676 research outputs found

    When the optimal is not the best: parameter estimation in complex biological models

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    Background: The vast computational resources that became available during the past decade enabled the development and simulation of increasingly complex mathematical models of cancer growth. These models typically involve many free parameters whose determination is a substantial obstacle to model development. Direct measurement of biochemical parameters in vivo is often difficult and sometimes impracticable, while fitting them under data-poor conditions may result in biologically implausible values. Results: We discuss different methodological approaches to estimate parameters in complex biological models. We make use of the high computational power of the Blue Gene technology to perform an extensive study of the parameter space in a model of avascular tumor growth. We explicitly show that the landscape of the cost function used to optimize the model to the data has a very rugged surface in parameter space. This cost function has many local minima with unrealistic solutions, including the global minimum corresponding to the best fit. Conclusions: The case studied in this paper shows one example in which model parameters that optimally fit the data are not necessarily the best ones from a biological point of view. To avoid force-fitting a model to a dataset, we propose that the best model parameters should be found by choosing, among suboptimal parameters, those that match criteria other than the ones used to fit the model. We also conclude that the model, data and optimization approach form a new complex system, and point to the need of a theory that addresses this problem more generally

    An HST Search for Lyman Continuum Emission From Galaxies at z=1.1--1.4

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    If enough of their Lyman limit continuum escapes, star-forming galaxies could be significant contributors to the cosmic background of ionizing photons. To investigate this possibility, we obtained the first deep imaging in the far ultraviolet of eleven bright blue galaxies at intermediate redshift (z=1.1--1.4). NO Lyman continuum emission was detected. Sensitive, model-independent, upper limits of typically 2 x 10**-19 erg/sec/cm2/Ang were obtained for the ionizing flux escaping from these normal galaxies. This corresponds to lower limits on the observed ratio of 1500 to 700Ang flux of 150 up to 1000. Based on a wide range of stellar synthesis models, this suggests that less than 6%, down to less than 1%, of the available ionizing flux emitted by hot stars is escaping these galaxies. The magnitude of this spectral break at the Lyman l imit confirms that the basic premise of `Lyman break' searches for galaxies at high redshift can also be applied at intermediate redshifts. This implies that the integrated contribution of galaxies to the UV cosmic background at z around 1.2 is less than 15%, and may be less than 2%.Comment: 20 manuscript pages, which includes two tables and two figures. To be published in 1 December 2003 issue of The Astrophysical Journa

    Ranking ligand affinity for the DNA minor groove by experiment and simulation

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    The structural and thermodynamic basis for the strength and selectivity of the interactions of minor-groove binders (MGBs) with DNA is not fully understood. In 2003 we reported the first example of a thiazole containing MGB that bound in a phase shifted pattern that spanned 6 base-pairs rather than the usual 4 (for tricyclic distamycin-like compounds). Since then, using DNA footprinting, nuclear magnetic resonance spectroscopy, isothermal titration calorimetry and molecular dynamics, we have established that the flanking bases around the central 4 being read by the ligand have subtle effects on recognition. We have investigated the effect of these flanking sequences on binding and the reasons for the differences and established a computational method to rank ligand affinity against varying DNA sequences

    Constraints on gamma-ray burst and supernova progenitors through circumstellar absorption lines. (II): Post-LBV Wolf-Rayet stars

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    Van Marle et al. (2005) showed that circumstellar absorption lines in early Type Ib/c supernova and gamma-ray burst afterglow spectra may reveal the progenitor evolution of the exploding Wolf-Rayet star. While the quoted paper deals with Wolf-Rayet stars which evolved through a red supergiant stage, we investigate here the initially more massive Wolf-Rayet stars which are thought to evolve through a Luminous Blue Variable (LBV) stage. We perform hydrodynamic simulations of the evolution of the circumstellar medium around a 60 Msol star, from the main sequence through the LBV and Wolf-Rayet stages, up to core collapse. We then compute the column density of the circumstellar matter as a function of radial velocity, time and angle. This allows a comparison with the number and blue-shifts, of absorption components in the spectra of LBVs, Wolf-Rayet stars, Type Ib/c supernovae and gamma-ray burst afterglows. Our simulation for the post-LBV stage shows the formation of various absorption components, which are, however, rather short lived; they dissipate on time scales shorter than 50,000yr. As the LBV stage is thought to occur at the beginning of core helium burning, the remaining Wolf-Rayet life time is expected to be one order of magnitude larger. When interpreting the absorption components in the afterglow spectrum of GRB-021004 as circumstellar, it can be concluded that the progenitor of this source did most likely not evolve through an LBV stage. However, a close binary with late common-envelope phase (Case C) may produce a circumstellar medium that closely resembles the LBV to Wolf-Rayet evolution, but with a much shorter Wolf-Rayet period.Comment: accepted for publication by A&

    Forming a constant density medium close to long gamma-ray bursts

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    The progenitor stars of long Gamma-Ray Bursts (GRBs) are thought to be Wolf-Rayet stars, which generate a massive and energetic wind. Nevertheless, about 25 percent of all GRB afterglows light curves indicate a constant density medium close to the exploding star. We explore various ways to produce this, by creating situations where the wind termination shock arrives very close to the star, as the shocked wind material has a nearly constant density. Typically, the distance between a Wolf-Rayet star and the wind termination shock is too large to allow afterglow formation in the shocked wind material. Here, we investigate possible causes allowing for a smaller distance: A high density or a high pressure in the surrounding interstellar medium (ISM), a weak Wolf-Rayet star wind, the presence of a binary companion, and fast motion of the Wolf-Rayet star relative to the ISM. We find that all four scenarios are possible in a limited parameter space, but that none of them is by itself likely to explain the large fraction of constant density afterglows. A low GRB progenitor metallicity, and a high GRB energy make the occurrence of a GRB afterglow in a constant density medium more likely. This may be consistent with constant densities beingpreferentially found for energetic, high redshift GRBs.Comment: 13 pages, 13 figures, new version: as accepted by Astronomy & Astrophysic

    Effect of family relatedness on characteristics of estimated IBD probabilities in relation to precision of QTL estimates

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    <p>Abstract</p> <p>Background</p> <p>A random QTL effects model uses a function of probabilities that two alleles in the same or in different animals at a particular genomic position are identical by descent (IBD). Estimates of such IBD probabilities and therefore, modeling and estimating QTL variances, depend on marker polymorphism, strength of linkage and linkage disequilibrium of markers and QTL, and the relatedness of animals in the pedigree. The effect of relatedness of animals in a pedigree on IBD probabilities and their characteristics was examined in a simulation study.</p> <p>Results</p> <p>The study based on nine multi-generational family structures, similar to a pedigree structure of a real dairy population, distinguished by an increased level of inbreeding from zero to 28% across the studied population. Highest inbreeding level in the pedigree, connected with highest relatedness, was accompanied by highest IBD probabilities of two alleles at the same locus, and by lower relative variation coefficients. Profiles of correlation coefficients of IBD probabilities along the marked chromosomal segment with those at the true QTL position were steepest when the inbreeding coefficient in the pedigree was highest. Precision of estimated QTL location increased with increasing inbreeding and pedigree relatedness. A method to assess the optimum level of inbreeding for QTL detection is proposed, depending on population parameters.</p> <p>Conclusions</p> <p>An increased overall relationship in a QTL mapping design has positive effects on precision of QTL position estimates. But the relationship of inbreeding level and the capacity for QTL detection depending on the recombination rate of QTL and adjacent informative marker is not linear.</p

    The PREP suite: predictive RNA editors for plant mitochondrial genes, chloroplast genes and user-defined alignments

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    RNA editing alters plant mitochondrial and chloroplast transcripts by converting specific cytidines to uridines, which usually results in a change in the amino acid sequence of the translated protein. Systematic studies have experimentally identified sites of RNA editing in organellar transcriptomes from several species, but these analyses have not kept pace with rate of genome sequencing. The PREP (predictive RNA editors for plants) suite was developed to computationally predict sites of RNA editing based on the well-known principle that editing in plant organelles increases the conservation of proteins across species. The PREP suite provides predictive RNA editors for plant mitochondrial genes (PREP-Mt), for chloroplast genes (PREP-Cp), and for alignments submitted by the user (PREP-Aln). These servers require minimal input, are very fast, and are highly accurate on all seed plants examined to date. PREP-Mt has proved useful in several research studies and the newly developed PREP-Cp and PREP-Aln servers should be of further assistance for analyses that require knowledge of the location of sites of RNA editing. The PREP suite is freely available at http://prep.unl.edu/

    A new mechanical stellar wind feedback model for the Rosette Nebula

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    The famous Rosette Nebula has an evacuated central cavity formed from the stellar winds ejected from the 2–6 Myr old codistant and comoving central star cluster NGC 2244. However, with upper age estimates of less than 110 000 yr, the central cavity is too young compared to NGC 2244 and existing models do not reproduce its properties. A new proper motion study herein using Gaia data reveals the ejection of the most massive star in the Rosette, HD 46223, from NGC 2244 occurred 1.73 (+0.34, −0.25) Myr (1σ uncertainty) in the past. Assuming this ejection was at the birth of the most massive stars in NGC 2244, including the dominant centrally positioned HD 46150, the age is set for the famous ionized region at more than 10 times that derived for the cavity. Here, we are able to reproduce the structure of the Rosette Nebula, through simulation of mechanical stellar feedback from a 40 Mₒ star in a thin sheet-like molecular cloud. We form the 135 000 Mₒ cloud from thermally unstable diffuse interstellar medium (ISM) under the influence of a realistic background magnetic field with thermal/magnetic pressure equilibrium. Properties derived from a snapshot of the simulation at 1.5 Myr, including cavity size, stellar age, magnetic field, and resulting inclination to the line of sight, match those derived from observations. An elegant explanation is thus provided for the stark contrast in age estimates based on realistic diffuse ISM properties, molecular cloud formation and stellar wind feedback
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