of these variances have generally assumed that the correct maternal pathway is known. A method is described that allows simultaneous estimation of additive maternal and cytoplasmic genetic variances as well as additive direct genetic variances and error variances using an animal model. Data were simulated assuming an additive maternal model, cytoplasmic model, or both. The method was tested by analyzing the data under the true or incorrect maternal model using REML with an animal model that accounted for additive genetic relationships. Additive direct, additive maternal, cytoplasmic, and error variances were correctly partitioned when estimated under the true model. However, when additive maternal or cytoplasmic genetic effects were ignored in the model used for analysis, estimates of additive direct variance were significantly inflated. Also, under an additive maternal genetic model, a small cytoplasmic variance was estimated although none was present in the data.

Analysis of Variance↗

PubMed1995

A model of the pentose phosphate pathway in rat liver cells.

A mathematical model based on kinetic data taken from the literature is presented for the pentose phosphate pathway in fasted rat liver steady-state. Since the oxidative and non oxidative pentose phosphate pathway can act independently, the complete (oxidative+non oxidative) and the non oxidative pentose pathway were stimulated. Sensitivity analyses are reported which show that the fluxes are mainly regulated by D-glucose-6-phosphate dehydrogenase (for the oxidative pathway) and by transketolase (for the non oxidative pathway). The most influent metabolites were the group ATP, ADP, P1 and the group NADPH, NADP+ (for the non oxidative pathway).

Animals↗

PubMed2004

The effect of vascular smooth muscle cell-targeted expression of tissue factor pathway inhibitor in a murine model of arterial thrombosis.

Tissue factor pathway inhibitor (TFPI) is a Kunitz-type protease inhibitor that regulates the extrinsic pathway of coagulation by inhibiting the factor VIIa/tissue factor (TF) catalytic complex. TFPI is expressed by both endothelial and smooth muscle cells in the vasculature and circulates at low levels. The role of local vascular TFPI in thrombosis and the development of vascular disease is unknown. To establish an experimental animal model to directly modulate smooth muscle cell-derived TFPI on the development of arterial thrombosis, transgenic mice in which a cDNA encoding murine TFPI is expressed from the murine SM22alpha promoter were generated. Expression of transgenic mRNA was 4-fold higher than the level of endogenous TFPI mRNA in arteries from transgenic mice. In situ hybridization confirmed that expression of the transgene was limited to medial vascular smooth muscle cells. Vascular TFPI activity was increased to 2 to 3-fold in carotid homogenates. There was no difference in plasma TFPI levels or hemostatic measures (PT, aPTT and tail vein bleeding times) between these mice and their wildtype littermates. In a ferric chloride-induced model of carotid thrombosis, homozygotic transgenic mice demonstrated resistance to thrombotic occlusion compared to wildtype littermates. In transgenic mice 22% occluded within 30 minutes of application while 84% of wild type mice occluded within the same time frame (p<0.01). Heterozygotic transgenic mice had an intermediate thrombotic phenotype. Taken together, these data indicated that local VSMC-specific TFPI overexpression attenuated ferric chloride-induced thrombosis without systemic or hemostatic effects. Furthermore, this transgenic mouse model should prove useful for studying the role of TFPI in the development and progression of vascular disease.

Animals↗

PubMed2001

The activity of tissue factor pathway inhibitor in experimental models of superantigen-induced shock and polymicrobial intra-abdominal sepsis.

OBJECTIVES: To study recombinant human tissue factor pathway inhibitor (rhTFPI) in a superantigen-induced shock model and in a cecal ligation and puncture (CLP) model of peritonitis in mice. DESIGN: Prospective, randomized, experimental study. SETTING: An experimental animal research laboratory. SUBJECTS: Eighty BALB/c mice for the superantigen model, and 56 BALB/c mice for the CLP model. INTERVENTIONS: In the superantigen-induced shock model, animals received rhTFPI (350 mg/kg) subcutaneously every 12 hrs (n = 30) or saline control (n = 30) for 60 hrs after staphylococcal enterotoxin B (SEB; 10 microg iv) and a sublethal dose of E. coli 0111:B4 lipopolysaccharide (LPS; 75 microg ip). Control groups received SEB alone (n = 10) and LPS alone (n = 10). In the CLP model, rhTFPI or saline was given every 8 hrs for 48 hrs by using a 21-gauge needle (n = 9) or 23-gauge needle (n = 14) for CLP. A sham surgery control group (n = 10) was also included. MEASUREMENTS AND MAIN RESULTS: There was 0% mortality in the SEB and LPS control groups. The mortality rate was 64% in the saline control group that received both SEB and LPS (19 of 30), whereas the rhTFPI- treated animals had a mortality rate of 20% (6 of 30; p < .01). The rhTFPI-treated group had significantly lower interleukin-6 levels (61.8 +/- 41 pg/mL vs. 285 +/- 63 pg/mL; p < .05) than the control group but no differences in tumor necrosis factor-alpha or interferon-gamma levels. In the CLP experiment, rhTFPI-treated animals did not have any survival advantage over the control group after the large-bore (21-gauge) needle puncture. The rhTFPI group had significantly improved 7-day mortality rate after CLP with the small-bore needle (23-gauge; 21.4% [rhTFPI] vs. 71.4% [control], p < .01). Plasma LPS, interleukin-6, interferon-gamma, and tumor necrosis factor-alpha levels were unchanged by rhTFPI treatment, but significantly reduced LPS (p = .006) and IFNgamma (p = .001) levels were found in the peritoneal fluid. CONCLUSIONS: Tissue factor pathway inhibitor significantly improves the mortality rate in models of superantigen-induced shock and polymicrobial intra-abdominal infection, supporting its potential use in clinical trials for septic shock.

Animals↗

PubMedDate not supplied

Sensory information processing in the frog olfactory pathways. Experimental basis for modeling studies.

In the frog, unitary electrophysiological recordings have been extensively used to investigate odor processing along the olfactory pathways. By comparing spontaneous and odor-evoked activities of neuroreceptor, mitral and cortical cells, we have collected fundamental data relating to coding abilities of the three olfactory levels, the olfactory mucosa, the bulb and the cortex. Based on a synthesis of our experimental data related to GABAergic and dopaminergic involvement in the olfactory bulb, this paper aims to match this information with computational data and to discuss some questions on bulbar processing. This paper is also devoted to further analyze original results on coding properties of two functionally evidenced neuron subpopulations in the olfactory cortex. Thus, the assumption according to which some cortical neurons may work as temporal integrators while others as coincidence detectors is presented. Moreover, the pertinence that the neural code may be carried by a single spike with varying latency was demonstrated.

Animals↗

PubMed2002

Activation of the c-Jun N terminal kinase pathway in an animal model of Parkinson's disease.

In neuronal stress and degeneration, mitogen-activated protein (MAP) kinase signaling pathways play an important role. We studied the pattern of activation of the c-Jun N terminal kinase (JNK) signal transduction pathway during the course of a subacute MPTP mouse model of Parkinson's disease. In this model, there was no significant neuronal loss, but the function of the dopaminergic neurons was significantly decreased. During MPTP administration, phosphorylation of p-Jun was increased in the substantia nigra, and MKK4 was increased both in the striatum and substantia nigra. We conclude that after MPTP intoxication in the mouse, activation of the JNK pathway occurs both in the striatum and in the substantia nigra. This activation does not seem to corrrelate with loss of neuronal cell bodies but might represent a response to damage/loss of axonal terminals.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2004

Genomic approaches in dissecting complex biological pathways.

Advances in genomic research have provided many types of large-scale data that contain rich information on various biological pathways. Intensive efforts have been made to qualitatively or quantitatively model biological pathways using these genomic data. Some general network properties, such as the scale-free property and network motifs, have been discussed and various network models have been applied to reconstruct pathways. However, there is a lack of systematic integration of prior knowledge and different genomic data in these analyses. In this review, we discuss pathway reconstruction under the consideration of the complexity embedded in the biological system, and the global and local properties of biological pathways. We review major methodologies, including clustering methods, scale-free networks models, Bayesian networks models, Boolean networks models, systems of differential equations, and data integration methods. We focus on the difficulty of each methodology in modeling biological pathways, and emphasize that different models capture different aspects of biological pathways or genomic data. The 'noisy' large-scale genomic data require the mathematical models and computational methods to be both robust and identifiable. In addition, we believe that ideal models should have the capability of incorporating various data types and these models need to be assessed through rigorous comparisons with empirical data.

Bayes Theorem↗

PubMed1984

A bilateral model for central neural pathways in vestibuloocular reflex.

It is argued that vestibular internuclear commissural pathways are functionally important in the vestibuloocular reflex (VOR), particularly since they appear to be modulated during nystagmus. A bilateral approach to VOR modeling is essential to an effective study of the effects of commissural connections on response dynamics. A bilateral model of the VOR central pathways is proposed, with three main postulates: neural filters (NF) on each side of the brain stem, each linked to tonic cells in the ipsilateral vestibular nuclei in negative feedback loops; strong coupling between these bilateral loops by reciprocal commissural connections that significantly affect response dynamics; and modulation of this coupling by inhibitory burst neurons during fast phases. Mathematical analysis of this model shows that the NF need not be good integrators. During slow-phase operation, commissural pathways provide a positive-feedback effect that improves the effective integration function of the bilateral system beyond that of the NF in each side. Analysis suggests that the time constant of the NF might even be as small as that of the eye plant (approximately 0.24 s), so that the NF might be considered to be internal models of the eye plant rather than pseudointegrators. In the model, modulation of commissural gains by burst cells is shown to be sufficient to cause the system to switch between a compensatory position-tracking mode (slow phases) and an anticompensatory velocity-tracking mode (fast phases) during nystagmus. The model simulates a number of behavioral and neurophysiological findings, such as a) tonic vestibular nuclei (VN) cells have sensitivities and decay times larger than primary vestibular fibers, and their response polarity may reverse after section of superficial commissural fibers; b) effective VOR integration deteriorates after cerebellectomy or commissurectomy; c) peak fast-phase eye velocity is modulated by the vestibular signal as well as by fast-phase amplitude. The model accounts for the modulation of central VN responses during nystagmus and, as a result, simulations strongly imply that envelopes of slow-phase eye velocity or smoothed central firing rates will depend on fast-phase strategy and, hence, may not always yield accurate estimates of VOR dynamics. Similarly, the model predicts that "apparent" disassociation between central and ocular responses may occur because of interactions during nystagmus, despite appropriate behavior within slow-phase segments (since VN responses are not simple estimates of eye velocity).(ABSTRACT TRUNCATED AT 400 WORDS)

Eye↗

PubMed1987

A model of status epilepticus based on electrical stimulation of hippocampal afferent pathways.

A new model of status epilepticus has been developed in the unanesthetized rat. The model involves repetitive tetanic stimulation of hippocampal afferent pathways. Pulse trains were delivered according to a fixed schedule (0.2 to 0.4-ms monophasic rectangular pulses, 20 Hz, stimulus current adjusted for maximal synaptic response in area CA3 of the hippocampus, 10-s train duration, 30-s intertrain interval) through electrodes chronically implanted in the angular bundle or fimbria. CA3 pyramidal cells responded to each stimulus in the train with little or no decrement. When 10 consecutive trains each produced 30 s of hippocampal afterdischarge, stimulation was terminated and self-sustained electrographic seizure activity was monitored. This procedure was repeated until it yielded at least 15 min of self-sustained seizure activity. Status epilepticus occurred in about 85% of subjects within less than 7 h. Self-sustained electrographic seizures were associated with limbic motor seizures and with brain lesions that resembled Ammon's horn sclerosis. This model holds promise for analyzing the biochemical and physiological bases of seizures, status epilepticus, and neuronal cell death, because the timing of these events during the stimulation protocol is fairly predictable and because seizures are self-sustaining without the need drugs, toxins, or prior kindling.

Animals↗

PubMed2002

Exhaustive and heuristic retrieval processes in person cognition: further tests of the TRAP model.

The twofold retrieval by associative pathways (TRAP) model (L. Garcia-Marques & D. L. Hamilton, 1996) proposes that two distinct modes of retrieval typically underlie recall and frequency estimation. The model accounts for the simultaneous occurrence of greater recall of incongruent information and higher frequency estimation of congruent information. Three experiments provided further tests of the TRAP model. Experiment 1 manipulated cognitive load (at encoding and at retrieval) and the selectivity of the retrieval goal. Under either high load or a selective retrieval goal, incongruent items ceased to be better recalled. Experiment 2 manipulated the accessibility of expectancy-congruent, -incongruent, or -neutral episodes and found corresponding effects in frequency estimates. Finally, Experiment 3 showed that providing part-list retrieval cues inhibits recall but increases frequency estimates. The TRAP model predicted these results.

Adult↗

PubMed1992

Structural modeling of functional visual pathways mapped with 2-deoxyglucose: effects of patterned light and footshock.

This paper describes the first application of structural modeling to the visual system. Structural modeling, or path analysis, is a mathematical method that allows for the quantification of the functional strengths of anatomical connections between the structures that form a neural system. The objective was to demonstrate how structural modeling can be used to determine the functional interrelationships between brain structures that form the visual system and how these interrelationships change under different conditions. Data were obtained from measures of 2-deoxyglucose uptake in the visual system of rats presented with either patterned light or darkness. The effects of arousing footshock on visual system operations were also investigated. Models based on the anatomical connections and the interregional correlations between metabolic activity data were used to determine path coefficients representing the magnitude of the influence of each directional path. Statistical evaluation of the models revealed that the dominant positive influences on visual system activity in the darkness were the tectocortical subsystem and the descending connections from secondary visual cortex. In the patterned light model, the total influence of the geniculocortical subsystem was higher than in the dark, and the tectocortical pathways showed both a reduction and a shift in the direction of effects. The models also revealed that the effects of footshock-induced arousal on visual system operations depended upon the visual environment and on extra-visual influences. The footshock led to an increase in the interaction of the two main subsystems at the level of connections between primary visual cortex and the lateral posterior nucleus, and a descending negative influence from the secondary visual cortex became dominant. The models are discussed in the context of conventional analyses to show how structural modeling allows for the determination of much more information about the functional interactions within the visual system of subjects under different experimental conditions.

Animals↗

PubMed2006

The kinetic model of the shikimate pathway as a tool to optimize enzyme assays for high-throughput screening.

Four-enzyme section of the shikimate pathway (Aro B, D, E, and K) of Streptococcus pneumoniae has been studied. Kinetic properties of the individual enzymes and three- and four-enzyme linked reactions have been characterized in vitro. On the basis of the data measured in spectrophotometric and LC-MS experiments, kinetic mechanisms of the enzymes have been suggested and all kinetic parameters have been identified. Kinetic models for these three- and four-enzyme sections of the shikimate pathway have been constructed and validated. The model of the four-enzyme section of shikimate pathway has been employed to design an inhibition-sensitive reconstituted pathway for a high-throughput screening effort on the shikimate pathway. It was demonstrated that using the model it was possible to optimize this reconstituted pathway in such a way to provide equal sensitivity of the enzymes to inhibition.

Alcohol Oxidoreductases↗

PubMed1995

Primary products of break-induced recombination by Escherichia coli RecE pathway.

Alternative models for break-induced recombination predict different distributions of primary products. The double-stranded break-repair model predicts a noncrossover product and equimolar amounts of two crossover products. The one-end pairing model predicts two crossover products, but not necessarily in equimolar amounts, and the single-stranded annealing model predicts deletion of the fragment between the pairing sequences. Depending on the structure of the recombining substrate(s) and the nature of the resectioning step that precedes strand annealing, the single-stranded annealing mechanism would yield only one or both crossover products. We tested these predictions for the RecE recombination pathway of Escherichia coli. Nonreplicating intramolecular recombination substrates with a double-stranded break (DSB) within one copy of a direct repeat were released from chimera lambda phage by in vivo restriction, and the distribution of primary circular recombination products was determined. Noncrossover products were barely detectable, and the molar ratio of the two crossover products was proportional to the length ratio of the homologous ends flanking the DSB. These results suggest an independent pairing of each end with the intact homolog and argue against the double-stranded break-repair model. However, the results do not distinguish alternative pairing mechanisms (strand invasion and strand annealing). The kinetics of heteroduplex formation and heteroduplex strand polarity were investigated. Immediately following the DSB induction, heteroduplex formation was done by pairing the strands ending 3' at the break. A slow accumulation of the complementary heteroduplex made by the pairing of the strands ending 5' at the break (5' heteroduplexes) was observed at a larger stage. The observed bias in heteroduplex strand polarity depended on DSB induction at a specific site. The 5' heteroduplexes may have been generated by reciprocal strand exchange, pairing that is not strand specific, or strand-specific pairing induced at random breaks.

Crossing Over, Genetic↗

PubMed2003

Analysis and modelling of signal transduction pathways in systems biology.

There is general agreement that a systems approach is needed for a better understanding of causal and functional relationships that generate the dynamics of biological networks and pathways. These observations have been the basis for efforts to get the engineering and physical sciences involved in life sciences. The emergence of systems biology as a new area of research is evidence for these developments. Dynamic modelling and simulation of signal transduction pathways is an important theme in systems biology and is getting growing attention from researchers with an interest in the analysis of dynamic systems. This paper introduces systems biology in terms of the analysis and modelling of signal transduction pathways. Focusing on mathematical representations of cellular dynamics, a number of emerging challenges and perspectives are discussed.

Computational Biology↗

PubMed2005

A hybrid approach for efficient and robust parameter estimation in biochemical pathways.

Developing suitable dynamic models of biochemical pathways is a key issue in Systems Biology. Predictive models for cells or whole organisms could ultimately lead to model-based predictive and/or preventive medicine. Parameter estimation (i.e. model calibration) in these dynamic models is therefore a critical problem. In a recent contribution [Moles, C.G., Mendes, P., Banga, J.R., 2003b. Parameter estimation in biochemical pathways: a comparison of global optimisation methods. Genome Res. 13, 2467-2474], the challenging nature of such inverse problems was highlighted considering a benchmark problem, and concluding that only a certain type of stochastic global optimisation method, Evolution Strategies (ES), was able to solve it successfully, although at a rather large computational cost. In this new contribution, we present a new integrated optimisation methodology with a number of very significant improvements: (i) computation time is reduced by one order of magnitude by means of a hybrid method which increases efficiency while guaranteeing robustness, (ii) measurement noise (errors) and partial observations are handled adequately, (iii) automatic testing of identifiability of the model (both local and practical) is included and (iv) the information content of the experiments is evaluated via the Fisher information matrix, with subsequent application to design of new optimal experiments through dynamic optimisation.

Algorithms↗

PubMedDate not supplied

Modeling and simulation of pathways in menopause.

The analytical representation and simulation of complex molecular pathways can contribute to understanding and evaluating physiological as well as pathological processes. We are interested in modeling the processes of menopause to stratify women in terms of the genotypic and environmental components and their implications for development of individualized risk of postmenopausal disorders, e.g., breast and ovarian cancer, cardiovascular disease, and osteoporosis. We have initiated this study using the UltraSAN package to analyze the pathway associated with estrogen production. This model incorporates detailed information about the hormone factors affecting estrogen production, and the simulations carried out are based on published experimental data corresponding to hormone levels during the course of the normal female reproductive cycle. The agreement between the experimental data and the simulation is typically less than 2 ng/ml or 2 pg/ml respectively for progesterone and estradiol output. This approach further permits inclusion of information about an SNP observed in the gene coding for the enzyme aromatase as a model to study the impact of reduced enzymatic activity on hormone levels.

Climacteric↗

PubMed1999

Assessment of complex peptide degradation pathways via structured multicompartmental modeling approaches: the metabolism of dynorphin A1-13 and related fragments in human plasma.

Peptide metabolic pathways in blood or other tissues are often complex because multiple enzyme systems are involved in the degradation of parent drug and its metabolites. Michaelis-Menten-type studies with isolated enzymes have been frequently employed for evaluating the metabolism of peptides. Alternatively, studies with selective enzyme inhibitors or the evaluation of the area under the drug- or metabolite-time profiles have been employed. We tested in this study the usefulness of a multicompartmental pharmacokinetic approach for the assessment of the apparent first-order metabolism of dynorphin A1-13 up to the fourth metabolite generation in human plasma. This multicompartmental kinetic analysis proved instrumental in clarifying ambiguous degradation pathways not easily detectable by the other methods of assessment (enzyme inhibition studies and noncompartmental analysis) because of the lack of specific enzyme inhibitors or specificity problems of the analytical technique employed. The proposed multicompartmental fitting approach was also highly suitable to verify the overall metabolic pathways suggested by the other methods up to the fourth metabolite by testing whether the rate constants obtained by these methods are suitable to describe the overall degradation profile after Dyn A1-13 degradation. Local sensitivity analysis for the degradation of DYNA 1-13 revealed that the model was, however, not able to adequately identify on its own all of the parameters involved in the degradation of dynorphin A1-13. Thus, the method proved beneficial in evaluating and testing the correctness of the overall degradation pathways suggested by other methods.

Algorithms↗

PubMed2005

Activation of the mitochondrial apoptotic pathway in a rat model of central retinal artery occlusion.

PURPOSE: Apoptosis is known to play a role in cell death in transient retinal ischemia. Little is known about the specific molecular pathways involved. The purpose of the current study was to evaluate a rat model of central retinal artery occlusion (CRAO) that simulates the clinical features of CRAO in humans and to elucidate whether the mitochondrial apoptotic pathway is involved. METHODS: CRAO was induced in the central retinal artery by intravenous injection of rose bengal and green laser irradiation of the artery. CRAO was documented at 1, 3, 6, and 24 hours after laser irradiation. Changes in Bax (proapoptotic Bcl-2-associated X protein), cytochrome c, and caspase-9 cleavage in the cytosolic and mitochondrial fractions of neural retinal tissues were measured by Western blot analysis. Apoptosis within the retina was examined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). RESULTS: Complete CRAO was induced; however, occlusion became incomplete with spontaneous reperfusion of branch arteries, starting at 3 hours after laser irradiation. Only one or two branch arteries remained occluded at the 24-hour time point. Time-dependent, apoptotic changes were observed in inner and outer retinal cell layers. Western blot analysis revealed mitochondrial translocation of Bax from the cytoplasm, starting at 3 hours and peaking at 6 hours after laser irradiation. This translocation was accompanied by cytosolic accumulation of cytochrome c and cleavage of caspase-9. CONCLUSIONS: This model is highly relevant to clinical manifestations of CRAO and is an ideal animal model for research. These findings indicate the activation of the mitochondrial pathway in ischemic retina induced by CRAO. The model provides a better understanding of ischemia-induced retinal apoptosis. Antiapoptosis therapy directly targeting the mitochondrial pathway in CRAO or other retinal ischemic diseases may be beneficial.

Amacrine Cells↗