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PubMed1989

The use of a non-linear regression approach for the analysis of the ouabain-K+ interaction with (Na+ + K+)-ATPase from guinea pig and rat hearts.

1. The interaction between ouabain and K+ and their effects on (Na+ + K+)-ATPase activity were studied using microsomes from guinea pig and rat heart. 2. Microsomes were incubated in the presence of various concentrations of K+ and ouabain and ATPase activity was estimated by measuring the inorganic phosphate liberated. The experimental data were analyzed statistically by micro-computer, using a non-linear regression program based on the steepest descent technique. 3. The experimental data were best fitted by a model which assumes that ouabain acts like a mixed inhibitor with respect to the apparently cooperative K+ activation of (Na+ + K+)-ATPase. This quantitative approach provided estimates (with approximate standard deviations) of all the parameters involved in the model. 4. The inhibition constant for the uncompetitive term of the effect was 7- to 9-fold higher than the inhibition constant for the competitive term for both the guinea pig and rat heart preparations. 5. The present results indicate that graphical analyses are helpful for illustrative purposes but suggest that a computerized, non-linear regression program simultaneously analyzing all the non-linearized data should be used to quantify the complex kinetic parameters and to discriminate objectively among possible models.

Animals↗
PubMed1993

Allosterism and Na(+)-D-glucose cotransport kinetics in rabbit jejunal vesicles: compatibility with mixed positive and negative cooperativities in a homo- dimeric or tetrameric structure and experimental evidence for only one transport protein involved.

We first present two simple dimeric models of cotransport that may account for all of the kinetics of Na(+)-D-glucose cotransport published so far in the small intestine. Both the sigmoidicity in the Na+ activation of transport (positive cooperativity) and the upward deviations from linearity in the Eadie-Hofstee plots relative to glucose concentrations (negative cooperativity) can be rationalized within the concept of allosteric kinetic mechanisms corresponding to either of two models involving sequential or mixed concerted and sequential conformational changes. Such models also allow for 2 Na+: 1 S and 1 Na+: 1 S stoichiometries of cotransport at low and high substrate concentrations, respectively, and for partial inhibition by inhibitors or substrate analogues. Moreover, it is shown that the dimeric models may present physiological advantages over the seemingly admitted hypothesis of two different cotransporters in that tissue. We next address the reevaluation of Na(+)-D-glucose cotransport kinetics in rabbit intestinal brush border membrane vesicles using stable membrane preparations, a dynamic approach with the Fast Sampling Rapid Filtration Apparatus (FSRFA), and both nonlinear regression and statistical analyses. Under different conditions of temperatures, Na+ concentrations, and membrane potentials clamped using two different techniques, we demonstrate that our data can be fully accounted for by the presence of only one carrier in rabbit jejunal brush border membranes since transport kinetics relative to glucose concentrations satisfy simple Michaelis-Menten kinetics. Although supporting a monomeric structure of the cotransporter, such a conclusion would conflict with previous kinetic data and more recent studies implying a polymeric structure of the carrier protein. We thus consider a number of alternatives trying to reconcile the observation of Michaelis-Menten kinetics with allosteric mechanisms of cotransport associated with both positive and negative cooperativities for Na+ and glucose binding, respectively. Such models, implying energy storage and release steps through conformational changes associated with ligand binding to an allosteric protein, provide a rational hypothesis to understand the long-time debated question of energy transduction from the Na+ electrochemical gradient to the transporter.

Allosteric Regulation↗
PubMed2004

A model-based optimization framework for the inference on gene regulatory networks from DNA array data.

MOTIVATION: Identification of the regulatory structures in genetic networks and the formulation of mechanistic models in the form of wiring diagrams is one of the significant objectives of expression profiling using DNA microarray technologies and it requires the development and application of identification frameworks. RESULTS: We have developed a novel optimization framework for identifying regulation in a genetic network using the S-system modeling formalism. We show that balance equations on both mRNA and protein species led to a formulation suitable for analyzing DNA-microarray data whereby protein concentrations have been eliminated and only mRNA relative concentrations are retained. Using this formulation, we examined if it is possible to infer a set of possible genetic regulatory networks consistent with observed mRNA expression patterns. Two origins of changes in mRNA expression patterns were considered. One derives from changes in the biophysical properties of the system that alter the molecular-interaction kinetics and/or message stability. The second is due to gene knock-outs. We reduced the identification problem to an optimization problem (of the so-called mixed-integer non-linear programming class) and we developed an algorithmic procedure for solving this optimization problem. Using simulated data generated by our mathematical model, we show that our method can actually find the regulatory network from which the data were generated. We also show that the number of possible alternate genetic regulatory networks depends on the size of the dataset (i.e. number of experiments), but this dependence is different for each of the two types of problems considered, and that a unique solution requires fewer datasets than previously estimated in the literature. This is the first method that also allows the identification of every possible regulatory network that could explain the data, when the number of experiments does not allow identification of unique regulatory structure.

Algorithms↗
PubMed1987

A record of polycyclic aromatic hydrocarbon (PAH) pollution obtained from accreting sediments of the Tamar Estuary, U.K.: evidence for non-equilibrium behaviour of PAH.

Concentrations of polycyclic aromatic hydrocarbons (PAH) were quantified throughout a 210Po-dated inter-tidal sediment core from the Tamar Estuary, U.K. in order to reconstruct the input history and investigate environmental reactivity of PAH in sediments. The profile recorded is similar to those reported in other aquatic sedimentary studies, with an approximately exponential increase in the concentrations of individual PAH from less than 30 ng (g dry sediment)-1 prior to 1940 to between 100 and 1000 ng (g dry sediment)-1 in contemporary surface sediments. This corresponds to an increased input of total PAH from 0.23 to 21 mg m-2 year-1. The PAH composition is dominated by parent compounds rather than alkylated homologues and is characteristic of pyrogenic sources correlating with increased motor vehicle activity and road runoff into the Tamar. There is a remarkable compositional uniformity of PAH throughout the polluted sediment core, indicating that the biogeochemical transformation and exchange processes (sorption/leaching; microbial breakdown; photo-degradation; etc.) which are known to govern the fate of experimentally-added or petroleum-derived PAH, and which exhibit compound discrimination, appear not to affect PAH in the sediments. Using a linear free energy sediment-water exchange model to simulate the repartitioning and exchange of individual PAH between the surface-mixed layer of sediment and water, we demonstrate that the current PAH concentrations in sediments are between 2 and 5 orders of magnitude greater than those expected from equilibrium partitioning with observed water concentrations. This implies that the PAH input to the sediments has been compositionally uniform and that the PAH are chemically inert. Sorptive exchange with the aqueous phase and hence the potential bioavailability of PAH appear restricted by the existence of occluded and other micro-morphologically inert forms of particle-bound PAH.

Biodegradation, Environmental↗
PubMed2002

Application of a normalised plot to the study of uni-uni enzyme-inhibitor systems.

Normalisation of kinetic data is a useful tool in the study of complex enzyme systems. In the present paper, we have applied the premises of the normalised plot to the description of uni-uni enzyme inhibition. Guidelines to the design of the experiments and to data managing using the freeware program SIMFIT (http:\\www.simfit.man.ac.uk) are offered. The treatment has a lessened demand in experimental data while ensuring biological consistence of the results. Moreover, the results are obtained without resorting to secondary plots, and the election between rival mechanisms is statistically granted. Hyperbolic mixed-type inhibition is studied as a general model for enzyme-inhibitor/activator interaction, and equations describing classical cases of linear inhibition are also considered.

Enzyme Inhibitors↗
PubMed2000

Indoor air quality in a middle school, Part II: Development of emission factors for particulate matter and bioaerosols.

A middle school (grades 6 to 8) in a residential section of Springfield, Illinois, with no known air quality problems, was selected for a baseline indoor air quality survey. The study was designed to measure and evaluate air quality at the middle school with the objective of providing a benchmark for comparisons with measurements in schools with potential air quality problems. The focus of this article is on the development of emission factors for particulate matter and bioaerosols. The school was characterized as having no health complaints and good maintenance schedules. Four indoor locations including the cafeteria, a science classroom, an art classroom, the lobby outside the main office, and one outdoor location were sampled for various environmental comfort and pollutant parameters for one week in February 1997. Integrated samples (eight-hour sampling time) for respirable and total particulate matter, and short-term measurements (two-minute samples, three times per day) for bioaerosols were collected on three consecutive days at each of the sampling sites. Continuous measurements of carbon dioxide were logged at all locations for five days. Continuous measurements of respirable particulate matter were also collected in the lobby area. A linear relationship between occupancy and corresponding carbon dioxide and particle concentrations was seen. A completely mixed space, one compartment mass balance model with estimated CO2 generation rates and actual CO2 and particulate matter concentrations was used to model ventilation and pollutant emission rates. Emission factors for occupancy were represented by the slope of emission rate versus occupancy scatter plots. The following particle and bioaerosol emission factors were derived from the indoor measurements: total particles: 1.28 mg/hr/person-hr; respirable particles: 0.154 g/hr/person-hr; total fungi: 167 CFU/hr/person-min; thermophilic fungi: 35.8 CFU/hr/person-min; mesophilic fungi: 119 CFU/hr/person-min; total bacteria: 227 CFU/hr/person-min; gram-negative bacteria: 69.5 CFU/hr/person-min; gram-positive bacteria: 191 CFU/hr/person-min; Aspergillus: 17.0 CFU/hr/person-min; Penicillium: 161 CFU/hr/person-min; and yeasts: 16.4 CFU/hr/person-min.

Adolescent↗
PubMed2005

Response properties of an integrate-and-fire model that receives subthreshold inputs.

A computational technique is described for calculation of the interspike interval and poststimulus time histograms for the responses of an integrate-and-fire model to arbitrary inputs. The effects of the model parameters on the response statistics were studied systematically. Specifically, the probability distribution of the membrane potential was calculated as a function of time, and the mean interspike interval and PST histogram were calculated for arbitrary inputs. For stationary inputs, the regularity of the output was studied in detail for various model parameters. For nonstationary inputs, the effects of the model parameters on the output synchronization index were explored. The results show that enhanced synchronization in response to low-frequency stimuli required a large number (n > 25) of weak inputs. Irregular responses and a linear input-output rate relationship required strong (but subthreshold) inputs with a small time constant. A model cell with mixed-amplitude synaptic inputs can respond to stationary inputs irregularly and have enhanced synchronization to nonstationary inputs that are phase-locked to low-frequency inputs. Both of these response properties have been reported for some cells in the ventral cochlear nucleus in the auditory brainstem.

Action Potentials↗
PubMed2005

Broiler litter as a micronutrient source for cotton: concentrations in plant parts.

Analytically, poultry litter contains nearly all essential micronutrients but the extent of phytoavailability of these nutrients and whether cotton (Gossypium hirsutum L.) and other crop plants can receive adequate amounts of these nutrients from litter is not fully known. The objective of this research was to determine whether cotton receives sufficient amounts of Fe, Cu, Mn, and Zn from litter and estimate the efficiency of cotton in extracting these metal nutrients from litter in the absence of any other source of the micronutrients. The greenhouse research used plastic pots filled with approximately 11 kg of a 2:1 (v/v) sand to vermiculite growing mix. Cotton (cv. Stoneville 474) was grown in the pots fertilized with broiler litter at rates of 30, 60, 90, or 120 g pot(-1) in a factorial combination with four supplemental nutrient solution (NS) treatments. The nutrient solutions consisted of full Hoagland's nutrient solution (NS-full); a solution of the macronutrients N, P, K, Ca, and Mg (NS-macro); a solution of the micronutrients Fe, Zn, Mn, Cu, B, and Mo (NS-micro); and water (NS-none). Based on tissue nutrient analysis, a one-time broiler litter application supplied adequate amounts of Fe, Cu, and Mn to bring the concentration of these nutrients in upper leaves within published sufficiency ranges. Zinc, with <17 mg kg(-1) concentration in the upper leaves, was the only micronutrient below the established sufficiency range regardless of the rate of applied litter. Cotton extracted Fe and Mn more efficiently than Cu or Zn, removing as much as 8.8% of Fe and 7.2% of Mn supplied by 30 g litter pot(-1). In contrast, the extraction efficiency was 1.7% for Cu and 1.9% for Zn. Roots accumulated 58% of the total absorbed Fe and 64% of Cu, and leaves accumulated 32% of the Fe and only 13% of the Cu supplied by litter. In contrast, only 16% of the total absorbed Mn and 23% of Zn accumulated in roots while leaves accumulated 64% of the total Mn and 37% of Zn. These results demonstrate that broiler litter is a valuable source of the metal nutrients supplying Fe, Cu, and Mn in full and Zn in part, but a very large fraction of the litter-supplied metal nutrients remained in the growing mix.

Agriculture↗
PubMed1995

Comparison of Landim and Africander cattle in southern Mozambique: I. Body weights and growth.

The growth performance of Landim and Africander breeds was compared using data collected from 1968 to 1981 at the Chobela Research Station in Mozambique. Animals from both breeds were managed together in groups by age and sex, except when separated for breeding. Growth traits were body weights at birth, weaning at 7 mo, 18 mo, and first calving, and pre- and postweaning daily growth rates. These traits were analyzed using a mixed-effects least squares model containing breed, year-season of birth, sex, the nested effect of parity within breed, a linear regression on dam's age, and the random effect of sire within breed. Africander calves were 16, 9, and 7% heavier (P < .01) than Landim calves at birth, weaning, and 18 mo (18 +/- 6 kg heavier than the 237-kg Landim average). However, there was no detectable difference for age-adjusted weight at first calving and postweaning daily growth rate. Diminishing weight and growth differences with advancing age may indicate adaptation by the Landim to the prevailing environmental limitations in southern Mozambique, especially through younger ages at puberty and at first calving.

Animals↗
PubMed1987

Computing for incomplete repeated measures.

Repeated-measures experiments involve two or more intended measurements per subject. If the within-subjects design is the same for each subject and no data are missing, then the analysis is relatively simple and there are readily available programs that do the analysis automatically. However, if the data are incomplete, and do not have the same arrangement for each subject, then the analysis becomes much more difficult. Beginning with procedures that are not optimal but are comparatively simple, we discuss unbalanced linear model analysis and then normal maximum likelihood (ML) procedures. Included are ML and REML (restricted maximum likelihood) estimators for the mixed model and also estimators for a model that allows arbitrary within-subject covariance matrices. The objective is to give procedures that can be implemented with available software.

Analysis of Variance↗
PubMed1998

Concentration-effect relationship of l-propranolol and metoprolol in spontaneous hypertensive rats after exercise-induced tachycardia.

The concentration-effect relationship of l-propranolol and dl-metoprolol were investigated in spontaneous hypertensive rats using reduction in exercise-induced tachycardia as a pharmacodynamic endpoint. The influence of protein binding on the effect relationship was also assessed. The rats were assigned to treatment or placebo groups, where each group received three randomly selected consecutively increasing steady-state infusions. Different pharmacodynamic effect models were fitted to the data, using nonlinear mixed effect modeling. The data were best described by a combined effect model, with a sum of an ordinary Imax and a linear model. At the lower concentration range, the ordinary Imax model dominated, although at higher concentrations, the effect was linearly related to the antagonist concentration. The Imax were 83 +/- 6 and 103 +/- 6 beats . min-1 and the IC50 were 18.1 +/- 4.3 and 50.6 +/- 15.2 ng/ml for l-propranolol and dl-metoprolol, respectively. The slope in the linear model was steeper for l-propranolol than for dl-metoprolol, 28.9 +/- 2.8 and 4.48 +/- 0.39 beats . ml . (min . microgram)-1, respectively. Plasma protein binding of l-propranolol was saturable. The unbound IC50 for l-propranolol was 1.14 +/- 0.27 ng/ml. The concentration-effect relationship of l-propranolol was altered at higher plasma concentrations, due to saturable protein binding. The Imax and the linear concentration-effect relationship may be interpreted as a specific beta-antagonist effect and a membrane-stabilizing effect, respectively. Using exercise-induced tachycardia as a pharmacodynamic endpoint, to study the effect of beta-antagonists in spontaneous hypertensive rats, seems to give reliable results and can be a useful model to extrapolate to humans.

Adrenergic beta-Antagonists↗
PubMed2001

Quantitative structure-transformation relationships of phenylurea herbicides.

Quantitative relationships between the structure of phenylurea herbicides and their transformation in different matrices have been developed. Experimental data on microbial transformation by pure and mixed cultures of soil micro-organisms in inoculated and native soil, as well as on chemical transformation by hydrolysis in sterile soil and water, were available from previous studies. Around 60 experimental or calculated descriptors were used. Quantum chemical calculations were performed with three different semi-empirical methods. Models developed with multiple linear regression were generally easier to interpret than those derived with partial least-squares projection to latent structures. Quite simple and interpretable models could be found to predict transformation rates by pure cultures from lipophilicity, by mixed cultures from adsorption distribution coefficients, and by chemical or enzymatic hydrolysis from electronic properties. Transformation in inoculated soil could not be predicted, but for native soil the use of a quantum chemical descriptor for reactivity (energy of LUMO) together with molar refraction resulted in a general model.

Adsorption↗
PubMedDate not supplied

Use of regression analysis and flow cytometry for determining levels of mixed semiallogeneic immune chimerism.

It has been shown that tolerance or specific immunologic nonresponsiveness in various lymphohemopoietic transplant models can be associated with the development of mixed lymphoid chimerism. As a specific example, composite tissue (limb) allografts were studied as a model for vascularized bone marrow transplantation (VBMT) and it was demonstrated that development of stable cellular immune chimerism is associated with long-term allograft survival. Recently, studies were initiated using a new parental to hybrid VBMT model, but the detection of donor cells is complicated, due to the fact that they share one parental allotypic determinant. Therefore, regression analysis with a flow cytometric immunofluorescent staining assay was evaluated for the assessment of cellular lymphoid chimerism in donor parental to hybrid (P-->F1) lymphohemopoietic transplant models. Standard curves consisting of known mixed populations of parental donor (Lewis, LEW) and hybrid host F1 (Lew x BN, LBN) lymphocytes were established. Standard curves were analyzed by linear regression statistics and excellent coefficients of determination (r > .881) were obtained for all standard curves. A highly statistically significant (p < .016) linear relationship between level of donor cell chimerism (independent variable) and percent stained (dependent variable) was determined. The technique was then evaluated using the parental to hybrid VBMT model. Levels of donor LEW lymphoid chimerism in all VBMT LBN recipients were successfully assessed by regression analysis and inverse prediction using distinct recipient allodeterminant markers. In conclusion, this technique was proven to be reliable and accurate for the detection of of chimerism in parental to F1 lymphohemopoietic allograft models.

Animals↗
PubMed2006

[Study of the dento-facial features in children of Han nationality with normal occlusion in Shandong district].

PURPOSE: To establish the standard values of roentgengraphic cephalometry in children with normal occlusion in Shandong district and to make the facial model. METHODS: 156 children were selected to take lateral cephalograph, and were divided into two groups: mixed dentition and early permanent dentition. Cephalograms were analyzed for all subjects with WinCeph7.0. Data were obtained for student's t test between the two groups and between males and females. RESULTS: The norms with derivation for all measurement of X ray cephalometrical analysis on hard tissues were established. Meanwhile, the difference between males and females was compared and the facial model of children with normal occlusion was made. CONCLUSION: Gender difference was shown in linear measurements, with greater growth in males in general. The growing tendency of children from mixed dentition to early permanent dentition was that the maxilla of the male grows faster while the mandible of the female grows faster.

Cephalometry↗
PubMed2002

A semi-microscopic model for the evaluation of radiation damage.

A model for the biological effects of the energy deposited by ion beams on irradiated tissues is presented. The relevant parameters are the fractions of undamaged cells (where of course the definition of damaged cell depends on the biological end point under consideration, e.g. surviving cells) after the sensitive target of the cells has been traversed by any given number of ionising particles. The experimental parameters of the dose response curves offer a way to determine those of the model. The model can be formulated both for the simpler case of cells traversed by only one radiation quality, i.e. by a monoenergetic beam of a given ion, and for the general case of irradiation by a mixed field. A possible application in experimental data analysis is presented.

Animals↗
PubMed2003

Prediction of unconfined compressive strength of cement paste containing industrial wastes.

Neural network analysis was used to construct models of unconfined compressive strength (UCS) as a function of mix composition using existing data from literature studies of Portland cement containing real industrial wastes. The models were able to represent the known non-linear dependency of UCS on curing time and water content, and generalised from the literature data to find relationships between UCS and quantities of five waste types. Substantial decreases in UCS were caused by all wastes; except for EAF dust, the effect was nonlinear with the greatest decrease caused initially by approx. 12% plating sludge, 40% foundry dust, 58% other ash, and 72% MSWI fly ash by mass of dry product. It appears that the maximum waste additions used in modelling may approximate the practical limits of waste additions used in modelling may approximate the practical limits of waste addition to Portland cement, i.e., 50% plating sludge or EAF dust, 64% foundry dust, 92% other ash, and 85% MSWI fly ash by mass of dry product. The laboratory was found to be a key predictive variable and acted as a surrogate for laboratory-specific variables related to cement composition, strength and hardening class, product mixing and preparation details, laboratory conditions, and testing details. While the neural network modelling approach has been shown to be feasible, development of better models would require larger data sets with more complete information regarding laboratory-specific variables and waste composition.

Compressive Strength↗
PubMed2000

Application of a mixed normal mixture model for the estimation of Mastitis-related parameters.

The current methodology for estimating genetic parameters for SCC (SCS) does not account for the difference in SCS between healthy cows and cows with an intramammary infection (IMI). We propose a two-component finite mixed normal mixture model to estimate IMI prevalence, separate SCS subpopulation means, individual posterior probabilities of IMI, and SCS variance components. The theory is presented and the expectation-conditional maximization algorithm is utilized to compute maximum likelihood estimates. The methodology is illustrated on two simulated data sets based on the current knowledge of SCS parameters. Maximum likelihood estimates of IMI prevalence and SCS subpopulation means were close to simulated values, except for the estimate of IMI prevalence when both subpopulations were almost confounded. Individual posterior probabilities of IMI were always higher among infected than among healthy cows. Error and additive variance components obtained under the mixture model were closer to simulated values than restricted maximum likelihood estimates obtained assuming a homogeneous SCS distribution, especially when subpopulations were completely separated and when mixing proportion was highest. Convergence was linear and rapid when priors were chosen with caution. The advantages of the methodology are demonstrated, and its feasibility for large data sets is discussed.

Algorithms↗
PubMed1999

A general maximum likelihood analysis of variance components in generalized linear models.

This paper describes an EM algorithm for nonparametric maximum likelihood (ML) estimation in generalized linear models with variance component structure. The algorithm provides an alternative analysis to approximate MQL and PQL analyses (McGilchrist and Aisbett, 1991, Biometrical Journal 33, 131-141; Breslow and Clayton, 1993; Journal of the American Statistical Association 88, 9-25; McGilchrist, 1994, Journal of the Royal Statistical Society, Series B 56, 61-69; Goldstein, 1995, Multilevel Statistical Models) and to GEE analyses (Liang and Zeger, 1986, Biometrika 73, 13-22). The algorithm, first given by Hinde and Wood (1987, in Longitudinal Data Analysis, 110-126), is a generalization of that for random effect models for overdispersion in generalized linear models, described in Aitkin (1996, Statistics and Computing 6, 251-262). The algorithm is initially derived as a form of Gaussian quadrature assuming a normal mixing distribution, but with only slight variation it can be used for a completely unknown mixing distribution, giving a straightforward method for the fully nonparametric ML estimation of this distribution. This is of value because the ML estimates of the GLM parameters can be sensitive to the specification of a parametric form for the mixing distribution. The nonparametric analysis can be extended straightforwardly to general random parameter models, with full NPML estimation of the joint distribution of the random parameters. This can produce substantial computational saving compared with full numerical integration over a specified parametric distribution for the random parameters. A simple method is described for obtaining correct standard errors for parameter estimates when using the EM algorithm. Several examples are discussed involving simple variance component and longitudinal models, and small-area estimation.

Adrenergic beta-Antagonists↗