Inferring qualitative relations in genetic networks and metabolic pathways.
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MOTIVATION: Inferring genetic network architecture from time series data of gene expression patterns is an important topic in bioinformatics. Although inference algorithms based on the Boolean network were proposed, the Boolean network was not sufficient as a model of a genetic network. RESULTS: First, a Boolean network model with noise is proposed, together with an inference algorithm for it. Next, a qualitative network model is proposed, in which regulation rules are represented as qualitative rules and embedded in the network structure. Algorithms are also presented for inferring qualitative relations from time series data. Then, an algorithm for inferring S-systems (synergistic and saturable systems) from time series data is presented, where S-systems are based on a particular kind of nonlinear differential equation and have been applied to the analysis of various biological systems. Theoretical results are shown for Boolean networks with noises and simple qualitative networks. Computational results are shown for Boolean networks with noises and S-systems, where real data are not used because the proposed models are still conceptual and the quantity and quality of currently available data are not enough for the application of the proposed methods. (+info)
Non-invasive quantification of liver perfusion with dynamic computed tomography and a dual-input one-compartmental model.
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Various liver diseases lead to significant alterations of the hepatic microcirculation. Therefore, quantification of hepatic perfusion has the potential to improve the assessment and management of liver diseases. Most methods used to quantify liver perfusion are invasive or controversial. This paper describes and validates a non-invasive method for the quantification of liver perfusion using computed tomography (CT). Dynamic single-section CT of the liver was performed after intravenous bolus administration of a low-molecular-mass iodinated contrast agent. Hepatic, aortic and portal-venous time-density curves were fitted with a dual-input one-compartmental model to calculate liver perfusion. Validation studies consisted of simultaneous measurements of hepatic perfusion with CT and with radiolabelled microspheres in rabbits at rest and after adenosine infusion. The feasibility and reproducibility of the CT method in humans was assessed by three observers in 10 patients without liver disease. In rabbits, significant correlations were observed between perfusion measurements obtained with CT and with microspheres (r=0.92 for total liver perfusion, r=0.81 for arterial perfusion and r=0.85 for portal perfusion). In patients, total liver plasma perfusion measured with CT was 112+/-28 ml.min(-1).100 ml(-1), arterial plasma perfusion was 18+/-12 ml.min(-1).100 ml(-1) and portal plasma perfusion was 93+/-31 ml.min(-1).100 ml(-1). The measurements obtained by the three observers were not significantly different from each other (P>0.1). Our results indicate that dynamic CT combined with a dual-input one-compartmental model provides a valid and reliable method for the non-invasive quantification of perfusion in the normal liver. (+info)
Extending the method of mathematically controlled comparison to include numerical comparisons.
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MOTIVATION: The method of mathematically controlled comparison has been used for some time to determine which of two alternative regulatory designs is better according to specific quantitative criteria for functional effectiveness. In some cases, the results obtained using this technique are general and independent of parameter values and the answers are clear-cut. In others, the result might be general, but the demonstration is difficult and numerical results with specific parameter values can help to clarify the situation. In either case, numerical results with specific parameter values can also provide an answer to the question of how much larger the values might be. In contrast, a more ambiguous result is obtained when either of the alternatives can have the larger value for a given systemic property, depending on the specific values of the parameters. In any case, introduction of specific values for the parameters reduces the generality of the results. Therefore, we have been motivated to develop and apply statistical methods that would permit the use of numerical values for the parameters and yet retain some of the generality that makes mathematically controlled comparison so attractive. RESULTS: We illustrate this new numerical method in a step-by-step application using a very simple didactic example. We also validate the results by comparison with the corresponding results obtained using the previously developed analytical method. The analytical approach is briefly present for reference purposes, since some of the same key concepts are needed to understand the numerical method and the results are needed for comparison. The numerical method confirms the qualitative differences between the systemic behavior of alternative designs obtained from the analytical method. In addition, the numerical method allows for quantification of the differences and it provides results that are general in a statistical sense. For example, the older analytical method showed that overall feedback inhibition in an unbranched pathway makes the system more robust whereas it decreases the stability margin of the steady state. The numerical method shows that the magnitudes of these differences are not comparable. The differences in stability margins (1-2% on average) are small when compared to the differences in robustness (50-100% on average). Furthermore, the numerical method shows that the system with overall feedback responds more quickly to change than the otherwise equivalent system without overall feedback. These results suggest reasons why overall feedback inhibition is such a prevalent regulatory pattern in unbranched biosynthetic pathways. (+info)
A kinetically significant intermediate in the folding of barnase.
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A series of studies on the small protein barnase in the 1990s established it as a paradigm for protein folding in which there is a kinetically important intermediate. But, a recent study in PNAS claims that there are no stable intermediates on the folding pathway. I summarize the evidence that proves that the folding kinetics of barnase is inconsistent with the absence of a folding intermediate. I reinterpret the major evidence presented against the intermediate (an inflection in the unfolding limb of a chevron plot) and show that the inflection is precisely what is predicted from the energy diagram for a three-state reaction with a kinetically significant on-pathway intermediate. The inflection is indicative of a change of rate determining step from the formation to breakdown of an intermediate on unfolding. Other evidence presented against the intermediate is, in fact, consistent with a kinetically important intermediate. I show how the complexities in the kinetics provide a means for measuring otherwise unobtainable rate constants and provide a strategy for mapping the structure of the early transition state in folding. Rather than refute multistate kinetics, the presence of the inflection in the unfolding plot constitutes a novel type of evidence for on-pathway folding intermediates. (+info)
Evolutionary biology of language.
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Language is the most important evolutionary invention of the last few million years. It was an adaptation that helped our species to exchange information, make plans, express new ideas and totally change the appearance of the planet. How human language evolved from animal communication is one of the most challenging questions for evolutionary biology The aim of this paper is to outline the major principles that guided language evolution in terms of mathematical models of evolutionary dynamics and game theory. I will discuss how natural selection can lead to the emergence of arbitrary signs, the formation of words and syntactic communication. (+info)
Calibration of the paediatric index of mortality in UK paediatric intensive care units.
(70/647)
AIM: To test a paediatric intensive care mortality prediction model for UK use. METHOD: Prospective collection of data from consecutive admissions to five UK paediatric intensive care units (PICUs), representing a broad cross section of paediatric intensive care activity. A total of 7253 admissions were analysed using tests of the discrimination and calibration of the logistic regression equation. RESULTS: The model discriminated and calibrated well. The area under the ROC plot was 0.84 (95% CI 0.819 to 0.853). The standardised mortality ratio was 0.87 (95% CI 0.81 to 0.94). There was remarkable concordance in the performance of the paediatric index of mortality (PIM) within each PICU, and in the performance of the PICUs as assessed by PIM. Variation in the proportion of admissions that were ventilated or transported from another hospital did not affect the results. CONCLUSION: We recommend that UK PICUs use PIM for their routine audit needs. PIM is not affected by the standard of therapy after admission to PICU, the information needed to calculate PIM is easy to collect, and the model is free. (+info)
Stiles-Crawford effect of the first kind: assessment of photoreceptor alignments following dark patching.
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Properties of presumed mechanisms controlling photoreceptor alignments are partially defined. A phototropic mechanism normally dominates alignment, but do modest changes in orientations occur with dark patching? Here, new photopic Stiles-Crawford (SCE-I) determinations were made before patching (pre-patch), just after 8-days of dark-patching (post-patch), and 3 days after patch removal (recovery test). We tested at 0, 11 and 22 degrees in the temporal retina of both eyes. Ten eyes of adult subjects were tested. SCE-I peak positions and Stile's parameter 'rho' were assessed. Dark-patching effects were small. Observations revealed meaningful corrective alignment overshoots with recovery in the light. Results suggest (1) the presence of multiple weak mechanisms affecting receptor alignments in the dark; (2) the phototropic mechanism to be dominant in the light; (3) the need for multiple test loci to be sampled in such studies, and (4) small changes in the SCE-I in the pupil plane can reflect meaningful events occurring at the retina. (+info)
The spherical aberration of the crystalline lens of the human eye.
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The in vivo spherical aberration of the lenses of 26 subjects was estimated from the measured total aberration of the eye and that predicted from the measured shape of the anterior corneal surface. Since it was only possible to estimate the aberration contribution from the posterior corneal surface, its value led to an uncertainty in the final aberration level of the lens. For all the subjects and for a wide range of possible aberration levels at the posterior corneal surface, the spherical aberration of the relaxed lens was found to be negative. (+info)