256 research outputs found

    Verified global optimization for estimating the parameters of nonlinear models

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    Nonlinear parameter estimation is usually achieved via the minimization of some possibly non-convex cost function. Interval analysis allows one to derive algorithms for the guaranteed characterization of the set of all global minimizers of such a cost function when an explicit expression for the output of the model is available or when this output is obtained via the numerical solution of a set of ordinary differential equations. However, cost functions involved in parameter estimation are usually challenging for interval techniques, if only because of multi-occurrences of the parameters in the formal expression of the cost. This paper addresses parameter estimation via the verified global optimization of quadratic cost functions. It introduces tools for the minimization of generic cost functions. When an explicit expression of the output of the parametric model is available, significant improvements may be obtained by a new box exclusion test and by careful manipulations of the quadratic cost function. When the model is described by ODEs, some of the techniques available in the previous case may still be employed, provided that sensitivity functions of the model output with respect to the parameters are available

    Protein disulfide-isomerase interacts with a substrate protein at all stages along its folding pathway

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    In contrast to molecular chaperones that couple protein folding to ATP hydrolysis, protein disulfide-isomerase (PDI) catalyzes protein folding coupled to formation of disulfide bonds (oxidative folding). However, we do not know how PDI distinguishes folded, partly-folded and unfolded protein substrates. As a model intermediate in an oxidative folding pathway, we prepared a two-disulfide mutant of basic pancreatic trypsin inhibitor (BPTI) and showed by NMR that it is partly-folded and highly dynamic. NMR studies show that it binds to PDI at the same site that binds peptide ligands, with rapid binding and dissociation kinetics; surface plasmon resonance shows its interaction with PDI has a Kd of ca. 10−5 M. For comparison, we characterized the interactions of PDI with native BPTI and fully-unfolded BPTI. Interestingly, PDI does bind native BPTI, but binding is quantitatively weaker than with partly-folded and unfolded BPTI. Hence PDI recognizes and binds substrates via permanently or transiently unfolded regions. This is the first study of PDI's interaction with a partly-folded protein, and the first to analyze this folding catalyst's changing interactions with substrates along an oxidative folding pathway. We have identified key features that make PDI an effective catalyst of oxidative protein folding – differential affinity, rapid ligand exchange and conformational flexibility

    Functions of Intermittent Locomotion in Mustached Tamarins (Saguinus mystax)

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    Many animals interrupt their moving with brief pauses, which appear to serve several different functions. We examined the function of such intermittent locomotion in wild living mustached tamarins (Saguinus mystax), small arboreal New World primates that form mixed-species groups with saddleback tamarins (Saguinus fuscicollis). We investigated how different environmental and social factors affect pausing during locomotion and used these data to infer the function of this behavior. As measures of intermittent locomotion, we used percentage of time spent pausing and pause rate. We considered 3 possible functions that are not mutually exclusive: increased endurance, route planning, and antipredator vigilance. Mustached tamarins spent on average (mean ± SE) 55.1 ± 1.0% of time pausing, which makes effective resource exploitation more time consuming and needs to be outweighed by correspondingly large benefits. Percentage of time spent pausing decreased in larger mixed-species groups vs. smaller mixed-species groups and decreased with height and in monkeys carrying infants. It was not affected by sex, age, spatial arrangement, or single-species group size. Pause rate increased in individuals traveling independently compared to those traveling in file, but was not affected by other factors. The group size effect in mixed-species groups lends support to the notion that pausing during locomotion is an antipredator tactic that can be reduced in the increased safety of larger groups, but other results suggest that additional functions, particularly route planning, are also of great importance. Benefits in terms of predator confusion and group movement coordination are also likely to play a role and remain a topic for further research

    Combining eye and hand in search is suboptimal

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    When performing everyday tasks, we often move our eyes and hand together: we look where we are reaching in order to better guide the hand. This coordinated pattern with the eye leading the hand is presumably optimal behaviour. But eyes and hands can move to different locations if they are involved in different tasks. To find out whether this leads to optimal performance, we studied the combination of visual and haptic search. We asked ten participants to perform a combined visual and haptic search for a target that was present in both modalities and compared their search times to those on visual only and haptic only search tasks. Without distractors, search times were faster for visual search than for haptic search. With many visual distractors, search times were longer for visual than for haptic search. For the combined search, performance was poorer than the optimal strategy whereby each modality searched a different part of the display. The results are consistent with several alternative accounts, for instance with vision and touch searching independently at the same time

    The placebo effect in the motor domain is differently modulated by the external and internal focus of attention

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    Among the cognitive strategies that can facilitate motor performance in sport and physical practice, a prominent role is played by the direction of the focus of attention and the placebo effect. Consistent evidence converges in indicating that these two cognitive functions can influence the motor outcome, although no study up-to-now tried to study them together in the motor domain. In this explorative study, we combine for the first time these approaches, by applying a placebo procedure to increase force and by manipulating the focus of attention with explicit verbal instructions. Sixty healthy volunteers were asked to perform abduction movements with the index finger as strongly as possible against a piston and attention could be directed either toward the movements of the finger (internal focus, IF) or toward the movements of the piston (external focus, EF). Participants were randomized in 4 groups: two groups underwent a placebo procedure (Placebo-IF and Placebo-EF), in which an inert treatment was applied on the finger with verbal information on its positive effects on force; two groups underwent a control procedure (Control-IF and Control-EF), in which the same treatment was applied with overt information about its inefficacy. The placebo groups were conditioned about the effects of the treatment with a surreptitious amplification of a visual feedback signalling the level of force. During the whole procedure, we recorded actual force, subjective variables and electromyography from the hand muscles. The Placebo-IF group had higher force levels after the procedure than before, whereas the Placebo-EF group had a decrease of force. Electromyography showed that the Placebo-IF group increased the muscle units recruitment without changing the firing rate. These findings show for the first time that the placebo effect in motor performance can be influenced by the subject\u2019s attentional focus, being enhanced with the internal focus of attention

    Influence of Low-Level Stimulus Features, Task Dependent Factors, and Spatial Biases on Overt Visual Attention

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    Visual attention is thought to be driven by the interplay between low-level visual features and task dependent information content of local image regions, as well as by spatial viewing biases. Though dependent on experimental paradigms and model assumptions, this idea has given rise to varying claims that either bottom-up or top-down mechanisms dominate visual attention. To contribute toward a resolution of this discussion, here we quantify the influence of these factors and their relative importance in a set of classification tasks. Our stimuli consist of individual image patches (bubbles). For each bubble we derive three measures: a measure of salience based on low-level stimulus features, a measure of salience based on the task dependent information content derived from our subjects' classification responses and a measure of salience based on spatial viewing biases. Furthermore, we measure the empirical salience of each bubble based on our subjects' measured eye gazes thus characterizing the overt visual attention each bubble receives. A multivariate linear model relates the three salience measures to overt visual attention. It reveals that all three salience measures contribute significantly. The effect of spatial viewing biases is highest and rather constant in different tasks. The contribution of task dependent information is a close runner-up. Specifically, in a standardized task of judging facial expressions it scores highly. The contribution of low-level features is, on average, somewhat lower. However, in a prototypical search task, without an available template, it makes a strong contribution on par with the two other measures. Finally, the contributions of the three factors are only slightly redundant, and the semi-partial correlation coefficients are only slightly lower than the coefficients for full correlations. These data provide evidence that all three measures make significant and independent contributions and that none can be neglected in a model of human overt visual attention

    Patterns of nucleotide diversity at the regions encompassing the Drosophila insulin-like peptide (dilp) genes: demography vs positive selection in Drosophila melanogaster.

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    In Drosophila, the insulin-signaling pathway controls some life history traits, such as fertility and lifespan, and it is considered to be the main metabolic pathway involved in establishing adult body size. Several observations concerning variation in body size in the Drosophila genus are suggestive of its adaptive character. Genes encoding proteins in this pathway are, therefore, good candidates to have experienced adaptive changes and to reveal the footprint of positive selection. The Drosophila insulin-like peptides (DILPs) are the ligands that trigger the insulin-signaling cascade. In Drosophila melanogaster, there are several peptides that are structurally similar to the single mammalian insulin peptide. The footprint of recent adaptive changes on nucleotide variation can be unveiled through the analysis of polymorphism and divergence. With this aim, we have surveyed nucleotide sequence variation at the dilp1-7 genes in a natural population of D. melanogaster. The comparison of polymorphism in D. melanogaster and divergence from D. simulans at different functional classes of the dilp genes provided no evidence of adaptive protein evolution after the split of the D. melanogaster and D. simulans lineages. However, our survey of polymorphism at the dilp gene regions of D. melanogaster has provided some evidence for the action of positive selection at or near these genes. The regions encompassing the dilp1-4 genes and the dilp6 gene stand out as likely affected by recent adaptive events
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