Bayesian inference of agent-based models: a tool for studying kidney branching morphogenesis

The adult mammalian kidney has a complex, highly-branched collecting duct epithelium that arises as a ureteric bud sidebranch from an epithelial tube known as the nephric duct. Subsequent branching of the ureteric bud to form the collecting duct tree is regulated by subcellular interactions between the epithelium and a population of mesenchymal cells that surround the tips of outgrowing branches. The mesenchymal cells produce glial cell-line derived neurotrophic factor (GDNF), that binds with RET receptors on the surface of the epithelial cells to stimulate several subcellular pathways in the epithelium. Such interactions are known to be a prerequisite for normal branching development, although competing theories exist for their role in morphogenesis. Here we introduce the first agent-based model of ex vivo kidney uretic branching. Through comparison with experimental data, we show that growth factor-regulated growth mechanisms can explain early epithelial cell branching, but only if epithelial cell division depends in a switch-like way on the local growth factor concentration; cell division occurring only if the driving growth factor level exceeds a threshold. We also show how a recently-developed method, "Approximate Approximate Bayesian Computation", can be used to infer key model parameters, and reveal the dependency between the parameters controlling a growth factor-dependent growth switch. These results are consistent with a requirement for signals controlling proliferation and chemotaxis, both of which are previously identified roles for GDNF

Observation of the screening signature in the lateral photovoltage of electrons in the Quantum Hall regime

The lateral photovoltage generated in the plane of a two-dimensional electron system (2DES) by a focused light spot, exhibits a fine-structure in the quantum oscillations in a magnetic field near the Quantum Hall conductivity minima. A double peak structure occurs near the minima of the longitudinal conductivity oscillations. This is the characteristic signature of the interplay between screening and Landau quantization.Comment: 4 pages, 4 figures, to be published in Phys. Rev.

Reduced basis isogeometric mortar approximations for eigenvalue problems in vibroacoustics

We simulate the vibration of a violin bridge in a multi-query context using reduced basis techniques. The mathematical model is based on an eigenvalue problem for the orthotropic linear elasticity equation. In addition to the nine material parameters, a geometrical thickness parameter is considered. This parameter enters as a 10th material parameter into the system by a mapping onto a parameter independent reference domain. The detailed simulation is carried out by isogeometric mortar methods. Weakly coupled patch-wise tensorial structured isogeometric elements are of special interest for complex geometries with piecewise smooth but curvilinear boundaries. To obtain locality in the detailed system, we use the saddle point approach and do not apply static condensation techniques. However within the reduced basis context, it is natural to eliminate the Lagrange multiplier and formulate a reduced eigenvalue problem for a symmetric positive definite matrix. The selection of the snapshots is controlled by a multi-query greedy strategy taking into account an error indicator allowing for multiple eigenvalues

Dibaryon Spectroscopy

The AdS/CFT correspondence relates dibaryons in superconformal gauge theories to holomorphic curves in Kaehler-Einstein surfaces. The degree of the holomorphic curves is proportional to the gauge theory conformal dimension of the dibaryons. Moreover, the number of holomorphic curves should match, in an appropriately defined sense, the number of dibaryons. Using AdS/CFT backgrounds built from the generalized conifolds of Gubser, Shatashvili, and Nekrasov (1999), we show that the gauge theory prediction for the dimension of dibaryonic operators does indeed match the degree of the corresponding holomorphic curves. For AdS/CFT backgrounds built from cones over del Pezzo surfaces, we are able to match the degree of the curves to the conformal dimension of dibaryons for the n'th del Pezzo surface, n=1,2,...,6. Also, for the del Pezzos and the A_k type generalized conifolds, for the dibaryons of smallest conformal dimension, we are able to match the number of holomorphic curves with the number of possible dibaryon operators from gauge theory.Comment: 30 pages, 6 figures, corrected refs; v3 typos correcte

Targeting BMI-1 to deplete antibody-secreting cells in autoimmunity

Objectives. B cells drive the production of autoreactive antibodysecreting cells, ASCs, in autoimmune diseases such as Systemic Lupus Erythematosus, SLE, and Sjogren, s syndrome, causing long-, term organ damage. Current treatments for antibody-mediated autoimmune diseases target B cells or broadly suppress the immune system. However, pre-existing long-lived ASCs are often refractory to treatment, leaving a reservoir of autoreactive cells that continue to produce antibodies. Therefore, the development of novel treatment methods targeting ASCs is vital to improve patient outcomes. Our objective was to test whether targeting the epigenetic regulator BMI-, could deplete ASCs in autoimmune conditions in vivo and in vitro. Methods. Use of a BMI-, inhibitor in both mouse and human autoimmune settings was investigated. Lyn, mice, a model of SLE, were treated with the BMI-, small molecule inhibitor PTC-, before assessment of ASCs, serum antibody and immune complexes. To examine human ASC survival, a novel human fibroblast-based assay was established, and the impact of PTC-, on ASCs derived from Sjogren, s syndrome, patients was evaluated. Results. BMI-, inhibition significantly decreased splenic and bone marrow ASCs in Lyn, mice. The decline in ASCs was linked to aberrant cell cycle gene expression and led to a significant decrease in serum IgG, immune complexes and anti-DNA IgG. PTC-, was also efficacious in reducing ex vivo plasma cell survival from both Sjogren, s syndrome, patients and age-matched healthy donors. Conclusion. These data provide evidence that inhibiting BMI-, can deplete ASC in a variety of contexts and thus BMI-, is a viable therapeutic target for antibody-mediated autoimmune diseases.Jack Polmear, Lauren Hailes, Moshe Olshansky, Maureen Rischmueller, Elan L'Estrange-Stranieri, Anne L Fletcher, Margaret L Hibbs, Vanessa L Bryant, Kim L Good-Jacobso

Magnetic Fields in the Milky Way

This chapter presents a review of observational studies to determine the magnetic field in the Milky Way, both in the disk and in the halo, focused on recent developments and on magnetic fields in the diffuse interstellar medium. I discuss some terminology which is confusingly or inconsistently used and try to summarize current status of our knowledge on magnetic field configurations and strengths in the Milky Way. Although many open questions still exist, more and more conclusions can be drawn on the large-scale and small-scale components of the Galactic magnetic field. The chapter is concluded with a brief outlook to observational projects in the near future.Comment: 22 pages, 5 figures, to appear in "Magnetic Fields in Diffuse Media", eds. E.M. de Gouveia Dal Pino and A. Lazaria