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PubMed2004

Extraribosomal cyclic tetradepsipeptides beauverolides: profiling and modeling the fragmentation pathways.

Profiling of cyclic tetradepsipeptides beauverolides was tested as a chemotaxonomic tool for fungal strain identification/discrimination. Two new tetradepsipeptides, beauverolides Q and R, were characterized by tandem mass spectrometry. Specific elimination of 113 atomic mass units from both protonated and sodiated molecules of beauverolides is ubiquitous for all 12 most dominant congeners evaluated in this profiling study. Reconstruction of the total ion chromatogram, according to this neutral fragment release, was used for data filtering and selectivity enhancement. Selective ring opening and fragment ion formation of beauverolide I are discussed in detail utilizing high-level theoretical modeling of the fragmentation pathways.

Biomarkers↗
PubMed2004

An enzyme mechanism language for the mathematical modeling of metabolic pathways.

MOTIVATION: As a first step toward the elucidation of the systems biology of complex biological systems, it was our goal to mathematically model common enzyme catalytic and regulatory mechanisms that repeatedly appear in biological processes such as signal transduction and metabolic pathways. RESULTS: We describe kMech, a Cellerator language extension that describes a suite of enzyme mechanisms. Each enzyme mechanism is parsed by kMech into a set of fundamental association-dissociation reactions that are translated by Cellerator into ordinary differential equations that are numerically solved by Mathematica. In addition, we present methods that use commonly available kinetic measurements to estimate rate constants required to solve these differential equations.

Algorithms↗
PubMed2006

Simplified modelling of metabolic pathways for flux prediction and optimization: lessons from an in vitro reconstruction of the upper part of glycolysis.

Explicit modelling of metabolic networks relies on well-known mathematical tools and specialized computer programs. However, identifying and estimating the values of the very numerous enzyme parameters inherent to the models remain a tedious and difficult task, and the rate equations of the reactions are usually not known in sufficient detail. A way to circumvent this problem is to use 'non-mechanistic' models, which may account for the behaviour of the systems with a limited number of parameters. Working on the first part of glycolysis reconstituted in vitro, we showed how to derive, from titration experiments, values of effective enzyme activity parameters that do not include explicitly any of the classical kinetic constants. With a maximum of only two parameters per enzyme, this approach produced very good estimates for the flux values, and enabled us to determine the optimization conditions of the system, i.e. to calculate the set of enzyme concentrations that maximizes the flux. This fast and easy method should be valuable in the context of integrative biology or for metabolic engineering, where the challenge is to deal with the dramatic increase in the number of parameters when the systems become complex.

Algorithms↗
PubMed1986

T cells can be cytotoxic without making interleukin 2: a model of separate pathways of induction.

The thoracic duct lymphocytes from rats previously injected with ultraviolet-light-irradiated allogeneic lymphocytes were grown for 4 days with alloantigen, with or without Con A-induced lymphokine factors, and then for 3 days with the lymphokines alone. They were then tested for their cytoxicity and for their capacity to make interleukin 2 (IL-2) in response to antigen. The results show that T helper cells specific for both class I and class II antigens of the major histocompatibility complex were removed from the circulation by the injection of ultraviolet-irradiated alloantigen. However, precursors of cytotoxic cells remained and appeared to lose their OX-19 markers during activation. We have interpreted the results by using a speculative model that involves separate pathways of induction to cytotoxicity and IL-2 synthesis. We propose that the OX-19 marker is associated with the interleukin 1 receptor and that the latter is required for the IL-2 production pathway but not for activation to cytotoxicity.

Animals↗
PubMed2005

Use of genetically modified mouse models to assess pathways of benzene-induced bone marrow cytotoxicity and genotoxicity.

Benzene induces bone marrow cytotoxicity and chromosomal breaks as a primary mode of action for the induction of bone marrow toxicity. Our research group has used genetically modified mouse models to examine metabolic and genomic response pathways involved in benzene induced cytotoxicity and genotoxicity in bone marrow and in hematopoietic stem cells (HSC). We review our studies using NQO1-/- mice and mEH-/- mice to examine the roles of these enzymes, NAD(P)H:quinone oxidoreductase-1 (NQO1) and microsomal epoxide hydrolase (mEH) in mediating benzene-induced toxicity. NQO1 catalyzes the detoxication of benzene quinone metabolites and mEH catalyzes the hydrolysis of benzene oxide. Our studies using gene expression profiling of bone marrow and enriched HSC populations isolated from the bone marrow of benzene-exposed mice demonstrate differential gene expression responses of key genes induced by inhaled benzene. These studies show that benzene toxicity is regulated by a number of genetic pathways that affect the production of reactive metabolites and DNA damage response pathways in a target tissue.

Animals↗
PubMed1993

Purine metabolic pathways in rat hindlimb perfusion model during ischemia and reperfusion.

The perfused rat hindlimb preparation was used with a blood cell-free perfusate to investigate alterations in the purine nucleotide metabolism, flow rate, perfusion pressure, and venous excretion in response to ischemia and ischemia followed by reperfusion in skeletal muscle. The development of a physical hindrance during postischemic reperfusion, indicated by an increase in reperfusion pressure and a decrease in flow rate, coincided with a 90% decrease in phosphocreatine and a 50-70% reduction in total adenine nucleotide pool. The reflow impairment could not be explained by blood cell plugging of the capillaries. Washout of several metabolites was demonstrated during reperfusion. Hypoxanthine accumulated intracellularly during ischemia, and a substantial amount of uric acid was excreted into the venous effluent during reperfusion. The experimental data were fitted into a computer simulation model of the purine pathways. The model indicated that AMP deaminase was the predominant enzymatic pathway for the AMP degradation. It was demonstrated that ATP preferably accumulated as inosine-5'-monophosphate during ischemia and that xanthine oxidase was undetectable in skeletal muscle tissue homogenates. However, vascular endothelial cell xanthine oxidase activity responsible for a free radical-induced reperfusion injury could not be excluded.

Adenine Nucleotides↗
PubMed1992

Effects of bleomycin on growth kinetics and survival of Saccharomyces cerevisiae: a model of repair pathways.

In order to analyze the roles of some repair genes in the processing of bleomycin-induced DNA damage and, especially, the interrelationships among the involved repair pathways, we investigated the potentially lethal effect of bleomycin on radiosensitive mutants of Saccharomyces cerevisiae defective in recombination, excision, and RAD6-dependent DNA repair. Using single, double, and triple rad mutants, we analyzed growth kinetics and survival curves as a function of bleomycin concentration. Our results indicate that genes belonging to the three epistasis groups interact in the repair of bleomycin-induced DNA damage to different degrees depending on the concentration of bleomycin. The most important mechanisms involved are recombination and postreplication repair. The initial action of a potentially inducible excision repair gene could provide intermediate substrates for the RAD6- and RAD52-dependent repair processes. Interaction between RAD6 and RAD52 genes was epistatic for low bleomycin concentrations. RAD3 and RAD52 genes act independently in processing DNA damage induced by high concentrations of bleomycin. The synergistic interaction observed at high concentrations in the triple mutant rad2-6 rad6-1 rad52-1 indicates partial independence of the involved repair pathways, with possible common substrates. On the basis of the present results, we propose a heuristic model of bleomycin-induced DNA damage repair.

Bleomycin↗
PubMed1995

Modelling the structural pathways for transcapillary exchange.

The ultrastructural pathways and mechanisms whereby endothelial cells and the clefts between the cells modulate capillary permeability to water and solutes have been a central unresolved question in microvessel transport since the early 1950s. Freeze-fracture studies and ultrathin serial sections have demonstrated that endothelial cells are joined by an array of junctional strands which are interrupted at intervals, allowing for the passage of water and solutes, whereas cytochemical studies have indicated that the endothelial surface and portions of the wide part of the cleft contain matrix components. Neither constricted slit models based on the classic pore theory nor fiber matrix models are able to explain the large body of existing permeability measurements. In this review, we shall describe new three-dimensional modelling approaches which have resulted in a major revision of current ideas about the pathways for water and solutes through the junction strand and the structures that determine the molecular filter. For frog mesentery capillaries, these models predict (i) that the primary pathway for small ions is a previously unrecognized family of 2nm small pores that are distributed along the length of the junction strand; (ii) that the primary pathway for water and intermediate-sized solutes (1-3.5 nm radius) is an infrequent 150 nm long orifice-like pore whose height is the same as that of the wide part of the cleft; (iii) that the sieving structure for these solutes is a fiber layer, typically 100 nm thick, which extends from the surface into the entrance region of the cleft and (i.v.) that the interpretation of low molecular weight tracer studies to define the permeability pathways depends on the time-dependent filling of the extravascular space.

Animals↗
PubMed1996

Characterization of crystallization pathways during cholesterol precipitation from human gallbladder biles: identical pathways to corresponding model biles with three predominating sequences.

In model biles, five crystallization sequences are present as functions of bile salt/lecithin (egg yolk) ratio and their positions on phase diagrams are influenced by bile salt hydrophobicity, temperature, and total lipid concentration (D. Q-H. Wang and M.C. Carey. J. Lipid Res. 1996.37: 606-630). To determine whether the same pathways occur ex vivo during cholesterol precipitation from human gallbladder biles, we examined 22 cholesterol gallstone (CSI = 1.56 +/- 0.26), 4 pigment gallstone (0.69 +/- 0.06), and 4 control biles (0.85 +/- 0.22) by microscopy and lipid analytic techniques for 30 days. Temperature was varied (4-45 degrees C) to move relative compositions into adjacent pathways or supersaturated zones to test whether the same bile could be forced to crystallize in different sequences. Sequences in native bile were identical to those in model systems composed of mixed bile salts-lecithin-cholesterol mixtures, and three corresponding pathways (B, C, D; op. cit.) were observed at 37 degrees C. With increasing lecithin content, we found i) B: plate-like cholesterol monohydrate crystals appeared before arc-shaped (putatively anhydrous cholesterol) crystals which transformed via helices and tubules into plate-like crystals and no liquid crystals formed; ii) C: lamellar liquid crystals, typified by birefringent multilamellar vesicles, were detected before cholesterol monohydrate crystals, and subsequently arc, helical and tubular crystals appeared; and iii) D: precipitation of lamellar liquid crystals was followed by cholesterol monohydrate crystals and no arc crystals were detected. Added EDTA prevented calcium bilirubinate formation, but crystallization sequences in these biles were identical to those without EDTA. We conclude that i) cholesterol crystallization pathways and sequences in human gallbladder biles are identical to model biles matched for appropriate physical-chemical conditions; ii) three of the five sequences observed in model biles were found in native bile; and iii) calcium bilirubinates neither promote biliary cholesterol crystallization nor influence crystal growth.

Bile Acids and Salts↗
PubMed1990

Mathematical modelling of metabolic pathways affected by an enzyme deficiency.

The regulation of metabolic pathways of the red cell affected by an enzyme deficiency is studied on the basis of comprehensive mathematical models. The main steps of such a theoretical approach are outlined considering individual alterations in the kinetic properties of two regulatory enzymes: pyruvate kinase and glucose-6-phosphate dehydrogenase. It is demonstrated that mathematical modelling helps to relate the observed changes of cellular quantities as shortened life-span, or as resistance against oxidative stress to alterations in the metabolic regulation.

Animals↗
PubMed2001

Role for tissue factor pathway in murine model of vascular remodeling.

Tissue factor (TF) is a low-molecular-weight glycoprotein that initiates the extrinsic clotting cascade and is considered a major regulator of arterial thrombogenicity. TF pathway inhibitor (TFPI) is a major physiological inhibitor of TF-initiated coagulation. The aim of this study was to define the complex interplay between TF and TFPI and the regulation of vascular thrombogenicity in a model of vascular remodeling. To determine the levels and pattern of vascular expression of TF and TFPI associated with vascular remodeling, a murine model of flow cessation was studied. TF activity of the arteries increased after ligation (P<0.05). Quantitative analysis of homogenates of remodeled carotid arteries revealed increased TF expression but unchanged TFPI expression compared with normal carotid arteries, resulting in enhanced TF activity. To determine the potential therapeutic role of TFPI in this thrombogenic state, mice were treated with intravascular adenoviral delivery of either murine TFPI (Ad-mTFPImyc) or a control adenovirus (Ad-DeltaE1). Overexpression of TFPI decreased vascular TF activity compared with viral control (P<0.01). Overexpression of TFPI inhibited neointimal formation (P=0.038), resulting in enhanced luminal area (P=0.001) 4 weeks after flow cessation. In this murine model of vascular remodeling, an imbalance between TF and TFPI expression is generated, resulting in increased TF activity. Overexpression of TFPI in this model inhibits vascular TF activity and results in attenuation of vascular remodeling associated with flow interruption.

Animals↗
PubMed2003

Evaluating the Navigate Care Model: clinical palliative care pathways based on anticipated care outcomes.

The Navigate Care Model (NCM) specifies clinical pathway assignments for hospice patients based on the anticipated outcomes of death, discharge home, or discharge into residential care. This study, set in a freestanding, inpatient hospice, evaluated the effects of NCM implementation on 338 patients, 154 family members and the organization, including 49 staff. Accuracy of pathway assignment on admission was also assessed. The results indicate that patients' symptoms were managed as well or better than previously, as compared with 1998 data. Discharged patients reported being highly satisfied with care and there were fewer readmissions. Families reported greater satisfaction with care than those surveyed previously, as compared with 1999 data. Staff reported initial negative effects but elected to retain a refined version of the model after the study. Pathway assignments on admission were correct 64% of the time, 92% correct when assignment was for terminal care. Clinical pathways based upon the expected outcomes of death or discharge appear to offer benefits for patients and families.

Adult↗
PubMedDate not supplied

[A simulated mathematical model of the blood coagulation system intrinsic pathway].

A mathematical model of the blood coagulation system intrinsic pathway is developed based on a reaction cascade scheme with two positive feedbacks. The model describes quantitatively well-known experimental data on blood plasma coagulation kinetics for various levels of activation and varying calcium concentrations. In the limit of experimental variety of the values of the rate for individual stages of coagulation cascade, obtained in [5-12], a good agreement with experimental data was shown for two discrete sets of the constants. The model relates unambiguously the threshold properties in coagulation activation by calcium with existence of the activation threshold. The model allows numerical estimates of the threshold activation values for various calcium concentrations. At calcium concentration of 0.2 mM, corresponding to normal calcium content in blood, the activation threshold is equal to 0.00016 nM and 0.0019 nM of Factor XIa for the first and the second sets of the system parameters, respectively.

Blood Coagulation↗
PubMed2004

Modeling of cell signaling pathways in macrophages by semantic networks.

BACKGROUND: Substantial amounts of data on cell signaling, metabolic, gene regulatory and other biological pathways have been accumulated in literature and electronic databases. Conventionally, this information is stored in the form of pathway diagrams and can be characterized as highly "compartmental" (i.e. individual pathways are not connected into more general networks). Current approaches for representing pathways are limited in their capacity to model molecular interactions in their spatial and temporal context. Moreover, the critical knowledge of cause-effect relationships among signaling events is not reflected by most conventional approaches for manipulating pathways. RESULTS: We have applied a semantic network (SN) approach to develop and implement a model for cell signaling pathways. The semantic model has mapped biological concepts to a set of semantic agents and relationships, and characterized cell signaling events and their participants in the hierarchical and spatial context. In particular, the available information on the behaviors and interactions of the PI3K enzyme family has been integrated into the SN environment and a cell signaling network in human macrophages has been constructed. A SN-application has been developed to manipulate the locations and the states of molecules and to observe their actions under different biological scenarios. The approach allowed qualitative simulation of cell signaling events involving PI3Ks and identified pathways of molecular interactions that led to known cellular responses as well as other potential responses during bacterial invasions in macrophages. CONCLUSIONS: We concluded from our results that the semantic network is an effective method to model cell signaling pathways. The semantic model allows proper representation and integration of information on biological structures and their interactions at different levels. The reconstruction of the cell signaling network in the macrophage allowed detailed investigation of connections among various essential molecules and reflected the cause-effect relationships among signaling events. The simulation demonstrated the dynamics of the semantic network, where a change of states on a molecule can alter its function and potentially cause a chain-reaction effect in the system.

Computer Simulation↗
PubMed2004

Simulation and sensitivity analysis of phosphorylation of EGFR signal transduction pathway in PC12 cell model.

The epidermal growth factor receptor (EGFR) signalling pathway is a complex signalling process with a wide network of interactions. The activation of the mitogen-activated protein kinases (MAPKs) cascade by this activated EGFR has been well studied. MAPKs form a highly integrated network, which is essential for certain specialised cell functions. This paper presents a kinetic model for the MAPK pathway downstream of the EGFR using a biochemical simulator. The model includes 30 signalling events and 29 signalling molecules. The time course data were examined for the activation of each signalling component. The simulation provides a large volume of data, by monitoring the kinetics of the signalling components, which were compared experimentally using the PC12 cell line. The kinetic model corresponded well with the experimental results observed in the EGFR induced activation of proteins. An examination of the kinetic analysis of the multiple signalling events provides a quantitative framework for representing the EGFR signalling network.

Animals↗
PubMed2002

A mathematical model of metabolic insulin signaling pathways.

We develop a mathematical model that explicitly represents many of the known signaling components mediating translocation of the insulin-responsive glucose transporter GLUT4 to gain insight into the complexities of metabolic insulin signaling pathways. A novel mechanistic model of postreceptor events including phosphorylation of insulin receptor substrate-1, activation of phosphatidylinositol 3-kinase, and subsequent activation of downstream kinases Akt and protein kinase C-zeta is coupled with previously validated subsystem models of insulin receptor binding, receptor recycling, and GLUT4 translocation. A system of differential equations is defined by the structure of the model. Rate constants and model parameters are constrained by published experimental data. Model simulations of insulin dose-response experiments agree with published experimental data and also generate expected qualitative behaviors such as sequential signal amplification and increased sensitivity of downstream components. We examined the consequences of incorporating feedback pathways as well as representing pathological conditions, such as increased levels of protein tyrosine phosphatases, to illustrate the utility of our model for exploring molecular mechanisms. We conclude that mathematical modeling of signal transduction pathways is a useful approach for gaining insight into the complexities of metabolic insulin signaling.

Animals↗