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PubMed1983

On the suitability of organotypic cultures of fetal rat lung type II cells for biochemical studies concerning development.

When organotypic cultures of fetal rat lung epithelial cells are initiated with undifferentiated cells, the cells differentiate into type II cells (Douglas, W.H.J., McAteer, J. A., Smith, J.R. and Braunschweiger, W.R. (1979) Int. Rev. Cytol., Suppl. 10, 45-65). This conclusion was based only on morphologic studies. The present study was undertaken to investigate whether such maturation in culture could also be demonstrated biochemically. In organotypic cultures initiated with epithelial cells from fetal rat lungs at 17-days gestation, the amount of phospholipids increased for at least 10 days. However, no change took place in the percentage of phosphatidylglycerol nor in the ratio of disaturated to total phosphatidylcholine. In cultures initiated with cells obtained at day 17 of gestation the specific activity of cholinephosphate cytidylyltransferase reached a maximum after approximately 3 days, followed by a decrease. A similar profile was obtained, however, if the culture was started at day 20 of gestation. This indicates that the activity profiles obtained in the organotypic cultures reflect changes caused by the culture conditions rather than changes caused by maturation. From these investigations it is concluded that biochemical studies on type II cell development using organotypic cultures as model should be interpreted with caution.

Animals↗

PubMed1991

Insulin and the paraventricular hypothalamus: modulation of energy balance.

The effects of insulin injections (0.1, 1, 10 and 40 mU) into the paraventricular hypothalamus (PVN) were investigated in an open-circuit calorimeter. Wistar rats were tested, with no food available during the tests. The 0.1 and 1 mU doses had no effects on either respiratory quotient or energy expenditure. The 10 mU dose increased respiratory quotient which indicates increased dependency on carbohydrates as an energy substrate. The same dose had no effects on thermogenesis. In contrast, the 40 mU dose decreased respiratory quotient which indicates increased dependency on fats as an energy substrate. The higher dose also increased thermogenesis. Since neither dose significantly affected locomotor activity, the metabolic data are not confounded with activity effects. These data indicate that insulin in the PVN produces a primary modulation of the metabolic parameters central to maintaining energy balance. In separate experiments, the 4 doses of insulin reduced food intake and body weight over a 24 h period. They also produced a dose-related increase in blood glucose concentration over a one hour period. Taken together, these findings are interpreted in a model in which insulin in the PVN acts as a signal indicating increased body fat. This increases thermogenesis, fat utilization and glycemic levels, and inhibits feeding. The net effect of this integrated metabolic-behavioural response is a regulatory reduction in body fat.

Animals↗

PubMed1993

Somatostatin and the paraventricular hypothalamus: modulation of energy balance.

The effects of somatostatin injections (0.1, 1 and 5 micrograms) into the paraventricular nucleus of the hypothalamus (PVN) were investigated in an open-circuit calorimeter. Wistar rats were tested, with no food available during the tests. The 0.1 and 1 microgram doses produced large and long-lasting decreases in respiratory quotient, which indicates the preferential utilization of fats as an energy substrate. The 5 micrograms dose produced a brief decrease in energy expenditure. Locomotor activity was not affected by any treatment which indicates that the effects on respiratory quotient and energy expenditure are not secondary to changes in activity. These findings demonstrate that somatostatin in the PVN inhibits thermogenesis and induces the preferential utilization of fats while sparing carbohydrate reserves. However, it is significant that the effects on energy expenditure and energy substrate utilisation occurred at different doses. These data constitute the first evidence that somatostatin in the PVN produces a primary modulation of the metabolic parameters central to energy balance. In separate experiments, all three doses of somatostatin increased blood glucose concentration over a one hour period, and the 5 micrograms dose decreased body weight over a 24 h period. Food and water intake were not affected by the somatostatin injections. Taken together, these findings are interpreted in a model in which somatostatin is a signal to the PVN of increased body fat. This mobilizes sympathetic mechanisms which increase fat utilization and blood glucose levels.

Animals↗

PubMed1989

87Rb NMR studies of the perfused rat heart.

We have studied 87Rb+ fluxes in the perfused rat heart using nuclear magnetic resonance spectroscopy (NMR). A simple model for the interpretation of the data is presented. A comparison of radioactively measured K+ fluxes and the K+ fluxes deduced from the 87Rb+ measurements shows them to be very similar. This method provides a means of noninvasively measuring uni-directional K+ fluxes in the heart.

Animals↗

PubMed1989

The determination of mass of metabolites with tracers.

Application of tracers in vivo for the determination of replacement and mass of bloodborne compounds at steady state is discussed. Theory and methods to determine mass with tracers (total amount of compound-tracee-within the body) for compartmental and noncompartmental systems are presented, and their limitations examined. Methods to derive mass from the specific activity curves after bolus injection or infusion of tracer are described using graphic procedures or by equations using the parameters of exponential curves. The relationship between assumed models and the interpretation of tracer data is examined. The determination of both replacement (appearance, which equals utilization at steady state) and mass of most compounds present in both extracellular and intracellular fluids (such as lactate and amino acids) requires the application of the A-V mode for tracer administration and sampling of blood. Recycling of carbon affects the determination of mass with 14C. Estimates of true mass are provided with tritium-labeled compounds, even when tritium loss is by exchange with protons or through futile cycling. Estimates of the amount (body mass) of lactate, alanine, glutamate, and proline obtained with tritium-labeled compounds are presented. Most of these masses are intracellular. The concentration of lactate in tissues equals or is greater, and that of amino acids much greater than that in plasma. Hence, the so-called "distribution space" for these compounds, calculated conventionally by dividing mass by plasma concentration, would appear to be equal to or greater than the body water of lactate, and several liters per kilogram for amino acids.

Alanine↗

PubMed1989

Receptive field properties of human motion detector units inferred from spatial frequency masking.

This study was designed to investigate the spatial frequency selectivity and spatial structure of receptive fields of motion sensitive mechanisms in human vision. Spatial frequency selectivity was inferred from masking measurements, using dynamic test and mask stimuli. For test frequencies between 0.025 and 15.0 c/deg, maximal masking occurred when the mask frequency matched that of the test, suggesting that the test was detected by mechanisms tuned to (or near to) that frequency. For tests below 0.025 c/deg or above 15.0 c/deg, maximal masking occurred at 0.025 and 15.0 c/deg, respectively, suggesting that there exist no mechanisms selective to frequencies outside these limits. A masking model, suitable for interpreting results obtained with drifting test stimuli, was developed and used to calculate spatial frequency selectivity functions from masking data. Assuming small signal linearity, and a constant phase spectrum, the selectivity functions were inverse-Fourier transformed to yield estimates of the extent and structure of receptive fields. Field width was found to vary with test spatial frequency from 5.8 deg at 0.03 c/deg to 0.05 deg at 10.0 c/deg. These estimates were compared with width estimates previously obtained by a summation technique (Anderson & Burr, 1987), and found to be similar over a wide range of spatial frequencies (2.5 log units). Gabor functions provided a reasonable fit to the calculated field profiles at high spatial frequencies (above 1.0 c/deg), but not at low frequencies.

Fourier Analysis↗

PubMed1994

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↗

PubMed1991

Quantal analysis and synaptic efficacy in the CNS.

Quantal analysis of synaptic transmission at connections between neurons in the CNS has provided insights concerning the structural constraints on transmitter release and postsynaptic responsiveness. However, it has proven difficult in many cases to resolve the size and variability of a single quantum or to distinguish clear peaks in amplitude histograms of evoked responses, due in part to the superposition of background instrumental and biological noise. These limitations raise questions about recent attempts to use direct or indirect methods of quantal analysis in order to distinguish between pre- and postsynaptic loci of the modifications underlying long-term potentiation, particularly since the interpretations are model-dependent and the statistical treatments and experimental techniques employed incorporate simplifying assumptions not yet proven.

Animals↗

PubMed1992

Adenosine deaminase from Saccharomyces cerevisiae: kinetics and interaction with transition and ground state inhibitors.

Several adenosine analogs, such as coformycin, 2'-deoxycoformycin and erythro-9-(3-nonyl-p-aminobenzyl)adenine (EHNA), which are strong inhibitors of mammalian adenosine deaminase, are much weaker inhibitors of the Saccharomyces cerevisiae enzyme. The specificity of the yeast enzyme is more restricted than that of mammalian adenosine deaminase, particularly towards the ribose moiety and around position 6 and 1 of the substrate. The sulphydryl group appears to be more masked in the yeast than in the mammalian enzyme. The kinetic effects of pH with adenosine substrate and with the inhibitor purine riboside are reported. The findings on specificity and pH kinetic effects can be interpreted in a model involving proton transfer from the -SH group of the enzyme to the N-1 atom of the substrate.

Adenine↗

PubMed1981

Genetics of insulin dependent diabetes mellitus in Israel: population and family study.

The association between insulin dependent diabetes mellitus (IDDM) and the HLA system was studied in two groups of Jewish patients: 50 Ashkenazim and 42 non-Ashkenazim. The pattern of association of HLA-A and B locus antigens was somewhat different from that observed in European Caucasian patients. HLA-B8 had a higher frequency; B15 and Cw3 were rare in the population studied and were less frequent in IDDM patients than in controls. On the other hand, the frequency of A26, B18, and Bw38 was increased in Ashkenazi patients, but not in non-Ashkenazim, who in turn showed an increase for Bw51. Although the association between IDDM and HLA-A and B locus antigens shows a marked variability in different populations, the association with HLA-DR3 and DR4 is constant feature. There was a typical excess of DR3/DR4 heterozygotes in both patient groups. This heterozygote type carries the highest relative risk, followed by DR4/DR4 homozygotes. These data can well be interpreted by a model of two different HLA-linked susceptibility genes, one associated with DR3 and the other one with DR4, that interact so that different genotypes are associated with different levels of penetrance. This model received further support from studies in 15 multiple case families where there is an excess of affected sib pairs sharing two DR antigens.

Adolescent↗

PubMed1991

Covalent binding of inhaled formaldehyde to DNA in the respiratory tract of rhesus monkeys: pharmacokinetics, rat-to-monkey interspecies scaling, and extrapolation to man.

DNA-protein cross-links were formed in the respiratory tract of rhesus monkeys exposed to [14C]formaldehyde (0.7, 2, or 6 ppm; 6 hr). Concentrations of cross-links (pmol/mg DNA) were highest in the mucosa of the middle turbinates; lower concentrations were produced in the anterior lateral wall/septum and nasopharynx. Very low concentrations were found in the larynx/trachea/carina and in the proximal portions of the major bronchi of some monkeys exposed to 6 ppm but not to 0.7 ppm. No cross-links were detected in the maxillary sinuses or lung parenchyma. The pharmacokinetics of cross-link formation in the nose were interpreted using a model in which the rate of formation is proportional to the tissue concentration of formaldehyde. The model includes both saturable and nonsaturable elimination pathways and describes regional differences in DNA binding as having an anatomical rather than a biochemical basis. Using this model, the concentration of cross-links formed in corresponding tissues of different species can be predicted by scaling the pharmacokinetic parameter that depends on minute volume (V) and quantity of nasal mucosal DNA (MDNA). The concentration-response curve for the average rate of cross-link formation in the turbinates, lateral wall, and septum of rhesus monkeys was predicted from that of F-344 rats exposed under similar conditions. There was significant overlap between predicted and fitted curves, implying that V and MDNA are major determinants of the rate of cross-link formation in the nasal mucosa of different species. Concentrations of cross-links that may be produced in the nasal mucosa of adult men were predicted based on experimental data in rats and monkeys. The results suggest that formaldehyde would generate lower concentrations of cross-links in the nasal mucosa of humans than of monkeys, and much lower concentrations in humans than in rats. The rate of formation of DNA-protein cross-links can be regarded as a surrogate for the delivered concentration of formaldehyde. Use of this surrogate should decrease the uncertainty of human cancer risk estimates derived by interspecies extrapolation by providing a more realistic measure of the delivered concentration at critical target sites.

Animals↗

PubMed1985

An economic approach to the daily activities of private general practitioners.

The present crisis in general medicine centres around the contents of the health-care services provided by general practitioners. These services were examined in a survey, carried out in 1975, of GP's daily activities. Collected data have been used to describe the characteristics of the daily activities of a typical general practitioner. Variations from this model have been interpreted in terms of three factors that characterize the local situation under which primary medical care is delivered: the nature of the health-care market, GPs' relationships with potential clients and their relationships with the local medical profession and environment.

Diagnosis↗

PubMed1994

H-NS over-expression induces an artificial stationary phase by silencing global transcription.

Bacteria organize their chromosomes in a complex interwound supercoiled structure called the nucleoid through the action of topoisomerases and a set of small (10-20 kDa) proteins. The two most abundant nucleoid-associated proteins are HU and H-NS. H-NS increases in abundance during stationary phase. Over-expression of HU is well tolerated and compatible with transcription and cell growth. Increasing the concentration of H-NS leads to a rapid silencing of global transcription and produces a growth-arrested state reminiscent of stationary phase. H-NS over-expression also induces a substantial loss of supercoiling in plasmid DNA during the time that transcription is arrested. Comparing the effects of over-expression of these two proteins gives some insight into the differential roles of these proteins in the activity of the chromosome. These observations are interpreted in a model of nucleoid organization.

Bacterial Outer Membrane Proteins↗

PubMed1992

Reduced lysozyme in solution and its interaction with non-ionic surfactants.

Reduced lysozyme at pH 2.5 bound poly(oxyethylene) alkylethers in two steps and the maximum bound amount Qmax of the surfactant reached as large as 0.5-0.7 mole per mole amino acid residue in the cooperative binding step. Binding isotherms were well superimposed when surfactant concentrations were normalized by respective values of the critical micelle concentration, cmc. In terms of the onset concentrations of the cooperative binding C*, hydrophobicity of reduced lysozyme was quantitatively defined as RT In (cmc/C*) which amounted to 670 J per mole surfactant and was unique to the protein irrespective of the kind of surfactant. Qmax could be used as another measure of the hydrophobicity of the protein. The binding isotherms were evaluated by two methods: equilibrium dialysis and surface tension. Their results were consistent with each other and rather complementary. Reduced lysozymes were molecularly dispersed at pH below 2.5 in 0.01 M NaCl but aggregation took place as pH increased. The aggregates could not be dissociated on dilution nor by the addition of nonionic surfactants but by lowering pH. The irreversible nature of the aggregation was reasonably interpreted with a model based on the 'entangled' arrangement of the beta-sheets, which could account for the irreversible aggregation of unfolded proteins in general.

Animals↗

PubMed1994

How random is a highly denatured protein?

There has been renewed interest in determining the physicochemical properties of denatured states of proteins. In many denatured states there is evidence for the existence of nonrandom configurational distributions. Here we examine the small-angle neutron scattering profile of yeast phosphoglycerate kinase in the native state and in highly denaturing conditions. We show that the denatured protein scattering profile can be interpreted using a model developed for synthetic polymers in which the chain behaves as a random coil in a good solvent, i.e. with excluded volume interactions. The implications of this result for our appreciation of the protein folding process are discussed.

Journal Article↗

PubMed1995

Transuranics in bone of deceased former residents of Rongelap Atoll, Marshall Islands.

Rongelap Atoll received intensive fallout from the 1 March 1954 Bravo thermonuclear test 105 miles upwind at Bikini. Fearful of their continued exposure to radiation, the residents of Rongelap Atoll went into voluntary exile in 1985. Transuranic soil concentrations on Rongelap Island are about 2-3 orders of magnitude greater than the average for the Northern hemisphere; the three dominating transuranics are 239,240Pu and 241Am. Only conflicting information has been available about the extent of transuranic uptake by the Rongelap community. As part of the Rongelap Resettlement Project, the community endorsed the exhumation of bones of deceased former atoll residents to provide an independent estimate of plutonium intake. This approach has the advantage of reducing the uncertainties associated with pathway modeling and the interpretation of urine data. Six graves (4 adults, 2 children) were selected for exhumation. Femora and tibiae were selected as well as humeri from the children's graves. The rest of the remains was left undisturbed. The results of the analysis of 239,240Pu and 241Am are presented. Assuming that the data can be considered as representative for the Rongelap population as a whole, the contamination with transuranics on Rongelap Atoll appears to result in radiation exposures in the order of 1% of the compliance limit of 100 mrem (1 mSv) effective dose equivalent per year.

Adult↗

PubMed2005

Quantitative atomic force microscopy image analysis of unusual filaments formed by the Acanthamoeba castellanii myosin II rod domain.

We describe a quantitative analysis of Acanthamoeba castellanii myosin II rod domain images collected from atomic force microscope experiments. These images reveal that the rod domain forms a novel filament structure, most likely requiring unusual head-to-tail interactions. Similar filaments are seen also in negatively stained electron microscopy images. Truncated myosins from Acanthamoeba and other model organisms have been visualized before, revealing laterally associated bipolar minifilaments. In contrast, the filament structures that we observe are dominated by axial rather than lateral polymerization. The unusually small features in this structure (1-5 nm) required the development of quantitative and statistical techniques for filament image analysis. These techniques enhance the extraction of features that hitherto have been difficult to ascertain from more qualitative imaging approaches. The heights of the filaments are observed to have a bimodal distribution consistent with the diameters of a single rod domain and a pair of close-packed rod domains. Further quantitative analysis indicates that in-plane association is limited to at most a pair of rod domains. Taken together, this implies that the filaments contain no more than four rod domains laterally associated with one another, somewhat less than that seen in bipolar minifilaments. Analysis of images of the filaments decorated with an anti-FLAG antibody reveals head-to-tail association with mean distances between the antibodies of 75 +/- 15 nm. We consider a set of molecular models to help interpret possible structures of the filaments.

Acanthamoeba castellanii↗

PubMed2005

Multiple-component radiation-measurement error models.

Measurement error modeling and assessment are crucial to any assay method. Realistic error models prioritize future efforts to reduce key error components and provide a way to estimate total ("random" and "systematic") measurement error. This paper describes multiple-component error models for radiation-based assay, gives example applications, and describes strategies for choosing and then fitting error models.

Data Interpretation, Statistical↗