Polarized cell motility induces hydrogen peroxide to inhibit cofilin via cysteine oxidation

Mesenchymal cell motility is driven by polarized actin polymerization [1]. Signals at the leading edge recruit actin polymerization machinery to promote membrane protrusion, while matrix adhesion generates tractive force to propel forward movement. To work effectively, cell motility is regulated by a complex network of signaling events that affect protein activity and localization. H2O2 has an important role as a diffusible second messenger [2], and mediates its effects through oxidation of cysteine thiols. One cell activity influenced by H2O2 is motility [3]. However, a lack of sensitive and H2O2-specific probes for measurements in live cells has not allowed for direct observation of H2O2 accumulation in migrating cells or protrusions. In addition, the identities of proteins oxidized by H2O2 that contribute to actin dynamics and cell motility have not been characterized. We now show, as determined by fluorescence lifetime imaging microscopy, that motile cells generate H2O2 at membranes and cell protrusions and that H2O2 inhibits cofilin activity through oxidation of cysteines 139 (C139) and 147 (C147). Molecular modeling suggests that C139 oxidation would sterically hinder actin association, while the increased negative charge of oxidized C147 would lead to electrostatic repulsion of the opposite negatively charged surface. Expression of oxidation-resistant cofilin impairs cell spreading, adhesion, and directional migration. These findings indicate that H2O2 production contributes to polarized cell motility through localized cofilin inhibition and that there are additional proteins oxidized during cell migration that might have similar roles

Excited Boundary TBA in the Tricritical Ising Model

By considering the continuum scaling limit of the $A_{4}$ RSOS lattice model of Andrews-Baxter-Forrester with integrable boundaries, we derive excited state TBA equations describing the boundary flows of the tricritical Ising model. Fixing the bulk weights to their critical values, the integrable boundary weights admit a parameter $\xi$ which plays the role of the perturbing boundary field $\phi_{1,3}$ and induces the renormalization group flow between boundary fixed points. The boundary TBA equations determining the RG flows are derived in the $\mathcal{B}_{(1,2)}\to \mathcal{B}_{(2,1)}$ example. The induced map between distinct Virasoro characters of the theory are specified in terms of distribution of zeros of the double row transfer matrix.Comment: Latex, 14 pages - Talk given at the Landau meeting "CFT and Integrable Models", Sept. 2002 - v2: some statements about $\phi_{1,2}$ perturbations correcte

A network analysis to identify pathophysiological pathways distinguishing ischaemic from non-ischaemic heart failure

Aims Heart failure (HF) is frequently caused by an ischaemic event (e.g. myocardial infarction) but might also be caused by a primary disease of the myocardium (cardiomyopathy). In order to identify targeted therapies specific for either ischaemic or non‐ischaemic HF, it is important to better understand differences in underlying molecular mechanisms. Methods and results We performed a biological physical protein–protein interaction network analysis to identify pathophysiological pathways distinguishing ischaemic from non‐ischaemic HF. First, differentially expressed plasma protein biomarkers were identified in 1160 patients enrolled in the BIOSTAT‐CHF study, 715 of whom had ischaemic HF and 445 had non‐ischaemic HF. Second, we constructed an enriched physical protein–protein interaction network, followed by a pathway over‐representation analysis. Finally, we identified key network proteins. Data were validated in an independent HF cohort comprised of 765 ischaemic and 100 non‐ischaemic HF patients. We found 21/92 proteins to be up‐regulated and 2/92 down‐regulated in ischaemic relative to non‐ischaemic HF patients. An enriched network of 18 proteins that were specific for ischaemic heart disease yielded six pathways, which are related to inflammation, endothelial dysfunction superoxide production, coagulation, and atherosclerosis. We identified five key network proteins: acid phosphatase 5, epidermal growth factor receptor, insulin‐like growth factor binding protein‐1, plasminogen activator urokinase receptor, and secreted phosphoprotein 1. Similar results were observed in the independent validation cohort. Conclusions Pathophysiological pathways distinguishing patients with ischaemic HF from those with non‐ischaemic HF were related to inflammation, endothelial dysfunction superoxide production, coagulation, and atherosclerosis. The five key pathway proteins identified are potential treatment targets specifically for patients with ischaemic HF

The dilute A_L models and the integrable perturbations of unitary minimal CFTs

Recently, a set of thermodynamic Bethe ansatz equations is proposed by Dorey, Pocklington and Tateo for unitary minimal models perturbed by \phi_{1,2} or \phi_{2,1} operator. We examine their results in view of the lattice analogues, dilute A_L models at regime 1 and 2. Taking M_{5,6}+\phi_{1,2} and M_{3,4}+\phi_{2,1} as the simplest examples, we will explicitly show that the conjectured TBA equations can be recovered from the lattice model in a scaling limit.Comment: 14 pages, 2 figure

Exact S-matrices for supersymmetric sigma models and the Potts model

We study the algebraic formulation of exact factorizable S-matrices for integrable two-dimensional field theories. We show that different formulations of the S-matrices for the Potts field theory are essentially equivalent, in the sense that they can be expressed in the same way as elements of the Temperley-Lieb algebra, in various representations. This enables us to construct the S-matrices for certain nonlinear sigma models that are invariant under the Lie ``supersymmetry'' algebras sl(m+n|n) (m=1,2; n>0), both for the bulk and for the boundary, simply by using another representation of the same algebra. These S-matrices represent the perturbation of the conformal theory at theta=pi by a small change in the topological angle theta. The m=1, n=1 theory has applications to the spin quantum Hall transition in disordered fermion systems. We also find S-matrices describing the flow from weak to strong coupling, both for theta=0 and theta=pi, in certain other supersymmetric sigma models.Comment: 32 pages, 8 figure

Mitogen and Stress-Activated Kinases 1 and 2 Mediate Endothelial Dysfunction

Inflammation promotes endothelial dysfunction, but the underlying mechanisms remain poorly defined in vivo. Using translational vascular function testing in myocardial infarction patients, a situation where inflammation is prevalent, and knock-out (KO) mouse models we demonstrate a role for mitogen-activated-protein-kinases (MAPKs) in endothelial dysfunction. Myocardial infarction significantly lowers mitogen and stress kinase 1/2 (MSK1/2) expression in peripheral blood mononuclear cells and diminished endothelial function. To further understand the role of MSK1/2 in vascular function we developed in vivo animal models to assess vascular responses to vasoactive drugs using laser Doppler imaging. Genetic deficiency of MSK1/2 in mice increased plasma levels of pro-inflammatory cytokines and promoted endothelial dysfunction, through attenuated production of nitric oxide (NO), which were further exacerbated by cholesterol feeding. MSK1/2 are activated by toll-like receptors through MyD88. MyD88 KO mice showed preserved endothelial function and reduced plasma cytokine expression, despite significant hypercholesterolemia. MSK1/2 kinases interact with MAPK-activated proteins 2/3 (MAPKAP2/3), which limit cytokine synthesis. Cholesterol-fed MAPKAP2/3 KO mice showed reduced plasma cytokine expression and preservation of endothelial function. MSK1/2 plays a significant role in the development of endothelial dysfunction and may provide a novel target for intervention to reduce vascular inflammation. Activation of MSK1/2 could reduce pro-inflammatory responses and preserve endothelial vasodilator function before development of significant vascular disease

Crossing probability and number of crossing clusters in off-critical percolation

We consider two-dimensional percolation in the scaling limit close to criticality and use integrable field theory to obtain universal predictions for the probability that at least one cluster crosses between opposite sides of a rectangle of sides much larger than the correlation length and for the mean number of such crossing clusters.Comment: 13 pages, 5 figures. Published version with references, appendix and comparison with numerics adde

Social assessment on an integrated intervention for the prevention of Zika and other Aedes-borne diseases in pregnant women and their families in Mexico

Results of the project show that pregnant women can be provided with free or low-cost integrated interventions with methods of known efficacy (topical repellent and insecticide-treated window screens) along with educative strategies, and that they are highly motivated to use these methods to enhance maternal-child health for Zika and other Aedes-borne diseases (ABD). This is a one-page assessment/synopsis of the integrated intervention