HIF-1 alpha-independent hypoxia-induced rapid PTK6 stabilization is associated with increased motility and invasion

© 2014 Landes Bioscience. PTK6/Brk is a non-receptor tyrosine kinase overexpressed in cancer. Here we demonstrate that cytosolic PTK6 is rapidly and robustly induced in response to hypoxic conditions in a HIF-1-independent manner. Furthermore, a proportion of hypoxic PTK6 subsequently re-localized to the cell membrane. We observed that the rapid stabilization of PTK6 is associated with a decrease in PTK6 ubiquitylation and we have identified c-Cbl as a putative PTK6 E3 ligase in normoxia. The consequences of hypoxia-induced PTK6 stabilization and subcellular re-localization to the plasma membrane include increased cell motility and invasion, suggesting PTK6 targeting as a therapeutic approach to reduce hypoxia-regulated metastatic potential. This could have particular significance for breast cancer patients with triple negative disease

Forward Modeling of Space-borne Gravitational Wave Detectors

Planning is underway for several space-borne gravitational wave observatories to be built in the next ten to twenty years. Realistic and efficient forward modeling will play a key role in the design and operation of these observatories. Space-borne interferometric gravitational wave detectors operate very differently from their ground based counterparts. Complex orbital motion, virtual interferometry, and finite size effects complicate the description of space-based systems, while nonlinear control systems complicate the description of ground based systems. Here we explore the forward modeling of space-based gravitational wave detectors and introduce an adiabatic approximation to the detector response that significantly extends the range of the standard low frequency approximation. The adiabatic approximation will aid in the development of data analysis techniques, and improve the modeling of astrophysical parameter extraction.Comment: 14 Pages, 14 Figures, RevTex

Inference on inspiral signals using LISA MLDC data

In this paper we describe a Bayesian inference framework for analysis of data obtained by LISA. We set up a model for binary inspiral signals as defined for the Mock LISA Data Challenge 1.2 (MLDC), and implemented a Markov chain Monte Carlo (MCMC) algorithm to facilitate exploration and integration of the posterior distribution over the 9-dimensional parameter space. Here we present intermediate results showing how, using this method, information about the 9 parameters can be extracted from the data.Comment: Accepted for publication in Classical and Quantum Gravity, GWDAW-11 special issu

Time-symmetric initial data for binary black holes in numerical relativity

We look for physically realistic initial data in numerical relativity which are in agreement with post-Newtonian approximations. We propose a particular solution of the time-symmetric constraint equation, appropriate to two momentarily static black holes, in the form of a conformal decomposition of the spatial metric. This solution is isometric to the post-Newtonian metric up to the 2PN order. It represents a non-linear deformation of the solution of Brill and Lindquist, i.e. an asymptotically flat region is connected to two asymptotically flat (in a certain weak sense) sheets, that are the images of the two singularities through appropriate inversion transformations. The total ADM mass M as well as the individual masses m_1 and m_2 (when they exist) are computed by surface integrals performed at infinity. Using second order perturbation theory on the Brill-Lindquist background, we prove that the binary's interacting mass-energy M-m_1-m_2 is well-defined at the 2PN order and in agreement with the known post-Newtonian result.Comment: 27 pages, to appear in Phys. Rev.

Post-Newtonian approximation for isolated systems calculated by matched asymptotic expansions

Two long-standing problems with the post-Newtonian approximation for isolated slowly-moving systems in general relativity are: (i) the appearance at high post-Newtonian orders of divergent Poisson integrals, casting a doubt on the soundness of the post-Newtonian series; (ii) the domain of validity of the approximation which is limited to the near-zone of the source, and prevents one, a priori, from incorporating the condition of no-incoming radiation, to be imposed at past null infinity. In this article, we resolve the problem (i) by iterating the post-Newtonian hierarchy of equations by means of a new (Poisson-type) integral operator that is free of divergencies, and the problem (ii) by matching the post-Newtonian near-zone field to the exterior field of the source, known from previous work as a multipolar-post-Minkowskian expansion satisfying the relevant boundary conditions at infinity. As a result, we obtain an algorithm for iterating the post-Newtonian series up to any order, and we determine the terms, present in the post-Newtonian field, that are associated with the gravitational-radiation reaction onto an isolated slowly-moving matter system.Comment: 61 pages, to appear in Phys. Rev.

Dense active matter model of motion patterns in confluent cell monolayers

Epithelial cell monolayers show remarkable displacement and velocity correlations over distances of ten or more cell sizes that are reminiscent of supercooled liquids and active nematics. We show that many observed features can be described within the framework of dense active matter, and argue that persistent uncoordinated cell motility coupled to the collective elastic modes of the cell sheet is sufficient to produce swirl-like correlations. We obtain this result using both continuum active linear elasticity and a normal modes formalism, and validate analytical predictions with numerical simulations of two agent-based cell models, soft elastic particles and the self-propelled Voronoi model together with in-vitro experiments of confluent corneal epithelial cell sheets. Simulations and normal mode analysis perfectly match when tissue-level reorganisation occurs on times longer than the persistence time of cell motility. Our analytical model quantitatively matches measured velocity correlation functions over more than a decade with a single fitting parameter.Comment: updated version accepted for publication in Nat. Com

To wet or not to wet: that is the question

Wetting transitions have been predicted and observed to occur for various combinations of fluids and surfaces. This paper describes the origin of such transitions, for liquid films on solid surfaces, in terms of the gas-surface interaction potentials V(r), which depend on the specific adsorption system. The transitions of light inert gases and H2 molecules on alkali metal surfaces have been explored extensively and are relatively well understood in terms of the least attractive adsorption interactions in nature. Much less thoroughly investigated are wetting transitions of Hg, water, heavy inert gases and other molecular films. The basic idea is that nonwetting occurs, for energetic reasons, if the adsorption potential's well-depth D is smaller than, or comparable to, the well-depth of the adsorbate-adsorbate mutual interaction. At the wetting temperature, Tw, the transition to wetting occurs, for entropic reasons, when the liquid's surface tension is sufficiently small that the free energy cost in forming a thick film is sufficiently compensated by the fluid- surface interaction energy. Guidelines useful for exploring wetting transitions of other systems are analyzed, in terms of generic criteria involving the "simple model", which yields results in terms of gas-surface interaction parameters and thermodynamic properties of the bulk adsorbate.Comment: Article accepted for publication in J. Low Temp. Phy

WSB-1 regulates the metastatic potential of hormone receptor negative breast cancer

© 2018 Cancer Research UK. Background: Metastatic spread is responsible for the majority of cancer-associated deaths. The tumour microenvironment, including hypoxia, is a major driver of metastasis. The aim of this study was to investigate the role of the E3 ligase WSB-1 in breast cancer biology in the context of the hypoxic tumour microenvironment, particularly regarding metastatic spread. Methods: In this study, WSB-1 expression was evaluated in breast cancer cell lines and patient samples. In silico analyses were used to determine the impact of WSB-1 expression on distant metastasis-free survival (DMFS) in patients, and correlation between WSB1 expression and hypoxia gene expression signatures. The role of WSB-1 on metastasis promotion was evaluated in vitro and in vivo. Results: High WSB1 expression was associated with decreased DMFS in ER-breast cancer and PR-breast cancer patients. Surprisingly, WSB1 expression was not positively correlated with known hypoxic gene expression signatures in patient samples. Our study is the first to show that WSB-1 knockdown led to decreased metastatic potential in breast cancer hormone receptor-negative models in vitro and in vivo. WSB-1 knockdown was associated with decreased metalloproteinase (MMP) activity, vascular endothelial growth factor (VEGF) secretion, and angiogenic potential. Conclusions: Our data suggests that WSB-1 may be an important regulator of aggressive metastatic disease in hormone receptor-negative breast cancer. WSB-1 could therefore represent a novel regulator and therapeutic target for secondary breast cancer in these patients