Computational Modeling of Interacting VEGF and Soluble VEGF Receptor Concentration Gradients

Experimental data indicates that soluble vascular endothelial growth factor (VEGF) receptor 1 (sFlt-1) modulates the guidance cues provided to sprouting blood vessels by VEGF-A. To better delineate the role of sFlt-1 in VEGF signaling, we have developed an experimentally based computational model. This model describes dynamic spatial transport of VEGF, and its binding to receptors Flt-1 and Flk-1, in a mouse embryonic stem cell model of vessel morphogenesis. The model represents the local environment of a single blood vessel. Our simulations predict that blood vessel secretion of sFlt-1 and increased local sFlt-1 sequestration of VEGF results in decreased VEGF–Flk-1 levels on the sprout surface. In addition, the model predicts that sFlt-1 secretion increases the relative gradient of VEGF–Flk-1 along the sprout surface, which could alter endothelial cell perception of directionality cues. We also show that the proximity of neighboring sprouts may alter VEGF gradients, VEGF receptor binding, and the directionality of sprout growth. As sprout distances decrease, the probability that the sprouts will move in divergent directions increases. This model is a useful tool for determining how local sFlt-1 and VEGF gradients contribute to the spatial distribution of VEGF receptor binding, and can be used in conjunction with experimental data to explore how multi-cellular interactions and relationships between local growth factor gradients drive angiogenesis

Interacting damage models mapped onto Ising and percolation models

We introduce a class of damage models on regular lattices with isotropic interactions, as e.g. quasistatic fiber bundles. The system starts intact with a surface-energy threshold required to break any cell sampled from an uncorrelated quenched-disorder distribution. The evolution of this heterogeneous system is ruled by Griffith's principle which states that a cell breaks when the release in elastic energy in the system exceeds the surface-energy barrier necessary to break the cell. By direct integration over all possible realizations of the quenched disorder, we obtain the probability distribution of each damage configuration at any level of the imposed external deformation. We demonstrate an isomorphism between the distributions so obtained and standard generalized Ising models, in which the coupling constants and effective temperature in the Ising model are functions of the nature of the quenched-disorder distribution and the extent of accumulated damage. In particular, we show that damage models with global load sharing are isomorphic to standard percolation theory, that damage models with local load sharing rule are isomorphic to the standard Ising model, and draw consequences thereof for the universality class and behavior of the autocorrelation length of the breakdown transitions corresponding to these models. We also treat damage models having more general power-law interactions, and classify the breakdown process as a function of the power-law interaction exponent. Last, we also show that the probability distribution over configurations is a maximum of Shannon's entropy under some specific constraints related to the energetic balance of the fracture process, which firmly relates this type of quenched-disorder based damage model to standard statistical mechanics.Comment: 16 pages, 3 figure

Shear stress fluctuations in the granular liquid and solid phases

We report on experimentally observed shear stress fluctuations in both granular solid and fluid states, showing that they are non-Gaussian at low shear rates, reflecting the predominance of correlated structures (force chains) in the solidlike phase, which also exhibit finite rigidity to shear. Peaks in the rigidity and the stress distribution's skewness indicate that a change to the force-bearing mechanism occurs at the transition to fluid behaviour, which, it is shown, can be predicted from the behaviour of the stress at lower shear rates. In the fluid state stress is Gaussian distributed, suggesting that the central limit theorem holds. The fibre bundle model with random load sharing effectively reproduces the stress distribution at the yield point and also exhibits the exponential stress distribution anticipated from extant work on stress propagation in granular materials.Comment: 11 pages, 3 figures, latex. Replacement adds journal reference and addresses referee comment

Burst avalanches in solvable models of fibrous materials

We review limiting models for fracture in bundles of fibers, with statistically distributed thresholds for breakdown of individual fibers. During the breakdown process, avalanches consisting of simultaneous rupture of several fibers occur, and the distribution $D(\Delta)$ of the magnitude $\Delta$ of such avalanches is the central characteristics in our analysis. For a bundle of parallel fibers two limiting models of load sharing are studied and contrasted: the global model in which the load carried by a bursting fiber is equally distributed among the surviving members, and the local model in which the nearest surviving neighbors take up the load. For the global model we investigate in particular the conditions on the threshold distribution which would lead to anomalous behavior, i.e. deviations from the asymptotics $D(\Delta) \sim \Delta^{-5/2}$, known to be the generic behavior. For the local model no universal power-law asymptotics exists, but we show for a particular threshold distribution how the avalanche distribution can nevertheless be explicitly calculated in the large-bundle limit.Comment: 28 pages, RevTeX, 3 Postscript figure

Existence of solutions for a higher order non-local equation appearing in crack dynamics

In this paper, we prove the existence of non-negative solutions for a non-local higher order degenerate parabolic equation arising in the modeling of hydraulic fractures. The equation is similar to the well-known thin film equation, but the Laplace operator is replaced by a Dirichlet-to-Neumann operator, corresponding to the square root of the Laplace operator on a bounded domain with Neumann boundary conditions (which can also be defined using the periodic Hilbert transform). In our study, we have to deal with the usual difficulty associated to higher order equations (e.g. lack of maximum principle). However, there are important differences with, for instance, the thin film equation: First, our equation is nonlocal; Also the natural energy estimate is not as good as in the case of the thin film equation, and does not yields, for instance, boundedness and continuity of the solutions (our case is critical in dimension $1$ in that respect)

Using gene expression databases for classical trait QTL candidate gene discovery in the BXD recombinant inbred genetic reference population: Mouse forebrain weight

<p>Abstract</p> <p>Background</p> <p>Successful strategies for QTL gene identification benefit from combined experimental and bioinformatic approaches. Unique design aspects of the BXD recombinant inbred line mapping panel allow use of archived gene microarray expression data to filter likely from unlikely candidates. This prompted us to propose a simple five-filter protocol for candidate nomination. To filter more likely from less likely candidates, we required candidate genes near to the QTL to have mRNA abundance that correlated with the phenotype among the BXD lines as well as differed between the parental lines C57BL/6J and DBA/2J. We also required verification of mRNA abundance by an independent method, and finally we required either differences in protein levels or confirmed DNA sequence differences.</p> <p>Results</p> <p>QTL mapping of mouse forebrain weight in 34 BXD RI lines found significant association on chromosomes 1 and 11, with each C57BL/6J allele increasing weight by more than half a standard deviation. The intersection of gene lists that were within ± 10 Mb of the strongest associated location, that had forebrain mRNA abundance correlated with forebrain weight among the BXD, and that had forebrain mRNA abundance differing between C57BL/6J and DBA/2J, produced two candidates, <it>Tnni1 </it>(troponin 1) and <it>Asb3 </it>(ankyrin repeat and SOCS box-containing protein 3). Quantitative RT-PCR confirmed the direction of an increased expression in C57BL/6J genotype over the DBA/2J genotype for both genes, a difference that translated to a 2-fold difference in Asb3 protein. Although Tnni1 protein differences could not be confirmed, a 273 bp indel polymorphism was discovered 1 Kb upstream of the transcription start site.</p> <p>Conclusion</p> <p>Delivery of well supported candidate genes following a single quantitative trait locus mapping experiment is difficult. However, by combining available gene expression data with QTL mapping, we illustrated a five-filter protocol that nominated <it>Asb3 </it>and <it>Tnni1 </it>as candidates affecting increased mouse forebrain weight. We recommend our approach when (1) investigators are working with phenotypic differences between C57BL/6J and DBA/2J, and (2) gene expression data are available on <url>http://www.genenetwork.org</url> that relate to the phenotype of interest. Under these circumstances, measurement of the phenotype in the BXD lines will likely also deliver excellent candidate genes.</p

Explaining Evidence Denial as Motivated Pragmatically Rational Epistemic Irrationality

This paper introduces a model for evidence denial that explains this behavior as a manifestation of rationality and it is based on the contention that social values (measurable as utilities) often underwrite these sorts of responses. Moreover, it is contended that the value associated with group membership in particular can override epistemic reason when the expected utility of a belief or belief system is great. However, it is also true that it appears to be the case that it is still possible for such unreasonable believers to reverse this sort of dogmatism and to change their beliefs in a way that is epistemically rational. The conjecture made here is that we should expect this to happen only when the expected utility of the beliefs in question dips below a threshold where the utility value of continued dogmatism and the associated group membership is no longer sufficient to motivate defusing the counter-evidence that tells against such epistemically irrational beliefs