A priori estimation of accuracy and of the number of wells to be employed in limiting dilution assays.
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The use of limiting dilution assay (LDA) for assessing the frequency of responders in a cell population is a method extensively used by immunologists. A series of studies addressing the statistical method of choice in an LDA have been published. However, none of these studies has addressed the point of how many wells should be employed in a given assay. The objective of this study was to demonstrate how a researcher can predict the number of wells that should be employed in order to obtain results with a given accuracy, and, therefore, to help in choosing a better experimental design to fulfill one's expectations. We present the rationale underlying the expected relative error computation based on simple binomial distributions. A series of simulated in machina experiments were performed to test the validity of the a priori computation of expected errors, thus confirming the predictions. The step-by-step procedure of the relative error estimation is given. We also discuss the constraints under which an LDA must be performed. (+info)
Exploring the dynamics of light adaptation: the effects of varying the flickering background's duration in the probed-sinewave paradigm.
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In the probed-sinewave paradigm, threshold for detecting a probe is measured at various phases with respect to a sinusoidally-flickering background. Here we vary the duration of the flickering background before (and after) the test probe is presented. The adaptation is rapid; after approximately 10-30 ms of the flickering background, probe threshold is the same as that on a continually-flickering background. It is interesting that this result holds at both low (1. 2 Hz) and middle (9.4 Hz) frequencies because at middle frequencies (but not at low) there is a dc-shift, i.e. probe threshold is elevated at all phases relative to that on a steady background (of the same mean luminance). We compare our results to predictions from Wilson's model [Wilson (1997), Visual Neuroscience, 14, 403-423; Hood & Graham (1998), Visual Neuroscience, 15, 957-967] of light adaptation. The model predicts the rapid adaptation, and the dc-shift, but not the detailed shape of the probe-threshold-versus-phase curve at middle frequencies. (+info)
Developmental control of stress stimulons in Streptomyces coelicolor revealed by statistical analyses of global gene expression patterns.
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Stress-induced regulatory networks coordinated with a procaryotic developmental program were revealed by two-dimensional gel analyses of global gene expression. Four developmental stages were identified by their distinctive protein synthesis patterns using principal component analysis. Statistical analyses focused on five stress stimulons (induced by heat, cold, salt, ethanol, or antibiotic shock) and their synthesis during development. Unlike other bacteria, for which various stresses induce expression of similar sets of protein spots, in Streptomyces coelicolor heat, salt, and ethanol stimulons were composed of independent sets of proteins. This suggested independent control by different physiological stress signals and their corresponding regulatory systems. These stress proteins were also under developmental control. Cluster analysis of stress protein synthesis profiles identified 10 different developmental patterns or "synexpression groups." Proteins induced by cold, heat, or salt shock were enriched in three developmental synexpression groups. In addition, certain proteins belonging to the heat and salt shock stimulons were coregulated during development. Thus, stress regulatory systems controlling these stimulons were implicated as integral parts of the developmental program. This correlation suggested that thermal shock and salt shock stress response regulatory systems either allow the cell to adapt to stresses associated with development or directly control the developmental program. (+info)
Autosomal dominant type IIa hypercholesterolemia: evaluation of the respective contributions of LDLR and APOB gene defects as well as a third major group of defects.
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Autosomal dominant type IIa hypercholesterolaemia (ADH) is characterised by an elevation of total plasma cholesterol associated with increased LDL particles. Numerous different molecular defects have been identified in the LDL receptor (LDLR) and few specific mutations in the apolipoprotein B (APOB) gene resulting in familial hypercholesterolaemia and familial defective apoB-100 respectively. To estimate the respective contribution of LDLR, APOB and other gene defects in this disease, we studied 33 well characterised French families diagnosed over at least three generations with ADH through the candidate gene approach. An estimation of the proportions performed with the HOMOG3R program showed that an LDLR gene defect was involved in approximately 50% of the families (P = 0.001). On the other hand, the estimated contribution of an APOB gene defect was only 15%. This low estimation of ADH due to an APOB gene defect is further strengthened by the existence of only two probands carrying the APOB (R3500Q) mutation in the sample. More importantly and surprisingly, 35% of the families in the sample were estimated to be linked to neither LDLR nor APOB genes. These data were confirmed by the exclusion of both genes through direct haplotyping in three families. Our results demonstrate that the relative contributions of LDLR and APOB gene defects to the disease are very different. Furthermore, our results also show that genetic heterogeneity is, generally, underestimated in ADH, and that at least three major groups of defects are involved. At this point, the contribution of the recently mapped FH3 gene to ADH cannot be assessed nor its importance in the group of 'non LDLR/non APOB' families. (+info)
Application of direct search optimization for pharmacokinetic parameter estimation.
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PURPOSE: For simple pharmacokinetic compartmental models, analytical solution to the governing differential equations along with common graphical methods provide a mean to evaluate the associated rate constants. These graphical methods, however, can not be used for the more complex multi-compartment models. Furthermore, parameter estimation using slope and intercept values from the graphical methods is often accompanied with error. In this study a numerical solution is applied for the solution of the governing differential equations and a simple direct search optimization procedure utilizing random numbers is used for pharmacokinetic parameter estimation. METHOD: The methodology is demonstrated with reference to experimental literature data for ciprofloxacin and ofloxacin whose pharmacokinetic behavior has been reported in terms of a two-compartment model. RESULTS: Examination of the predicted drug concentrations from the graphical method and the optimization methodology indicate that both methods have comparable accuracy in predicting the drug concentrations. The graphical method, however, only shows good accuracy in the early stages both after i.v. and oral drug administration whereas the optimization procedure, due to the nature of the objective function formulation, provides good accuracy over the entire range of times after drug administration. CONCLUSIONS: The methodology is simple, provides optimized parameters which accurately predict drug concentrations, and is flexible to include more weight on the early-time data or be extended to multi-compartment models. (+info)
Independent mechanisms produce visually perceived eye level (VPEL) and perceived visual pitch (PVP).
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Two aspects of the perception of extrapersonal space undergo systematic changes with variations in the pitch of the visual environment: (1) the physical elevation perceived to correspond to eye level (VPEL); and (2) the perception of the pitch of the visual environment (PVP). Thus, one might assume that both discriminations are controlled by a common mechanism utilizing visual information from the pitched surface. In fact this assumption has been made frequently, and - in different forms - underlies three substantial but very different historical streams in the literature. A quantitative theoretical development shows that two of these streams, although derived from very different viewpoints and appearing very different themselves (it is assumed that the basis for both PVP and VPEL is information about the pitch of the visual field in one, and information about the location of the subject's eye level within the visual field in the other), make identical predictions: each requires that the weighted sum of PVP and VPEL equal the magnitude of physical pitch and that the weighted sum of their first derivatives equal a constant. The third stream, which assumes that an internal representation of the visual field gives rise to both PVP and VPEL, requires that a weighted difference of PVP and VPEL be proportional to physical pitch and that the weighted difference of their derivatives equal a constant. In an experiment designed to examine the relation between VPEL and PVP, psychophysical measurements of VPEL and PVP were made on 20 subjects across a range of pitches from -30 degrees to +20 degrees. Contrary to the predictions from all three interpretations, we find no significant correlation between the two perceptual variables when the influence of pitch itself is removed, despite the fact that VPEL and PVP each increased systematically with increasing visual field pitch. The results not only rule out the specific predictions derived from all three historical streams, they also rule out any theoretical viewpoint that requires control of both perceptual responses by a single mechanism. The statistical independence between VPEL and PVP implies independence between the mechanisms that give rise to them. The correlation observed here and elsewhere between individual PVP and VPEL settings when the influence of the systematic variation of pitch is not eliminated is a consequence of the way in which variations in the two perceptions are generated experimentally, and not on an identity of the mechanisms mediating the generation of the two perceptual variables themselves. (+info)
Occlusions and their relationship with the distribution of contrasts in natural images.
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An Information-Theory-like hypothesis recently proposed for early visual processing (the Minimal Local-Asperity hypothesis) accounts for the adaptive behavior with intensity of horizontal cells. It has been shown that for this to hold, the probability that a point is traversed by an occluding border must increase supralinearly (that is, with a positive second derivative) as a function of contrast. We test this condition by analyzing the distribution of contrasts and their relationship with occluding borders in natural images. We find that the distribution of contrasts in natural images falls exponentially as a function of contrast. Moreover, the probability that a point is traversed by an occluding border in natural images always rises with contrast until reaching one. This rise tends to be supralinear and addition of noise (at low intensities) increases the supralinearity, shifting the rising portion of the curve towards higher contrasts. These findings lend support to the Minimal Local-Asperity hypothesis, which proposes that one of the main roles of early retinal processing is to extract optimally edge, contrast, and luminance attributes from the visual world based on previous knowledge about natural images. (+info)
A hierarchical neural system with attentional top-down enhancement of the spatial resolution for object recognition.
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We present a hierarchical neurodynamical system for object recognition based on attentional control of the spatial resolution with which an object is analyzed during an iterative hypothesis testing cycle. Psychophysical evidence strongly suggests that attentional processing results in the enhancement of the spatial resolution in the input region corresponding to the focus of attention. We adopt a computational neuroscience approach in order to analyze this attentional enhancement of the spatial resolution for object recognition. The system consists of a where- and a what-module which include networks with feedforward and feedback interconnections describing the mutual links between different areas of the visual cortex. (+info)