Non-canonical Hedgehog signaling mediates profibrotic hematopoiesis-stroma crosstalk in myeloproliferative neoplasms.

The role of hematopoietic Hedgehog signaling in myeloproliferative neoplasms (MPNs) remains incompletely understood despite data suggesting that Hedgehog (Hh) pathway inhibitors have therapeutic activity in patients. We aim to systematically interrogate the role of canonical vs. non-canonical Hh signaling in MPNs. We show that Gli1 protein levels in patient peripheral blood mononuclear cells (PBMCs) mark fibrotic progression and that, in murine MPN models, absence of hematopoietic Gli1, but not Gli2 or Smo, significantly reduces MPN phenotype and fibrosis, indicating that GLI1 in the MPN clone can be activated in a non-canonical fashion. Additionally, we establish that hematopoietic Gli1 has a significant effect on stromal cells, mediated through a druggable MIF-CD74 axis. These data highlight the complex interplay between alterations in the MPN clone and activation of stromal cells and indicate that Gli1 represents a promising therapeutic target in MPNs, particularly that Hh signaling is dispensable for normal hematopoiesis

Simulation of Three Phase Flow in Porous Media Using a High-Resolution Central Scheme

This article aims to demonstrate the advantages of using a high resolution central scheme in the field of multiphase flow in porous media. The black oil model, used in the petroleum reservoir engineering, is employed as it generally provides an acceptable model for most reservoirs and recovery processes. The governing equations are split into a parabolic equation for pressure variations and a system of hyperbolic equations for species transport. The hyperbolic part has non-convex degenerate flux functions which presents a major challenge to the robustness of numerical schemes. The two sets of equations are discretized on a triangular unstructured grid. A semi-discrete CFL-independent high-resolution central scheme due to Kurganov and Tadmor is employed in this work. Two test cases, one with top view and the other with cross sectional view, are solved to assess the performance of the proposed approach. Comparing the obtained results with those of the previous works indicates the robustness and accuracy of the scheme used. The simplicity of derivation and implementation of the numerical method used here makes it a viable choice for dealing with degenerate reservoir problems. Simulations show that inclusion of the gravitational effects in the second test case does not introduce any additional complications in the numerical method. This is in contrast to those schemes which require eigenvalue computations and therefore face substantial difficulty when eigenvalues change dramatically