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Multisensory contributions to the shelter-seeking behavior of a mormyrid fish, Gnathonemus petersii Günther (Mormyridae, Teleostei): the role of vision, and the passive and active electrosenses.

This study examined how weakly electric fish, Gnathonemus petersii, integrate multiple sensory modalities (passive and active electrosenses, and vision) to maintain proximity to tubular structures, serving as the fish's hiding place or shelter during the daytime. By moving the shelter along a linear 2-meter path, causing a mechanical disturbance, we challenged the fish's shelter-seeking behavior and used the length of travel that shelter proximity was maintained (contact distance) as an indicator of how well the animal maintained its shelter. In order to determine the contribution of vision and electrosense to this behavior, four groups of fish were tested in which: (1) all three modalities were intact; (2) vision alone was eliminated by optic nerve transection; (3) the active electrosense was silenced by spinal cord transection rendering the electric organ inoperative; and (4) both vision and active electrosense were deactivated. Further elimination or minimization of various sensory cues was achieved by testing the fish with optically transparent, acrylic shelters (Plexiglas) that stimulate active, but not passive, electrosense, and aluminum shelters that theoretically stimulate all three modalities. As expected, performance was optimal when all three modalities were operating, but better than expected from quantitative models based on additive processes alone. Although the absence of one sense (vision or active electrosense) caused initial deficits, these were fully compensated for over repeated daily exposure to the task, suggesting that learning might generate sensory substitution and/or the formation of sensory expectation. Finally, environmental conditions, such as shelter opacity, also affected shelter-seeking performance, sometimes in a negative direction. These results demonstrate that: (1) the integration of multiple sensory inputs in G. petersii can be synergistic, additive, redundant, or even inhibitory, and (2) multisensory processes also take into account the respective sensory cues; i.e. (a) the prevailing ambient light intensity and optical qualities of the object; (b) the geometry and strength of the DC potential emanating from the object ('battery effect'); and (c) the complex perceived impedance differential with the surrounding medium.

Animals↗

Influence of oral detergents and chlorhexidine on soft-layer electrokinetic parameters of the acquired enamel pellicle.

Electron microscopy has described the salivary pellicle as an 'uneven, knotted structure'. This study describes a novel soft-layer model of salivary pellicles, based on measured electrophoretic mobilities and the influence of dentifrices and a chlorhexidine mouthwash on the parameters of the model. The enamel surface was found to possess a high number of fixed, negative charges (zN = -62 mM) and to be electrophoretically hard (1/lambda = 0.6 nm), i.e. impenetrable to fluid flow. Adsorption of a salivary pellicle resulted in a fourfold reduction in the surface fixed charge density (zN = -15 mM) along with an increase in electrophoretic softness (1/lambda = 2.3 nm). Exposure of pellicles to various dentifrices containing sodium fluoride as an active component and sodium lauryl sulfate as a detergent had little effect on the surface fixed charge densities (varying between -15 and -30 mM, depending on the dentifrice involved) and electrophoretic softnesses (varying between 2.3 and 3.4 nm). Exposure of pellicles to a dentifrice containing sodium fluoride and hexametaphosphate as an additional detergent yielded soft (8.0 nm) pellicles, penetrable to fluid flow, with few fixed, negative charges (1 mM). This is opposite to the effects of chlorhexidine, which created an electrophoretically hard pellicle (1.7 nm). This soft-layer electrokinetic model quantitatively shows that the degree to which pellicles are penetrable to fluid flow differs upon exposure to dentifrices, with relevance for plaque formation, de- and remineralization and staining processes.

Adsorption↗

Tumor-promoter-enhanced destruction of noninvasive human benign colon tumor cells by cocultivated carcinoma cells.

Colon carcinoma cells are first found as microscopic foci within benign tumors or adenomas. The carcinoma must invade the adenoma which protrudes into the colon lumen before it can infiltrate the bowel wall. A quantitative model for this process has been developed in tissue culture in which human colon carcinoma cells destroy cocultivated adenoma colonies. 43 adenoma colonies were assayed by cocultivation with carcinoma cells. Constitutive secretion of the urokinase form of plasminogen activator by carcinoma cells apparently plays some role in adenoma destruction as inhibition of this protease by the competitive inhibitor benzamidine reversibly inhibited adenoma destruction (p less than 0.01). Elevation of plasminogen activator secretion by addition of the tumor promoter 12-tetradecanoylphorbol-13-acetate significantly enhanced the destruction of colonies cultured from tubular adenomas with only mild dysplasia (p less than 0.025) and from villous, villotubular and tubular adenomas with moderate to severe dysplasia (p less than 0.0005).

Adenoma↗

Effect of suleparoide on fibrinolysis in the anterior chamber of rabbits.

Intra-ocular fibrin deposition following ocular surgery is a serious postoperative complication. The current management of severe postoperative fibrin response is usually ineffective. A quantitative model of fibrin deposition in the rabbit anterior chamber was used to assess the efficacy of Suleparoide I.N.N. (HHS-5) in preventing fibrin formation and in promoting the clearance of fibrinous membranes. Citrated human plasma was injected intracamerally after paracentesis to induce the formation of fibrin clots: 10 min or 24 h after plasma injection, solutions of HHS-5 at different concentrations were injected into the anterior chamber of rabbits. Intra-ocular HHS-5 injection 10 min after plasma injection prevented the formation of fibrinous membranes in a dose-dependent fashion in almost all treated animals. When HHS-5 was injected at 24 h after fibrin clot formation, a reduction of clot areas was observed but the membranes did not completely disappear. No evidence of ocular toxicity was detected by slit-lamp biomicroscopy, intra-ocular pressure and corneal thickness measurements. On the basis of the results obtained with the present animal model, HHS-5 appears as an effective and safe agent for the prevention of fibrinous membrane formation. The data suggest a potential use of HHS-5 for the prophylaxis of fibrin formation in human eyes undergoing extensive intraocular surgery, or in diabetic patients where a hypercoagulable state may be present.

Analysis of Variance↗

Lipoprotein heterogeneity and apolipoprotein B metabolism.

The apolipoprotein B containing lipoproteins VLDL, IDL, and LDL exhibit variation in their structure, function, and metabolism. These major lipoprotein classes can be fractionated into apparently discrete components by density gradient centrifugation or affinity chromatography. Examination of the behavior of subfractions in vivo reveals the presence of metabolic channels within the VLDL-LDL delipidation cascade so that the pedigree of a lipoprotein in part determines its metabolic fate. Evidence from VLDL and LDL apoB turnovers together with epidemiological data allows the construction of a quantitative model for the generation of small, dense LDL. This lipoprotein subspecies is one component of the dyslipidemic syndrome known as the atherogenic lipoprotein phenotype, a common disorder in those at risk for coronary heart disease. Understanding lipoprotein heterogeneity is an essential step in the further discovery of the pathogenesis of atherosclerosis and in the tailoring of pharmacologic treatment for subjects at risk.

Apolipoproteins B↗

Relationship between intracellular calcium and contractile force in stunned myocardium. Direct evidence for decreased myofilament Ca2+ responsiveness and altered diastolic function in intact ventricular muscle.

To elucidate the abnormalities of excitation-contraction coupling in stunned myocardium, we measured [Ca2+]i and force in thin fura 2-loaded ventricular trabeculae from control or stunned (20 minutes ischemia followed by 20 minutes reflow at 37 degrees C) rat hearts. At any given [Ca2+]o, force development was significantly lower in the stunned trabeculae than in control trabeculae. In contrast, there was no difference in the amplitude of Ca2+ transients between the two groups. The steady state force-[Ca2+]i relationship, assessed by tetanization in the presence of ryanodine, revealed both a decrease in maximal Ca(2+)-activated force and an increase in the [Ca2+]i required for 50% activation in stunned trabeculae. Postischemic myocardium also exhibited an accelerated rate of diastolic relaxation that was not due to changes in the rate of Ca2+ transient decay. Destabilization of attached cross-bridges in a quantitative model of cardiac myofibrils accurately reproduced the salient systolic and diastolic features of the stunned phenotype, suggesting an abnormality of the thin filaments. In response to supraphysiological increases in [Ca2+]o, diastolic [Ca2+]i and diastolic tone increased much more in stunned trabeculae than in controls, with the frequent occurrence of aftercontractions. This novel experimental model lends further support to the hypothesis that the primary lesion of excitation-contraction coupling resides at the level of the contractile proteins. The finding of enhanced susceptibility to calcium overload helps to rationalize the functional deterioration of stunned myocardium during intense inotropic stimulation and additionally suggests that stunned myocardium may represent a favorable substrate for triggered arrhythmias.

Actin Cytoskeleton↗

Molecular interactions between two long-QT syndrome gene products, HERG and KCNE2, rationalized by in vitro and in silico analysis.

The cardiac delayed rectifier potassium current mediates repolarization of the action potential and underlies the QT interval of the ECG. Mutations in either of the two molecular components of the rapid delayed rectifier (I(K,r)), HERG and KCNE2, have been linked to heritable or acquired long-QT syndrome. Mechanisms whereby mutations of KCNE2 produce fatal cardiac arrhythmias characteristic of long-QT syndrome remain unclear. In this study, we characterize functional interactions between HERG and KCNE2 with a view to defining underlying mechanisms for action potential prolongation and long-QT syndrome. Whereas coexpression of hKCNE2 with HERG alters both kinetics and density of ionic current, incorporation of these effects into a quantitative model of the action potential predicts that only changes in current density significantly affect repolarization. Thus, the primary functional consequence of hKCNE2 on action potential morphology is through modulation of I(K,r) density, as predicted by the model. Mutations associated with long-QT syndrome that result only in modest changes of gating kinetics may be epiphenomena or may modulate action potential repolarization via interaction with alternative pore-forming potassium channel alpha subunits.

Action Potentials↗

Grating and plaid masks indicate linear summation in a contrast gain pool.

In human vision, the response to luminance contrast at each small region in the image is controlled by a more global process where suppressive signals are pooled over spatial frequency and orientation bands. But what rules govern summation among stimulus components within the suppressive pool? We addressed this question by extending a pedestal plus pattern mask paradigm to use a stimulus with up to three mask components: a vertical 1 c/deg pedestal, plus pattern masks made from either a grating (orientation = -45 degrees ) or a plaid (orientation = +/-45 degrees ), with component spatial frequency of 3 c/deg. The overall contrast of both types of pattern mask was fixed at 20% (i.e., plaid component contrasts were 10%). We found that both of these masks transformed conventional dipper functions (threshold vs. pedestal contrast with no pattern mask) in exactly the same way: The dipper region was raised and shifted to the right, but the dipper handles superimposed. This equivalence of the two pattern masks indicates that contrast summation between the plaid components was perfectly linear prior to the masking stage. Furthermore, the pattern masks did not drive the detecting mechanism above its detection threshold because they did not abolish facilitation by the pedestal (Foley, 1994). Therefore, the pattern masking could not be attributed to within-channel masking, suggesting that linear summation of contrast signals takes place within a suppressive contrast gain pool. We present a quantitative model of the effects and discuss the implications for neurophysiological models of the process.

Adaptation, Ocular↗

The highest luminance anchoring rule in achromatic color perception: some counterexamples and an alternative theory.

It has been hypothesized that lightness is computed in a series of stages involving: (1) extraction of local contrast or luminance ratios at borders; (2) edge integration, to combine contrast or luminance ratios across space; and (3) anchoring, to relate the relative lightness scale computed in Stage 2 to the scale of real-world reflectances. The results of several past experiments have been interpreted as supporting the highest luminance anchoring rule, which states that the highest luminance in a scene always appears white. We have previously proposed a quantitative model of achromatic color computation based on a distance-dependent edge integration mechanism. In the case of two disks surrounded by lower luminance rings, these two theories--highest luminance anchoring and distance--dependent edge integration-make different predictions regarding the luminance of a matching disk required to for an achromatic color match to a test disk of fixed luminance. The highest luminance rule predicts that luminance of the ring surrounding the test should make no difference, whereas the edge integration model predicts that increasing the surround luminance should reduce the luminance required for a match. The two theories were tested against one another in two experiments. The results of both experiments support the edge integration model over the highest luminance rule.

Color Perception↗

Neural losses correlated with visual losses in clinical perimetry.

PURPOSE: The validity of clinical perimetry for evaluation of the pathology of glaucoma is based on correlated losses in retinal ganglion cells and visual sensitivity, but procedures to quantify neural losses from visual field defects have not been developed. The purpose of the present study was to investigate the neural and sensitivity losses from experimental glaucoma to establish the framework for a quantitative model for the structure-function relationships of standard clinical perimetry. METHODS: Perimetry, by behavioral testing, and retinal histology data were obtained from rhesus monkeys with significant visual field defects caused by experimental glaucoma. Ganglion cell densities were obtained from sections of retina that corresponded to 16 perimetry test locations. Perimetry sensitivity as a function of ganglion cell density at corresponding retina/visual field locations was analyzed. RESULTS: The structure-function relationships were linear on log-log coordinates, with parameters that varied systematically with eccentricity. The slope value varied from 1.25 dB/dB at 4.2 degrees from fixation to a value of 2.32 dB/dB at 24 degrees from fixation, whereas the intercept value varied from -25.2 dB to -55.7 dB over the same range of eccentricities. The structure-function relationships produced a model to predict the ganglion cell density underlying a given level of visual sensitivity and location in the visual field. The model, with no free parameters, produced an accurate and relatively precise quantification of retinal ganglion cell losses caused by experimental glaucoma in monkeys. However, because the early detection of glaucoma is limited by intersubject variability, ganglion cell losses of 40% to 50% were necessary before visual sensitivity losses exceeded the normal 95% confidence limits. CONCLUSIONS: With retinal eccentricity as a factor, the neural losses from glaucoma are predictable from visual sensitivity measurements by clinical perimetry. The relationships derived from experimental glaucoma in monkeys also accurately predict the rate of age-related losses of retinal ganglion cells in humans, based on the normative perimetry data for age-related reductions in visual sensitivity. The success of the model in this study suggested that it is potentially applicable to the clinical interpretation of the state of glaucomatous optic neuropathy.

Animals↗

Ectopic expression of KCNE3 accelerates cardiac repolarization and abbreviates the QT interval.

Regulatory subunit KCNE3 (E3) interacts with KCNQ1 (Q1) in epithelia, regulating its activation kinetics and augmenting current density. Since E3 is expressed weakly in the heart, we hypothesized that ectopic expression of E3 in cardiac myocytes might abbreviate action potential duration (APD) by interacting with Q1 and augmenting the delayed rectifier current (I(K)). Thus, we transiently coexpressed E3 with Q1 and KCNE1 (E1) in Chinese hamster ovary cells and found that E3 coexpression increased outward current at potentials by > or = -80 mV and accelerated activation. We then examined the changes in cardiac electrophysiology following injection of adenovirus-expressed E3 into the left ventricular cavity of guinea pigs. After 72 hours, the corrected QT interval of the electrocardiogram was reduced by approximately 10%. APD was reduced by >3-fold in E3-transduced cells relative to controls, while E-4031-insensitive I(K) and activation kinetics were significantly augmented. Based on quantitative modeling of a transmural cardiac segment, we demonstrate that the degree of QT interval abbreviation observed results from electrotonic interactions in the face of limited transduction efficiency and that heterogeneous transduction of E3 may actually potentiate arrhythmias. Provided that fairly homogeneous ectopic ventricular expression of regulatory subunits can be achieved, this approach may be useful in enhancing repolarization and in treating long QT syndrome.

Animals↗

A cost-effectiveness analysis of screening for hepatitis B surface antigen in India.

We have developed a quantitative model to study the impact of screening for the hepatitis B surface antigen using either second-generation (counterimmunoelectrophoresis) or third-generation (radioimmunoassay) tests. This model was fashioned for general use but was applied to data on hepatitis for India, in an attempt to determine what factors would most influence the decision to institute a screening program for the surface antigen in that country. Screening for the surface antigen should reduce post-transfusion hepatitis B significantly--second-generation testing by 81% and third-generation testing by 99.4%. The marginal cost of substituting counter-immunoelectrophoresis testing for no testing is 557 rupees per case averted, and that of substituting radioimmunoassay for counterimmunoelectrophoresis testing is 1,120 rupees per case averted. Sensitivity analyses suggest that the major impact on costs will result not from changes in the sensitivity or specificity of new screening tests, but rather in their costs.

Cost-Benefit Analysis↗

Suicide gene therapy of graft-versus-host disease induced by central memory human T lymphocytes.

In allogeneic hematopoietic cell transplantation (allo-HCT), the immune recognition of host antigens by donor T lymphocytes leads to a beneficial graft-versus-leukemia (GvL) effect as well as to life-threatening graft-versus-host disease (GvHD). Genetic modification of T lymphocytes with a retroviral vector (RV) expressing the herpes simplex virus-thymidine kinase (TK) suicide gene confers selective sensitivity to the prodrug ganciclovir (GCV). In patients, the infusion of TK+ lymphocytes and the subsequent administration of GCV resulted in a time-wise modulation of antihost reactivity for a GvL effect, while controlling GvHD. Because activation required for genetic modification with RV may reduce antihost reactivity, we investigated the requirements for maximizing the potency of human TK+ lymphocytes. Whereas T-cell receptor triggering alone led to effector memory (EM) TK+ lymphocytes, the addition of CD28 costimulation through cell-sized beads resulted in the generation of central memory (CM) TK+ lymphocytes. In a quantitative model for GvHD using nonobese diabetic/severely combined immunodeficient mice, CM TK+ lymphocytes were more potent than EM TK+ lymphocytes. GCV administration efficiently controlled GvHD induced by CM TK+ lymphocytes. These results warrant the clinical investigation of CM suicide gene-modified human T lymphocytes for safe and effective allo-HCT.

Animals↗

Optimized Particle Swarm Optimization (OPSO) and its application to artificial neural network training.

BACKGROUND: Particle Swarm Optimization (PSO) is an established method for parameter optimization. It represents a population-based adaptive optimization technique that is influenced by several "strategy parameters". Choosing reasonable parameter values for the PSO is crucial for its convergence behavior, and depends on the optimization task. We present a method for parameter meta-optimization based on PSO and its application to neural network training. The concept of the Optimized Particle Swarm Optimization (OPSO) is to optimize the free parameters of the PSO by having swarms within a swarm. We assessed the performance of the OPSO method on a set of five artificial fitness functions and compared it to the performance of two popular PSO implementations. RESULTS: Our results indicate that PSO performance can be improved if meta-optimized parameter sets are applied. In addition, we could improve optimization speed and quality on the other PSO methods in the majority of our experiments. We applied the OPSO method to neural network training with the aim to build a quantitative model for predicting blood-brain barrier permeation of small organic molecules. On average, training time decreased by a factor of four and two in comparison to the other PSO methods, respectively. By applying the OPSO method, a prediction model showing good correlation with training-, test- and validation data was obtained. CONCLUSION: Optimizing the free parameters of the PSO method can result in performance gain. The OPSO approach yields parameter combinations improving overall optimization performance. Its conceptual simplicity makes implementing the method a straightforward task.

Algorithms↗

SVRMHC prediction server for MHC-binding peptides.

BACKGROUND: The binding between antigenic peptides (epitopes) and the MHC molecule is a key step in the cellular immune response. Accurate in silico prediction of epitope-MHC binding affinity can greatly expedite epitope screening by reducing costs and experimental effort. RESULTS: Recently, we demonstrated the appealing performance of SVRMHC, an SVR-based quantitative modeling method for peptide-MHC interactions, when applied to three mouse class I MHC molecules. Subsequently, we have greatly extended the construction of SVRMHC models and have established such models for more than 40 class I and class II MHC molecules. Here we present the SVRMHC web server for predicting peptide-MHC binding affinities using these models. Benchmarked percentile scores are provided for all predictions. The larger number of SVRMHC models available allowed for an updated evaluation of the performance of the SVRMHC method compared to other well- known linear modeling methods. CONCLUSION: SVRMHC is an accurate and easy-to-use prediction server for epitope-MHC binding with significant coverage of MHC molecules. We believe it will prove to be a valuable resource for T cell epitope researchers.

Amino Acid Sequence↗

Hubs of knowledge: using the functional link structure in Biozon to mine for biologically significant entities.

BACKGROUND: Existing biological databases support a variety of queries such as keyword or definition search. However, they do not provide any measure of relevance for the instances reported, and result sets are usually sorted arbitrarily. RESULTS: We describe a system that builds upon the complex infrastructure of the Biozon database and applies methods similar to those of Google to rank documents that match queries. We explore different prominence models and study the spectral properties of the corresponding data graphs. We evaluate the information content of principal and non-principal eigenspaces, and test various scoring functions which combine contributions from multiple eigenspaces. We also test the effect of similarity data and other variations which are unique to the biological knowledge domain on the quality of the results. Query result sets are assessed using a probabilistic approach that measures the significance of coherence between directly connected nodes in the data graph. This model allows us, for the first time, to compare different prominence models quantitatively and effectively and to observe unique trends. CONCLUSION: Our tests show that the ranked query results outperform unsorted results with respect to our significance measure and the top ranked entities are typically linked to many other biological entities. Our study resulted in a working ranking system of biological entities that was integrated into Biozon at http://biozon.org.

Abstracting and Indexing↗

Quasispecies theory in the context of population genetics.

BACKGROUND: A number of recent papers have cast doubt on the applicability of the quasispecies concept to virus evolution, and have argued that population genetics is a more appropriate framework to describe virus evolution than quasispecies theory. RESULTS: I review the pertinent literature, and demonstrate for a number of cases that the quasispecies concept is equivalent to the concept of mutation-selection balance developed in population genetics, and that there is no disagreement between the population genetics of haploid, asexually-replicating organisms and quasispecies theory. CONCLUSION: Since quasispecies theory and mutation-selection balance are two sides of the same medal, the discussion about which is more appropriate to describe virus evolution is moot. In future work on virus evolution, we would do good to focus on the important questions, such as whether we can develop accurate, quantitative models of virus evolution, and to leave aside discussions about the relative merits of perfectly equivalent concepts.

Biological Evolution↗

An automated system for measuring parameters of nematode sinusoidal movement.

BACKGROUND: Nematode sinusoidal movement has been used as a phenotype in many studies of C. elegans development, behavior and physiology. A thorough understanding of the ways in which genes control these aspects of biology depends, in part, on the accuracy of phenotypic analysis. While worms that move poorly are relatively easy to describe, description of hyperactive movement and movement modulation presents more of a challenge. An enhanced capability to analyze all the complexities of nematode movement will thus help our understanding of how genes control behavior. RESULTS: We have developed a user-friendly system to analyze nematode movement in an automated and quantitative manner. In this system nematodes are automatically recognized and a computer-controlled microscope stage ensures that the nematode is kept within the camera field of view while video images from the camera are stored on videotape. In a second step, the images from the videotapes are processed to recognize the worm and to extract its changing position and posture over time. From this information, a variety of movement parameters are calculated. These parameters include the velocity of the worm's centroid, the velocity of the worm along its track, the extent and frequency of body bending, the amplitude and wavelength of the sinusoidal movement, and the propagation of the contraction wave along the body. The length of the worm is also determined and used to normalize the amplitude and wavelength measurements. To demonstrate the utility of this system, we report here a comparison of movement parameters for a small set of mutants affecting the Go/Gq mediated signaling network that controls acetylcholine release at the neuromuscular junction. The system allows comparison of distinct genotypes that affect movement similarly (activation of Gq-alpha versus loss of Go-alpha function), as well as of different mutant alleles at a single locus (null and dominant negative alleles of the goa-1 gene, which encodes Go-alpha). We also demonstrate the use of this system for analyzing the effects of toxic agents. Concentration-response curves for the toxicants arsenite and aldicarb, both of which affect motility, were determined for wild-type and several mutant strains, identifying P-glycoprotein mutants as not significantly more sensitive to either compound, while cat-4 mutants are more sensitive to arsenite but not aldicarb. CONCLUSIONS: Automated analysis of nematode movement facilitates a broad spectrum of experiments. Detailed genetic analysis of multiple alleles and of distinct genes in a regulatory network is now possible. These studies will facilitate quantitative modeling of C. elegans movement, as well as a comparison of gene function. Concentration-response curves will allow rigorous analysis of toxic agents as well as of pharmacological agents. This type of system thus represents a powerful analytical tool that can be readily coupled with the molecular genetics of nematodes.

Acetylcholine↗