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At least 577 records · Page 32Linked to original sources
PubMed2005

A new type of scorpion Na+-channel-toxin-like polypeptide active on K+ channels.

We have purified and characterized two peptides, named KAaH1 and KAaH2 (AaH polypeptides 1 and 2 active on K+ channels, where AaH stands for Androctonus australis Hector), from the venom of A. australis Hector scorpions. Their sequences contain 58 amino acids including six half-cysteines and differ only at positions 26 (Phe/Ser) and 29 (Lys/Gln). Although KAaH1 and KAaH2 show important sequence similarity with anti-mammal beta toxins specific for voltage-gated Na+ channels, only weak beta-like effects were observed when KAaH1 or KAaH2 (1 microM) were tested on brain Nav1.2 channels. In contrast, KAaH1 blocks Kv1.1 and Kv1.3 channels expressed in Xenopus oocytes with IC50 values of 5 and 50 nM respectively, whereas KAaH2 blocks only 20% of the current on Kv1.1 and is not active on Kv1.3 channels at a 100 nM concentration. KAaH1 is thus the first member of a new subfamily of long-chain toxins mainly active on voltage-gated K+ channels. NMR spectra of KAaH1 and KAaH2 show good dispersion of signals but broad lines and poor quality. Self-diffusion NMR experiments indicate that lines are broadened due to a conformational exchange on the millisecond time scale. NMR and CD indicate that both polypeptides adopt a similar fold with alpha-helical and b-sheet structures. Homology-based molecular models generated for KAaH1 and KAaH2 are in accordance with CD and NMR data. In the model of KAaH1, the functionally important residues Phe26 and Lys29 are close to each other and are located in the alpha-helix. These residues may constitute the so-called functional dyad observed for short alpha-KTx scorpion toxins in the beta-sheet.

Amino Acid Sequence↗
PubMed2002

Estimates of lateral and longitudinal bond energies within the microtubule lattice.

We developed a stochastic model of microtubule (MT) assembly dynamics that estimates tubulin-tubulin bond energies, mechanical energy stored in the lattice dimers, and the size of the tubulin-GTP cap at MT tips. First, a simple assembly/disassembly state model was used to screen possible combinations of lateral bond energy (DeltaG(Lat)) and longitudinal bond energy (DeltaG(Long)) plus the free energy of immobilizing a dimer in the MT lattice (DeltaG(S)) for rates of MT growth and shortening measured experimentally. This analysis predicts DeltaG(Lat) in the range of -3.2 to -5.7 k(B)T and DeltaG(Long) plus DeltaG(S) in the range of -6.8 to -9.4 k(B)T. Based on these estimates, the energy of conformational stress for a single tubulin-GDP dimer in the lattice is 2.1-2.5 k(B)T. Second, we studied how tubulin-GTP cap size fluctuates with different hydrolysis rules and show that a mechanism of directly coupling subunit addition to hydrolysis fails to support MT growth, whereas a finite hydrolysis rate allows growth. By adding rules to mimic the mechanical constraints present at the MT tip, the model generates tubulin-GTP caps similar in size to experimental estimates. Finally, by combining assembly/disassembly and cap dynamics, we generate MT dynamic instability with rates and transition frequencies similar to those measured experimentally. Our model serves as a platform to examine GTP-cap dynamics and allows predictions of how MT-associated proteins and other effectors alter the energetics of MT assembly.

Dimerization↗
PubMed2002

The benefits of 3D modelling and animation in medical teaching.

Three-dimensional models created using materials such as wax, bronze and ivory, have been used in the teaching of medicine for many centuries. Today, computer technology allows medical illustrators to create virtual three-dimensional medical models. This paper considers the benefits of using still and animated output from computer-generated models in the teaching of medicine, and examines how three-dimensional models are made.

Computer Simulation↗
PubMed2006

Multispecies grand-canonical models for networks with reciprocity.

Reciprocity is a second-order correlation that has been recently detected in all real directed networks and shown to have a crucial effect on the dynamical processes taking place on them. However, no current theoretical model generates networks with this nontrivial property. Here we propose a grand-canonical class of models reproducing the observed patterns of reciprocity by regarding single and double links as Fermi particles of different "chemical species" governed by the corresponding chemical potentials. Within this framework we find interesting special cases such as the extensions of random graphs, the configuration model, and hidden-variable models. Our theoretical predictions are also in excellent agreement with the empirical results for networks with well-studied reciprocity.

Journal Article↗
PubMed2001

Similarity in perception: a window to brain organization.

This paper presents a neural model of similarity perception in identification tasks. It is based on self-organizing maps and population coding and is examined through five different identification experiments. Simulating an identification task, the neural model generates a confusion matrix that can be compared directly with that of human subjects. The model achieves a fairly accurate match with the pertaining experimental data both during training and thereafter. To achieve this fit, we find that the entire activity in the network should decline while learning the identification task, and that the population encoding of the specific stimuli should become sparse as the network organizes. Our results, thus, suggest that a self-organizing neural model employing population coding can account for identification processing while suggesting computational constraints on the underlying cortical networks.

Brain↗
PubMed2001

Estimating probability of non-response to treatment using mixture distributions.

Repeat measurements of patient characteristics are often used to assess response to treatment. In this paper we discuss a normal mixture model for the observed change in the characteristic of interest in treated patients. The methods described can be used to estimate the overall proportion of non-response to treatment and also the probability that a patient has not responded to treatment given his or her observed change. The model parameters are estimated using maximum likelihood, and the delta method is used to construct a pointwise confidence band for the conditional probability that a patient is a non-responder to treatment. The work was initially motivated by analysis issues in the Fracture Intervention Trial (FIT), a randomized trial of the osteoporosis drug alendronate, and the method is illustrated with data from that study. We also evaluate key aspects of the estimation procedure with two simulation studies. In the first, the data generation model is the assumed normal mixture model, and in the second, the data are generated according to a shifted and scaled central t-distribution model suggested by the FIT data.

Aged↗
PubMed1989

The generation of socioeconomic surfaces for public policymaking.

The development is explained of a technique to generate 'modeled' surfaces of census-type socioeconomic survey data that offer the potential to overcome many of the problems inherent in the analysis and presentation of such data in conventional area-based form. Potential benefits of the modeled surfaces include a level of resolution that arguably can provide a more finely focused spatial basis for the generation of a wide range of spatial indicators that can aid public policy making. This type of application requires that the method is set within a flexibly managed information framework and includes suitable tests for the reliability of the generated surfaces.

Demography↗
PubMed2004

Transgenic mouse models of Alzheimer's disease: how useful have they been for therapeutic development?

Transgenic mice have been created in an attempt to generate models of human Alzheimer's disease, but success has been partial and unpredictable. The overall aim of this paper is to illustrate how genomics can be used in translational research, turning genetic information in the form of pathogenic mutations into clinically useful drugs against a major human disease. This paper will illustrate how genetic information allows researchers to dissect the aetiology of a disease and then replicate the disease in vivo through the process of transgenesis. The limitations of recreating a condition like Alzheimer's disease in a transgenic mouse, how far the mice have advanced understanding of the disease and how useful they have been for the development of therapeutics will then be discussed.

Alzheimer Disease↗
PubMed2002

Prediction of aqueous solubility of organic compounds using a quantitative structure-property relationship.

A quantitative structure-property relationship (QSPR) was developed for predicting the aqueous solubility of drug-like compounds from their chemical structures. A set of 321 structurally diverse drugs or related compounds, with their intrinsic aqueous solubility collected from literature, was used in this analysis. The data were divided into a training set (n = 267) for building the model and a randomly chosen testing set (n = 54) for assessing the predictive ability of the model. A series of molecular descriptors was calculated directly from chemical structures and a set of eight descriptors, including dipole moment, surface area, volume, molecular weight, number of rotatable bonds/total bonds, number of hydrogen-bond acceptors, number of hydrogen-bond donors and density, was chosen for the final model. The eight-descriptor model generated by multiple linear regression was further optimized by a genetic algorithm guided selection method. The model has a correlation coefficient (r) of 0.95 and a root-mean-square (rms) error of 0.56 log unit. It predicts the solubility of testing set compounds with a reasonable degree of accuracy (r = 0.84 and rms = 0.86 log unit). The present model can serve as a tool for medicinal chemists to guide their early synthetic efforts in arriving at appropriate analogs.

Algorithms↗
PubMed1996

Extended glycoprotein structure of the seven domains in human carcinoembryonic antigen by X-ray and neutron solution scattering and an automated curve fitting procedure: implications for cellular adhesion.

Carcinoembryonic antigen (CEA) is one of the most widely used cell-surface tumour markers for tumour monitoring and for targeting by antibodies. It is heavily glycosylated (50% carbohydrate) and a monomer is constructed from one V-type and six C2-type fold domains of the immunoglobulin superfamily. The solution arrangement at low resolution of the seven domains in CEA cleaved from its membrane anchor was determined by X-ray and neutron scattering. Guinier analyses showed that the X-ray radius of gyration RG of CEA was 8.0 nm. The length of CEA was 27 to 33 nm, and is consistent with an extended arrangement of seven domains. The X-ray cross-sectional radius of gyration RXS was 2.1 nm, and is consistent with extended carbohydrate structures in CEA. The neutron data gave CEA a relative molecular mass of 150,000, in agreement with a value of 152,500 from composition data, and validated the X-ray analyses. The CEA scattering curves were analysed using an automated computer modelling procedure based on the crystal structure of CD2. The V-type and C2-type domains in CD2 were separated, and the C2-type domain was duplicated five times to create a linear seven-domain starting model for CEA. A total of 28 complex-type oligosaccharide chains in extended conformations were added to this model. By fixing the six interdomain orientations to be the same, three-parameter searches of the rotational orientations between the seven domains gave 4056 possible CEA models. The best curve fits from these corresponded to a family of zig-zag models. The long axis of each domain was set at 160(+/-25) degrees relative to its neighbour, and the two perpendicular axes were orientated at 10(+/-30) degrees and -5(+/-35) degrees. Interestingly, the curve fit from this model is within error of that calculated from a CEA model generated directly from the CD2 crystal structure by the superposition of adjacent domains. Zig-zag models of this type imply that the protein face of the GFCC' beta-sheet in neighbouring CEA domains lie on alternate sides of the CEA structure. Such a model has implications for the adhesion interactions between CEA molecules on adjacent cells or for the antibody targeting of CEA.

Amino Acid Sequence↗
PubMed1990

The impact of taxation on the distribution of wealth in an economy with changing population.

The authors examine the determinants of the personal distribution of income and wealth using an overlapping generations model in which all individuals are assumed to be identical except for their inherited wealth. "It is shown that, in general, higher tax rates reduce distributive inequality as long as the rate of interest is exogenously given. In steady state, however, where the rate of interest is determined endogenously, increasing taxation and higher social security payments both diminish the capital labor ratio so that the rate of interest rises. If this interest effect is strong enough then it may outbalance the tendency toward more equality because higher interest rates enhance initial differences in the distribution of both income and wealth and, eventually, the inequality in the distribution of income and wealth in the society." The geographical focus is on developed countries.

Developed Countries↗
PubMed2006

Three-dimensional recording of the human face with a 3D laser scanner.

Three-dimensional recording of the surface of the human body or of certain anatomical areas has gained an ever increasing importance in recent years. When recording living surfaces, such as the human face, not only has a varying degree of surface complexity to be accounted for, but also a variety of other factors, such as motion artefacts. It is of importance to establish standards for the recording procedure, which will optimise results and allow for better comparison and validation. In the study presented here, the faces of five male test persons were scanned in different experimental settings using non-contact 3D digitisers, type Minolta Vivid 910). Among others, the influence of the number of scanners used, the angle of recording, the head position of the test person, the impact of the examiner and of examination time on accuracy and precision of the virtual face models generated from the scanner data with specialised software were investigated. Computed data derived from the virtual models were compared to corresponding reference measurements carried out manually between defined landmarks on the test persons' faces. We describe experimental conditions that were of benefit in optimising the quality of scanner recording and the reliability of three-dimensional surface imaging. However, almost 50% of distances between landmarks derived from the virtual models deviated more than 2mm from the reference of manual measurements on the volunteers' faces.

Adult↗
PubMed2005

Bifurcations in a mathematical model for circadian oscillations of clock genes.

Circadian oscillations with a period of about 24h are observed in nearly all living organisms as conspicuous biological rhythms. In this paper, we investigate various kinds of bifurcation phenomena produced in a circadian oscillator model of Drosophila. In Drosophila, it is known that circadian oscillations in the levels of two proteins, PER and TIM, result from the negative feedback exerted by a PER-TIM complex on the expression of the per and tim genes that code for the two proteins. For studying circadian oscillations of proteins in Drosophila, a mathematical model has been proposed. The model cannot only account for regular circadian oscillations in environmental conditions such as constant darkness, but also give rise to more complex oscillatory phenomena including chaos and birhythmicity. By calculating bifurcations using Kawakami's method, we obtain detailed bifurcation diagrams related to stable and unstable invariant sets, and identify parameter regions in which the model generates complex oscillations as well as regular circadian oscillations. Moreover, we study bifurcations observed in the model incorporating the effect on a light-dark (LD) cycle and show that the waveform of the periodic variation in the light-induced parameter has a marked influence on the global bifurcation structure or the type of dynamic behavior resulting from the forcing term of the circadian oscillator by the LD cycles.

Animals↗
PubMed2006

Validation of the exposure assessment for veterinary medicinal products.

Under the EU Directive 2004/28/EC, an environmental risk assessment of new veterinary medicinal products is required. Given the nature of risk assessment for new applications, there is a need to model exposure concentrations. Critical evaluations are essential to ensure that the use of models by regulators does not result in the propagation of misleading information. The empirical validations of soil exposure models, previously discussed in this journal, indicate that it is impossible to analyse the contribution of every model parameter to the variability in the predictions. In particular, the prediction of the slurry concentration is challenged by uncertainties concerning dilution, mixing and dissipation of residues. Surface water and groundwater models generated highly deviating results compared to the field results, questioning the usefulness of the available screening models. Animal husbandry, slurry handling and environmental conditions throughout Europe are considered in order to define realistic worst case scenarios, to be used in conjunction with distribution models for the environmental risk assessment of veterinary medicinal products at registration. Given the variability in manure management practice throughout Europe, a deterministic approach for the manure-to-soil model was selected. Both worst case and best case scenario were developed. Several modelling assumptions applied in the surface water exposure model for fish nursery effluent were validated against newly available data. Since the available data give no proof that a settling tank contributes to the removal of pesticides from waste water, it is recommended for risk assessment purposes to consider the contribution of the settling tank to removal of pesticides and medicines to be negligible. Surface water dilution factors may be considered to be rather small, a factor of 2, for low flow situations.

Animal Husbandry↗
PubMed1998

Identification of a model cardiac glycoside receptor: comparisons with Na+,K+-ATPase.

The availability of high-affinity anti-digoxin monoclonal antibodies (mAbs) offers the potential for their use as models for the characterization of the relationship between receptor structure and cardiac glycoside binding. We have characterized the binding of anthroylouabain (AO), a fluorescent derivative of the cardiac glycoside ouabain, to mAbs 26-10, 45-20, and 40-50 [Mudgett-Hunter, M., et al. (1995) Mol. Immunol. 22, 477] and lamb kidney Na+, K+-ATPase by monitoring the resultant AO fluorescence emission spectra, anisotropy, lifetime values, and Förster resonance energy transfer (FRET) from protein tryptophan(s) (Trp) to AO. These data suggest that the structural environment in the vicinity of the AO-binding site of Na+,K+-ATPase is similar to that of mAb 26-10 but not mAbs 45-20 and 40-50. A model of AO complexed to the antigen binding fragment (Fab) of mAb 26-10 which was generated using known X-ray crystal structural data [Jeffrey, P. D., et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 10310] shows a heavy chain Trp residue (Trp-H100) that is close ( approximately 3 A) to the anthroyl moiety. This is consistent with the energy transfer seen upon AO binding to mAb 26-10 and suggests that Trp-H100, which is part of the antibody's cardiac glycoside binding site, is a major determinant of the fluorescence properties of bound AO. In contrast, the generated model of AO complexed to Fab 40-50 [Jeffrey, P. D., et al. (1995) J. Mol. Biol. 248, 344] shows a heavy chain Tyr residue (Tyr-H100) which is part of the cardiac glycoside binding site, located approximately 10 A from the anthroyl moiety. The closest Trp residues (H52 and L35) are located approximately 17 A from the anthroyl moiety, and no FRET is observed despite the fact that these Trp residues are close enough for significant FRET to occur. The energy transfer seen upon AO binding to Na+,K+-ATPase suggests the presence of one completely quenched or two highly quenched enzyme Trp residues approximately 10 and approximately 17 A, respectively, from the anthroyl moiety. These data suggest that the Na+,K+-ATPase Trp residue(s) involved in fluorescence energy transfer to AO is likely to be part of the cardiac glycoside binding site.

Animals↗
PubMedDate not supplied

Determining the validity of a QSAR model--a classification approach.

The determination of the validity of a QSAR model when applied to new compounds is an important concern in the field of QSAR and QSPR modeling. Various scoring techniques can be applied to specific types of models. We present a technique with which we can state whether a new compound will be well predicted by a previously built QSAR model. In this study we focus on linear regression models only, though the technique is general and could also be applied to other types of quantitative models. Our technique is based on a classification method that divides regression residuals from a previously generated model into a good class and bad class and then builds a classifier based on this division. The trained classifier is then used to determine the class of the residual for a new compound. We investigated the performance of a variety of classifiers, both linear and nonlinear. The technique was tested on two data sets from the literature and a hand built data set. The data sets selected covered both physical and biological properties and also presented the methodology with quantitative regression models of varying quality. The results indicate that this technique can determine whether a new compound will be well or poorly predicted with weighted success rates ranging from 73% to 94% for the best classifier.

Algorithms↗
PubMed2005

Testing prediction capabilities of an 131I terrestrial transport model by using measurements collected at the Hanford nuclear facility.

A model describing transport of 131I in the environment was developed by SENES Oak Ridge, Inc., for assessment of radiation doses and excess lifetime risk from 131I atmospheric releases from Oak Ridge Reservation in Oak Ridge, Tennessee, and from Idaho National Engineering and Environmental Laboratory in southeast Idaho. This paper describes the results of an exercise designed to test the reliability of this model and to identify the main sources of uncertainty in doses and risks estimated by this model. The testing of the model was based on materials published by the International Atomic Energy Agency BIOMASS program, specifically environmental data collected after the release into atmosphere of 63 curies of 131I during 2-5 September 1963, after an accident at the Hanford PUREX Chemical Separations Plant, in Hanford, Washington. Measurements of activity in air, vegetation, and milk were collected in nine counties around Hanford during the first couple of months after the accident. The activity of 131I in the thyroid glands of two children was measured 47 d after the accident. The model developed by SENES Oak Ridge, Inc., was used to estimate concentrations of 131I in environmental media, thyroid doses for the general population, and the activity of 131I in thyroid glands of the two children. Predicted concentrations of 131I in pasture grass and milk and thyroid doses were compared with similar estimates produced by other modelers. The SENES model was also used to estimate excess lifetime risk of thyroid cancer due to the September 1963 releases of 131I from Hanford. The SENES model was first calibrated and then applied to all locations of interest around Hanford without fitting the model parameters to a given location. Predictions showed that the SENES model reproduces satisfactorily the time-dependent and the time-integrated measured concentrations in vegetation and milk, and provides reliable estimates of 131I activity in thyroids of children. SENES model generated concentrations of 131I closer to observed concentrations, as compared to the predictions produced with other models. The inter-model comparison showed that variation of thyroid doses among all participating models (SENES model included) was a factor of 3 for the general population, but a factor of 10 for the two studied children. As opposed to other models, SENES model allows a complete analysis of uncertainties in every predicted quantity, including estimated thyroid doses and risk of thyroid cancer. The uncertainties in the risk-per-unit-dose and the dose-per-unit-intake coefficients are major contributors to the uncertainty in the estimated lifetime risk and thyroid dose, respectively. The largest contributors to the uncertainty in the estimated concentration in milk are the feed-to-milk transfer factor (F(m)), the dry deposition velocity (V(d)), and the mass interception factor (r/Y)dry for the elemental form of iodine (I2). Exposure to the 1963 PUREX/Hanford accident produced low doses and risks for people living at the studied locations. The upper 97.5th percentile of the excess lifetime risk of thyroid cancer for the most extreme situations is about 10(-4). Measurements in pasture grass and milk at all locations around Hanford indicate a very low transfer of 131I from pasture to cow's milk (e.g., a feed-to-milk transfer coefficient, F(m), for commercial cows of about 0.0022 d L(-1)). These values are towards the low end of F(m) values measured elsewhere and they are low compared to the F(m) values used in other dose reconstruction studies, including the Hanford Environmental Dose Reconstruction.

Adolescent↗
PubMed1997

A dynamic model of ventricular interaction and pericardial influence.

A mathematical model describing the dynamic interaction between the left and the right ventricle over the complete cardiac cycle is presented. The pericardium-bound left and right ventricles are represented as two coupled chambers consisting of the left and right free walls and the interventricular septum. Time-varying pressure-volume relationships characterize the component compliances, and the interaction of these components produces the globally observed ventricular pump properties (total chamber pressure and volume). The model 1) permits the simulation of passive (diastolic) and active (systolic) ventricular interaction, 2) provides temporal profiles of hemodynamic variables (e.g., ventricular pressures, volumes, and flow) that agree well with reported observations, and 3) can be used to examine the effect of the pericardium on ventricular interaction and ventricular mechanics. It can be reduced to equivalency with models previously reported by invoking simplifying assumptions. Furthermore, model-generated "dynamic interaction gains" are employed to quantify the mode and degree of ventricular interaction. The model also yields qualitative predictions of septal and free wall displacements similar to those detected experimentally via M-mode echocardiography. Such analogies may be extended easily to the study of pathophysiological states via appropriate modifications to 1) the pressure-volume characteristics of the component walls (and/or pericardium) and/or 2) the specific time course of activation of the ventricular free wall or the septum. A limited number of examples are included to demonstrate the utility of the model, which may be used as an adjunct to new experimental investigations into ventricular interaction.

Blood Volume↗