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PubMed1993

Recognition of errors in three-dimensional structures of proteins.

A major problem in the determination of the three-dimensional structure of proteins concerns the quality of the structural models obtained from the interpretation of experimental data. New developments in X-ray crystallography and nuclear magnetic resonance spectroscopy have accelerated the process of structure determination and the biological community is confronted with a steadily increasing number of experimentally determined protein folds. However, in the recent past several experimentally determined protein structures have been proven to contain major errors, indicating that in some cases the interpretation of experimental data is difficult and may yield incorrect models. Such problems can be avoided when computational methods are employed which complement experimental structure determinations. A prerequisite of such computational tools is that they are independent of the parameters obtained from a particular experiment. In addition such techniques are able to support and accelerate experimental structure determinations. Here we present techniques based on knowledge based mean fields which can be used to judge the quality of protein folds. The methods can be used to identify misfolded structures as well as faulty parts of structural models. The techniques are even applicable in cases where only the C alpha trace of a protein conformation is available. The capabilities of the technique are demonstrated using correct and incorrect protein folds.

Models, Molecular↗

PubMed1990

Use of the ferret for a myocardial ischemia/salvage model.

Exploratory work was undertaken in the anesthetized ferret to determine if it is an applicable species for use as an in vivo ischemic model and suitable for recovery surgical procedures. Experimental protocols utilizing varying combinations of left anterior descending (LAD) coronary artery occlusion (30, 60, 90 min) and reperfusion (4, 6, 18-24 hr) were evaluated. The results indicated that a 90-min/6-hr combination led to the production of an infarct equivalent, or slightly greater, in size to that observed following coronary artery occlusion either with and without reflow during an 18-24-hr recovery period prior to sacrifice. A combination of 90 min occlusion/4 hr reperfusion yielded an infarct area ca. 50% of that associated with 6 hr interval of reflow. An occlusive interval of 60 min or less combined with any reperfusion interval lack reproducibility. The administration of saline in varying volumes by different routes (IV versus left atrial) had no influence on either the absolute or, more especially, the relative (i.e., as a percent of left ventricle) tissue damage provoked by a 90-min/6-hr occlusion/reperfusion maneuver of the LAD coronary artery. When evaluated as a reference standard, superoxide dismutase (SOD) infused via the left atrium at a dose of 5 mg/kg afforded a 36% reduction in the area of ischemic damage in this model. These studies demonstrated that the ferret represents a useful species for initial, rapid, and economic--both in terms of cost and drug substance utilization--in vivo myocardial salvage screening assessments. The model permits an interpretation of potential test agent efficacy, dosage requirements, and hemodynamic actions, and it is suitable for basing a go/no-go decision that continued experimental development in more labor intense preparations is warranted.

Animals↗

PubMed1985

On the mathematics of digesta flow kinetics.

A unifying mathematical analysis of the use of compartmental models with and without time lags is given, with particular reference to the use of such models for digesta movement along the gastro-intestinal tract of the ruminant. First the generalized compartmental model without time lags is developed, and then it is shown how discrete time lags may be incorporated into this formalism. The important relationship between distributed lags, especially the gamma-distributed time lags, and the equivalent compartmental scheme, is emphasized. It is shown how distributed time lags can be included in a general compartmental model. The treatment covers, as special cases, some widely used models, and shows their relationship to each other and to other possible models. Finally a compartmental interpretation is outlined for a recently proposed double-exponential model.

Animals↗

PubMed1988

Estimating the production of faeces by ruminants from faecal marker concentration curves.

The use of faecal marker concentration curves, in conjunction with compartmental analysis, is examined as a method for predicting faecal output in ruminants. Formulae for faecal production are derived for the various multicompartment models currently used to interpret marker concentration data. A comparison of observed and model-derived estimates of faecal dry matter production using three different markers is given for sheep consuming hay or a mixed diet.

Animals↗

PubMed2003

Rotational diffusion of the 7-diethylamino-4-methylcoumarin C1 dye molecule in polar protic and aprotic solvents.

Fluorescence anisotropy decays of the 7-diethylamino-4-methylcoumarin C1 in various polar solvents of different viscosities and hydrogen bond donor/acceptor character have been recorded by means of the fluorescence upconversion and time-correlated single photon counting techniques. The resulting characteristic times for the rotational diffusion fall into two classes with regards to the viscosity-dependency: n-alcohols and "other" solvents. This deviation from the simple Stokes-Einstein-Debye model may be interpreted in terms of rotation of the coumarin molecule under two different hydrodynamic boundary-conditions ("stick" or "slip") in the two solvent classes. Possible explanations for this behaviour are discussed, and in particular solvent attachment and additional dielectric friction. Both these phenomena may in fact, under certain conditions, explain our findings. Our opinion, however, is that the dielectric friction model offers a more realistic picture of the additional rotational friction experienced by C1 in n-alcohols.

Journal Article↗

PubMed2006

Schizophrenia as a dynamical disease.

It is demonstrated that schizophrenia is a dynamical disease, i. e. that important aspects of schizophrenia can be understood on the basis of concepts of the theory of nonlinear dynamical systems. In particular, the gradual shift of a single parameter may result in completely different kinds of behavior of the entire system just like water can be in three qualitatively different states depending on the single parameter temperature. Transitions between these different states are called bifurcations or phase transitions. In case of schizophrenia the parameter may be the neurotransmitter dopamine (or serotonin or glutamate). With a high level of dopamine transmission the symptoms of schizophrenia appear, and with rather low levels those of Morbus Parkinson. In between a healthy state prevails. With respect to neuronal activity the effects of dopamine are demonstrated by a mathematical model which can be interpreted in two ways: on the one hand as a model of typical excitatory-inhibitory circuits in the cortex, on the other hand of a negative feedback loop between thalamus, prefrontal cortex and striatum. The model exhibits different types of firing patterns and their bifurcation, from various kinds of periodicities up to erratic or chaotic behavior, corresponding to different levels of dopamine concentration.

Animals↗

PubMed1980

H-2 restriction: independent recognition of H-2 and foreign antigen by a single receptor.

We describe two situations in which the recognition of hapten can compensate for the lack of recognition of appropriate H-2 gene products in hapten-specific, H-2 restricted, T lymphocyte-mediated cytolysis. First, we show that although recognition of appropriate H-2 gene products is essential for the lysis of target cells bearing a low hapten density, significant hapten-specific lysis of H-2 inappropriate target cells is observed at high levels of target cell derivatization. Secondly, we show that hapten-conjugated anti-H-2 antibody inhibits cytolysis poorly even though its binding to target cell H-2 antigens is equivalent to that of underivatized antibody. These results suggest that hapten and H-2 are recognized independently and are therefore inconsistent with the altered-self model. Although our data do not exclude the dual-recognition model, we prefer to interpret them within the framework of a single-receptor model in which hapten and H-2 are recognized independently by receptors of identical idiotype on the T cell. We postulate that the affinity of these receptors for the relevant H-2 gene product is low enough so that the T cell is not activated by encounters with normal-self cells expressing that H-2 gene product. However, when self cells express in addition a foreign antigen that can also be recognized by the same receptor, then the force of T cell-target cell interaction may be increased sufficiently to activate T cell effector function.

Animals↗

PubMed2006

Computer-aided molecular design of highly potent HIV-1 RT inhibitors: 3D QSAR and molecular docking studies of efavirenz derivatives.

Ligand- and structure-based design approaches have been applied to an extended series of 74 efavirenz compounds effectively inhibiting wild type (WT) and mutant type (K103N) HIV-1 reverse transcriptase (RT). For ligand-based approach, three dimensional quantitative structure-activity relationship (3D-QSAR) methods, comparative molecular field analysis (CoMFA) and comparative similarity indices analysis (CoMSIA), were performed. The starting geometry of efavirenz was obtained from X-ray crystallographic data. The efavirenz derivatives were constructed and fully optimized by ab-initio molecular orbital method at HF/3-21G level. Reliable QSAR models for high predictive abilities were developed. Regarding WT and K103N inhibitions, CoMFA models with r2/cv = 0.651 and 0.678 and CoMSIA models with r2/cv = 0.662 and 0.743 were derived, respectively. The interpretation obtained from the models highlights different structural requirements for inhibition of WT and K103N HIV-1 RT. To elucidate potential binding modes of efavirenz derivatives in the binding pocket of WT and K103N HIV-1 RT, structure-based approach based on computational docking studies of selected efavirenz compounds were performed by using GOLD and FlexX programs. The results derived from docking analysis give additional information and further probe the inhibitor-enzyme interactions. The correlation of the results obtained from 3D QSAR and docking models validate each other and lead to better understanding of the structural requirements for the activity. Therefore, these integrated results are informative to provide key features and a helpful guideline for novel compound design active against HIV-1 RT.

Alkynes↗

PubMed2005

Model uncertainty--parameter uncertainty versus conceptual models.

Uncertainties in model structures have been recognised often to be the main source of uncertainty in predictive model simulations. Despite this knowledge, uncertainty studies are traditionally limited to a single deterministic model and the uncertainty addressed by a parameter uncertainty study. The extent to which a parameter uncertainty study may encompass model structure errors in a groundwater model is studied in a case study. Three groundwater models were constructed on the basis of three different hydrogeological interpretations. Each of the models was calibrated inversely against groundwater heads and streamflows. A parameter uncertainty analysis was carried out for each of the three conceptual models by Monte Carlo simulations. A comparison of the predictive uncertainties for the three conceptual models showed large differences between the uncertainty intervals. Most discrepancies were observed for data types not used in the model calibration. Thus uncertainties in the conceptual models become of increasing importance when predictive simulations consider data types that are extrapolates from the data types used for calibration.

Denmark↗

PubMed1991

Modelling digit preference in fecundability studies.

Retrospective studies of fecundability, in which women are asked how many cycles they required to become pregnant, are often affected by problems of digit preference. A probability model for such digit preference is proposed in which misreporting favours 6 or 12 (and possibly also 3) cycles. It is assumed that in the absence of misreporting the number of cycles follows a beta-geometric distribution. The model is applied to two data sets, with clear-cut results: The inclusion of additional parameters to model the misreporting can lead to substantial improvements in fit, but causes little change to the estimated parameters of the underlying beta-geometric distribution. In some cases misreporting parameters may be regarded as nuisance parameters, while in others they may be of interest. We have found estimates of these parameters to vary between different categories of women in an interpretable manner. The models may also be used to estimate the percentage of couples in any study that misreport their conception waiting time.

Biometry↗

PubMedDate not supplied

[Mathematical modeling of cyclic kinetics of hematopoiesis].

Mathematical models of the time course of formation of platelets, erythrocytes, granulocytes and lymph cells of mammals have been developed. They are systems of nonlinear differential equations where concentrations of mature blood cells and their bone marrow precursors are the variables. The models represent the main stages in the development of the various types of blood cells and allow for specific formation of red and white blood cells. Verification with the aid of oscilation theory methods and computer-aided numerical calculations have shown that the models reproduce all dynamic variations of the hemopoietic system, including stable fluctuations of concentrations of the various types of blood cells and their precursors (limiting cycles). Calculated parameters of stable fluctuations are in good agreement with experimental data. Within the framework of the models the origination of limiting cycles is described and their interpretation is given. These models can be used to simulate monthly biologic rhythms inherent in the various types of hemopoiesis as well as to analyze flight biomedical data and to discriminate space flight effects on hemopoiesis.

Blood Cells↗

PubMed1986

Orientation of collagen fibers at the boundary between two successive osteonic lamellae and its mechanical interpretation.

By applying an original technique, an investigation has been carried out to determine the orientation of collagen fibrils at the boundary between two successive lamellae in alternate osteons. Evidence is reported that the predominant fiber direction does not change abruptly from one lamella to the next; there is an intermediate system of criss-crossed fibers whose main orientation makes an angle of nearly 45 degrees with the direction of the fibers in the two adjacent lamellae. Taking a composite orthogonally reinforced laminate as a model, a mechanical interpretation of this intermediate system of collagen fibers is given.

Adult↗

PubMed1998

Observer biases in the 3D interpretation of line drawings.

Line drawings produced by contours traced on a surface can produce a vivid impression of the surface shape. The stability of this perception is notable considering that the information provided by the surface contours is quite ambiguous. We have studied the stability of line drawing perception from psychophysical and computational standpoints. For a given family of simple line drawings, human observers could perceive the drawings as depicting either an elliptic (egg-shaped) or hyperbolic (saddle-shaped) smooth surface patch. Rotation of the image along the line of sight and change in aspect ratio of the line drawing could bias the observer toward either interpretation. The results were modeled by a simple Bayesian observer that computes the probability to choose either interpretation given the information in the image and prior preferences. The model's decision rule is noncommitting: for a given input image its responses are still probabilistic, reflecting variability in the modeled observers' judgements. A good fit to the data was obtained when three observer assumptions were introduced: a preference for convex surfaces, a preference for surface contours aligned with the principal lines of curvature, and a preference for a surface orientation consistent with an object viewed from above. We discuss how these assumptions might reflect regularities of the visual world.

Adult↗

PubMed1996

Lack of autoimmune serological reactions in rodent models of insulin dependent diabetes mellitus.

Spontaneous insulitis with insulin-dependent diabetes mellitus (IDDM) in rodent models, the BB rat and NOD mouse, has clarified the pathogenesis of and guided decisions on interventional therapy for human IDDM. However, the occurrence in such models of a standard marker of human IDDM, autoantibodies to beta islet cell constituents, has been controversial. Hence we assessed diabetes-prone rodents for the frequencies of raised levels of auto-antibodies to glutamic acid decarboxylase GAD (anti-GAD), insulin and heat shock protein 65 (HSP-65) in relation to levels in non-diabetes-prone animals and levels in human diabetic sera. Assays were performed sequentially at various ages of life. The immunoassays used for anti-GAD and anti-insulin were those validated for sensitivity and specificity for detection of the corresponding autoantibodies in human IDDM sera at international workshops. Positive controls included human IDDM sera with reactivity with GAD or insulin and, for mouse anti-GAD, the highly reactive monoclonal antibody, GAD-6. The results were that levels of autoantibodies in diabetes-prone BB rats or NOD mice to the "IDDM-relevant' autoantigens in our panel did not exceed levels in control rats or mice, and were much lower than levels in humans with IDDM. We conclude that the BB rat and NOD mouse represent a model, but not a facsimile, of human IDDM and that therapeutic successes in such models should be interpreted with caution in relation to interventional therapy for human IDDM.

Animals↗

PubMed1996

HIV-1 infection kinetics in tissue cultures.

Despite intensive experimental work on HIV-1, very little theoretical work has focused on HIV-1 spread in tissue culture. This article uses two systems of ordinary differential equations to model two modes of viral spread, cell-free virus and cell-to-cell contact. The two models produce remarkably similar qualitative results. Simulations using realistic parameter regimes showed that starting with a small fraction of cells infected, both cell-free viral spread and direct cell-to-cell transmission give an initial exponential phase of viral growth, followed by either a crash or a gradual decline, extinguishing the culture. Under some conditions, an oscillatory phase may precede the extinction. Some previous models of in vivo HIV-1 infection oscillate, but only in unrealistic parameter regimes. Experimental tissue infections sometimes display several sequential cycles of oscillation, however, so our models can at least mimic them qualitatively. Significantly, the models show that infective oscillations can be explained by infection dynamics; biological heterogeneity is not required. The models also display proportionality between infected cells and cell-free virus, which is reassuringly consistent with assumptions about the equivalence of several measures of viral load, except that the proportionality requires a relatively constant total cell concentration. Tissue culture parameter values can be determined from accurate, controlled experiments. Therefore, if verified, our models should make interpreting experimental data and extrapolating it to in vivo conditions sharper and more reliable.

CD4-Positive T-Lymphocytes↗

PubMed1983

Adaptation in chronic illness: an eclectic model for nurses.

The growing prevalence of chronic illness is due, in large part, to the control and/or eradication of infectious diseases as well as, in North America, the increasingly aged population and overall lengthening life span. Although the trajectory of chronic illness is in a generally downward direction, the rate of progression may vary as plateaux an remissions occur. As these changes occur, the individual and his family move through a process of continual adjustment. This paper presents a conceptual model of the process of adaptation in chronic illness. The primary concept in the model is appraisal (Lazarus, 1966) and the thought that continuous appraisal/reappraisal of the individual's progress toward the goal of adaptation is required by the individual, his family, and the nurse. The focus of the model is the chronically ill individual and his family. The goal is movement toward adaptation to the illness and its ramifications. The process is caring, which facilitates movement towards the goal. The model and its interpretation are outlined in the paper. Finally, some strategies for nurses, and others, are suggested as ways in which the concepts may be applied and implemented in practice.

Adaptation, Psychological↗

PubMed2006

Stages of abstraction and exemplar memorization in pigeon category learning.

It has been proposed that human category learning consists of an early abstraction-based stage followed by a later exemplar-memorization stage. To investigate whether similar processing stages extend to category learning in a nonverbal species, we applied a prototype-exception paradigm to investigating pigeon category learning. Five birds and 8 humans learned six-dimensional perceptual categories constructed to include prototypes, typical items, and exceptions. We evaluated the birds' and humans' categorization strategies at different points during learning. Early on in both species, prototype performance improved rapidly as exception performance remained below chance, indicating an initial mastery of the categories' general structure. Later on, exception performance improved selectively and dramatically, indicating exception-item resolution and exemplar memorization. Abstraction- and exemplar-based formal models reinforced these interpretations. The results suggest a psychological transition in pigeon category learning from abstraction- to exemplar-based processing similar to that found in humans.

Animals↗

PubMed1992

Kinetics and mechanism of the folding of cytochrome c.

The reversible folding of cytochrome c in urea at pH 4.0 was investigated by repetitive pressure perturbation kinetics and by equilibrium spectroscopic methods. Two folding reactions were observed in the 1 ms to 10 s time range. The rates and amplitudes of these reactions depend on urea concentration in a complex manner, which is different for each process. The absorbance spectra of the kinetic amplitudes of the two reactions also differ from each other. A model with a three-state mechanism can quantitatively account for all of the kinetic and equilibrium data, and it enables us to determine the rate constants and volume changes of the two steps. If a rapid protonation step is added to the mechanism, the analysis can be extended to calculate the pH dependence of the rate and amplitude of the faster folding step. This pH dependence is in excellent agreement with previously published data [Tsong, T. Y. (1977) J. Biol. Chem. 252, 8778-8780]. Kinetic experiments in the 695-nm band show clearly that the axial ligand methionine-80 is involved in the slow folding process and the other axial ligand, histidine-18, is involved in the fast process. Additional experiments with a cyanogen bromide fragment of the protein, and fluorescence detection of the folding kinetics of the intact protein, support an interpretation of the model in terms of known structural elements of cytochrome c. This work provides new information about the mechanism of the folding of cytochrome c, resolves conflicts in earlier interpretations, and demonstrates the applicability of the repetitive pressure perturbation kinetics method to protein folding.

Animals↗