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At least 1,063 records · Page 59Linked to original sources
PubMed1998

Identification and determination of material properties for porohyperelastic analysis of large arteries.

A "porohyperelastic" (PHE) material model is described and the theoretical framework presented that allows identification of the necessary material properties functions for soft arterial tissues. A generalized Fung form is proposed for the PHE constitutive law in which the two fundamental Lagrangian material properties are the effective strain energy density function, W(e), and the hydraulic permeability, kij. The PHE model is based on isotropic forms using W(e) = Ue (phi) = 1/2C0(e phi - 1) and the radial component of permeability, kRR = kRR(phi), with phi = C1'(I1 - 3) + C2'(I2 - 3) + K'(J - 1)2. The methods for determination of these material properties are illustrated using experimental data from in situ rabbit aortas. Three experiments are described to determine parameters in Ue and kRR for the intima and media of the aortas, i.e., (1) undrained tests to determine C0, C1', and C2'; (2) drained tests to determine K'; and (3) steady-state pressurization tests of intact and de-endothelialized vessels to determine intimal and medial permeability (adventitia removed in these models). Data-reduction procedures are presented that allow determination of kRR for the intima and media and Ue for the media using experimental data. The effectiveness and accuracy of these procedures are studied using input "data" from finite element models generated with the ABAQUS program. The isotropic theory and data-reduction methods give good approximations for the PHE properties of in situ aortas. These methods can be extended to include arterial tissue remodeling and anisotropic behavior when appropriate experimental data are available.

Animals↗
PubMed2003

Protein-protein docking with simultaneous optimization of rigid-body displacement and side-chain conformations.

Protein-protein docking algorithms provide a means to elucidate structural details for presently unknown complexes. Here, we present and evaluate a new method to predict protein-protein complexes from the coordinates of the unbound monomer components. The method employs a low-resolution, rigid-body, Monte Carlo search followed by simultaneous optimization of backbone displacement and side-chain conformations using Monte Carlo minimization. Up to 10(5) independent simulations are carried out, and the resulting "decoys" are ranked using an energy function dominated by van der Waals interactions, an implicit solvation model, and an orientation-dependent hydrogen bonding potential. Top-ranking decoys are clustered to select the final predictions. Small-perturbation studies reveal the formation of binding funnels in 42 of 54 cases using coordinates derived from the bound complexes and in 32 of 54 cases using independently determined coordinates of one or both monomers. Experimental binding affinities correlate with the calculated score function and explain the predictive success or failure of many targets. Global searches using one or both unbound components predict at least 25% of the native residue-residue contacts in 28 of the 32 cases where binding funnels exist. The results suggest that the method may soon be useful for generating models of biologically important complexes from the structures of the isolated components, but they also highlight the challenges that must be met to achieve consistent and accurate prediction of protein-protein interactions.

Algorithms↗
PubMed1980

Influence of cholecalciferol on tissue zinc homeostasis in the rat.

A role for calciferol in zinc homeostasis was investigated by radioisotope uptake and compartmental analysis techniques. cholecalciferol was injected into rats 4-5 days prior to radioisotopic study of rapidly exchangeable pools (< 4 h). Kidney, liver, and duodenum had significant increases in zinc uptake rates. Bone and skeletal muscle had significant decreases. No other tissues had significant differences. Compartmental analysis models generated by the SAAM-25 digital computer program suggested a decrease in the fractional tissue to plasma coefficient to be the mechanism for the observed changes in the serum zinc concentration and tissue zinc accumulation rates. It is not clear whether this is a specific effect of calciferol on zinc homeostasis or is a nonspecific response which may reflect some role for zinc in calciferol metabolism.

Animals↗
PubMed2006

Modeling the ligand-receptor interaction for a series of inhibitors of the capsid protein of enterovirus 71 using several three-dimensional quantitative structure-activity relationship techniques.

The structure of enterovirus 71 (EV71) capsid protein VP1 has been constructed by using homology modeling and molecular dynamics simulation techniques. The ligand structures were a series of EV71 VP1 inhibitors synthesized by Shia et al. in 2002 and Chern et al. in 2004. The training set was selected by the VOLSURF4.1/PCA program and the IC50 values varied from 0.06 to 10.83 microm. Then, the training set was analyzed by the following three-dimensional quantitative structure-activity relationship techniques: CoMFA, CoMSIA, CATALYST4.9, and VOLSURF4.1/PCA. The model generated by a two-stage flexible docking procedure and without any structural alignment has far more significant statistics. Highly accurate activities for the test sets were then predicted by the top hypothesis of the CATALYST program and were compared with those predicted by CoMFA, CoMSIA, and VOLSURF. These studies identified some important clues for searching or making more potent inhibitors against the EV71 infection.

Binding Sites↗
PubMed1998

Characterization of the dose-dependent time of peak effect in indirect response models.

The general conceptual model for non-steady state pharmacokinetic/pharmacodynamic data includes a distribution phase between the plasma and the biophase compartments, which can be expressed by a link model, and inhibition or stimulation of the production or removal of a mediator, which can be expressed by an indirect response model. The inhibition or the stimulation step modeled by an indirect response model generates dose-dependent time of peak effect. This report provides a mathematical expression for this time of peak effect which is then used to determine how this time depends on dose, the endogenous elimination rate of the mediator, and the pharmacokinetic parameters of the drug. The report then uses this time of peak effect to find the response versus time curve. The mathematical relationship for the time of peak effect and the response vs. time curve are then developed for a cascade of two indirect steps. The approach presented here is easily implemented on a spreadsheet and does not require numerically solving nonlinear differential equations. The approach should help to analyze various issues related to fitting indirect response models to non-steady state pharmacokinetic/pharmacodynamic data, especially, when one is trying to fit data to a cascade of indirect steps.

Humans↗
PubMed1991

Modeling symbiotic performance of introduced rhizobia in the field by use of indices of indigenous population size and nitrogen status of the soil.

The ability to predict the symbiotic performance of rhizobia introduced into different environments would allow for a more judicious use of rhizobial inoculants. Data from eight standardized field inoculation trials were used to develop models that could be used to predict the success of rhizobial inoculation in diverse environments based on indices of the size of indigenous rhizobial populations and the availability of mineral N. Inoculation trials were conducted at five diverse sites on the island of Maui, Hawaii, with two to four legumes from among nine species, yielding 29 legume-site observations. The sizes of indigenous rhizobial populations were determined at planting. Soil N mineralization potential, total soil N, N accumulation and seed yield of nonnodulating soybean, and N derived from N(2) fixation in inoculated soybean served as indices of available soil N. Uninoculated, inoculated, and fertilizer N treatments evaluated the impact of indigenous rhizobial populations and soil N availability on inoculation response and crop yield potential. The ability of several mathematical models to describe the inverse relationship between numbers of indigenous rhizobia and legume inoculation responses was evaluated. Power, exponential, and hyperbolic functions yielded similar results; however, the hyperbolic equation provided the best fit of observed to estimated inoculation responses (r = 0.59). The fact that 59% of the observed variation in inoculation responses could be accounted for by the relationship of inoculation responses to numbers of indigenous rhizobia illustrates the profound influence that the size of soil rhizobial populations has on the successful use of rhizobial inoculants. In the absence of indigenous rhizobia, the inoculation response was directly proportional to the availability of mineral N. Therefore, the hyperbolic response function was subsequently combined with several indices of soil N availability to generate models for predicting legume inoculation response. Among the models developed, those using either soil N mineralization potential or N derived from N(2) fixation in soybean to express the availability of mineral N were most useful in predicting the success of legume inoculation. Correlation coefficients between observed and estimated inoculation responses were r = 0.83 for the model incorporating soil N mineralization potential and r = 0.96 for the model incorporating N derived from N(2) fixation. Several equations collectively termed "soil N deficit factors" were also found to be useful in estimating inoculation responses. In general, models using postharvest indices of soil N were better estimators of observed inoculation responses than were those using laboratory measures of soil N availability. However, the latter, while providing less precise estimates, are more versatile because all input variables can be obtained through soil analysis prior to planting. These models should provide researchers, as well as regional planners, with a more precise predictive capability to determine the inoculation requirements of legumes grown in diverse environments.

Journal Article↗
PubMed1988

A model of encounters between host and parasite populations.

A simulation model of the encounter between host and parasite populations is described. The model is two-dimensional in that it represents hosts and parasites as sums of random numbers. It allows for the manipulation of host and parasite numbers, areas of interaction, congruity of geographic ranges, parasite infectivity, and reproduction, or non-reproduction, of the parasite. The model generates parasite distributions (number of hosts vs. parasite/host classes) and their parameters (prevalence, mean number of parasites/host, variance/mean ratio as a measure of aggregation), and thus reveals the manner in which these parameters vary under different encounter conditions, i.e. their "behavior". Simulation results indicated that the behavior of parasite population mean, prevalence, and degree of aggregation was primarily a function of the rate at which infective stages were supplied to the system. In cases in which infective stages were continuously available, prevalence rose rapidly to nearly 100%, with increasing infectivity and parasite numbers, and the populations were not particularly aggregated. When infective stages were introduced in single large waves, both mean and prevalence remained low and the parasite populations were highly aggregated. Model results were compared with published data sets. The latter were also seen to fall into the two general categories of parameter behavior.

Animals↗
PubMed1991

Structure of flagellar microtubules.

There is a widely perceived and growing need for a reliable high-resolution three-dimensional structural model of MT. One contributor to this need has been the enormous burst of new information from molecular biological manipulations of tubulin primary sequence and pattern of expression in cells. A second contributor has been the astounding progress in defining the MT-dynein motors of cytoplasmic motility. To interpret this new information in terms of MT assembly and function, we simply must have the structure of tubulin to atomic resolution and know the arrangement of tubulin in MT to an accuracy of better than 1 nm. The best experimental system for understanding the structural basis of MT-dependent motility is the eukaryotic flagellum. Therefore, the MT whose structure we need to know first is the flagellar doublet MT. The most generally accepted specific model for flagellar MT structure was proposed by Amos and Klug in 1974. The impact of their model has been enormous. It has provided the structural framework for thinking about MT function and has influenced the interpretation of a vast body of experimental observation over the intervening 15 years. As a first approximation to the structure of the native MT, in flagellar doublets and cytoplasmic singlets, it has served superbly. Now, we face an accumulation of new information on the nature of the intersubunit bond gleaned from assembly reactions of tubulin, on the nature and probable structure of nontubulin components of flagellar MT, and on the appearance of MT in their native hydrated state. We are compelled by this new evidence to look for the next approximation to the three-dimensional structure of the flagellar doublet MT. This second generation model is not yet formulated in sufficient detail to serve as a replacement for the Amos and Klug model. What we can say at this point is that the new model will be much more complex than the old one, having only axial periodicity in both A and B subfibers rather than full helical symmetry. The model must include at least one tektin filament at the medial (in the flagellum) A-B junction, and perhaps another in a location yet to be determined. It may also include other nontubulin components. The axial period of the MT itself, free of attached cross-bridging structure from the flagellum, must be at least 32.8 nm.(ABSTRACT TRUNCATED AT 400 WORDS)

Flagella↗
PubMed2005

Analysis of peptide-protein binding using amino acid descriptors: prediction and experimental verification for human histocompatibility complex HLA-A0201.

Amino acid descriptors are often used in quantitative structure-activity relationship (QSAR) analysis of proteins and peptides. In the present study, descriptors were used to characterize peptides binding to the human MHC allele HLA-A0201. Two sets of amino acid descriptors were chosen: 93 descriptors taken from the amino acid descriptor database AAindex and the z descriptors defined by Wold and Sandberg. Variable selection techniques (SIMCA, genetic algorithm, and GOLPE) were applied to remove redundant descriptors. Our results indicate that QSAR models generated using five z descriptors had the highest predictivity and explained variance (q2 between 0.6 and 0.7 and r2 between 0.6 and 0.9). Further to the QSAR analysis, 15 peptides were synthesized and tested using a T2 stabilization assay. All peptides bound to HLA-A0201 well, and four peptides were identified as high-affinity binders.

Algorithms↗
PubMed2005

An anatomically constrained, stochastic model of eye movement control in reading.

This article presents SERIF, a new model of eye movement control in reading that integrates an established stochastic model of saccade latencies (LATER; R. H. S. Carpenter, 1981) with a fundamental anatomical constraint on reading: the vertically split fovea and the initial projection of information in either visual field to the contralateral hemisphere. The novel features of the model are its simulation of saccade latencies as a race between two stochastic rise-to-threshold LATER units and its probabilistic selection of the target for the next saccade. The model generates simulated eye movement behavior that exhibits important characteristics of actual eye movements made during reading; specifically, simulations produce realistic saccade target distributions and replicate a number of critical reading phenomena, including the effects of word frequency on fixation durations, the inverted optimal viewing position effect, the trade-off between first and second fixation durations of refixated words, and the dependence of parafoveal preview benefit on eccentricity.

Eye Movements↗
PubMed2005

Pharmacophore modeling, docking, and principal component analysis based clustering: combined computer-assisted approaches to identify new inhibitors of the human rhinovirus coat protein.

The development and application of a sophisticated virtual screening and selection protocol to identify potential, novel inhibitors of the human rhinovirus coat protein employing various computer-assisted strategies are described. A large commercially available database of compounds was screened using a highly selective, structure-based pharmacophore model generated with the program Catalyst. A docking study and a principal component analysis were carried out within the software package Cerius and served to validate and further refine the obtained results. These combined efforts led to the selection of six candidate structures, for which in vitro anti-rhinoviral activity could be shown in a biological assay.

Antiviral Agents↗
PubMed1997

Extracting protein alignment models from the sequence database.

Biologists often gain structural and functional insights into a protein sequence by constructing a multiple alignment model of the family. Here a program called Probe fully automates this process of model construction starting from a single sequence. Central to this program is a powerful new method to locate and align only those, often subtly, conserved patterns essential to the family as a whole. When applied to randomly chosen proteins, Probe found on average about four times as many relationships as a pairwise search and yielded many new discoveries. These include: an obscure subfamily of globins in the roundworm Caenorhabditis elegans ; two new superfamilies of metallohydrolases; a lipoyl/biotin swinging arm domain in bacterial membrane fusion proteins; and a DH domain in the yeast Bud3 and Fus2 proteins. By identifying distant relationships and merging families into superfamilies in this way, this analysis further confirms the notion that proteins evolved from relatively few ancient sequences. Moreover, this method automatically generates models of these ancient conserved regions for rapid and sensitive screening of sequences.

Algorithms↗
PubMed2005

Development of a new mouse model (xeroderma pigmentosum a-deficient, stem cell factor-transgenic) of ultraviolet B-induced melanoma.

It is well established that exposure to sunlight or ultraviolet radiation (UVR) is the major environmental risk factor for the development of skin neoplasms. To date, however, there have been few appropriate mouse models available for studying the role of UVR in melanoma carcinogenesis, mainly because of the murine lack of the epidermal melanocyte, which is a major source of origin of human melanoma. In this study, we established xeroderma pigmentosum group A gene-deficient, stem cell factor-transgenic mice, which are defective in the repair of damaged DNA and do have epidermal melanocytes. The mice were exposed to UVR three times a week for 10 wk. More than 30% of the irradiated mice developed tumors of melanocyte origin that metastasized to the lymph nodes. Histologically, proliferated cells exhibited lentigo maligna melanoma or nodular melanoma. Immunohistochemistry confirmed that the tumor cells were characteristic of melanoma. Non-irradiated mice did not develop skin tumors spontaneously. The newly generated model mouse might be useful for studying the photobiological aspects of human melanoma, because the mice developed melanoma from epidermal melanocytes only after UVR exposures.

Animals↗
PubMed1990

A critical review of the use of Rogers' model within a special hospital: a single case study.

This case study presents a problematic patient who has been resident in a special hospital for mentally handicapped people for years due to a gross sexual fantasy disorder, continuous self-injurious behaviour and an array of disordered conducts which resulted in negative nursing reports. The introduction of Rogers' model, with its abstract finer conceptualizations produced an alternative framework by which to assess the patient. This holistic interactive model generated a paradigmatic shift in the nursing perceptions, at a conceptual level, which was manifested in their reporting behaviours. The results appeared to indicate a sudden and dramatic change in the patient's behaviour. However, alternative interpretations proved the more convincing on closer analysis. The use of Rogers' framework proved difficult in its practical application due to its underpinning requirements for role adoption and negotiation, both being problematic in a secure environment.

Adult↗
PubMed2001

Fluorosulfonyl- and bis-(beta-chloroethyl)amino-phenylamino functionalized pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine derivatives: irreversible antagonists at the human A3 adenosine receptor and molecular modeling studies.

A series of pyrazolotriazolopyrimidines was previously reported to be highly potent and selective human A(3) adenosine receptor antagonists (Baraldi et al. J. Med. Chem. 2000, 43, 4768-4780). A derivative having a methyl group at the N(8) pyrazole combined with a 4-methoxyphenylcarbamoyl moiety at N(5) position, displayed a K(i) value at the hA(3) receptor of 0.2 nM. We now describe chemically reactive derivatives which act as irreversible inhibitors of this receptor. Electrophilic groups, specifically sulfonyl fluoride and nitrogen mustard (bis-(beta-chloroethyl)amino) moieties, have been incorporated at the 4-position of the aryl urea group. Membranes containing the recombinant hA(3) receptor were preincubated with the compounds and washed exhaustively. The loss of ability to bind radioligand following this treatment indicated irreversible binding. The most potent compound in irreversibly binding to the receptor was 14, which contained a sulfonyl fluoride moiety and a propyl group at the N(8) pyrazole nitrogen. The bis-(beta-chloroethyl)amino derivatives displayed a much smaller degree of irreversible binding than the sulfonyl fluoride derivatives. A computer-generated model of the human A(3) receptor was built and analyzed to help interpret these results. The model of the A(3) transmembrane region was derived using primary sequence comparison, secondary structure predictions, and three-dimensional homology building, using the recently published crystal structure of rhodopsin as a template. According to our model, sulfonyl fluoride derivatives could dock within the hypothetical TM binding domain, adopting two different energetically favorable conformations. We have identified two amino acids, Ser247 and Cys251, both in TM6, as potential nucleophilic partners of the irreversible binding to the receptor.

Aniline Compounds↗
PubMed2005

Agonist-induced conformational changes in thyrotropin-releasing hormone receptor type I: disulfide cross-linking and molecular modeling approaches.

The conformational changes at the cytoplasmic ends of transmembrane helices 5 and 6 (TMH5 and TMH6) of thyrotropin-releasing hormone (TRH) receptor type I (TRH-R1) during activation were analyzed by cysteine-scanning mutagenesis followed by disulfide cross-linking and molecular modeling. Sixteen double cysteine mutants were constructed by substitution of one residue at the cytoplasmic end of TMH5 and the other at that of TMH6. The cross-linking experiments indicate that four mutants, Q263C/G212C, Q263C/Y211C, T265C/G212C, and T265C/Y211C, exhibited disulfide bond formation that was sensitive to TRH occupancy. We refined our previous TRH-R1 models by embedding them into a hydrated explicit lipid bilayer. Molecular dynamics simulations of the models, as well as in silico double cysteine models, generated trajectories that were in agreement with experimental results. Our findings suggest that TRH binding induces a separation of the cytoplasmic ends of TMH5 and TMH6 and a rotation of TMH6. These changes likely increase the surface accessible area at the juxtamembrane region of intracellular loop 3 that could promote interactions between G proteins and key residues within the receptor.

Amino Acid Sequence↗
PubMed1999

Three-dimensional pharmacophore hypotheses for the locust neuronal octopamine receptor (OAR3). Part 2: agonists.

Three-dimensional pharmacophore hypotheses were built from a set of 43 agonists against octopamine receptor class 3 (OAR3) in locust nervous tissue. Among the 10 chemical-featured models generated by program Catalyst/Hypo, a hypothesis including hydrogen-bond acceptor (HBA), hydrophobic (Hp), and hydrophobic aliphatic (HpA1) features was considered to be important and predictive in evaluating OAR3 agonists. While the ideal and null hypotheses had a cost of 156.40 and 239.20, respectively, the 10 resulting hypotheses possessed costs from 169.89 to 175.81. The best hypothesis that was confirmed to have a 95% chance of true correlation yielded a low RMS of 0.757 and high regression r of 0.933. Active agonists mapped well onto all the features of the hypothesis such as HBA, Hp, and HpA1. On the other hand, inactive compounds were shown to be difficult to achieve the energetically favorable conformation which is found in the active molecules in order to fit the 3-D chemical feature pharmacophore models.

Animals↗
PubMed1998

Dose-dependence and repeated-dose studies for receptor/gene-mediated pharmacodynamics of methylprednisolone on glucocorticoid receptor down-regulation and tyrosine aminotransferase induction in rat liver.

Dose-dependent and repeated-dose effects of methylprednisolone (MPL) on down-regulation of glucocorticoid receptor messenger RNA (GR mRNA) and GR density, as well as tyrosine aminotransferase (TAT) mRNA and TAT induction by receptor/gene-mediated mechanisms in rat liver were examined. A previously developed pharmacokinetic/pharmacodynamic (PK/PD) model was used to design these studies which sought to challenge the model. Three groups of male adrenalectomized Wistar rats received MPL by i.v. injection: low-dose (10 mg/kg at Time 0), high-dose (50 mg/kg at Time 0), and dual-dose (50 mg/kg at Time 0 and 24 hr). Plasma concentrations of MPL, and hepatic content of free GR, GR mRNA, TAT mRNA, and TAT activity were determined. The P-Pharm program was applied for population analysis of MPL PK revealing low interindividual variation in CL and Vc values (3-14%). Two indirect response models were applied to test two competing hypotheses for GR mRNA dynamics. Indirect Pharmacodynamic Response Model I (Model A) where the complex in the nucleus decreases the transcription rate of GR mRNA better described GR mRNA/GR down-regulation. Levels of TAT mRNA began to increase at 1-2 hr, reached a maximum at 5-6 hr, and declined to the baseline at 12-14 hr after MPL dosing. The induction of TAT activity followed a similar pattern with a delay of about 1-2 hr. The low-dose group had 50-60% of the TAT mRNA and TAT induction compared to the high-dose group. Since the GR density returned to about 70% of the baseline level before the second 50 mg/kg dose at 24 hr, tolerance was found for TAT mRNA/TAT induction where only 50-60% of the initial responses were produced. Our fourth-generation model describes the dose dependence and tolerance effects of TAT mRNA/TAT induction by MPL involving multiple-step signal transduction controlled by the steroid regimen, free GR density, and GR occupancy. This model may provide the foundation for studying other induced proteins or enzymes mediated by the similar receptor/nuclear events.

Animals↗