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At least 163 records · Page 9Linked to original sources
PubMed1998

Bacteriophage T4, a model system for understanding the mechanism of type II topoisomerase inhibitors.

Bacteriophage T4 provides a simple model system for analyzing the mechanism of action of antitumor agents that inhibit DNA topoisomerases. The phage-encoded type II topoisomerase is sensitive to many of the same antitumor agents that inhibit mammalian type II topoisomerase, including m-AMSA, ellipticines, mitoxantrone and epipodophyllotoxins. Results from the T4 model system provided a convincing demonstration that topoisomerase is the physiological drug target and strong evidence that the drug-induced cleavage complex is important for cytotoxicity. The detailed molecular steps involved in cytotoxicity, and the mechanism of recombinational repair of inhibitor-induced DNA damage, are currently being analyzed using this model system. Studies with the T4 topoisomerase have also provided compelling evidence that topoisomerase inhibitors interact with DNA at the active site of the enzyme, with each class of inhibitor favoring a different subset of cleavage sites based on DNA sequence. Finally, analysis of drug-resistance mutations in the T4 topoisomerase have implicated certain regions of the protein in drug interaction and provided a strong link between the mechanism of action of the antibacterial quinolones, which inhibit DNA gyrase, and the various antitumor agents, which inhibit mammalian type II topoisomerase.

Amsacrine↗
PubMed1990

The relationships among the subsystems of Johnson's Behavioral System Model.

The major premise of the Johnson (1980) Behavioral System Model is that the eight subsystems (domains) are interactive, interdependent and integrated. Relationships among the subsystems were hypothesized, placing the Aggressive/Protective subsystem centrally as having direct and indirect relationships to the other seven subsystems. In the present study, the Behavioral System Model instrument generated two sets of scales that indicated changes as increase or decrease and positive or negative in the subsystem resulting from illness. Two causal models were tested, one for each set of scales, both supporting the hypotheses pertaining to the relationships between the Aggressive/Protective subsystem and the other subsystems. The findings warrant further investigation of these relationships and imply that changes in a domain resulting from illness cannot be well understood without understanding their relationship to changes in other domains.

Adolescent↗
PubMed2003

Model systems in drug discovery: chemical genetics meets genomics.

Animal model systems are an intricate part of the discovery and development of new medicines. The sequencing of not only the human genome but also those of the various pathogenic bacteria, the nematode Caenorhabditis elegans, the fruitfly Drosophila, and the mouse has enabled the discovery of new drug targets to push forward at an unprecedented pace. The knowledge and tools in these "model" systems are allowing researchers to carry out experiments more efficiently and are uncovering previously hidden biological connections. While the history of bacteria, yeast, and mice in drug discovery are long, their roles are ever evolving. In contrast, the history of Drosophila and C. elegans at pharmaceutical companies is short. We will briefly review the historic role of each model organism in drug discovery and then update the readers as to the abilities and liabilities of each model within the context of drug development.

Animals↗
PubMedDate not supplied

Mechanistic systems models of cell signaling networks: a case study of myocyte adrenergic regulation.

Signal transduction networks coordinate a wide variety of cellular functions, including gene expression, metabolism, and cell fate processes. Understanding biological networks quantitatively is a major challenge to post-genomic biology, and mechanistic systems models will be crucial for this task. Here, we review approaches towards developing mechanistic systems models of established cell signaling networks. The ability of mechanistic system models to generate testable biological hypotheses and experimental strategies is discussed. As a case study of model development and analysis, we examined the functional roles of phospholamban, the L-type calcium channel, the ryanodine receptor, and troponin I phosphorylation upon beta-adrenergic stimulation in the rat ventricular myocyte. Model analysis revealed that while protein kinase A-mediated phosphorylation of the ryanodine receptor greatly increases its calcium sensitivity, calcium autoregulation may adapt quickly by negating potential increases in contractility. Systematic combinations of in silico perturbations supported the conclusion that phospholamban phosphoregulation is the primary mechanism for increased sarcoplasmic reticulum load and calcium relaxation rate during beta-adrenergic stimulation, while both phospholamban and the L-type calcium channel contribute to increased systolic calcium. Combined with detailed experimental studies, mechanistic systems models will be valuable for developing a quantitative understanding of cell signaling networks.

Animals↗
PubMed2001

Model system for the management of nitrogen leaching at the scale of river basins and regions.

In the framework of the EU-project RANR (Regional analysis of subsurface nitrogen retention and its impact on the nitrogen export from land to sea) a model system was developed to estimate groundwaterborne nitrogen inputs into river systems. The core of this model system is composed of a soil nitrogen leaching model (SOIL-N) and a groundwater residence time/denitrification model (WEKU). The application of the model system was carried out for the study catchment areas of the Uecker basin (ca. 2400 km2, Germany) and the Gjern basin (ca. 200 km2, Denmark). For both catchment areas, the modelled average nitrogen loads leached into the groundwater were about 40 kg N/ha a, while the remaining groundwaterborne nitrogen intake to rivers was quantified to an average of about 2 kg/ha a. The comparision with observed groundwaterborne riverine nitrogen loads showed a very good agreement, proofing the key role nitrogen retention in groundwater plays in the two catchment areas. With regard to the generalisation and transfer of the SOIL-N/WEKU model concept we assume that the model can be applicated in catchment areas in the European Pleistocene Lowland, which ranges from the Netherlands in the west to the Baltic States and the Ukraine in the east.

Agriculture↗
PubMed1993

Induction of vascular endothelial tubular morphogenesis by human glioma cells. A model system for tumor angiogenesis.

We have developed two different models of tumor angiogenesis by human brain tumors: one being tube formation by bovine aortic endothelial (BAE) cells cocultured with tumor cells in vitro, and other being in vivo angiogenesis in mice when tumor cells are transplanted into the dorsal sac. We investigated whether tube formation could be induced in BAE cells in type I collagen gel when these cells were cocultured with seven human glioma cell lines. Four of the seven glioma cell lines, which had high levels of basic fibroblast growth factor (bFGF) mRNA, induced tube formation by BAE cells. The tube formation was blocked by coadministration of anti-bFGF antibody. In in vivo model system of tumor angiogenesis in mice, these four cell lines were highly angiogenic. In contrast, with the other three glioma cell lines, which had poor expression of bFGF, BAE cells showed no apparent tube formation. These three cell lines did not efficiently develop capillary networks in mice. The results demonstrated a correlative relationship in the tubulogenesis of BAE cells, bFGF mRNA levels and angiogenesis in mice. The present study with two model systems of tumor angiogenesis suggests that the angiogenesis of some human glioma cell lines is mediated by bFGF, possibly via paracrine control.

Animals↗
PubMed2006

The pea aphid, Acyrthosiphon pisum: an emerging genomic model system for ecological, developmental and evolutionary studies.

Aphids display an abundance of adaptations that are not easily studied in existing model systems. Here we review the biology of a new genomic model system, the pea aphid, Acyrthosiphon pisum. We then discuss several phenomena that are particularly accessible to study in the pea aphid: the developmental genetic basis of polyphenisms, aphid-bacterial symbioses, the genetics of adaptation and mechanisms of virus transmission. The pea aphid can be maintained in the laboratory and natural populations can be studied in the field. These properties allow controlled experiments to be performed on problems of direct relevance to natural aphid populations. Combined with new genomic approaches, the pea aphid is poised to become an important model system for understanding the molecular and developmental basis of many ecologically and evolutionarily relevant problems.

Adaptation, Biological↗
PubMed1990

A systems model of training responses and its relationship to hormonal responses in elite weight-lifters.

A systems model, providing an estimation of fatigue and fitness levels was applied to a 1-year training period of six elite weight-lifters. The model parameters were individually determined by fitting the predicted performance (calculated as the difference between fitness and fatigue) to the actual one. The purpose of this study was to validate the systems model by comparing the estimated levels of fatigue and fitness with biological parameters external to the model calculation. The predicted and the actual performances were significantly correlated in each subject. The calculated fitness and fatigue levels were related to serum testosterone concentration, testosterone: cortisol and testosterone: sex hormone binding globulin ratios. The best results were obtained by the comparison between fitness and testosterone levels, which varied in parallel in each subject. In two subjects this correlation was significant (r = 0.91, P less than 0.05, and r = 0.92, P less than 0.01). The fitness changes calculated in each subject between the 15th and the 51st weeks of training were significantly correlated with the changes in serum testosterone concentration measured in the same period (r = 0.99, P less than 0.001). For the whole group testosterone and fitness variations were also significantly intercorrelated (r = 0.73, P less than 0.001). Correlations, less homogeneous and less significant, were calculated also for other hormones and ratios. These results suggest that (1) the relationships between training and performance can be described by the systems model, (2) the estimated index of fitness has a physiological meaning. The fatigue index remains to be clarified.

Adult↗
PubMedDate not supplied

Differentiating astroglia in nervous tissue histogenesis/regeneration: studies in a model system of regenerating peripheral nerve.

The role of astroglia in nervous system histogenesis/regeneration (morphogenesis) was studied as a function of cell age. The effect of inoculated astroglia at different cell maturation stages on axonal growth was examined in a peripheral nerve regenerating model system. This model system consists of rat sciatic nerve stumps that regenerate through an empty silicone chamber (Lundborg et al.: Journal of Neuropathology and Experimental Neurology 41:412-422, 1982). Rat astroglial cell populations grown in cell culture were suspended either in a liquid (physiological solution) or in a solid (isotonic collagen gel) medium and inoculated within the silicone chamber at the time of surgery. Immature and mature cell populations, at ages corresponding to 9-69 postnatal days (P9-P69), were inoculated, and their effect on neural growth was analyzed by histological, immunocytochemical, and ultrastructural techniques, 2-6 weeks later. Astroglial cells differentially modulated the process of nerve regeneration, an effect that is a function of the cells' developmental stage. P19 astroglia and older cells inhibited the regeneration process, encapsulating the axons in a glia-limitans-like structure. Immature astrocytes (P9) did not seem to interfere with the regeneration process; nerve outgrowth in their presence resembled and was comparable to the ones obtained in the presence of inoculated Schwann cells. The differential effects of the developing astroglia were not significantly changed by the inoculation media, e.g., liquid or solid, and were already pronounced 2 weeks after neural transection. It is suggested by the results of the study that the role and function of astroglia in nervous system morphogenesis are changing with cell differentiation. Adult astrocytes seem to downregulate axonal growth; presumably, their function is to confine the neurites within designated structural and functional boundaries.

Animals↗
PubMed2006

Stage matters: choosing relevant model systems to address hypotheses in diet and cancer chemoprevention research.

Clinical evidence reveals that the efficacy of dietary factors to prevent cancer is probably stage-dependent. The ability to demonstrate stage-specific effects of dietary compounds on normal, preneoplastic and malignant cell models may provide insights into puzzling clinical results from cancer chemoprevention trials. The relevance of these models to the field of cancer prevention is immense and will undoubtedly facilitate the ability to discover which dietary factors are most effective at preventing cancer and which, if any, specific steps in neoplastic transformation render cells refractory to the effects of dietary compounds. There are illustrative examples where exposure of high-risk individuals to dietary chemopreventive agents increases rather than decreases cancer risk. While geneticists and clinical oncologists acknowledge the morphological continuum along which tumors develop in specific tissues, tumor cells, rather than normal and preneoplastic cells, continue to be the primary in vitro reductionist tool employed to elucidate mechanisms underlying disease progression and to investigate the potential utility of dietary as well as other chemopreventive agents. Currently, there are few relevant model systems to study the progression of neoplastic transformation, especially in epithelial cells. We highlight examples of model systems isolated from prostate, breast, endometrial and intestinal tissue, with special emphasis on a specific set of non-tumorigenic, conditionally immortal cell lines derived from C57/BL6 mice [YAMC (Young Adult Mouse Colon cells; Apc+/+) cells and IMCE (Immorto-Min Colonic Epithelium cells; ApcMin/+) cells] that have yielded important information on early events in colorectal neoplasia development. These cell lines are an illustrative example of how researchers can examine stage-dependent effects of specific dietary components on carcinogenesis. The utilization of cell culture systems modeling early, middle and late stages of tumorigenesis will yield important insights into mechanisms by which dietary components impact cancer progression.

Animals↗
PubMed2003

Changes in macroscopic viscosity do not affect the release of aroma aldehydes from a pectinaceous food model system of low sucrose content.

The effects of pectin and viscosity on the release of a systematic series of aldehydes (alkanals, methyl-alkanals, alkenals, and alkandienals) were studied in a food model system of low sucrose content (10% w/w). The viscosity was varied by adding different amounts of Ca(2+) (0, 13.5, and 27 mg/g pectin) to the model system of constant pectin concentration (0.4% w/w). Air-liquid partition coefficients, K (37 degrees C), of the aroma compounds were determined in aqueous and pectin-thickened solutions. Diffusivities of the aroma compounds in water and three pectin-thickened solutions were estimated from release rate constants that were obtained via timed collection of volatiles in the gas phase and quantifications by dynamic headspace-gas chromatography. The partition coefficients increased as the carbon chain increased within each homologous series. Overall, no significant difference was found between partition coefficients of aldehydes in water and in pectin solutions except for 2-methyl-propanal and butanal that showed higher K values when pectin was present. Furthermore, the diffusional properties of the model system with a constant pectin level (0.4% w/w) remained constant when the viscosity was increased from 0.001 to 150 Pa s. It was concluded that neither pectin nor alterations in macroscopic viscosity as such influenced the release of aldehydes from the pectin-thickened food model system.

Aldehydes↗
PubMed2002

Biomimetic oxidation of 2-methylimidazole derivative with a chemical model system for cytochrome P-450.

A chemical model system for cytochrome P-450, consisting of tetraphenylporphyrin manganese chloride (TPPMnCl) and iodosylbenzene, efficiently oxidized 2-methylimidazole to 2-methylimidazolone. This system was next applied to 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutyramide, a muscarinic acetylcholine receptor antagonist under clinical trial, affording the previously unisolated imidazole ring 5-mono-oxidized derivative that is considered to be the precursor of the main metabolites. This system, which is superior to the copper-ascorbate system, should be applicable to in vitro studies of various drugs containing the 2-methylimidazole moiety.

Biomimetics↗
PubMed2003

An in vitro cell model system for the study of the effects of ozone and other gaseous agents on phagocytic cells.

Ozone (O(3)), a major component of air pollution and a very strong oxidizing agent, can lead to lung injury associated with edema, inflammation, and epithelial cell damage. The ozone effects on pulmonary immune cells have been studied by various in vivo and in vitro systems. In this report, we characterized a model system of cells of monocyte/macrophage lineage (THP-1 cells) exposed to ozone in vitro by studying cell viability and cell surface marker expression. THP-1 cells exposed to ozone in concentrations ranging from 0.1 to 0.5 ppm for 1 h were analyzed for cell viability and apoptosis (Annexin V/7-Amino-actinomycin D (7-AAD) flow cytometric assay) either immediately after ozone exposure or at later time points. This analysis showed absence of apoptosis and a small decrease in cell viability (5-17%) in ozone-exposed THP-1 cells. Cell surface protein expression (CD14 and CD11b) did not change following ozone exposure, but the effect of lipopolysaccharride (LPS) on TNF-alpha production following ozone exposure changed compared to filtered air/LPS-exposed cells. These findings indicate that this in vitro ozone cell-exposure system may be used in studies where the effects of various agents (physiological and non-physiological) on phagocytic cells can be analyzed. This model system offers conditions where the experimental results are not due to cell death, but rather due to the effects of ozone and/or agents under investigation.

Air Pollutants↗
PubMed2005

Membrane interactions of host-defense peptides studied in model systems.

Host-defense, antibiotic peptides are believed to generate their cytolytic effects by interacting with the membranes of bacterial cells. Direct analyses of peptide interactions with real cellular membranes are difficult, however, due to the high complexity of physiological membranes. This review summarizes experimental work aiming to understand peptide-membrane interactions and their relationships with the peptides' biological actions using specific model systems. Varied model assemblies have been constructed that generally aim to mimic the fundamental lipid bilayer organization of the membrane. The model systems we will describe include multilamellar and unilamellar vesicles, planar lipid bilayers, lipid monolayers and micelles, and colorimetric biomimetic membranes. The different artificial models have facilitated examination of specific biological or chemical parameters affecting peptide action, for example the effect of membrane lipid composition on peptide affinities and membrane penetration, the relationship between membrane fluidity and peptide interactions, the conformations of active peptides, and other factors. We evaluate the strengths and limitations of the various approaches, and point to future directions in the field.

Antimicrobial Cationic Peptides↗
PubMed1998

A model system for studying the integration of molecular biology databases.

MOTIVATION: Integration of molecular biology databases remains limited in practice despite its practical importance and considerable research effort. The complexity of the problem is such that an experimental approach is mandatory, yet this very complexity makes it hard to design definitive experiments. This dilemma is common in science, and one tried-and-true strategy is to work with model systems. We propose a model system for this problem, namely a database of genes integrating diverse data across organisms, and describe an experiment using this model. RESULTS: We attempted to construct a database of human and mouse genes integrating data from GenBank and the human and mouse genome-databases. We discovered numerous errors in these well-respected databases: approximately 15% of genes are apparently missing from the genome-databases; links between the sequence and genome-databases are missing for another 5-10% of the cases; about a third of likely homology links are missing between the genome-databases; 10-20% of entries classified as 'genes' are apparently misclassified. By using a model system, we were able to study the problems caused by anomalous data without having to face all the hard problems of database integration. CONTACT: nat@jax.org

Animals↗
PubMedDate not supplied

Determination of acrylamide formed in asparagine/D-glucose maillard model systems by using gas chromatography with headspace solid-phase microextraction.

A gas chromatographic method, along with a headspace solid-phase microextraction (HS-SPME), was developed for the determination of acrylamide formed in Maillard reaction model systems. The developed method was validated by liquid chromatography/mass spectrometry. A headspace sample was collected from an aqueous acrylamide solution (100 microg/mL) by SPME and directly injected into a gas chromatograph equipped with a nitrogen-phosphorus detector. The recovery of acrylamide from an aqueous solution was satisfactory, i.e, >93% under the conditions used. Acrylamide formed in an asparagine/D-glucose (molar ratio, 1/2) Maillard reaction model system heated at 150 and 170 degrees C for 20 min was collected and analyzed by the newly developed method using gas chromatography with nitrogen-phosphorus detection and HS-SPME. The amounts of acrylamide were 318 +/- 33 microg/g asparagine from a sample heated at 150 degrees C and 3329 +/- 176 microg/g asparagine from a sample heated at 170 degrees C. Addition of cysteamine or glutathione to the above model system reduced acrylamide formation. Acrylamide formation was not observed when cysteamine or glutathione was added to asparagine in the above model systems to obtain equimolar concentrations of both compounds. This newly developed method is simple and sensitive, and requires no solvent extraction.

Acrylamide↗
PubMed1998

Minimal model systems for beta sheet secondary structure in proteins.

Use of model systems to explore the forces that control beta sheet formation was stymied for many years by the perception that small increments of beta sheet necessarily aggregate. Recently, however, a number of short peptides (9-16 residues in length) that fold into two-stranded antiparallel beta sheets ('beta hairpins') have been reported; several short peptides (20-24 residues in length) that fold into three-stranded antiparallel beta sheets have also been described. These model systems are beginning to provide fundamental insights into the origins of beta sheet conformational stability.

Amino Acid Sequence↗