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PubMed2003

The Database of Quantitative Cellular Signaling: management and analysis of chemical kinetic models of signaling networks.

MOTIVATION: Analysis of cellular signaling interactions is expected to pose an enormous informatics challenge, perhaps even larger than analyzing the genome. The complex networks arising from signaling processes are traditionally represented as block diagrams. A key step in the evolution toward a more quantitative understanding of signaling is to explicitly specify the kinetics of all chemical reaction steps in a pathway. Technical advances in proteomics and high-throughput protein interaction assays promise a flood of such quantitative data. While annotations, molecular information and pathway connectivity have been compiled in several databases, and there are several proposals for general cell model description languages, there is currently little experience with databases of chemical kinetics and reaction level models of signaling networks. RESULTS: The Database of Quantitative Cellular Signaling is a repository of models of signaling pathways. It is intended both to serve the growing field of chemical-reaction level simulation of signaling networks, and to anticipate issues in large-scale data management for signaling chemistry. AVAILABILITY: The Database of Quantitative Cellular Signaling is available at http://doqcs.ncbs.res.in. Links to the signaling model simulator, GENESIS/Kinetikit are at http://www.ncbs.res.in/~bhalla/kkit/index.html and are also provided from within the database. The database source code is available under the GNU Public License.

Abstracting and Indexing↗
PubMed2005

Discrete time model for chemical or biological decay in chaotic flows: reentrance phase transitions.

We consider a discrete time model of advection, reaction, and diffusion on a lattice to investigate the steady-state spatial structure of chemically decaying substances. The time discretization of the dynamics has a considerable impact on these structures. Additional smooth-filamental phase transitions, nonexistent in the continuous-time description, appear. We show how these structures and their scaling properties depend on the time step of the discrete dynamics. Exploiting the analogies of this discrete model with the logistic map, some general features are discussed.

Journal Article↗
PubMed1983

Cell cycle kinetic data can be simulated by a simple chemical kinetic model.

This paper develops a model of the cell cycle from the assumption that the rate of progression from one mitosis to the next is limited by the time taken to complete a defined sequence of rate-limiting chemical reactions. The model is shown to be related to earlier models which represent limiting forms of this more rigorous description. Earlier models were classified as stochastic or deterministic, but in this case, while the overall structure is deterministic, the individual steps are stochastically variable. Thus, this description demonstrates that both views were partially correct but were incomplete in detail. By applying the model to several experimental cell cycle curves, sets of coefficients corresponding to reaction rate constants could be obtained. A striking feature of these results is that only a small number (1-3) of slow steps dominated the rate of cell division. A discussion of some recent experimental results suggests possible candidates for the few slow rate-limiting steps, and outlines a rigorous method of testing the model.

Cell Cycle↗
PubMed2005

Modeling of chemical control of human respiratory system.

This paper addresses the fundamental understanding of the chemical control of respiratory system that would be needed to improve the efficiency of artificial ventilators and implement appropriate controllers. Hence, non-linear model for simulation of chemical control of human respiratory system under different physiological conditions is presented. The paper also presents the non-linear dissociation behaviors for oxygen and carbon dioxide solutions in the blood and the Bohr-Haldane effects as well as a new controller model. Tests were conducted on the model under different conditions such as hypoxia, hypercapnia, hypoventilation, and hyperventilation with some combination tests, in order to verify the validity of the assumptions that were made. Results indicate a very close agreement between the responses obtained from the present model and other published experimental and theoretical results. This model can be used to design a novel artificial respirator controller meeting the bodily requirements of the patient under mechanical ventilation.

Carbon Dioxide↗
PubMed1995

Modeling organic chemical fate in aquatic systems: significance of bioaccumulation and relevant time-space scales.

The importance of aquatic food chain bioaccumulation of organic chemicals in contributing to human dose is derived. It is shown that for chemicals with log octanol water partition coefficients greater than about 3, the role of food chain transfer to fish consumed by humans becomes the more dominant route over drinking water. Modeling of aquatic food chain bioaccumulation then becomes necessary to accurately estimate dose of such chemicals to humans. The relevant time and space scales for groundwater and surface water also indicate a division of organic chemicals at a log octanol water partition coefficient of about 3. For chemicals greater than that level, groundwater transport is minimal, while for chemicals with log octanol water coefficients of less than about 3, detention times are long relative to surface water and biodegradation processes become more significant. An illustration is given of modeling the groundwater transport of two organic chemicals (BCEE and benzene) and a metal (chromium) at a Superfund site. The model indicates that after 10 years only a relatively small fraction of the chemicals had traveled in the groundwater about 300 m to the point of release from the site to surface water. On the other hand, steady state in the adjacent stream and lake is reached rapidly over a distance of 2000 m, illustrating the difference in spatial and temporal scales for the groundwater and surface water.

Animals↗
PubMed1997

HCN formation under electron impact: experimental studies and application to Neptune's atmosphere.

Laboratory experiments simulating organic synthesis in Neptune's atmosphere have been performed. We have submitted to a spark discharge gaseous mixtures containing 9 mbar of molecular nitrogen and 3 mbar of methane (the p(N2)/p(CH4) ratio is compatible with upper limits in Neptune's stratosphere) with varying quantities of molecular hydrogen. The spark discharge is used to model the energetic electrons produced by the impact of cosmic rays on the high atmosphere of Neptune. HCN is synthesized in the described experimental conditions, even with a low mixing ratio of molecular nitrogen. Studying the variation of HCN production with the initial composition of the gas mixture and extrapolating to high mixing ratio of molecular hydrogen allows to estimate HCN production in Neptune's atmosphere. The computed HCN production flux is 7x10(7) m-2 s-1, which is two orders of magnitude lower than the value predicted by chemical models for an internal source of N atoms. The major uncertainty in our extrapolation is the energetic distribution of electrons, implicitly assumed comparable in the discharge and in Neptune's atmosphere. We note that this distribution is also a source of uncertainty in chemical models. The chemical mechanism responsible for the local formation of HCN in the stratosphere probably occurs in the reactor too. We propose a simple characterization of the spark discharge. We thus link the molecular nitrogen dissociation cross section by electron impact to the measured parameters of the experiments (current, voltage, initial partial pressures) and to the resulting HCN partial pressures. However, other laboratory experiments with larger hydrogen pressures, requiring a more powerful electric source, have to be performed to yield a value of the cross section.

Atmosphere↗
PubMed2000

The p53 heterozygous knockout mouse as a model for chemical carcinogenesis in vascular tissue.

Heterozygous p53 knockout mice were investigated as a potential model for vascular tumor carcinogenesis. Groups of 20 male mice were exposed by gavage for 6 months to the vascular carcinogen urethane at 1, 10, or 100 mg/kg body weight/day. Wild-type and heterozygous p53 knockout control groups were exposed by gavage to the vehicle alone. Another group of 20 male mice received d-limonene by gavage (d-limonene is noncarcinogenic in mice). The high dose of urethane caused early mortality in the majority of mice associated with histopathologic evidence of toxicity and tumors, including a high incidence of benign and malignant vascular tumors, in all animals. At the intermediate dose, toxicity was less marked and 3 of 20 mice had tumors; mice that received the low dose did not have signs of toxicity or neoplasia. The two control groups had no tumors and the d-limonene group had one tumor of the prostate, which was considered spontaneous. We conclude that the p53 knockout mouse is a useful tool for investigating vascular tumorogenesis.

Animals↗
PubMed2004

Effects of Boswellia serrata in mouse models of chemically induced colitis.

Extracts from Boswellia serrata have been reported to have anti-inflammatory activity, primarily via boswellic acid-mediated inhibition of leukotriene synthesis. In three small clinical trials, boswellia was shown to improve symptoms of ulcerative colitis and Crohn's disease, and because of its alleged safety, boswellia was considered superior over mesalazine in terms of a benefit-risk evaluation. The goal of this study was to evaluate the effectiveness of boswellia extracts in controlled settings of dextran sulfate- or trinitrobenzene sulfonic acid-induced colitis in mice. Our results suggest that boswellia is ineffective in ameliorating colitis in these models. Moreover, individual boswellic acids were demonstrated to increase the basal and IL-1beta-stimulated NF-kappaB activity in intestinal epithelial cells in vitro as well as reverse proliferative effects of IL-1beta. We also observed hepatotoxic effect of boswellia with pronounced hepatomegaly and steatosis. Hepatotoxity and increased lipid accumulation in response to boswellia were further confirmed in vitro in HepG2 cells with fluorescent Nile red binding/resazurin reduction assay and by confocal microscopy. Microarray analyses of hepatic gene expression demonstrated dysregulation of a number of genes, including a large group of lipid metabolism-related genes, and detoxifying enzymes, a response consistent with that to hepatotoxic xenobiotics. In summary, boswellia does not ameliorate symptoms of colitis in chemically induced murine models and, in higher doses, may become hepatotoxic. Potential implications of prolonged and uncontrolled intake of boswellia as an herbal supplement in inflammatory bowel disease and other inflammatory conditions should be considered in future clinical trials with this botanical.

Animals↗
PubMed1987

Antisera to the variable region of ras oncogene proteins, and specific detection of H-ras expression in an experimental model of chemical carcinogenesis.

Antisera were prepared in mice, rats and rabbits by immunization with peptides corresponding to regions of highest variability, located near the C-termini of four ras proteins. Two of these, H-ras (171-189) and K-rasB (171-186), react uniquely with H-ras and K-rasB gene products in immunoblots and immunoprecipitation reactions. Affinity-purified rabbit H-ras (171-189) antibody detects H-ras p21 in tissue culture cells and in tissue sections. Epithelial cells in normal mouse skin and cells in papillomas and carcinomas, in a mouse model system of chemical carcinogenesis in which mutational activation of H-ras occurs with high frequency, express high levels of H-ras p21 protein. These results suggest an hypothesis to explain the mechanism and preferential activation of particular ras loci in certain neoplasia.

Amino Acid Sequence↗
PubMed2001

Effect of amino acids on goat cauda epididymal sperm cryopreservation using a chemically defined model system.

Studies were carried out to analyze the cryoprotecting efficacy of several amino acids by use of a chemically defined synthetic medium (modified Ringer's solution) and goat cauda epididymal sperm as the model system. Motile goat cauda sperm dispersed in the synthetic medium were subjected to a freezing protocol in a computer-controlled bio-freezer, cooling 0.25 degrees C x min(-1) to 5 degrees C, 5 degrees C x min(-1) to -20 degrees C, and 20 degrees C x min(-1) to -100 degrees C, prior to being plunged into liquid nitrogen. In the absence of amino acids, sperm cells completely lost their flagellar motility. Of all the amino acids tested, l-alanine showed maximal cryoprotection potential. l-Alanine at 135 mM offered optimum cryoprotection potential: recovery of sperm forward motility and total motility were 14 +/- 2% and 19 +/- 2%, respectively. l-Glutamine, l-proline, and glycine at optimum concentration (100-150 mM) cryopreserved approx. 11-17% total motility of the sperm cells, whereas amino acids such as l-arginine, l-lysine, and l-histidine offered little cryoprotection (0-5%) to the cells. Increasing the amino acid concentration beyond the optimum level sharply decreased the recovery of the sperm motility, which therefore showed a biphasic cryoprotection profile. Addition of amino acids enhanced (approx. 7-10%) the cryoprotection efficacy of the well-known cryoprotectants glycerol and a combination of glycerol and dimethyl sulfoxide. The presence of glycerol caused a marked reduction (from 100-150 mM to 20-70 mM levels) in the optimal cryoprotective concentration of the amino acids. The combined cryoprotecting action of glycerol, dimethyl sulfoxide, and amino acids provided motility recovery as high as 52%. The observation that amino acids and dimethyl sulfoxide had an additive effect in augmenting the cryoprotecting potential of glycerol suggests that the mechanism of their action is different from that of glycerol. This cocktail of cryoprotectants may be useful for cryopreservation of semen of various species.

Amino Acids↗
PubMed1999

A chemical kinetics model for microtubule oscillations

A model for microtubule oscillations is presented based on a set of chemical reaction equations. The rate constants for these reactions are largely determined from experimental data. The plots of assembled tubulin and the phase diagram for assembly are compared with the experimental findings and are found to agree quite well. Copyright 1999 Academic Press.

Journal Article↗
PubMed2001

Direct measurement of OH radicals from ozonolysis of selected alkenes: a EUPHORE simulation chamber study.

Reactions of ozone with alkenes can be a significant source of hydroxyl radicals in the atmosphere. In the present paper, the formation of OH radicals in the ozonolysis of selected alkenes under atmospheric conditions was directly observed. The experiments were carried out in the European photoreactor EUPHORE (Valencia, Spain). OH radicals were quantitatively detected by means of laser-induced fluorescence (LIF) using a new analytical instrument, which has been constructed on the basis of an existing setup already established in field studies. The OH radicals observed resulted directly from the reaction of ozone with the corresponding alkene. There was no indication that OH radicals were produced in the system by secondary processes. The experimentally observed concentration-time profiles of OH and ozone were excellently described by chemical modeling using explicit reaction mechanisms. The following OH yields were derived: 2,3-dimethyl-2-butene: (1.00 +/- 0.25); 2-methyl-2-butene: (0.89 +/- 0.22); trans-2-butene: (0.75 +/- 0.19); alpha-pinene: (0.91 +/- 0.23). In addition, the experiments carried out were modeled using the Regional Atmospheric Chemistry Mechanism (RACM), an established condensed chemical model applied in tropospheric chemistry. For 2,3-dimethyl-2-butene, 2-methyl-2-butene, and trans-2-butene the calculated concentration-time profiles of OH and ozone are in quite good agreement with the experimental data. However, in the case of alpha-pinene, the model fails for the simulation of OH due to the high grade of mechanism condensation, which results in a poor characterization of the primary reaction products.

Air Pollutants↗
PubMed1996

Effect of supplemental L-arginine in a chemical-induced model of colorectal cancer.

L-Arginine inhibits the development of spontaneous, transplantable solid tumors and chemically induced mammary tumors. The aim of the present study was to investigate the effect of l-arginine on chemically induced colorectal cancer in male Wistar rats. Colorectal cancer was induced in all animals by weekly subcutaneous injections of the colonic procarcinogen 1,2-dimethylhydrazine (DMH) at a dosage of 20 mg/kg body weight. Arginine was given in a 1% solution of drinking water. Group I was the DMH control; group II, arginine for 22 weeks; group III, arginine for the first 10 weeks only. Lymphocyte function was evaluated by measuring the thymic lymphocyte proliferative response to the T cell mitogen phytohemagglutinin. The results show that tumor incidence and tumor burden (tumors/rat and tumors/tumor-bearing rat) were significantly reduced in both groups of animals receiving arginine compared to DMH controls (p < 0.05). The tumor areas and volumes were also reduced in both arginine groups (p < 0.05). Thymic lymphocyte stimulation indices were significantly increased by arginine supplementation (p < 0.05). These results would be in keeping with the reduction in colorectal tumor production due to a "nonspecific" stimulation of the host immune system by L-arginine.

1,2-Dimethylhydrazine↗
PubMed1996

Characterization of a chemical anoxia model in cerebellar granule neurons using sodium azide: protection by nifedipine and MK-801.

Induction of chemical anoxia, using sodium azide in cerebellar granule cells maintained in primary culture, was evaluated as an in vitro assay for screening of potential neuroprotective compounds. The purpose of this study was to evaluate sodium azide as an alternative to cyanide salts, compounds which, despite their unfavorable characteristics, are often used in assays for chemical anoxia. The viability of neuronal cultures after treatment with azide, with or without preincubation with calcium channel blockers, tetrodotoxin (TTX), or glutamate receptor antagonists, was monitored by subsequent incubation with the tetrazolium dye MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), followed by isopropanol extraction and spectrophotometric quantification of cellularly reduced MTT. The azide-induced degeneration of neurons was shown to be dependent on the concentration as well as on the duration of incubation with submaximal concentrations of azide. Incubation of the neurons with nifedipine, a blocker of L-type voltage-sensitive calcium channels (L-VSCC), or with the noncompetitive N-methyl-D-aspartate (NMDA) subtype glutamate receptor antagonist MK-801, prior to addition of submaximal concentrations of azide, significantly attenuated azide-induced neuronal death. Blockers of N-type and Q-type VSCC (omega-conotoxin MVIIA and MVIIC, respectively) and the P-type VSCC blocker omega-agatoxin IVA had no effect in this assay. The sodium channel blocker TTX was without effect when added to neurons under depolarizing conditions, but potently and effectively protected cells when experiments were performed in a nondepolarizing buffer. The results show that chemical anoxia induced by incubation of cultured neurons with azide leads to detrimental effects, which may be quantitatively monitored by the capability of the cells to reduce MTT. This procedure is a suitable method for screening of compounds for possible protective effects against neuronal death induced by energy depletion. In addition, the results suggest involvement of L-type VSCC as well as of glutamate receptors in the pathways leading to neuronal degradation induced by energy depletion in cerebellar granule neurons. This would further support the notion that these pathways might be important in neurodegeneration induced by cerebral ischemia or anoxia.

Animals↗
PubMed1989

Modelling of chemical reactions catalysed by membrane-bound enzymes. Determination and significance of the kinetic constants.

A model of multiphasic systems, based on the assumption of zero-order partition of substrates and products into the membranes, is applied to reversible mono-substrate and bi-substrate reactions catalysed by membrane-bound enzymes. Apart from replacement of single-phase kinetic constants by apparent kinetic constants, the derived kinetic expressions are formally identical with those for corresponding single-phase systems. The model confers to the apparent kinetic constants an experimentally verifiable meaning. For full characterization of membrane-kinetic systems, experiments at various concentrations of enzyme-embedding phospholipid are required. Extrapolation to zero phospholipid concentration of each Km app then yields the corresponding true kinetic constant characteristic of the membrane-bound enzyme and also provides a technique for determination of the membrane-partition constants. The procedure implies that the phospholipid content should be assayed for full characterization of membrane-bound enzymes. If, for practical reasons, the assays have to be limited to a single enzyme concentration, correction of the apparent kinetic constants is still possible provided the phospholipid concentration and the partition constants of the reactants are known. The model has permitted prediction of a number of previous observations reflecting the multiphasic nature of the systems. The assumptions, underlying the model, and their implications are examined as well as some commonly used experimental designs for determination of the type of enzymic site.

Binding Sites↗
PubMed1999

Murine mercury-induced autoimmunity: a model of chemically related autoimmunity in humans.

Human exposure to certain compounds or therapeutic drugs can result in the development of an autoimmune syndrome. Mercury (Hg) induced autoimmunity is one of the few animal models in which administration of a chemical induces a specific loss of tolerance to self-antigens. After receiving subtoxic doses of Hg or other heavy metals, susceptible mouse strains rapidly develop highly specific antibodies to nucleolar antigens. In addition, these animals display a general activation of the immune system, especially pronounced for the Th2 subset and a transient glomerulonephritis with immunoglobulin deposits. Like many human autoimmune diseases, this syndrome is associated with the expression of susceptible major histocompatibility complex (MHC) class II genes. In this article, we review the essential features of this model, and we discuss the putative mechanisms by which Hg creates such a severe immune dysfunction.

Animals↗
PubMed1994

Empirical modelling of chemical exposure in the rubber-manufacturing industry.

As part of a study of working conditions chemical exposure was assessed in 10 rubber-manufacturing plants in The Netherlands. Personal exposures to airborne particulates, rubber fumes and solvents, and also dermal contamination, were measured. To identify factors affecting exposure the personal exposure levels and information on tasks performed, ventilation characteristics and production variables were used in multiple linear regression models. The exposure was generally very variable. The specific circumstances in each department of each plant determined the actual levels of exposure to a large extent. The factors affecting exposure turned out to be different for each of the types of exposure considered. The model for exposure to airborne particulates explained 40% of the total variability and incorporating the actual time spent on a task only slightly improved the model (R2 = 0.42). The handling of chemicals in powder form was the main factor affecting exposure, forced ventilation having a negligible effect. The model for exposure to curing fumes (measured as the cyclohexane-soluble fraction of the particulate matter) explained 50% of the variability. Both curing temperature and pressure determined the level of rubber fumes. Local exhaust ventilation showed a significant exposure reducing effect. The effect of curing different elastomers was not statistically significant. Dermal exposure to cyclohexane-soluble matter could only be explained to a limited extent (R2 = 0.22). Tasks with frequent contact with (warm) compound and maintenance tasks in the engineering services departments resulted in high dermal exposure. Tasks in which solvents were directly used explained 56% of the variation in solvent exposures. Exposure data, together with information on tasks, methods of work, ventilation and production throughout a branch of industry, can be used to derive empirical statistical models which occupational hygienists can apply to study factors affecting exposure. These determining factors are of crucial importance, whenever hazard control or epidemiological research is the ultimate goal.

Air Pollutants, Occupational↗