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PubMed1995

Cyclosporine-induced apoptosis in CD4+ T lymphocytes and computer-simulated analysis: modeling a treatment scenario for HIV infection.

Cyclosporine A (CsA) is a potent immunosuppressive drug which interferes in vitro and in vivo with T-cell function. CsA has been shown to arrest T-cell maturation intrathymically and to inhibit T-cell proliferation. In this study, we demonstrate that CsA induces apoptosis in the canine CD4+ CD8- T-lymphocyte cell line 401 in a dose- and time-dependent fashion. Similar results could also be obtained from human peripheral blood lymphocytes. Apoptosis is observed within 4 hours after CsA application and is not prevented by excessive addition of ConA supernatant as a source of interleukins. The induction of apoptosis in CD4+ T lymphocytes suggests a possible treatment option for human immunodeficiency virus (HIV) infections, since the major target population for the HIV would be ablated at short term. A computer-simulated analysis with the "Cybermouse" HIV model confirmed that the virus would eventually disappear and HIV-infected macrophages would also be substantially reduced if CsA were given in combination with drugs which block viral replication (3'-azido 3'-deoxythymidine or 2',3'-dideoxycytidine). This treatment scenario could be applied under controlled conditions and with supportive patient care. A further review of the literature also suggests the positive impact of CsA treatment on the progression and outcome of AIDS-related mortality.

Animals↗

PubMed1994

Teaching cancer chemotherapy by means of a computer simulation.

BIO-1014 is an educational computer-based program written in TURBO PASCAL 3.01 which simulates experiments of antitumour activity. Basically, this program offers the user the possibility of checking the therapeutical efficiency of anticancer drugs as applied to different tumors, but many other types of experiment can be also performed with BIO-1014. Drugs such as methotrexate, cyclophosphamide and arabinosylcytosine can be tested on the following tumors: sarcoma, carcinoma, leukemia and melanoma. The dose, the number of treatments per day, the total number of treatments and the time interval between the treatments are the parameters to be adjusted for each therapeutical schedule. Tumoral growth, cause of death and survival are among the results that are generated after each simulation. These results are either tabulated or plotted. In addition, four statistical tests have also been integrated to the program in order to provide with a way to check whether or not there is a significant difference in terms of survival between two groups of mice differently treated. Furthermore, the program has been elaborated to also consider some physiological phenomena met within an anticancer drug screening programme. The potential and the performance of the program BIO-1014 is presented and discussed.

Animals↗

PubMed1994

Structural features of the bradykinin receptor as determined by computer simulations, mutagenesis experiments, and conformationally constrained ligands: establishing the framework for the design of new antagonists.

1. In recent years, two classes of second generation bradykinin receptor antagonists have been reported. Both are of the general sequence D-Arg0-Arg1-Pro2-W3-Gly4-X5-Ser6-Y7-Z8+ ++-Arg9, where W is either Pro or Hyp, and X is an aromatic or aliphatic side chain-containing amino acid. Y and Z are unnatural amino acids, presumed to enforce a beta-turn structure. The de novo design of a non-peptide receptor antagonist (or the optimization of a lead discovered by random screening) will ultimately require knowledge about the receptor topology. In the absence of an experimentally determined structure of the bradykinin-bradykinin receptor complex, we have attempted to gain insights from other sources. 2. We have synthesized conformationally constrained ligands and completed extensive computer modeling on the bradykinin receptor. Moreover, using systematic synthetic modifications, we have explored the relative importances of selected amide bonds and side chains in second generation peptides and have made a series of C alpha- and/or N-methyl substitutions at positions four and five which led to the discovery of two new cyclic peptide antagonists. 3. Computational simulations led to a proposed model of bradykinin bound to its receptor which was found to be in good agreement with mutagenesis results. This model led ultimately to the design and synthesis of D-Arg0-Arg1-(12-aminododecanoyl)2-Ser3-D-Tic4-Oic5+ ++-Arg6. Consideration of this new lead compound, together with the extensive structure-activity relationship (SAR) which has been developed for peptide ligands and the receptor, represents a tangible framework for the design of more potent and longer-lasting antagonists of the bradykinin receptor.

Amino Acid Sequence↗

PubMed2002

Stepping out: a computer simulation of hominid dispersal from Africa.

A succession of new discoveries and the recent application of new dating methods provide strong evidence that Eurasia was colonized soon after 2.0m.y.a. In light of this new evidence many scenarios have been proposed regarding the influence of glacial/interglacial cycles on hominid dispersal, the role of mountain chains and deserts as barriers, the significance of land bridges and the possibility of sea-crossings. Such factors have been proposed to explain the apparent early arrival of hominids in East Asia and relatively late arrival in Europe, although the evidence in both regions remains open to various interpretations. While it is relatively easy to propose environmental factors that may have influenced dispersal patterns, it is more difficult to evaluate such proposals and to establish what the combined impact of several factors might have been. Moreover, the role of historical contingency in creating the observed pattern of dispersal has yet to be considered. This paper describes a computer simulation model of hominid dispersal which seeks to provide a means to evaluate environmental and ecological factors in hominid dispersal. It creates probability distributions for arrival dates at six key localities and compares these with current estimates from the archaeological and fossil records. It uses these to support some of the current arguments about dispersal and to challenge others.

Africa↗

PubMed1989

Perceived distributions of the characteristics of in-group and out-group members: empirical evidence and a computer simulation.

This research studied 2 properties of perceived distributions of the characteristics of social category members: the probability of differentiating (making distinctions) among category members and the perceived variability (variance) of category members. The results of 4 experiments supported the hypothesis that greater familiarity with a social group leads to greater perceived differentiation and variability regarding that group. In-group members formed more differentiated and variable distributions for groups defined by age and more differentiated distributions for groups defined by nationality. For gender (where students were roughly equally familiar with people of both genders), no in-group--out-group differences occurred. Also, students perceived greater differentiation and variability among classmates over the course of a semester. To explain these results, we developed PDIST, a multiple exemplar model that assumes that people form perceived distributions by activating a set of category exemplars and then judging the relative likelihoods of different feature values on the basis of the relative activation strengths of these feature values. The results of a computer simulation experiment indicated that PDIST is sufficient to explain the results of our 4 experiments. According to the perceived distributions formed by PDIST, increasing familiarity leads to greater differentiation and variability, has a concave impact, and has greater impact on differentiation than on variability.

Adult↗

PubMed1996

Quantification of remodeling parameter sensitivity--assessed by a computer simulation model.

During normal aging and menopause, cancellous bone is lost at all skeletal sites due to remodeling-related factors: negative formation balance; temporarily increased remodeling space; and osteoclastic perforations. The relative importance of the various factors in inducing bone mass loss and perforations is still controversial. We have previously used a computer simulation model to describe the effect of several bone remodeling parameters on vertebral cancellous bone loss. The model focused on two different scenarios for the menopause and three different treatment regimens. The aim of the present study was to extend the previous study by quantifying remodeling parameter sensitivity for changes in the bone mass with the use of the computer model we had previously formulated. The menopause scenario, with increased activation frequency and increased resorption depth, was chosen as the base case scenario, and the following parameters were investigated in the sensitivity analysis: activation frequency; formation balance; resorption depth; and critical trabecular thickness. Simulations were performed for a period of 20 years starting at the age of 48 years. The analysis showed that the number of perforations and the perforation-related mass loss both exhibited a large sensitivity toward variations in the final resorption depth. However, the formation balance was the factor that was responsible for the greater part of the bone mass loss. The computer model allowed us to quantify the sensitivity of different output variables with respect to changes in some of the model parameters. This can give information about the biological mechanisms responsible for bone mass loss around the surgically induced or natural menopause and also provide an indication of the type of treatment that would be most useful in preventing the deterioration of the cancellous network.

Adult↗

PubMed2003

Understanding pH-dependent selectivity of alamethicin K18 channels by computer simulation.

Alamethicin K18 is a covalently linked alamethicin dimer in which the glutamine residue at position 18 in each helix has been replaced by a lysine residue. As described in previous work, channels formed by this peptide show pH-dependent selectivity. The maximum anion selectivity of the putative octameric conducting state is obtained at pH 7 or lower. Inasmuch as no change in selectivity is seen between pH 7 and pH 3, and because protons are expected to be in equilibrium with the open state of the channel during a selectivity measurement, the channel is believed to be fully charged (i.e., all eight lysines protonated) at pH 7. In an effort to understand how such a highly charged channel structure is stable in membranes and why it is not more selective for anions, we have performed a number of computer simulations of the system. Molecular dynamics simulations of 10 ns each of the octameric bundle in a lipid bilayer environment are presented, with either zero, four, or eight lysines charged in the absence of salt, and with eight lysines charged in the presence of 0.5 M and 1 M KCl. When no salt is present and all lysines are charged, on average 1.9 Cl(-) ions are inside the channel and the channel significantly deforms. With 0.5 M KCl present, 2.9 Cl(-) ions are inside the channel. With 1 M KCl present, four Cl(-) ions are present and the channel maintains a regular structure. Poisson-Boltzmann calculations on models of the octameric channel also predict an average of 2-4 Cl(-) ions near the lysine residues as a function of ionic strength. These counterions lower the apparent charge of the channel, which may underlie the decrease in selectivity observed experimentally with increasing salt concentrations. We suggest that to increase the selectivity of Alm K18 channels, positive charges could be engineered in a narrower part of the channel.

Alamethicin↗

PubMed2006

Computational simulations of HIV-1 proteases--multi-drug resistance due to nonactive site mutation L90M.

Human immunodeficiency virus type 1 protease (HIV-1 PR) is one of the proteins that currently available anti-HIV-1 drugs target. Inhibitors of HIV-1 PR have become available, and they have lowered the rate of mortality from acquired immune deficiency syndrome (AIDS) in advanced countries. However, the rate of emergence of drug-resistant HIV-1 variants is quite high because of their short retroviral life cycle and their high mutation rate. Serious drug-resistant mutations against HIV-1 PR inhibitors (PIs) frequently appear at the active site of PR. Exceptionally, some other mutations such as L90M cause drug resistance, although these appear at nonactive sites. The mechanism of resistance due to nonactive site mutations is difficult to explain. In this study, we carried out computational simulations of L90M PR in complex with each of three kinds of inhibitors and one typical substrate, and we clarified the mechanism of resistance. The L90M mutation causes changes in interaction between the side chain atoms of the 90th residue and the main chain atoms of the 25th residue, and a slight dislocation of the 25th residue causes rotation of the side chain at the 84th residue. The rotation of the 84th residue leads to displacement of the inhibitor from the appropriate binding location, resulting in a collision with the flap or loop region. The difference in levels of resistance to the three inhibitors has been explained from energetic and structural viewpoints, which provides the suggestion for promising drugs keeping its efficacy even for the L90M mutant.

Base Sequence↗

PubMed1994

Computer simulation of cell growth governed by stochastic processes: application to clonal growth cancer models.

Cancer is a multistage process in which cell proliferation determines the growth of cells within stages and is associated with the transition of cells from one stage to the next. The usual model for cancer risk assessment, the linearized multistage model, does not explicitly include cell proliferation. More realistic cancer models are needed to reduce uncertainty in cancer risk assessment and to provide basic insights into the quantitative roles of cell proliferation and mutation. This report describes a simulation model for the transition of cells from one stage to the next and for clonal growth within stages. The model is intended to facilitate the use of experimental data on cell replication and preneoplastic lesions in risk assessment. When a population of cells is small its growth may be governed by stochastic processes. Such a population may disappear by chance even when the probability of cell division on a given time interval exceeds the probability of cell death. Procedures for estimating cell proliferation and mutation parameters from data for use in risk assessment should account for this random aspect of growth. The present model describes cell growth governed by stochastic processes, is consistent with earlier analytical expressions for such growth (Dewanjii et al., Risk Anal. 9, 179, 1989), and is flexible with respect to time-dependent data. A data set for spontaneous basophilic clones in male F344 rats (Popp et al., Fundam. Appl. Toxicol. 5, 314, 1985) is analyzed and predictions are made for (a) the probability of mutation to the basophilic genotype per division of a normal hepatocyte (3.5 x 10(-8)), (b) number of basophilic clones too small to be detected, and (c) number of basophilic clones that disappear by chance. This work illustrates the potential of computer simulation for quantitative analysis of the roles of cell division, cell death, and mutation in cancer.

Animals↗

PubMed2006

A new method for spatially selective, non-invasive activation of neurons: concept and computer simulation.

Currently available non-invasive neurostimulation devices, using skin electrodes or externally applied magnetic coils, are not capable of producing a local stimulation maximum deep inside a homogeneous conductor, because of a fundamental limitation inherent to the Laplace equation. In this paper, a new neurostimulation method (the DeepFocus method) is presented, which avoids this limitation by using an indirect method of producing electric currents inside tissues: First, cylinder-shaped ferromagnetic rotating disks of non-permanent magnetic material are placed near the skin and magnetized by a non-rotating magnetic coil. Each of the disks rotates at high speed around its own axis of symmetry, thus producing a purely electric Lorentz force field having a non-zero divergence outside the disk, and therefore giving rise to charge accumulations inside the tissues. Subsequently, the magnetic field is switched off suddenly, causing a re-distribution of charge, and hence short-lived electrical currents, which can be used to activate neurons. Two magnet configurations are presented in this paper, and analyzed by computer simulation, showing that the DeepFocus method produces a maximum current density (the 'focus') deep inside the conducting body. The field strength thus created in the focus (7.9 V/m) is strong enough to activate thick myelinated fibers, but can be kept below the threshold for C-fibers, which makes the new method a possible tool for pain mitigation by targeted neurostimulation.

Back Pain↗

PubMed2004

Design, synthesis, structural studies, biological evaluation, and computational simulations of novel potent AT(1) angiotensin II receptor antagonists based on the 4-phenylquinoline structure.

Novel AT(1) receptor antagonists bearing substituted 4-phenylquinoline moieties instead of the classical biphenyl fragment were designed and synthesized as the first step of an investigation devoted to the development of new antihypertensive agents and to the understanding of the molecular basis of their pharmacodynamic and pharmacokinetic properties. The newly synthesized compounds were tested for their potential ability to displace [(125)I]Sar(1),Ile(8)-Ang II specifically bound to AT(1) receptor in rat hepatic membranes. These AT(1) receptor binding studies revealed nanomolar affinity in several of the compounds under study. The most potent ligands 4b,t were found to be equipotent with losartan and possessed either a 3-tetrazolylquinoline or a 2-amino-3-quinolinecarboxylic moiety, respectively. Moreover, some selected compounds were evaluated for antagonism of Ang II-induced contraction in rabbit aortic strips, and the most potent compounds in the binding test 4b,t were slightly more potent than losartan in inhibiting Ang II-induced contraction. Finally, the most relevant structure-affinity relationship data were rationalized by means of computational studies performed on the isolated ligands as well as by computational simulations on the ligands complexed with a theoretical AT(1) receptor model.

Angiotensin II Type 1 Receptor Blockers↗

PubMed1976

Computer simulation of brainstem respiratory activity.

A mathematical model of the medullary respiratory oscillator, composed of two mutually inhibiting populations (inspiratory and expiratory) of computer-simulated neurons, is presented. Each population consists of randomly interconnected subpopulations of excitatory and inhibitory neurons, is presented. Each population consists of randomly interconnected subpopulations of excitatory and inhibitory neurons. Neuronal coupling is such that either the inspiratory or expiratory population alone is capable of cyclic activity. Weak inhibitory connections between inspiratory and expiratory populations provide satisfactory reciprocating activity independent of the natural frequency of either population alone. Initiation and persistence of rhythmic activity is dependent on a diffused noncyclic excitatory input. Vagal discharge, simulated by phasic inhibition of inspiratory neurons, results in increased respiratory frequency with decreased inspiratory activity. In the absence of simulated vagal discharge, uniform facilitation of synaptic connections increases averaged activities of inspiratory and expiratory populations, with minor effect on frequency. In the presence of simulated vagal discharge, facilitation of synaptic connections increases both frequency and amplitude. The simulated effects of synaptic facilitation, with and without vagal discharge, mimic the physiological response to CO2 in the intact and vagotimized animal.

Computers↗

PubMed1997

Use of 1H NMR spectroscopy and computer simulations To analyze histidine pKa changes in a protein tyrosine phosphatase: experimental and theoretical determination of electrostatic properties in a small protein.

In bovine low Mr protein tyrosine phosphatase, the pKa values of His-66 and His-72 are 8.3 and 9.2, respectively. These unusually high values were hypothesized to be caused by electrostatic interactions with several nearby negatively charged groups. To test this, mutant enzymes were made in which one or more carboxylate side chains were removed or introduced near the histidines. Michaelis kinetic parameters, measured using p-nitrophenyl phosphate as a substrate, indicated that all mutant enzymes retained approximately 50% or more of the activity of wild-type enzyme. The effect that each mutation had on the pKa of the nearby histidine was monitored by 1H NMR spectroscopy using the MLEV-17 pulse sequence to filter out the broad interfering amide resonances in the spectra. Independently, computer simulations of the pKas were obtained using the finite difference method to solve the linear Poisson-Boltzmann equation. The proximity of a charged residue to the titrating histidine imidazole largely determined the extent of the pKa perturbation. The change in pKa for His-72 in the mutant enzymes was -1.69 units for D42A, -2.36 units for E23A, -2.99 units for E23A/D42A, and unchanged for E139A and Q143E. Thus, the pKa of His-72 in the double mutant E23A/D42A decreased to nearly that of a free histidine imidazole group. The His-66 pKa change was -1.25 units for E139A and was not significant for the other mutants. His-66, Glu-139, and Gln-143 are at the protein surface and much more exposed to the higher solvent dielectric compared to His-72, Glu-23, and Asp-42. These structural characteristics explain the smaller decrease in the observed pKa of His-66 for the E139A mutant compared to the decrease in the pKa of His-72 when a single nearby carboxylate was removed. These observations were adequately predicted by theoretical electrostatic calculations using the Poisson-Boltzmann equation as a model for a solute molecule of low dielectric in solution of high dielectric.

Animals↗

PubMed2004

Scrutiny of annexin A1 mediated membrane-membrane interaction by means of a thickness shear mode resonator and computer simulations.

The dissipational quartz crystal microbalance (D-QCM) technology was applied to monitor the adsorption of vesicles to membrane-bound annexin A1 by simultaneously reading out the shifts in resonance frequency and dissipation. Solid-supported membranes (SSMs) composed of a chemisorbed octanethiol monolayer and a physisorbed 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoserine monolayer were immobilized on the gold electrode of a 5 MHz quartz plate. Adsorption and desorption of annexin A1 to the SSM was followed by means of the QCM technique. After nonbound annexin A1 was removed from solution, the second membrane binding was monitored by the D-QCM technique, which allowed distinguishing between adsorbed and ruptured vesicles. The results show that vesicles stay always intact independent of the amount of bound annexin and the vesicle and buffer composition. It was shown that the vesicle adsorption process to membrane-bound annexin A1 is fully irreversible and is mediated by two-dimensional annexin clusters. For N-terminally truncated annexin A1, a decrease in the amount of bound vesicles was observed, which might be the result of fewer binding sites presented by the annexin A1 core. Supported by computer simulations, the results demonstrate that the vesicle adsorption process is electrostatically driven, but compared to those of sole electrostatic binding, the rate constants of adsorption are 1-2 orders of magnitude smaller, indicating the presence of a potential barrier.

Adsorption↗

PubMed1999

Design of appointment systems for preanesthesia evaluation clinics to minimize patient waiting times: a review of computer simulation and patient survey studies.

Anesthesiologists can use the science of clinic scheduling to design appointment systems for preanesthesia evaluation clinics. The principal reasons reported for inappropriately [or arguably unethically] long patient waiting times are provider tardiness, lack of patient punctuality, patient no-shows, and improperly designed appointment systems. However, the fundamental reason why anesthesia clinics have such long patient waiting times is because of their relatively long mean (and consequently standard deviation) of consultation times. If commonly applied valuations of provider idle time to patient waiting time are used in anesthesia clinics, appointment intervals will be sufficiently brief that the mean patient waiting time will be at least the mean consultation time or half an hour. Patients will be dissatisfied with this level of service. Therefore, efforts to decrease the mean patient waiting time in anesthesia clinics should focus foremost on minimizing the mean consultation time and its variability, which can most likely be achieved by assuring that providers have rapid access to relevant clinical information, including external medical records, surgical dictations, etc. Anesthesiologists managing anesthesia clinics may find it valuable to apply other interventions to decrease patient waiting times. Scheduling of preanesthesia evaluation and surgical clinics should be coordinated to assure patient punctuality. Providers should be on time for the start of their sessions. If an add-on patient cannot be seen during a scheduled clinic session, because all appointment times have been assigned to other patients, the add-on patient should be seen by a different provider or at the end of the regularly scheduled clinic session. Mean consultation times should be measured accurately for each provider. Substantial provider idle time should be expected. Appropriate values for breaks, appointment intervals, and percentage no-shows should be determined by computer simulation, using parameters appropriate for each provider and anesthesia clinic. Finally, traditional efforts at making waiting for a consultation tolerable should be made.

Anesthesia Department, Hospital↗

PubMed2005

Synthesis and structure-activity relationships of a new model of arylpiperazines. 8. Computational simulation of ligand-receptor interaction of 5-HT(1A)R agonists with selectivity over alpha1-adrenoceptors.

We have designed and synthesized a new series of arylpiperazines V exhibiting high 5-HT(1A)R affinity and selectivity over alpha(1)-adrenoceptors. The new selective 5-HT(1A)R ligands contain a hydantoin (m = 0) or diketopiperazine (m = 1) moiety and an arylpiperazine moiety separated by one methylene unit (n = 1). The aryl substituent of the piperazine moiety (Ar) consists of different benzofused rings mimicking the favorable voluminous substituents at ortho and meta positions predicted by 3D-QSAR analysis in the previously reported series I. In particular, (S)-2-[[4-(naphth-1-yl)piperazin-1-yl]methyl]-1,4-dioxoperhydropyrrolo[1,2-a]pyrazine [(S)-9, CSP-2503] (5-HT(1A), K(i) = 4.1 nM; alpha(1), K(i) > 1000 nM) has been pharmacologically characterized as a 5-HT(1A)R agonist at somatodendritic and postsynaptic sites, endowed with anxiolytic properties. Ligand (S)-9 is predicted, in computer simulations, to bind Asp(3.32) in TMH 3, Thr(5.39) and Ser(5.42) in TMH 5, and Trp(6.48) in TMH 6. We propose that agonists modify, by means of an explicit hydrogen bond, the conformation of Trp(6.48) from pointing toward TMH 7, in the inactive gauche+ conformation, to pointing toward the ligand binding site, in the active trans conformation.

Adenylyl Cyclases↗

PubMed1991

Secondary and tertiary structures of hyaluronan in aqueous solution, investigated by rotary shadowing-electron microscopy and computer simulation. Hyaluronan is a very efficient network-forming polymer.

1. Hyaluronan from mesothelioma fluid, rooster comb and streptococci was examined by rotary shadowing and electron microscopy. All preparations showed extensive branched networks, but high-viscosity hyaluronan networks were essentially infinite, with no individual 'molecules' that were not integrated via multiple branched points into the meshwork. Low-viscosity hyaluronan, recovered after papain digestion of mesothelioma fluid, showed occasional single filaments that were independent of the main aggregates, some of which were themselves independent of other aggregates. 2. Hyaluronan is a polymer with a very marked capability to form meshworks at very low dilution (less than 1 microgram/ml). The longer the hyaluronan molecule, the more branching is potentially possible, and the more extensive and coherent is the network, with every hyaluronan molecule in contact with every other in the solution, via the network. This behaviour accounts for the mechanical properties of the soft tissues (e.g. vitreous humour) and fluids (e.g. synovial fluid) of which hyaluronan is a major component. 3. The hyaluronan twofold helix, previously demonstrated to be present in solution [Heatley & Scott (1988) Biochem. J. 254, 489-493] was shown by computer simulation and energy calculations to be sterically capable of extensive duplex formation, probably driven by interactions between the large hydrophobic patches on alternate sides of the tape-like polymer, forming stable aggregates at biological temperatures in water. This 'stickiness' is postulated to be the basis of the network-forming and laterally aggregating behaviour of hyaluronan. 4. The tertiary structures formed by hyaluronan may not be possible in the case of chondroitin 4-sulphate.

Animals↗

PubMed1998

Focused attention and the detectability of weak gustatory stimuli. Empirical measurement and computer simulations.

Attentional processes can modulate the detectability of weak stimuli; for example, the detectability of visual or auditory signals can depend on whether attention is allocated to the appropriate spatial location (vision) or acoustic frequency (hearing). Earlier attempts in the first author's laboratory to find analogous effects of focused attention on the detectability of taste stimuli were equivocal, in part it seems because human gustatory sensitivity can fluctuate substantially over time, a serious problem when using procedures that track sensitivity (d') to a constant stimulus concentration. To circumvent this problem, we adopted an adaptive psychophysical procedure, the transformed up-down method, using a 3-down/1-up rule to determine how the threshold to detect weak concentrations of sucrose and citric acid depended on whether the stimulus presented in a given two-alternative, forced-choice trial was expected or unexpected. The results showed threshold sensitivity to be slightly but consistently poorer when the test stimulus was unexpected (e.g., sucrose presented when citric acid was expected) than it was when the test stimulus was expected (e.g., sucrose presented when sucrose was expected). In this attentional paradigm, the unexpected stimulus must perforce be presented on only a small fraction of the trials. In selecting a procedure, we chose a 3-down/1-up adaptive rule rather than the more popular 2-down/1-up rule, a choice that turned out to be in line with results of Monte Carlo computer simulations. These simulations suggest that across a wide range of conditions (starting stimulus concentrations, step sizes), the variability in threshold measurements can be smaller with a 3-down/1-up rule than with a 2-down/1-up rule, even when the total number of trials is the same and not very great.

Attention↗