Stealth Proteins: In Silico Identification of a Novel Protein Family Rendering Bacterial Pathogens Invisible to Host Immune Defense

There are a variety of bacterial defense strategies to survive in a hostile environment. Generation of extracellular polysaccharides has proved to be a simple but effective strategy against the host's innate immune system. A comparative genomics approach led us to identify a new protein family termed Stealth, most likely involved in the synthesis of extracellular polysaccharides. This protein family is characterized by a series of domains conserved across phylogeny from bacteria to eukaryotes. In bacteria, Stealth (previously characterized as SacB, XcbA, or WefC) is encoded by subsets of strains mainly colonizing multicellular organisms, with evidence for a protective effect against the host innate immune defense. More specifically, integrating all the available information about Stealth proteins in bacteria, we propose that Stealth is a D-hexose-1-phosphoryl transferase involved in the synthesis of polysaccharides. In the animal kingdom, Stealth is strongly conserved across evolution from social amoebas to simple and complex multicellular organisms, such as Dictyostelium discoideum, hydra, and human. Based on the occurrence of Stealth in most Eukaryotes and a subset of Prokaryotes together with its potential role in extracellular polysaccharide synthesis, we propose that metazoan Stealth functions to regulate the innate immune system. Moreover, there is good reason to speculate that the acquisition and spread of Stealth could be responsible for future epidemic outbreaks of infectious diseases caused by a large variety of eubacterial pathogens. Our in silico identification of a homologous protein in the human host will help to elucidate the causes of Stealth-dependent virulence. At a more basic level, the characterization of the molecular and cellular function of Stealth proteins may shed light on fundamental mechanisms of innate immune defense against microbial invasion

The Numb/p53 circuitry couples replicative self-renewal and tumor suppression in mammary epithelial cells

The cell fate determinant Numb orchestrates tissue morphogenesis and patterning in developmental systems. In the human mammary gland, Numb is a tumor suppressor and regulates p53 levels. However, whether this function is linked to its role in fate determination remains unclear. Here, by exploiting an ex vivo system, we show that at mitosis of purified mammary stem cells (SCs), Numb ensures the asymmetric outcome of self-renewing divisions by partitioning into the progeny that retains the SC identity, where it sustains high p53 activity. Numb also controls progenitor maturation. At this level, Numb loss associates with the epithelial-to-mesenchymal transition and results in differentiation defects and reacquisition of stemness features. The mammary gland of Numb-knockout mice displays an expansion of the SC compartment, associated with morphological alterations and tumorigenicity in orthotopic transplants. This is because of low p53 levels and can be inhibited by restoration of Numb levels or p53 activity, which results in successful SC-targeted treatment

Topology analysis and visualization of Potyvirus protein-protein interaction network

Background: One of the central interests of Virology is the identification of host factors that contribute to virus infection. Despite tremendous efforts, the list of factors identified remains limited. With omics techniques, the focus has changed from identifying and thoroughly characterizing individual host factors to the simultaneous analysis of thousands of interactions, framing them on the context of protein-protein interaction networks and of transcriptional regulatory networks. This new perspective is allowing the identification of direct and indirect viral targets. Such information is available for several members of the Potyviridae family, one of the largest and more important families of plant viruses. Results: After collecting information on virus protein-protein interactions from different potyviruses, we have processed it and used it for inferring a protein-protein interaction network. All proteins are connected into a single network component. Some proteins show a high degree and are highly connected while others are much less connected, with the network showing a significant degree of dissortativeness. We have attempted to integrate this virus protein-protein interaction network into the largest protein-protein interaction network of Arabidopsis thaliana, a susceptible laboratory host. To make the interpretation of data and results easier, we have developed a new approach for visualizing and analyzing the dynamic spread on the host network of the local perturbations induced by viral proteins. We found that local perturbations can reach the entire host protein-protein interaction network, although the efficiency of this spread depends on the particular viral proteins. By comparing the spread dynamics among viral proteins, we found that some proteins spread their effects fast and efficiently by attacking hubs in the host network while other proteins exert more local effects. Conclusions: Our findings confirm that potyvirus protein-protein interaction networks are highly connected, with some proteins playing the role of hubs. Several topological parameters depend linearly on the protein degree. Some viral proteins focus their effect in only host hubs while others diversify its effect among several proteins at the first step. Future new data will help to refine our model and to improve our predictions.This work was supported by the Spanish Ministerio de Economia y Competitividad grants BFU2012-30805 (to SFE), DPI2011-28112-C04-02 (to AF) and DPI2011-28112-C04-01 (to JP). The first two authors are recipients of fellowships from the Spanish Ministerio de Economia y Competitividad: BES-2012-053772 (to GB) and BES-2012-057812 (to AF-F).Bosque, G.; Folch Fortuny, A.; Picó Marco, JA.; Ferrer, A.; Elena Fito, SF. (2014). Topology analysis and visualization of Potyvirus protein-protein interaction network. 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XFEM coupling of granular flows interacting with surrounding fluids

In this paper, ideas for the simulation of sliding dry granular materials interacting with surrounding fluids are presented and first results are presented. The compressible granular material is modeled as a medium which can show solid-like and fluid-like characteristics. Therefore a weighted decomposition of stress tensors of a solid-like and a fluid-like phase is applied. The surrounding incompressible fluids are described with a Newtonian constitutive model. Interface dynamics are handled with the level-set method. The model equations are discretized with the space-time finite element method. Discontinuous solution characteristics across interfaces are captured numerically by the extended finite element method (XFEM). For all discontinuities the space of ansatz functions is enriched with Heaviside functions

Projection-based reduction of fluid-structure interaction systems using monolithic space-time modes

The focus of this work is the development of reduced models for engineering applications in complex bidirectional fluid-structure interaction. In the simultaneous solution procedure, velocity variables are used for both fluid and solid, and the whole set of model equations is discretized by a stabilized time-discontinuous space-time finite element method. Flexible structures are modeled using a three-dimensional continuum approach in a total Lagrangian setting considering large displacements and rotations. In the flow domain the incompressible Navier-Stokes equations describe the Newtonian fluid. A continuous finite element mesh is applied to the entire spatial domain, and the discretized model equations are assembled in a single set of algebraic equations, considering the two-field problem as a whole. The continuous fluid-structure mesh with identical orders of approximation for both solid and fluid in space and time automatically yields conservation of mass, momentum and energy at the fluid-structure interface. A mesh-moving scheme is used to adapt the nodal coordinates of the fluid space-time finite element mesh to the structural deformation. The computational approach for strongly coupled fluid-structure interaction is used to create suitable reduced models of generic nonlinear problems. Reduction is performed with monolithic projection-based space-time modes, ensuring strong coupling of fluid and structure in the reduced model. The contribution discusses results using proper orthogonal decomposition (POD) for determination of monolithic space-time modes in the reduction of fluid-structure systems. © 2009 Elsevier B.V. All rights reserved

Extended space-time finite elements for landslide dynamics

The paper introduces a methodology for numerical simulation of landslides experiencing considerable deformations and topological changes. Within an interface capturing approach, all interfaces are implicitly described by specifically defined level-set functions allowing arbitrarily evolving complex topologies. The transient interface evolution is obtained by solving the level-set equation driven by the physical velocity field for all three level-set functions in a block Jacobi approach. The three boundary-coupled fluid-like continua involved are modeled as incompressible, governed by a generalized non-Newtonian material law taking into account capillary pressure at moving fluid-fluid interfaces. The weighted residual formulation of the level-set equations and the fluid equations is discretized with finite elements in space and time using velocity and pressure as unknown variables. Non-smooth solution characteristics are represented by enriched approximations to fluid velocity (weak discontinuity) and fluid pressure (strong discontinuity). Special attention is given to the construction of enriched approximations for elements containing evolving triple junctions. Numerical examples of three-fluid tank sloshing and air-water-liquefied soil landslides demonstrate the potential and applicability of the method in geotechnical investigations. © 2012 John Wiley & Sons, Ltd

Finite element method for strongly-coupled systems of fluid-structure interaction with application to granular flow in silos

A monolithic approach to fluid-structure interactions based on the space-time finite element method (STFEM) is presented. The method is applied to the investigation of stress states in silos filled with granular material during discharge. The thin-walled siloshell is modeled in a continuum approach as elastic solid material, whereas the flowing granular material is described by an enhanced viscoplastic non-Newtonian fluid model. The weak forms of the governing equations are discretized by STFEM for both solid and fluid domain. To adapt the matching mesh nodes of the fluid domain to the structural deformations, a mesh-moving scheme using a neo-Hookean pseudo-solid is applied. The finite element approximation of non-smooth solution characteristics is enhanced by the extended finite element method (XFEM). The proposed methodology is applied to the 4D (space-time) investigation of deformation-dependent loading conditions during silo discharge

Weiterentwicklung eines mechanischen Modells zur Beschreibung Regen-Wind induzierter Schwingungen: Zwischenbericht März 2007

Der vorliegende Bericht gibt einen Überblick über den derzeitigen Stand des vom Graduiertenkolleg "Wechselwirkung von Struktur und Fluid" der TU Braunschweig geförderten Forschungsvorhabens zum Thema "Regen-Wind induzierte Seilschwingungen"