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A systemic model is proposed to be applied for various types of radiation. The bases for the model are substantiated and mathematical survival equations developed.
The EPR spectra of the nitric oxide (NO) derivatives of structurally perturbed Fe (II) hemeproteins show various patterns, all of which are characterized by the conspicuous three-line hyperfine splitting due to 14NO, in contrast to that of the native proteins. For the purpose of obtaining structural information from these three line spectra, the model systems were studied, which consist of NO, heme (or TPP-Fe(II), where TTP means alpha, beta, gamma, delta-tetraphenylporphine) and the nitrogenous base, pyridine or quinoline, which, respectively, give the native type or the three line (perturbed type) EPR spectrum. The ring proton paramagnetic shift of quinoline in this system shows that it is not coordinated to NO-TPP-Fe(II) as a normal axial ligand, in contrast to pyridine which gives the shift pattern of the ordinary axial ligation. This observation suggests that in the NO-hemeproteins some perturbations of the protein structure cause the rupture or distortion of the bond between the imidazole nitrogen on the fifth coordination site and the heme iron, resulting in the three line spectrum. The EPR study of the model systems, the pentacoordinated complex, NO-heme and NO-TPP-Fe(II), in various media revealed that the pentacoordinated species indeed exhibits, depending upon its environment, a variety of spectra, which closely reproduce the three line patterns observed in the perturbed proteins and some related model systems. Such spectral variation can be attributed to the difference in the degree of quenching the internal motion and/or the structural heterogeneity caused by molecular environment.
Recent studies provide extensive evidence for the importance of carotenoids in protecting against oxidative stress associated with a number of diseases. In particular, reactions of carotenoids with phenoxyl radicals generated by peroxidase-catalyzed one-electron metabolism of phenolic compounds may represent an important antioxidant function of carotenoids. To further our understanding of the antioxidant mechanisms of carotenoids, we used in the present work two different phenolic compounds, phenol and a polar homologue of vitamin E (2,2,5,7,8-pentamethyl-6-hydroxychromane, PMC), as representatives of two different types of phenols to study reactions of their respective phenoxyl radicals with carotenoids in cells and in model systems. We found that phenoxyl radicals of PMC did not oxidize beta-carotene in either HL-60 cells or in model systems with horseradish peroxidase (HRP)/H2O2. In contrast, the phenoxyl radicals generated from phenol (by native myeloperoxidase in HL-60 cells or HRP/H2O2 in model systems) effectively oxidized beta-carotene and other carotenoids (canthaxanthin, lutein, lycopene). One-electron reduction of the phenoxyl radical by ascorbate (assayed by electron spin resonance-detectable formation of semidehydroascorbyl radicals) prevented HRP/H2O2-induced oxidation of beta-carotene. PMC, but not phenol, protected beta-carotene against oxidation induced by a lipid-soluble azo-initiator of peroxyl radicals. No adducts of peroxidase/phenol/H2O2-induced beta-carotene oxidation intermediates with phenol were detected by high-performance liquid chromatography-mass spectrometry analysis of the reaction mixture. Since carotenoids are essential constituents of the antioxidant defenses in cells and biological fluids, their depletion through the reaction with phenoxyl radicals formed from endogenous, nutritional and environmental phenolics, as well as phenolic drugs, may be an important factor in the development of oxidative stress.
This report describes an in vitro model system in which monodisperse fetal rat lung cells reorganize to form alveolar-like structures when cultured on a gelatin sponge matrix. The alveolar-like structures are composed of cells that have morphologic characteristics like those of the type II alveolar pneumonocytes of intact lung. These morphologic characteristics include lightly stained nuclei, microvilli on the apical surface, and osmiophilic lamellar bodies in the cytoplasm. The presence of osmiophilic lamellar bodies and tubular myelin in the lumen of the alveolar-like structures suggests that the cells in these structures are producing pulmonary surfactant. The formation and long-term maintenance of these alveolar-like structures provide a unique in vitro model system for studies of the synthesis, storage, and secretion of pulmonary surfactant.
This article presents a conceptual model for occupational therapy: the ecological systems model. The developing individual is viewed as an open system interacting with the environment. Both humans and their environment are interconnected, joined in shaping each other. States of health and illness can be seen as reflections of ecological adaptation. Function or dysfunction is evaluated in terms of persons' effectiveness in achieving their own goals, for their own quality of life, in their interactions in the ecosystem. If performance of necessary tasks ane roles is effective in achieving those goals and in harmony with the needs and goals of the external systems, then behavior is functional.
Patients with ataxia-telangiectasia (AT), a human autosomal recessive genetic disease, are uniformly hypersensitive to ionizing radiation as measured by colony-forming ability and by chromosomal aberrations. Obligate heterozygotes, i.e., parents of AT patients, are slightly more radiosensitive than normal humans in terms of both colony-forming ability and chromosomal aberrations formed in G2. Thus, this system not only furnishes a model system to study factors that are responsible for radioresistance in normal human beings, but is also a unique tool for determining the role of gene dosage on radiation-induced cell killing. Because AT cells seem to be hypomutable to ionizing radiation, they also can be used to study the relationship between radiosensitivity and mutability and, therefore, carcinogenesis. Isolation of the defective gene that causes hypersensitivity in AT cells and its counterpart in normal cells should lead to a breakthrough in our understanding of radiation effects and how they can be prevented in human beings.
Several epidemiological studies have implicated low dietary and serum levels of retinol with an increased risk for the development of human prostate cancer. In a recent report, dietary fenretinide [N-[(4-hydroxyphenyl)] retinamide], a synthetic retinoid with low toxicity, decreased the incidence of experimentally induced prostate cancer. Fenretinide is currently being evaluated in phase I and phase II clinical trials as an agent for both the treatment and chemoprevention of human prostate cancer. Because of these findings, we investigated whether dietary fenretinide could alter the incidence of phenotype of oncogene-induced prostate cancer in the mouse prostate reconstitution model system. When compared to control-fed animals, dietary fenretinide reduced the tumor incidence by 49% and the tumor mass by 52% of ras+myc-induced cancers in the mouse prostate reconstitution model system, which was modified to prolong the latency period before cancer development. Retinoids have a wide ranging effect on cellular differentiation, growth factor synthesis, and immune function. While its mechanism of action in this system remains unclear, fenretinide is an effective agent for the chemoprevention and growth modulation of oncogene-induced prostate cancer in the mouse prostate reconstitution model system and may be effective for the chemoprevention of human prostate cancer.
This article describes a community nursing center that provided clinical learning experiences for students from two schools of nursing. Work at the center was based on the Neuman systems model, which views the client as a system in interaction with environmental stressors. Nursing interventions focused on health promotion services for an underserved elderly population. The benefits of using the Neuman systems model for patient care, education, and research are outlined.
Factors that regulate various pathways of Maillard reaction leading to aroma, color, or carcinogen generation have not been identified, due to the difficulties associated with analyzing complex reaction mixtures. In particular, the role played by oxidation in directing aromagenic, chromogenic, or carcinogenic pathways is not well understood. In order to overcome the analytical difficulties, novel Py-GC/MS-based methodologies were developed to analyze volatile and nonvolatile residues of Maillard reaction products generated from the same model system under air or helium atmosphere. The analysis of nonvolatiles was achieved through a postpyrolytic in situ derivatization technique using hexamethyldisilazane, and pyrolysis under air was achieved through modification of the GC equipped with sample concentration trap to allow gas stream switching and subsequent isolation of the pyrolysis chamber from the analytical stream. In this approach label incorporation from the starting materials can be observed in both volatile and nonoxidative conditions for mechanistic studies. In addition, monitoring of redox potentials, oxygen consumption, and color generation of relevant model systems over time were also carried out at different temperatures. The data collected have indicated that perturbation in the redox potential of Maillard model systems by external (oxidizing conditions) or internal (formation of reductones) factors can alter the balance among the four critically important groups of precursors: alpha-dicarbonyl, alpha-hydroxycarbonyl, 2-aminocarbonyls, and 2-(amino acid)-carbonyl compounds and hence control the relative importance of aromagenic versus chromogenic pathways.
Nitrosamines are environmental carcinogens, and their relevance to human cancer is highly suspected. Dialkylnitrosamines require activation through metabolizing enzymes before they become ultimate electrophilic active species. This review summarizes two model systems for metabolic oxidation of dialkylnitrosamines. One system utilizes porphyrin and oxidant as a model for shunt pathway in the metabolizing pathway of cytochrome P450, and the other one utilizes Fenton reagent. Porphyrin and oxidant activated nitrosodialkylamines into direct acting mutagen by releasing aldehydes. During the process the alkylating activity was observed and alcohols are formed from the alkylation of water. Fenton reagent, consisting of iron salt and hydrogen peroxide supplemented with copper salt, activated dialkylnitrosamines into mutagens of a novel type containing an oxadiazine ring as their proposed structures. These works with model systems open a new aspect into the elucidation of the mechanism of xenobiotic metabolism.
We have established an in vitro angiogenesis model using human omental microvascular endothelial (HOME) cells, in which epidermal growth factor (EGF) or transforming growth factor-alpha (TGF-alpha) stimulated cell migration and tube formation. In this study, we examined whether alpha-guaiaconic acid (GR-12) and its synthetic 20 derivatives showed inhibition of cell migration and tubular formation of HOME cells. We found that GR-12 inhibits arachidonic acid metabolism, while GR-12 and one derivative, GS-01, inhibit tubular formation of endothelial cells in our model system. Confluent monolayers of HOME cells were damaged with a razor blade and incubated with or without TGF-alpha; HOME cell migration was stimulated about 1.5-fold over control values in the presence of TGF-alpha. Treatment of HOME cells with GR-12 or GS-01 inhibited both spontaneous and TGF-alpha-stimulated migration. GR-12 or GS-01 inhibited TGF-alpha-induced HOME-cell tube formation in type-1 collagen gels. We examined whether these compounds could modulate tubular formation of HOME cells induced by human cancer cells. Enhanced tube formation of HOME cells by co-cultured esophageal cancer cells was almost completely inhibited by co-administration of GR-12 or GS-01. Both compounds also inhibited formation of tubular networks of HOME cells on Matrigels. We also examined anti-angiogenic activity of these compounds in an in vivo model system of tumor angiogenesis in mice. In this system, GS-01 inhibited development of capillary networks at a rate comparable to that of a well-known anti-angiogenic compound, fumagillin, but GR-12 did not. The inhibitor of arachidonic acid metabolism is thus expected to modulate tumor angiogenesis.
Computational tools utilizing a unique empirical modeling system based on the hydrophobic effect and the measurement of logP(o/w) (the partition coefficient for solvent transfer between 1-octanol and water) are described. The associated force field, Hydropathic INTeractions (HINT), contains much rich information about non-covalent interactions in the biological environment because of its basis in an experiment that measures interactions in solution. HINT is shown to be the core of an evolving virtual screening system that is capable of taking into account a number of factors often ignored such as entropy, effects of solvent molecules at the active site, and the ionization states of acidic and basic residues and ligand functional groups. The outline of a comprehensive modeling system for virtual screening that incorporates these features is described. In addition, a detailed description of the Computational Titration algorithm is provided. As an example, three complexes of dihydrofolate reductase (DHFR) are analyzed with our system and these results are compared with the experimental free energies of binding.
The cytochemical technique of Lee and Torack for the demonstration of aspartate aminotransferase activity was tested on a model system consisting of either total liver homogenate or the mitochondrial or soluble cytoplasmic fraction, incorporated in polyacrylamide film. After incubation of portions of film in a medium of alpha-ketoglutarate, L-aspartate, and lead nitrate, the lead oxaloacetate formed was converted to lead sulfide. The absorbance determined at 520 nm in a film spectrophotometer and expressed in terms of unit weight of film provided a measure of the contained enzymatic activity, and was directly proportional to the concentration of chemically determined oxaloacetate in the film. Both mitochondrial and "soluble" isozymes of aspartate aminotransferase reacted with the cytochemical media to a quantitatively similar degree, but were considerably inactivated after 15 min of treatment with 1% glutaraldehyde or 3.7% formaldehyde in imidazole buffer, the rate of inactivation being greater for the soluble isozyme. Application of the principle of substrate protection delayed inactivation. Thus, for both isozymes the rate of inactivation decreased if ketoglutarate was added to the fixative. Similarly, it was shown that the optimal incubation medium for the demonstration of the soluble isozyme must contain 4 mM of alpha-ketoglutarate and 20 mM of L-aspartate. Under these conditions the turnover-number for the cytochemical system is 70% of the value obtained from biochemical estimations. Cytochemical K(m) values differed for each isozyme and were in accord with values determined by biochemical techniques, indicating that the model system can be used as a link between biochemical and cytochemical data in enzymatic studies.
Pladmodium fragile and the Macaca mulatta monkey are presented as a model system for the study of malarial vaccines. Four animals were immunized with culture-grown P. fragile merozoites and subsequently challenged with culture-produced parasites. One animal failed to develop a detectable parasitemia following primary challenge. Two other immunized animals had primary infections which were short-term. the parasitemias in these three monkeys following secondary challenge were short-term and the immunity was apparently sterilizing. The fourth immunized monkeys had recrudescences of the primary and secondary infection but differed markedly from the four control animals. Indirect fluorescent antibody titers increased as a result of the immunization and were indicative of the level of immunity. Because of the many similarities to the human-P. falciparum model system, the P. fragile-M. mulatta system appears to be particularly well suited for a number of malaria vaccine studies.
A high-performance brain PET scanner, jPET-D4, which provides four-layer depth-of-interaction (DOI) information, is being developed to achieve not only high spatial resolution, but also high scanner sensitivity. One technical issue to be dealt with is the data dimensions which increase in proportion to the square of the number of DOI layers. It is, therefore, difficult to apply algebraic or statistical image reconstruction methods directly to DOI-PET, though they improve image quality through accurate system modelling. The process that requires the most computational time and storage space is the calculation of the huge number of system matrix elements. The DOI compression (DOIC) method, which we have previously proposed, reduces data dimensions by a factor of 1/5. In this paper, we propose a transaxial imaging system model optimized for jPET-D4 with the DOIC method. The proposed model assumes that detector response functions (DRFs) are uniform along line-of-responses (LORs). Then each element of the system matrix is calculated as the summed intersection lengths between a pixel and sub-LORs weighted by a value from the DRF look-up-table. 2D numerical simulation results showed that the proposed model cut the calculation time by a factor of several hundred while keeping image quality, compared with the accurate system model. A 3D image reconstruction with the on-the-fly calculation of the system matrix is within the practical limitations by incorporating the proposed model and the DOIC method with one-pass accelerated iterative methods.
Oxidation of 3-isobutyryl-2-isopropylpyrazolo[1,5-alpha]pyridine (IBPP) was carried out with various chemical model systems for cytochrome P-450 in comparison with the liver microsomal system of rats or humans. Alpha-hydroxylation of side chains and ring hydroxylation at the 6 and 7 positions were the main reactions in both systems. A pattern analysis of products using two dimensional thin layer chromatography was employed to compare the functions of the chemical model systems with those of microsomal systems. The reaction profile of IBPP by the catalyst/Pt-colloid/H2, O2 system was most similar to that of human or rat microsomal system. The utility of these chemical models is discussed from the viewpoint of drug metabolism.
Investigators have used the budding yeast Saccharomyces cerevisiae as a model system in which to study the beta-adrenergic receptor, the T-cell receptor pathway, initiation of mammalian DNA replication, initiation of mammalian transcription, secretion, the CDC2 kinase system, cell cycle control, and aging, as well as the function of oncogenes. This list continues to grow with the discovery of an immunoglobulin heavy-chain binding homologue in yeast, an Rb binding protein homologue, and a possible yeast arrestin. Yeast is relatively easy to maintain, to grow, and to genetically manipulate. A single gene can be overexpressed, selectively mutated or deleted from its chromosomal location. In this way, the in vivo function of a gene can be studied. It has become reasonable to consider yeast as a model system for studying the seven transmembrane segments (7-TMS) receptor family. Currently, subtypes of the beta-adrenergic receptor are being studied in yeast. The receptor and its G alpha-G-protein, trigger the mating pheromone receptor pathway. This provides a powerful assay for determining receptor function. Studies expressing the muscarinic cholinergic receptor in yeast are underway. The yeast pheromone receptor belongs to this receptor family, sharing sequence and secondary structure homology. An effective strategy has been to identify a yeast pathway or process which is homologous to a mammalian system. The pathway is delineated in yeast, identifying other genetic components. Then yeast genes are used to screen for human homologues of these components. The putative human homologues are then expressed in yeast and in mammalian cells to determine function. When this type of "mixing and matching" works, yeast genetics can be a powerful tool.
The formation of acrylamide was investigated in model systems based on asparagine and glucose under low moisture Maillard reaction conditions as a function of reaction temperature, time, physical state, water activity, and glass transition temperature. Equimolar amorphous glucose/asparagine systems with different water activities were prepared by freeze drying and were shown to quickly move to the rubbery state already at room temperature and a water activity of above 0.15. The acrylamide amounts were correlated with physical changes occurring during the reaction. Pyrolysis and kinetics of acrylamide release in amorphous and crystalline glucose/asparagine models indicated the importance of the physical state in acrylamide formation. In amorphous systems, acrylamide was generated in higher concentrations and at lower temperatures as compared to the crystalline samples. Time and temperature are covariant parameters in both systems affecting the acrylamide formation by thermal processes. On the other side, the water activity and glass transition temperature do not seem to be critical parameters for acrylamide formation in the systems studied.