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PubMedDate not supplied

A model of cytosolic calcium regulation and autacoids production in vascular endothelial cell.

A model of vascular endothelial cell is proposed to describe the mechanisms by which cytosolic calcium (Cai) is modulated and endothelium-derived relaxing factor (EDRF) and prostacyclin (PGI2) are released when the cell is stimulated by agonist. The intracellular Ca2+ store of the model cell is comprised of a superficial (sc) and a deep (dc) compartment. The dc Ca2+ content is refilled by the sc whose [Ca2+] is the same as extracellular Ca2+. Inositol (1,4,5)-trisphosphate (IP3) produced by agonist modifies the dc permeability which discharges its Ca2+ to the cytosol. The increase of Cai induces Ca2+ released from the sc. Ca(2+)-activated K+ current hyperpolarises the cell. The raised Cai releases PGI2 in the presence of IP3 while EDRF is released by Cai. The model explains satisfactorily the Ca2+ transient and autacoids production of the aortic endothelial cell without the need of calcium influx from extracellular space. The cytoplasmic Ca2+ oscillations observed in human endothelial cell from umbilical veins were reproduced by the model. Production of EDRF by the artery due to increase in pressure was also simulated.

Autacoids↗

PubMed2002

Critical switch of the metabolic fluxes by phosphofructo-2-kinase:fructose-2,6-bisphosphatase. A kinetic model.

A kinetic model for the bifunctional enzyme, phosphofructo-2-kinase:fructose-2,6-bisphosphatase, is analysed by application of the graph-theoretical method, considering comparable levels for all participants. Certain elementary reactions, distributed on the enzyme surface, are considered to be co-ordinated in a single conformational transition (a model of parallel molecular operations). The method allows us to identify in the kinetic scheme its destabilising sub-scheme as a branched cycle of elementary reactions. Under certain conditions this sub-scheme induces critical phenomena (bistability or oscillations). The computer calculations for the estimated parameter values fit well the experimental observations for this system. The model explains the periodic or bistable counterphase changes of the two opposing activities of this enzyme, observed after glucose perfusion of rat hepatic enzyme samples, and predicts drastic critical changes in kinetic behaviour induced by small external signals. The model also shows the necessity of the phosphoryl intermediate in the mechanism of the bisphosphatase for the critical kind of kinetic behaviour.

Adenosine Triphosphate↗

PubMed1997

A novel approach to the understanding of human skin barrier function.

The basis for externally caused skin disorders is penetration of the skin barrier. A recent model for the skin barrier, the domain mosaic model, based on current knowledge of the physics of lipid bilayer organization gave tentative explanations for several aspects of function. It is demonstrated here that a development of the model explains how the requirements are met for a water-tight structure that will still allow a controlled, minute loss of water, the perspiratio insensibilis, necessary for maintaining plasticity of the keratin. A major advantage of the extended model is that it allows an interpretation of the changes imposed on the structure when in contact with detergents and/or penetration enhancers.

Administration, Cutaneous↗

PubMed2000

VolSurf: a new tool for the pharmacokinetic optimization of lead compounds.

A method for the modeling and prediction of pharmacokinetic properties based on computed molecular interaction fields and multivariate statistics has been investigated in different experimental datasets. The program VolSurf was used to correlate 3D molecular structures with physico-chemical and pharmacokinetic properties. In membrane partitioning, VolSurf produced a two-component model explaining 94% of the total variation with a predictive q(2) of 0.90. This result was achieved without conformational sampling and without any quantum-chemical calculation. For the prediction of blood-brain barrier penetration the VolSurf model was able to predict the BBB profile for most of the drugs in the external prediction set. In Caco-2 and MDCK permeation experiments, VolSurf was used with success to establish statistical models and to predict the behaviour of new compounds. The method thus appears as a valuable new property filter in virtual screening and as a novel tool in optimizing the pharmacokinetic profile of pharmaceutically relevant compounds.

Animals↗

PubMed2005

Molecular models of lipopeptide detergents: large coiled-coils with hydrocarbon interiors.

We have constructed molecular models of octameric micelles formed by a recently developed lipopeptide detergent consisting of a single amphipathic alpha-helix coupled to two acyl chains at either end of the helix. The models explain the experimentally observed aggregation behavior of peptides with different acyl chain lengths. The octameric micelles form a unique coiled-coil structure, with the acyl chains in a nearly frozen conformation inside the cylindrical assemblies. Two extreme models with helices either all parallel or in an alternating orientation suggest that the alternating orientation is energetically more favorable. The models suggest several new directions for further diversifying this new class of detergents for the structural studies of membrane proteins.

Detergents↗

PubMedDate not supplied

Psychological, neuropsychological, and medical considerations in assessment and management of pain.

Pain is a common yet challenging problem, particularly following traumatic injuries to the head or neck. It is a complex, multidimensional subjective experience with no clear or objective measures; yet it can have a significantly disabling effect across a wide range of functions. Persisting misconceptions owing to mind-body dualism have hampered advances in its understanding and treatment. In this article, a conceptualization of pain informed by recent research and derived from a more useful biopsychosocial model guides discussion of relevant medical, psychological, and neuropsychological considerations. This pain process model explains chronicity in terms of hyperresponsiveness and dysregulation of inhibitory or excitatory pain modulation mechanisms. Related neurocognitive effects of chronic pain are examined and recommendations for minimizing its confounding effects in neuropsychological evaluations are offered. A biopsychosocial assessment model is presented to guide understanding of the myriad of factors that contribute to chronicity. A brief survey of general classes and samples of the more useful pain assessment instruments is included. Finally, this model offers a rational means of organizing and planning individually tailored pain interventions, and some of the most useful pharmacologic, physical, and behavioral strategies are reviewed.

Acute Disease↗

PubMed2001

Ockham's razor modeling of the matrisome channels of the basal ganglia thalamocortical loops.

A functional model of the basal ganglia-thalamocortical (BTC) loops is described. In our modeling effort, we try to minimize the complexity of our starting hypotheses. For that reason, we call this type of modeling Ockham's razor modeling. We have the additional constraint that the starting assumptions should not contradict experimental findings about the brain. First assumption: The brain lacks direct representation of paths but represents directions (called speed fields in control theory). Then control should be concerned with speed-field tracking (SFT). Second assumption: Control signals are delivered upon differencing in competing parallel channels of the BTC loops. This is modeled by extending SFT with differencing that gives rise to the robust Static and Dynamic State (SDS) feedback-controlling scheme. Third assumption: Control signals are expressed in terms of a gelatinous medium surrounding the limbs. This is modeled by expressing parameters of motion in parameters of the external space. We show that corollaries of the model fit properties of the BTC loops. The SDS provides proper identification of motion related neuronal groups of the putamen. Local minima arise during the controlling process that works in external space. The model explains the presence of parallel channels as the means to avoiding such local minima. Stability conditions of the SDS predict that the initial phase of learning is mostly concerned with selection of sign for the inverse dynamics. The model provides a scalable controller. State description in external space instead of configurational space reduces the dimensionality problem. Falsifying experiment is suggested. Computer experiments demonstrate the feasibility of the approach. We argue that the resulting scheme has a straightforward connectionist representation exhibiting population coding and Hebbian learning properties.

Basal Ganglia↗

PubMed2001

Climate controls on dust storm occurrence in Maowusu Desert, Inner Mongolia, north China.

Dust storms occurring in arid and semi-arid regions play a main role in the evolution of landscapes. Climate is generally regarded to be important factors influencing the occurrence of dust storm, however, the way of climate controlling dust storms had been poorly understood. In this paper, we present the Ew Index model to describe the relationship between climate variables and dust storm frequency using the available meteorological data from three meteorological stations in Maowusu Desert. This index model explains 83.6%, 69.5% and 65.09% of the variance of dust storm frequency in three regions from the north to the south, respectively and this difference is probably caused by the difference of the human disturbance. The Ew Index model is an effective predictor of dust storm frequency and provides us a quite good understanding on the occurrence of dust storms in Maowusu Desert.

China↗

PubMed1984

A proposal for the metal geometry in yeast superoxide dismutase based on results from EXAFS spectroscopy.

Extended x-ray absorption fine structure (EXAFS) spectra have been recorded at the Cu edge and Zn edge in native yeast superoxide dismutase and at the Cu edge and Cd edge in the yeast superoxide dismutase derivative, where Zn has been substituted with Cd. Two different metal ligand distances in the range 1.9-2.0 A and 2.3-2.4 are determined for the Cu and Zn metals. For Cd in the Zn site two different metal ligand distances about 2.2 A and 2.6 A, respectively, were found. The striking feature is the similarity between the amplitude and radii determined for both the Cu and Zn sites. The increased distances for Cd can be explained by the increased ionic radius of Cd relative to Cu and Zn. Based on these EXAFS results and other relevant knowledge about the metal geometries, we propose that histidine 61 (63) positioned between the Cu and Zn metals are in one subunit bound to Zn and in the other to Cu. This model explains the recently observed difference between the two metal sites in each subunit.

Copper↗

PubMed2005

Interaction of sodium and potassium ions with sandwiched cytosine-, guanine-, thymine-, and uracil-base tetrads.

Nucleic acid tetraplexes and lipophilic self-assembling G-quadruplexes contain stacked base tetrads with intercalated metal ions as basic building blocks. Thus far, quantum-chemical studies have been used to explore the geometric and energetic properties of base tetrads with and without metal ions. Recently, for the first time, work on a sandwiched G-tetrad complex has been studied. We report here results of a systematic B3LYP density functional study on sandwiched G-, C-, U-, and T-tetrads with Na+ and K+ at different symmetries that substantially extend the recent work. The results include detailed information on total energies as well as on metal ion tetrad and base-base interaction energies. The geometrical parameters of the sandwiched metal ion complexes are compared to both experimental structures and to calculated geometries of complexes of single tetrads with metal ions. A microsolvation model explains the ion selectivity preference of K+ over Na+ in a qualitative sense.

Algorithms↗

PubMed1995

A simple model of blood flow rate reduction in haemodynamic disorders of the spleen.

The structural rearrangement of human sheathed capillaries in congestive splenomegaly has been considered. In abnormal spleens the external diameter and wall thickness were decreased, while the internal diameter was increased. Moreover, the total length and the absolute number of sheathed capillaries were increased, though not as much as the whole red pulp volume. Thus, in congestive splenomegaly, in addition to the well-known changes of the sinuses, the terminal arterial passages also appear to participate in the morphological rearrangement of the red pulp. The purpose of this paper is to formulate a simple dynamic model explaining the reduction of blood flow rate in the pathologically modified spleen. The main advantage of the present approach is that the coefficients inserted in equations describing the physical phenomena have been eliminated from the final formulae. Consequently, the model does not require the determination of parameters by means of difficult experimental measurements.

Blood Flow Velocity↗

PubMed2001

Defensive alliances in spatial models of cyclical population interactions.

As a generalization of the three-strategy Rock-Scissors-Paper game dynamics in space, cyclical interaction models of six mutating species are studied on a square lattice, in which each species is supposed to have two dominant, two subordinated, and a neutral interacting partner. Depending on their interaction topologies, all imaginable systems can be classified into four (isomorphic) groups exhibiting significantly different behaviors as a function of mutation rate. In three out of four cases three (or four) species form defensive alliances that maintain themselves in a self-organizing polydomain structure via cyclic invasions. Varying the mutation rate, this mechanism results in an ordering phenomenon analogous to that of magnetic Ising systems. The model explains a very basic mechanism of community organization, which might gain important applications in biology, economics, and sociology.

Ecology↗

PubMed2006

Predicting functional capacity outcome 12 months after hospitalized injury.

BACKGROUND: There is a recognized need to move from mortality to morbidity outcome predictions following traumatic injury. However, there are few morbidity outcome prediction scoring methods and these fail to incorporate important comorbidities or cofactors. This study aims to develop and evaluate a method that includes such variables. METHODS: This was a consecutive case series registered in the Queensland Trauma Registry that consented to a prospective 12-month telephone conducted follow-up study. A multivariable statistical model was developed relating Trauma Registry data to trichotomized 12-month post-injury outcome (categories: no limitations, minor limitations and major limitations). Cross-validation techniques using successive single hold-out samples were then conducted to evaluate the model's predictive capabilities. RESULTS: In total, 619 participated, with 337 (54%) experiencing no limitations, 101 (16%) experiencing minor limitations and 181 (29%) experiencing major limitations 12 months after injury. The final parsimonious multivariable statistical model included whether the injury was in the lower extremity body region, injury severity, age, length of hospital stay, pulse at admission and whether the participant was admitted to an intensive care unit. This model explained 21% of the variability in post-injury outcome. Predictively, 64% of those with no limitations, 18% of those with minor limitations and 37% of those with major limitations were correctly identified. CONCLUSION: Although carefully developed, this statistical model lacks the predictive power necessary for its use as a basis of a useful prognostic tool. Further research is required to identify variables other than those routinely used in the Trauma Registry to develop a model with the necessary predictive utility.

Adolescent↗

PubMedDate not supplied

Comparison of time-tradeoff utilities and rating scale values of cancer patients and their relatives: evidence for a possible plateau relationship.

Because they are easy to administer, rating scales are often used as proxies for utility measures. The authors investigated the relationship between time-tradeoff utilities and rating scale values in two populations: 124 cancer patients asked to evaluate their current states of health and 102 relatives and close friends of cancer patients asked to evaluate health-state scenarios. None of the models tested effectively described the relationship between individual patients' rating scale values and time-tradeoff utilities for their current states of health. In contrast, both a plateau and a power-function model explained the variability in the responses of the relatives reasonably well (R2 = 0.56 and R2 = 0.58, respectively). Given that many respondents who were unwilling to trade off any time assigned rating scale values of well below 100, a plateau model may represent the best approach to adjusting rating scale values for health-state scenarios when it is not feasible to elicit time-tradeoff utilities.

Activities of Daily Living↗

PubMed1978

The mathematics of repeat abortion: explaining the increase.

In any given population, an increase in the proportion of repeat abortions, and a repeat-abortion rate that is substantially higher than the first-abortion rate, can be anticipated to occur over a number of years after abortion has been legalized. These are the findings of an analysis of repeat abortion for a population of women aged 15--44, using simple mathematical models based on the assumptions that the risk of abortion is constant over time and independent of prior abortion experience. The data generated by the models explain both the rapidly increasing percentage and the high rate of repeat abortion following legalization and refute assertions that making abortion widely available discourages the practice of contraception.

Abortion, Induced↗

PubMed2001

Structural changes in the neck linker of kinesin explain the load dependence of the motor's mechanical cycle.

The two-headed motor protein kinesin hydrolyzes ATP and moves on microtubule tracks towards the plus end. The motor develops speeds and forces of the order of hundreds of nanometers per second and piconewtons, respectively. Recently, the dependence of the velocity, the dissociation rate and the displacement variance on the load and the ATP concentration were measured in vitro for individual kinesin molecules (Coppin et al., 1997; Visscher et al., 1999) over a wide range of forces. The structural changes in the kinesin motor that drive motility were discovered by Rice et al. (1999). Here we present a phenomenological model for force generation in kinesin based on the bi-stable, nucleotide-dependent behavior of the neck linker. We demonstrate that the model explains the mechanical, kinetic and statistical (experimental) data of Coppin et al. (1997). We also discuss the relationship between the model results and experimental data of Visscher et al. (1999).

Adenosine Diphosphate↗

PubMed1993

Dual sorption model for the nonlinear percutaneous permeation kinetics of timolol.

The nonlinear percutaneous permeation kinetics of timolol were studied in vitro with human cadaver skin. In the sorption isotherm (equilibrium) study, the plots of the amount of timolol per unit area of epidermis versus aqueous timolol concentration in equilibrium were curvilinear as the dual sorption model predicts. In the penetration study, several aqueous timolol concentrations were maintained in the donor cell for 25 h. The lag-time was prolonged as the timolol concentration in the donor cell was decreased. The change in the lag time was analyzed by a newly proposed method with the lag-time prolongation factor that is calculated from the parameter values obtained in the sorption isotherm study. The ratio of the lag-time to lag-time prolongation factor was of the same magnitude, indicating that the dual sorption model explains the nonlinear percutaneous permeation kinetics of timolol. Finally, the diffusion parameter for the mobile solute was estimated by fitting the data of the cumulative amount excreted into receptor cell versus time to the numerical solution of the dual sorption model. The observed data were roughly compatible with the values predicted by the dual sorption model.

Administration, Cutaneous↗

PubMed2001

Multiple DNA glycosylases for repair of 8-oxoguanine and their potential in vivo functions.

8-Oxoguanine (8-oxoG) is a critical mutagenic lesion because of its propensity to mispair with A during DNA replication. All organisms, from bacteria to mammals, express at least two types of 8-oxoguanine-DNA glycosylase (OGG) for repair of 8-oxoG. The major enzyme class (OGG1), first identified in Escherichia coli as MutM (Fpg), and later in yeast and humans, excises 8-oxoG when paired with C, T, and G but rarely with A. In contrast, a distinct and less abundant OGG, OGG2, prefers 8-oxoG when paired with G and A as a substrate, and has been characterized in yeast and human cells. Recently, OGG2 activity was detected in E. coli which was subsequently identified to be Nei (Endo VIII). In view of the ubiquity of OGG2, we have proposed a model named "bipartite antimutagenic processing of 8-oxoguanine" and is an extension of the original "GO model." The GO model explains the presence of OGG1 (MutM) that excises 8-oxoG from nonreplicated DNA. If 8-oxoG mispairs with A during replication, MutY excises A and provides an opportunity for insertion of C opposite 8-oxoG during subsequent repair replication. Our model postulates that whereas OGG1 (MutM) is responsible for global repair of 8-oxoG in the nonreplicating genome, OGG2 (Nei) repairs 8-oxoG in nascent or transcriptionally active DNA. Interestingly, we observed that MutY and MutM reciprocally inhibited each other's catalytic activity but observed no mutual interference between Nei and MutY. This suggests that the recognition sites on the same substrate for Nei and MutY are nonoverlapping. Human OGG1 is distinct from other oxidized base-specific DNA glycosylases because of its extremely low turnover, weak AP lyase activity, and nonproductive affinity for the abasic (AP) site, its first reaction product. OGG1 is activated nearly 5-fold in the presence of AP-endonuclease (APE) as a result of its displacement by the latter. These results support the "handoff" mechanism of BER in which the enzymatic steps are coordinated as a result of displacement of the DNA glycosylase by APE, the next enzyme in the pathway. The physiological significance of multiple OGGs and their in vivo reaction mechanisms remain to be elucidated by further studies.

Bacterial Proteins↗