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PubMed1998

Note: caution in use of empirical equations for pharmacodynamic indirect response models.

An empirical equation was recently proposed and used to characterize inhibitory drug effects on production of an endogenous substance. The limitations of this empirical equation are described utilizing mathematical equations and simulations based on the exact differential equation for Indirect Response Model I. The latter is preferable for fitting data using indirect response models.

Data Interpretation, Statistical↗

PubMed2001

Targeting of Pseudomonas aeruginosa in the bloodstream with bispecific monoclonal antibodies.

We examined the ability of a bispecific mAb reagent, consisting of a mAb specific for the primate erythrocyte complement receptor cross-linked with an anti-bacterial mAb, to target bacteria in the bloodstream in an acute infusion model in monkeys. In vitro studies demonstrated a variable level of complement-mediated binding (immune adherence) of Pseudomonas aeruginosa (strain PAO1) to primate E in serum. In vivo experiments in animals depleted of complement revealed that binding of bacteria to E was <1% before administration of the bispecific reagent, but within 5 min of its infusion, >99% of the bacteria bound to E. In complement-replete monkeys, a variable fraction of infused bacteria bound to E. This finding may have significant implications in the interpretation of animal models and in the understanding of bacteremias in humans. Treatment of these complement-replete monkeys with the bispecific reagent led to >99% binding of bacteria to E. Twenty-four-hour survival studies were conducted; several clinical parameters, including the degree of lung damage, cytokine levels, and liver enzymes in the circulation, indicate that the bispecific mAb reagent provides a degree of protection against the bacterial challenge.

Animals↗

PubMed2006

Nonadiabatic effects in C-Br bond scission in the photodissociation of bromoacetyl chloride.

Bromoacetyl chloride photodissociation has been interpreted as a paradigmatic example of a process in which nonadiabatic effects play a major role. In molecular beam experiments by Butler and co-workers [J. Chem. Phys. 95, 3848 (1991); J. Chem. Phys. 97, 355 (1992)], BrCH2C(O)Cl was prepared in its ground electronic state (S0) and excited with a laser at 248 nm to its first excited singlet state (S1). The two main ensuing photoreactions are the ruptures of the C-Cl bond and of the C-Br bond. A nonadiabatic model was proposed in which the C-Br scission is strongly suppressed due to nonadiabatic recrossing at the barrier formed by the avoided crossing between the S1 and S2 states. Recent reduced-dimensional dynamical studies lend support to this model. However, another interpretation that has been given for the experimental results is that the reduced probability of C-Br scission is a consequence of incomplete intramolecular energy redistribution. To provide further insight into this problem, we have studied the energetically lowest six singlet electronic states of bromoacetyl chloride by using an ab initio multiconfigurational perturbative electronic structure method. Stationary points (minima and saddle points) and minimum energy paths have been characterized on the S0 and S1 potential energy surfaces. The fourfold way diabatization method has been applied to transform five adiabatic excited electronic states to a diabatic representation. The diabatic potential energy matrix of the first five excited singlet states has been constructed along several cuts of the potential energy hypersurfaces. The thermochemistry of the photodissociation reactions and a comparison with experimental translational energy distributions strongly suggest that nonadiabatic effects dominate the C-Br scission, but that the reaction proceeds along the energetically allowed diabatic pathway to excited-state products instead of being nonadiabatically suppressed. This conclusion is also supported by the low values of the diabatic couplings on the C-Br scission reaction path. The methodology established in the present study will be used for the construction of global potential energy surfaces suitable for multidimensional dynamics simulations to test these preliminary interpretations.

Journal Article↗

PubMed1998

Simultaneous measurements of actin filament turnover, filament fraction, and monomer diffusion in endothelial cells.

The analogous techniques of photoactivation of fluorescence (PAF) and fluorescence recovery after photobleaching (FRAP) have been applied previously to the study of actin dynamics in living cells. Traditionally, separate experiments estimate the mobility of actin monomer or the lifetime of actin filaments. A mathematical description of the dynamics of the actin cytoskeleton, however, predicts that the evolution of fluorescence in PAF and FRAP experiments depends simultaneously on the diffusion coefficient of actin monomer, D, the fraction of actin in filaments, FF, and the lifetime of actin filaments, tau (, Biophys. J. 69:1674-1682). Here we report the application of this mathematical model to the interpretation of PAF and FRAP experiments in subconfluent bovine aortic endothelial cells (BAECs). The following parameters apply for actin in the bulk cytoskeleton of subconfluent BAECs. PAF: D = 3.1 +/- 0.4 x 10(-8) cm2/s, FF = 0.36 +/- 0.04, tau = 7.5 +/- 2.0 min. FRAP: D = 5.8 +/- 1.2 x 10(-8) cm2/s, FF = 0.5 +/- 0.04, tau = 4.8 +/- 0.97 min. Differences in the parameters are attributed to differences in the actin derivatives employed in the two studies and not to inherent differences in the PAF and FRAP techniques. Control experiments confirm the modeling assumption that the evolution of fluorescence is dominated by the diffusion of actin monomer, and the cyclic turnover of actin filaments, but not by filament diffusion. The work establishes the dynamic state of actin in subconfluent endothelial cells and provides an improved framework for future applications of PAF and FRAP.

Actins↗

PubMed2002

The systemic paradigm and its relevance to the modelling of biological functions.

If we are to make advances in the design of information systems for the processing of functional genomic data, we must carefully examine the concepts of gene and function. Therefore, we must consider the biological models that are used to acquire these data from an epistemological point of view. This article introduces three elements of this view: (i) we reviewed the major concepts and the axioms of the systemic paradigm; (ii) we considered their relevance for the modelling of the biological functions within the framework of an intracellular signalling process; (iii) we present an operational input founded on this methodological viewpoint to illustrate the coherence of a theoretical framework and the use of its formalism for the description and the representation of biological activities. This formalism will guide the modelling and the interpretation of molecular interactions in terms of organisational operations producing and transforming the genetic information; thus, providing a better understanding of the complex relationship between the generation, the circulation and the computation of information when biological systems are set up.

Animals↗

PubMed2005

Developing a cultural model of caregiving obligations for elderly Chinese wives.

This article addresses the dilemmas of elderly Chinese women as spousal caregivers in Hong Kong in the 1990s. An in-depth ethnographic approach was used to draw on a convenience sample of 20 elderly wives who were caregivers from Hong Kong. At the conceptual level, the discussion highlights how caregiving is rooted in complex, culturally-based models of contemporary practices, sociohistoric patterns, and gender-specific obligations. The key themes identified were marital duty-bound roles and responsibilities, reciprocity and burden, public guidelines and upholding reputations as Chinese wives, monetary restrictions, affection as an emotional force to sustain caregiving, effects of the caregiving role, and the creation of self-identity through caregiving. The model proposed for interpreting elderly Chinese wives' caregiving obligations highlights the tension-filled links between Confucianism and government guidelines, early and ongoing socializing experiences, and self-identity.

Aged↗

PubMed1998

Hepatic clearance models: comparison of the dispersion and Goresky models in outflow profiles from multiple indicator dilution rat liver studies.

The multiple indicator dilution (MID) technique is often used for investigation of the kinetic behavior of substrates and metabolites in eliminating organs. The present study was a systematic comparison of the utility of the Goresky model (GM) (a structural model) and the mixed-boundary dispersion model (DM) (a stochastic model) in the interpretation of influx, efflux, and removal (sequestration) coefficients, with data generated from rat liver-perfusion/MID studies. Although the GM and the DM are equivalent in their descriptions of membrane transport, they differ in their classifications of the dispersion of blood-borne elements. For the DM, the dispersion is an inverse Gaussian distribution of vascular transit times; for the GM, it is accounted for by the dispersion observed among noneliminated reference indicators (e.g. labeled red blood cells, albumin, sucrose, and H2O) or the derived reference. In this study, previously published rat liver-perfusion/MID data obtained for the glutathione conjugate of bromosulfophthalein and hippuric acid, compounds that exhibit saturable carrier-mediated transport, with the GM were reanalyzed with the two-compartment DM. When the fitted values for volume and transfer coefficients were compared, good correlation was found between the fitted vascular volume for the DM and the vascular volume for the reference indicator for the GM. The influx coefficients were generally similar between the models, but improved correspondence was observed when the DM was modified to include the large-vessel transit time. In contrast, the efflux and sequestration coefficients obtained for the DM did not correspond well to those from the GM. The disagreement was due, in part, to differences in the interpretation of the late-in-time component of the reference transit time distribution curve, which was not described well by the DM. Consequently, the residence time distribution and the relative dispersion were underestimated by the DM.

Animals↗

PubMed1998

Sugar-induced molten-globule model.

Proteins denature at low pH because of intramolecular electrostatic repulsions. The addition of salt partially overcomes this repulsion for some proteins, yielding a collapsed conformation called the A-state. A-states have characteristics expected for the molten globule, a notional kinetic protein folding intermediate. Here we show that the addition of neutral sugars to solutions of acid-denatured equine ferricytochrome c induces formation of the A-state in the absence of added salt. We characterized the structure and stability of the sugar-induced A-state with circular dichroism spectropolarimetry (CD) and NMR-monitored hydrogen-deuterium exchange experiments. We also examined the stability of the sugar-induced A-state as a function of sugar size and concentration. The results are interpreted using several models and we conclude that the stabilizing effect is consistent with increased steric repulsion between the protein and the sugar solutions.

Animals↗

PubMed1996

Interpretation of short-term test data: implications for assessment of chemopreventive activity.

The same short-term tests that have been used extensively to identify mutagens and potential carcinogens are increasingly being used to identify antimutagens and potential anticarcinogens. It is not yet known whether the inhibition of carcinogen-induced mutation is a good indicator of anticarcinogenicity, as the available data on the inhibition of both carcinogenicity and mutagenicity In vivo are still quite incomplete. Furthermore, in vitro tests will detect only those compounds that show an effect that is demonstrable in vitro, such as direct inhibition of the metabolism of the carcinogen or inactivation of the carcinogen by direct reaction. Thus it is essential to confirm putative antimutagenic activity observed in vitro through the use of animal models. Indeed, the interpretation of antimutagenicity data from short-term tests must be subjected to all of the considerations that apply in the interpretation of mutagenicity test results. Moreover, the experimental variable of the antimutagens used must be considered in addition to the variables of the mutagens and short-term tests used. To analyse published results on antimutagens in short-term tests, we have developed the concept of activity profile listings and plots for antimutagens - an approach already used successfully for mutagenicity data. The activity profiles permit rapid visualization of considerable data and experimental parameters, including the inhibition as well as enhancement of mutagenic activity. Here we focus on the use of this methodology to interpret antimutagenicity data for retinol and chlorophyllin against several classes of mutagens in short-term tests.

Anticarcinogenic Agents↗

PubMedDate not supplied

Mathematical model for the effects of epidermal growth factor receptor trafficking dynamics on fibroblast proliferation responses.

We apply a mathematical model for receptor-mediated cell uptake and processing of epidermal growth factor (EGF) to analyze and predict proliferation responses to fibroblastic cells transfected with various forms of the EGF receptor (EGFR) to EGF. The underlying conceptual hypothesis is that the mitogenic signal generated by EGF/EGFR binding on the cell surface, via stimulation of receptor tyrosine kinase activity, is attenuated when the receptors are downregulated and growth factor is depleted by endocytic internalization and subsequent intracellular degradation. Hence, the cell proliferation rate ought to depend on receptor/ligand binding and trafficking parameters as well as on intrinsic receptor signal transduction properties. The goal of our modeling efforts is to formulate this hypothesis in quantitative terms. The mathematical model consists of kinetic equations for binding, internalization, degradation, and recycling of EGF and EGFR, along with an expression relating DNA synthesis rate to EGF/EGFR complex levels. Parameter values have been previously determined from independent binding and trafficking kinetic experiments on B82 fibroblasts transfected with wild-type and mutant EGFR. We show that this model can successfully interpret literature data for EGF-dependent growth of NR6 fibroblasts transfected with wild-type EGFR. Moreover, it successfully predicts the literature observation that NR6 cells transfected with a delta 973 truncation mutant EGFR, which is kinase-active but internalization-deficient, require an order of magnitude lower EGF concentration than cells with wild-type EGFR for half-maximal proliferation rate. This result demonstrates that it may be feasible to genetically engineer mammalian cell lines with reduced growth factor requirements by a rational, nonempirical approach. We explore by further model computations the possibility of exploiting other varieties of EGFR mutants to alter growth properties of fibroblastic cells, based on relationships between changes in the primary structure of the EGF receptor and the rates of specific receptor/ligand binding and trafficking processes. Our studies show that the ability to predict cell proliferation as a function of serum growth factors such as EGF could lead to the designed development of cells with optimized growth responses. This approach may also aid in elucidation of mechanisms underlying loss of normal cell proliferation control in malignant transformation, by demonstrating that receptor trafficking dynamics may in some cases play as important a role as intrinsic signal transduction in determining the overall resulting mitogenic response.

Cell Division↗

PubMedDate not supplied

[A model of oligomeric enzymes explaining stepwise kinetic curves].

The complex kinetics of some oligomeric enzymes has been analysed. For interpreting such kinetics a theoretical model of an oligomeric enzyme is suggested, which is a modification of the "flip-flop" mechanism considered by Lazdunski et al. in 1971. Using our model, one can qualitatively interpret stepwise kinetic curves, i.e. the curves with few intermediate plateaus. Such curves are known from literature but have not exhaustively been explained. It is supposed that the enzyme kinetic curves can sometimes be of non-differential functions. The model used can also be applied to the kinetics of polyenzyme complexes.

Catalysis↗

PubMed1994

Age-period-cohort modelling of large-bowel-cancer incidence by anatomic sub-site and sex in Denmark.

In a previous investigation, statistical modelling was used to examine the relationship between large-bowel-cancer incidence and age, time period and birth cohort by anatomic sub-site and sex, using data from the Connecticut Tumor Registry (CTR) for the period 1950 to 1984. This analysis revealed differences in age-period-cohort patterns that suggested etiologic distinctions among sub-site groupings and between the sexes. To test the generalizability of the Connecticut findings, we have conducted a similar age-period-cohort analysis using data from the Danish Cancer Registry (DCR) for the period 1953 to 1987. Cancers of the large bowel were classified into 6 anatomic sub-sites: cecum, ascending colon, transverse colon, descending colon, sigmoid colon and rectum. Data were fitted to log-linear age-period-cohort models. If we interpret differences in age-period-cohort patterns as reflecting etiologic distinctions, the Denmark analysis, in conjunction with the Connecticut findings, was consistent with there being etiologic distinctions between cancers of the colon vs. the rectum in both males and females, between cancers of the cecum and the ascending colon vs. the remainder of the colon in females and between males vs. females for cancers of the sigmoid colon and rectum. Cancers of the cecum and the ascending colon were the most similar between males and females. Due to the ambiguities of age-period-cohort modelling, these should be considered only tentative conclusions that can be tested by analytical epidemiologic studies.

Adult↗

PubMed1992

Models for describing absorption rate and estimating extent of bioavailability: application to cefetamet pivoxil.

Five absorption rate models have been compared for describing cefetamet data in 34 adults after oral administration of cefetamet pivoxil with food alone or in combination with either an antacid or an H2 antagonist. A sequential zero- then first-order input process provided the most flexible description of the absorption rate of cefetamet. If the first-order rate constant is linked to the zero-order input parameters the model can be interpreted as the consequence of solubility-limited absorption. While a sequential input is theoretically reasonable to assume, the first-order process appeared to be independent of the zero-order input. A population-based approach was applied to estimate the effect of dose and gastric pH increase on absorption and disposition. There appeared to be a dose-associated change in several parameters. The most marked change was an increase in volume of distribution of cefetamet. Treatments expected to increase gastric pH slowed the first-order component of the absorption process. Three models for estimating the extent of bioavailability have been compared using observations from 18 adults and 13 children receiving iv cefetamet and oral cefetamet pivoxil on two separate occasions. The most consistent estimates of the disposition parameters and the extent of bioavailability were achieved with the sequential zero- and first-order model under the assumption that steady state volume of distribution and nonrenal clearance were the same after iv and oral treatment.

Absorption↗

PubMed2006

A phyloclimatic study of Cyclamen.

BACKGROUND: The impact of global climate change on plant distribution, speciation and extinction is of current concern. Examining species climatic preferences via bioclimatic niche modelling is a key tool to study this impact. There is an established link between bioclimatic niche models and phylogenetic diversification. A next step is to examine future distribution predictions from a phylogenetic perspective. We present such a study using Cyclamen (Myrsinaceae), a group which demonstrates morphological and phenological adaptations to its seasonal Mediterranean-type climate. How will the predicted climate change affect future distribution of this popular genus of garden plants? RESULTS: We demonstrate phylogenetic structure for some climatic characteristics, and show that most Cyclamen have distinct climatic niches, with the exception of several wide-ranging, geographically expansive, species. We reconstruct climate preferences for hypothetical ancestral Cyclamen. The ancestral Cyclamen lineage has a preference for the seasonal Mediterranean climate characteristic of dry summers and wet winters. Future bioclimatic niches, based on BIOCLIM and Maxent models, are examined with reference to a future climate scenario for the 2050s. Over the next 50 years we predict a northward shift in the area of climatic suitability, with many areas of current distribution becoming climatically unsuitable. The area of climatic suitability for every Cyclamen species is predicted to decrease. For many species, there may be no areas with a suitable climate regardless of dispersal ability, these species are considered to be at high risk of extinction. This risk is examined from a phylogenetic perspective. CONCLUSION: Examining bioclimatic niches from a phylogenetic perspective permits novel interpretations of these models. In particular, reconstruction of ancestral niches can provide testable hypothesis about the historical development of lineages. In the future we can expect a northwards shift in climatic suitability for the genus Cyclamen. If this proves to be the case then dispersal is the best chance of survival, which seems highly unlikely for ant-dispersed Cyclamen. Human-assisted establishment of Cyclamen species well outside their native ranges offers hope and could provide the only means of dispersal to potentially suitable future environments. Even without human intervention the phylogenetic perspective demonstrates that major lineages could survive climate change even if many species are lost.

Algorithms↗

PubMed1992

A parametric family of correlation structures for the analysis of longitudinal data.

In epidemiological settings, we are often faced with numerous short time series, and a parsimonious parametrization of the correlation structure is desired in order to optimize the efficiency of the estimation procedure. We propose a damped exponential correlation structure for modeling multivariate Gaussian outcomes. The correlation between two observations separated by s units of time is modeled as gamma s theta, where gamma is the correlation between elements separated by one s-unit, and theta is a damping parameter. For (theta = 0), (theta = 1), and theta----infinity), the correlation structures of compound symmetry, first-order autoregressive, and first-order moving average processes are obtained. Although the AR(2) dependency structure, and the combination of random effects and AR(1) errors are not special cases of the proposed parametric family, these structures can be well approximated within the family for short time series. Maximum likelihood methods for parameter estimation and interpretations of intermediate models (0 less than theta less than 1) are discussed in the context of modeling pulmonary function in an adult population in The Netherlands and T-cell subsets in homosexual men infected with human immunodeficiency virus Type I.

Adult↗

PubMed1993

The physiological properties of the band 3 anion exchanger as derived from pH and other studies with human red cells.

The kinetics of the erythrocyte anion exchanger which have been studied at high pH values have confirmed the importance of hydroxyl ions in the overall physiological roles of the band 3 protein in human red cells. Although usually characterised as a one-for-one anion exchanger, conditions have been identified which give the appearance of net transport. The present findings have uncovered new functional features consistent with the properties of anion transport in other tissues. The molecular models proposed to interpret the results could have wider applications to other cellular mechanisms. Some of these are discussed to illustrate the physiological implications which can be deduced from the novel kinetics of this unique membrane transport protein.

Anion Exchange Protein 1, Erythrocyte↗

PubMed2003

Primer on multiple regression models for diagnostic imaging research.

This article provides an introduction to multiple regression analysis and its application in diagnostic imaging research. We begin by examining why multiple regression models are needed in the evaluation of diagnostic imaging technologies. We then examine the broad categories of available models, notably multiple linear regression models for continuous outcomes and logistic regression models for binary outcomes. The purpose of this article is to elucidate the scientific logic, meaning, and interpretation of multiple regression models by using examples from the diagnostic imaging literature.

Confounding Factors, Epidemiologic↗

PubMed1984

Implications of repair models for LET effects and other radiobiological phenomena.

Repair models account for shoulders to survival curves by the postulate of a mode of repair which is depleted ("saturated") as dose increases, and which should therefore be distinguished, conceptually and linguistically, from what is commonly known as "repair of potentially lethal damage". Acceptance of repair models entails new interpretations of some radiobiological phenomena. "Recovery" of cells between dose fractions would be attributable to reconstitution or resynthesis of the putative agent of repair, so elucidation of the mechanism of such "recovery" requires a different approach from any that have been used in attempts to discover the nature of "sub-lethal lesions" or the mechanism of their repair--attempts that have not been attended by success. Even mammalian cells can yield exponential survival curves; but this fact has been ignored in some proposals for mechanisms of radiation-induced cell killing, and in "theories of RBE" based on multi-sublethal lesion models for shouldered survival curves. According to repair models, however, cells in general are basically single-hit detectors. Comparisons between the responses of repair-proficient cells and their deficient mutants to change in radiation quality support the hypothesis that increases in RBE are attributable to reduced capacity for some mode(s) of repair as LET increases; but there is evidence that some capacity remains, even at very high values of LET.

Animals↗