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Dose-response relationships of hepatic acyl-CoA oxidase and catalase activity and liver mitogenesis induced by the peroxisome proliferator ciprofibrate in C57BL/6N and BALB/c mice.

The dose-response for key hepatic effects of the peroxisome proliferator ciprofibrate, 2-[4-(2,2-dichlorocyclopropyl)phenoxy]-2- methylpropanoic acid, was delineated in mice and strain differences in response were demonstrated. Ciprofibrate was fed at concentrations ranging from 0.1 to 250 ppm to male C57BL/6N and BALB/c mice and the induction of hepatic acyl-CoA oxidase and catalase, peroxisomal enzymes involved in the formation and degradation of hydrogen peroxide, and liver hepatomegaly and mitogenesis were measured. No effect was found for enzyme induction at 5.0 ppm or less in either strain. Likewise, hepatomegaly was not found at 5.0 ppm, but mitogenesis was observed in BALB/c mice at 1.0 ppm. C57BL/6N mice demonstrated greater basal and postexposure acyl-CoA oxidase activity than BALB/c mice, while BALB/c mice demonstrated greater catalase activity and induction of liver mitogenesis. The threshold exposure level for induction of acyl-CoA oxidase activity was approximately the same as that for induction of mitogenesis in C57BL/6N mice; in contrast, the threshold exposure level for induction of acyl-CoA oxidase activity was at least one order of magnitude greater than that required for induction of mitogenesis in BALB/c mice. Thus, the induction of the peroxisomal enzyme involved in the formation of hydrogen peroxide and increased mitogenesis are not mechanistically linked. The differential effects observed in the two mouse strains provide the basis for development of a quantitative model of peroxisome proliferator-induced carcinogenicity in which cellular effects can be related to carcinogenicity.

Acyl-CoA Oxidase↗

Development of spatiotemporal mechanisms in infant vision.

In adult spatiotemporal vision information is processed in parallel by a number of mechanisms tuned for orientation and spatial frequency. An examination of infant neuroanatomical data suggests that three major factors are involved in the development of these mechanisms: (1) Growth of foveal cone outer segments causes an increase in mechanism sensitivity. (2) Migration of foveal cones produces a change in spatial scale and a progressive shift of mechanism tuning towards higher spatial frequencies. (3) Development of cortical inhibition transforms low-pass into bandpass spatial frequency and orientation tuning. These changes are developed into a quantitative model which is shown to provide a coherent interpretation of many of the psychophysical data on infant vision.

Adult↗

Individual differences in contrast sensitivity functions: the first four months of life in humans.

Contrast sensitivity functions of forty 4-month-old human infants were measured using a preferential-looking method and the method of constant stimuli. Circular sinewave gratings varied from 0.27 to 1.08 c/deg, contained eight unattenuated cycles (with edges tapered to uniform gray), and rose to the desired contrast in 2 sec. Log contrast sensitivities for variables close in spatial frequency correlated more highly than those that were farther apart in these data, and in data of 1-, 2-, and 3-month-olds from Banks and Salapatek [(1981) Journal of Experimental Child Psychology, 31, 1-45]. Factor analyses yielded at least two frequency-tuned factors per age group. Monte Carlo simulations of a quantitative model that shifts spatial mechanisms to higher frequencies with age reproduced the results for 4-month-olds, but simulations of adultlike, unshifting mechanisms did not. The data are consistent with the following conclusions: (a) individual differences in the sensitivity of spatial mechanisms may explain some individual differences in CSFs; (b) factor analysis may help to estimate mechanism tuning; and (c) spatial mechanisms may shift to higher frequencies during development.

Contrast Sensitivity↗

Dependence of plaid motion coherence on component grating directions.

We measured motion coherence for plaids composed of two different spatial frequency (SF) cosine grating components moving at various relative angles. The component SFs were in a ratio of 6:1, and several component motion directions were chosen to produce small to large angular differences. For angles of less than +/- 45 deg all subjects perceived rigid coherent motion, while for angles of +/- 45 deg or greater the components were perceived to slide transparently. The results were not altered when we changed the ratio of component contrasts or speeds over a factor of 2 and varied the SF ratio up to 9:1. These results show that transparency or coherence of moving plaids in different spatial scales depends on the relative component motion directions and is relatively independent of contrast, speed, and SF difference between the components. This angular dependence also explains recent data previously thought to be based on a visual computation of multiplicative transparency. A quantitative model in which the resultant motion on each scale provides a facilitative biasing signal to units tuned to similar directions (within +/- 30 deg) on other scales explains the experimental results.

Contrast Sensitivity↗

Chemical topology and ecotoxicology.

The experimental determination of environmental parameters (e.g. soil sorption, bioconcentration, biodegradation and biotransformation, toxic effects, etc.) of commercial chemicals is a costly and time-consuming process. Since there is a large number of chemicals currently in common use (approximately 100,000) and new chemicals are registered at a very high rate (1000/year) it is obvious that our human and material resources are insufficient to obtain experimentally even basic information on environmental fate and effects for all those chemicals. Thus, it is necessary to develop quantitative models that will accurately and rapidly predict environmental behaviour for large sets of chemicals. Thus far, molecular connectivity indices have been shown to be the most successful structural property for describing and predicting soil sorption coefficients, association with dissolved humic substances, Henry's law constants, bioconcentration factors in aquatic organisms and vegetation, biodegradation, and acute toxicity. We describe and discuss the most recent results on modelling environmental fate of organic pollutants by the application of molecular connectivity indices. Two sections describe the usefulness of environmental QSAR models based on n-octanol/water coefficients and the systematics and possible physical interpretation of molecular connectivity indices. Some practical and theoretical weaknesses and pitfalls are discussed concerning the use of n-octanol/water partition coefficients in environmental QSAR research.

Biodegradation, Environmental↗

Partial resolution of sources of n-alkanes in the saline portion of the Parachute Creek Member, Green River Formation (Piceance Creek Basin, Colorado).

Systematic variations in the 13C contents of individual extractable n-alkanes (C16-C29) can be modelled quantitatively and interpreted as indicating contributions from at least five distinct sources. These appear to be cyanobacterial (C16-C18, delta 13C = -37% vs PDB), phytoplanktonic (C16-C23, delta = -32%), chemoautotrophic bacterial (C20-C29, delta = -38%), phytoplanktonic or heterotrophic bacterial (C20-C29, delta = -30%), and vascular plants (C23-C29, delta = -29%). Hydrous pyrolysis of related kerogens yields large quantities of additional n-alkanes with different and much more uniform delta values. The latter materials are apparently derived from the thermolysis of aliphatic biopolymers whose presence in the Green River Oil Shale has been recognized visually.

Alkanes↗

Measurement of tachykinin-induced salivation in conscious rats.

A method of quantitatively measuring tachykinin-induced salivation in conscious, male, Sprague-Dawley rats is described. Salivation is quantified by determining the weight of a preweighed, absorbant foam cube after it has been used to swab the oral cavity of a tachykinin challenged rat. Salivation is induced by intravenous (i.v.) injection of sialogogues (microgram/kg) via the lateral tail vein. Measurements are made immediately after injection. Substance P (Sub.P), Sar9, Met (O2) 11Substance P (Sar9 Sub.P), a selective neurokinin (NK) 1 receptor agonist, Physalaemin and Eledoisin are equipotent sialogogues as determined by this method. Neurokinin A (NKA), the endogenous NK2 receptor agonist, is 0.27 (0.14-0.46) times as potent as Sub. P, while (Suc-[Asp6, MePhe8]Substance P(6-11), (senktide), a selective NK3 receptor agonist, only induced salivation at 300 microgram/kg. Acetylcholine (Ach) is only 0.006 (0.002-0.012) times as potent as Sub.P. Treatment with the neurokinin antagonist [D-Arg1, D-Trp7,9 Leu11]-Substance P (spantide) dose-dependently inhibits Sub. P stimulated salivation. Atropine dose-dependently inhibits Ach induced salivation but is inactive against Sub.P-induced salivation. These data are consistent with literature values and indicate that this method provides a simple, quantitative model, free of any possible anesthetic side effects, for the measurement of neurokinin stimulated salivation and the assessment of potential neurokinin antagonists in vivo.

Acetylcholine↗

Computer-assisted diabetic management: a complex approach.

This paper describes the architecture of, and the main reasoning methods involved in, a computer system developed to assist in diabetic management. The system integrates (i) a database module used for blood glucose monitoring, (ii) an interpreter module used to analyse the adequacy of diet and insulin treatment for diabetics, and (iii) an advisory module suggesting alterations in diet and/or insulin regimen in order to improve glycaemic control. The analysis of blood glucose profiles and hypoglycaemic episodes, as well as the suggestions for altered diet and insulin therapy, are based on qualitative and quantitative models of insulin effect and carbohydrate absorption using meal-time related glucose balance and distance from the preselected target (DFT) glucose values as focal concepts in the reasoning process. During the sequence of consultations with the system, a dynamic model of carbohydrate metabolism is gradually adjusted in order to constitute an appropriate simulation for the specific patient. This model is used to confirm the suggestions made by the ADVISOR program and to assist the health care professional in selecting the best control action by predicting the blood glucose profiles resulting from alternative control policies.

Algorithms↗

Estrogen-calcium interactions in the postmenopause: a quantitative description.

Accumulated data describing the time course of bone loss in postmenopausal women were combined with metabolic data on estrogen-calcium interactions to produce a comprehensive, quantitative model of involutional bone loss. The model was shown to be able to mimic results of published intervention studies with considerable fidelity. Implicit in existing understanding, and made explicit by the model, are such relationships as: (1) calcium deficiency, if present in a woman, is masked during the early years of estrogen withdrawal bone loss; (2) accordingly, except in severe deficiency states, it is unlikely that calcium supplementation can confer much benefit in the immediate postmenopause; (3) however, by 5-8 years postmenopause, an underlying calcium deficiency, if present, becomes manifest, and if uncorrected will greatly augment the bone loss produced by estrogen withdrawal; (4) estrogen replacement therapy, if stopped, does not produce a sustained difference in bone mass in calcium-replete women; however, (5) estrogen, by effectively reducing the level of any calcium deficiency that may be present, does produce a permanent benefit in women with such deficiency. These relationships suggest that late fracture protection from earlier estrogen therapy is either confined to women with calcium deficiency, or has a non-mass basis (or both).

Aged↗

The basis for choice reaction time slowing in Alzheimer's disease.

Slowed reaction time has been suggested as an early feature of Alzheimer's disease (AD), but the basis for this slowing has not been established. Patients with mild AD were compared with controls on a choice reaction time task, both cued (CCRT) and uncued (CRT). Initial and 1-year followup data were analyzed both as mean reaction times and as parameters of a fitted two-component quantitative model (the ex-Gaussian model). Slowing of CRT proved to be a sensitive test for AD. Slowing was due to changes in both the sensory/motor and the decisional components of the CRT model. However, these changes were found in both AD and slower, older controls. The modeling of CRT in AD is discussed.

Aged↗

Structure-activity relationships in allergic contact dermatitis.

Skin sensitization by simple chemicals involves reaction with nucleophilic groups on skin proteins or possibly on proteins in cell membranes to form haptenic groups, which act as allergenic determinants. A quantitative model for sensitization by 'alkylating agents', the RAI (Relative Alkylation Index) theory, has been devised and applied to the sensitization observed with three model series of compounds--p-nitrobenzyl halides and saturated and unsaturated sultones. Examination of chemical structures, and predictions of the types of chemical reaction that substances may undergo, can be used to assess the likely reactivity of unknown materials towards skin proteins. In addition such examinations of structure may be used to assess the likely cross-reactivity of materials. The pro-hapten concept of Dupuis & Benezra (Allergic Contact Dermatitis to Simple Chemicals. A Molecular Approach. Marcel Dekker, New York) offers an explanation for the sensitization potential of substances that do not contain chemically reactive groups prior to in vivo conversion and for cross-reactions between apparently unrelated chemicals.

Alkylation↗

Quantitative analysis of ventral denticular patterns of Drosophila melanogaster larvae and the regulation of the bithorax complex.

A quantitative model of the effect of the bithorax complex on segmentation is presented which could explain the known data of the spatiotemporal regulation of key gene complex during early Drosophila development, in relation to their effects on some of the segmentation landmarks. The model tries to put together the two different genetic levels, the genotypic and the phenotypic. At the genotypic level, a minimal cross-regulatory network of the different genes involved, Antp, Ubx, abd-A and Abd-B which explains the reported levels of expressions of these genes. At the phenotypic level, the pattern of the ventral denticle belts across the larva which are characteristics of the different segments have been compared by calculating a value of the degree of similarity in the case of the wild-type and several mutant combinations. Finally the two parts of the model are combined, showing that a satisfactory agreement between the two can be achieved. Therefore, this work is a first attempt to develop a method which will provide an explanatory solution of the old question in morphogenesis of how the phenotype is directed by the genotype of a cell or organism.

Animals↗

Quantitative evaluation of the role of a putative CO2-scavenging entity in the cyanobacterial CO2-concentrating mechanism.

This paper assesses the contribution of a postulated CO2-scavenging system to the efficient operation of the CO2-concentrating mechanism (CCM) in cyanobacteria. A quantitative model for the CCM is presented which incorporates an energy-dependent carbonic anhydrase-like entity located at or near the inner surface of the plasma membrane. This entity, which converts CO2 to HCO3- against the thermodynamic potential, scavenges CO2 leaking outward from the carboxysomes, and, further, converts CO2 entering from the medium to HCO3-, thus maintaining an inward diffusion gradient along which CO2 enters passively. The model resembles our earlier models in postulating that CO2 and HCO3- are not at equilibrium throughout the greater part of the cell, and that CO2 is generated in high concentration at carbonic anhydrase sites within the carboxysomes. The model further takes into account the concentric thylakoid membranes which surround the carboxysomes, and events in the periplasmic space and the unstirred layer surrounding the cell. Implications of the predicted steady state fluxes of CO2 and HCO3-, and of their steady state concentrations in various cellular compartments, are discussed. The plasma membrane carbonic anhydrase-like activity lowers the photosynthetic Km for external Ci, as well as decreasing the inorganic C 'leak', but it may not save on energy expenditure.

Bicarbonates↗

Tumor cell implantation with the use of Gelaspon gelatin sponge disc.

Myelomonocytic leukemia (My) mesoblastic nephroma (Ne) and hepatocellular carcinoma (He) cells were implanted under the renal capsule of F344, Long-Evans (LE) and BDIX rats. Gelaspon sponge discs were used in the implantation procedure, which were resorbed within a few days. The tumor cells, which were located on the surface of these discs could then attach themselves to the renal capsule and thus grow. There was a correlation between the number of tumor cells and the difference between the two kidney masses. The correlation was linear between 10(4) and 10(6) cells, thus the method proved to be a simple, fast and quantitative model in experimental cancer prevention and therapy.

9,10-Dimethyl-1,2-benzanthracene↗

Modulation of GABA-mediated inhibition in rat cerebellar slices by benzodiazepine receptor ligands.

1. Extracellular recordings were made from the Purkinje cell layer of rat cerebellar slices. Compounds were perfused over the slice and bipolar stimulating electrodes placed in the external layer of the slice close to the recording electrode. 2. Stimulus-evoked inhibition of Purkinje layer cell activity was sensitive to bicuculline methiodide and picrotoxin, suggesting it was gamma-aminobutyric acid (GABA) mediated. The benzodiazepine ligands RU 32007 and Ro 19-0528 reversibly increased the period of inhibition, as did pentobarbital. This benzodiazepine effect was antagonised by Ro 15-1788. 3. Five inverse agonists all reduced the period of stimulated inhibition and this effect was reversed by Ro 15-1788, suggesting the involvement of benzodiazepine receptors. 4. It is concluded that this system provides a convenient physiological and possibly quantitative model for studying the action of benzodiazepine receptor ligands.

Animals↗

Molecular and cellular radiobiology of heavy ions.

Quantitative studies at the BEVALAC have demonstrated some of the physical and radiobiological factors that promise to make accelerated heavy ions important for the therapy of cancer. The measured physical dose-biological effect relationships allow the safe and effective delivery of therapeutic schedules of heavy ions. Among the charged particle beams available, carbon, neon and helium ions in the "extended Bragg peak mode" have optimal physical and biological effectiveness for delivery of therapy to deep seated tumors. The depth-dose profiles of these beams protect intervening and adjacent tissues as well as tissues beyond the range of the particles. For the treatment of hypoxic tumors, silicon and argon beams are being considered because they significantly depress the radiobiological oxygen effect in the region of the extended Bragg ionization peak. The depth-effectiveness of the argon beam is somewhat limited, however, because of primary particle fragmentation. Silicon beams have a depth-dose profile which is intermediate between that of neon and argon, and are candidates to become the particle of choice for maximizing high LET particle effects. Heavy accelerated ions depress enzymatic repair mechanisms, decrease variations of radiosensitivity during the cell division cycle, cause greater than expected delays in cell division, and decrease the protective effects of neighboring cells in organized systems. Near the Bragg peak, enhancement of heavy particle effects are observed in split dose schedules. Late and carcinogenic effects are being studied. With the newly developed Repair-Misrepair theory we can quantitatively model most observations.

Animals↗

Primary cultures of stromal-vascular cells from pig adipose tissue: the influence of glucocorticoids and insulin as inducers of adipocyte differentiation.

Porcine stromal-vascular (S-V) cells from perirenal and subcutaneous fat depots were studied in a primary culture system. The ability of S-V cells to differentiate into adipocytes in response to insulin and to glucocorticoid treatments was determined. Treatments were either hydrocortisone plus insulin, dexamethasone plus isobutylmethylxanthine, or insulin. Insulin did not affect glycerol phosphate dehydrogenase (GPDH) activity or cytodifferentiation in porcine S-V cultures. All cultures differentiated in response to glucocorticoid addition. Glycerol phosphate dehydrogenase specific activity increased an average of 42.5% and the number of cell clusters with multilocular fat cells markedly increased. Cells receiving insulin after dexamethasone-stimulated differentiation had no greater ability to respond to the insulin than cells from control cultures. Glucocorticoids promoted cytodifferentiation of porcine S-V cells to adipocytes in a qualitative manner similar to other preadipocyte models; quantitatively, however, the response was greatly diminished.

1-Methyl-3-isobutylxanthine↗

A quantitative analysis of the role of K+ channels in mitogenesis of neuroblastoma cells.

The role of K+ channels in mitogenesis was studied on mouse neuroblastoma cells by analysing the effects of various chemical agents on the whole-cell K+ current and the cell proliferation. The outward current recorded during depolarizations on undifferentiated cells was made up of a small and slow inactivating K+ current. Foetal calf serum, which is mitogen for neuroblastoma cells, shifted in opposite directions by 7-10 mV peak activation and steady-state inactivation-voltage curves of the K+ current. The resulting effect was an increase in K+ conductance. The effect on the resting K+ flux of the classical K+ channel blockers tetraethylammonium, 4-aminopyridine and capsaicin, the anticancer agent tamoxifen, the heat inactivated serum and the increase in external K+ concentration were estimated from their effects on the K+ current. The cell proliferation was determined under the same conditions. The results indicate that cell proliferation is correlated to the resulting K+ flux. It is supposed that mitogenesis is controlled by the intracellular Na+ concentration which, via a cell volume regulation, is a function of the K+ flux. A quantitative model is developed on the basis of these hypotheses.

Cell Division↗