Novel Roles for Peroxynitrite in Angiotensin II and CaMKII Signaling

Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) oxidation controls excitability and viability. While hydrogen peroxide (H2O2) affects Ca(2+)-activated CaMKII in vitro, Angiotensin II (Ang II)-induced CaMKIIδ signaling in cardiomyocytes is Ca(2+) independent and requires NADPH oxidase-derived superoxide, but not its dismutation product H2O2. To better define the biological regulation of CaMKII activation and signaling by Ang II, we evaluated the potential for peroxynitrite (ONOO(-)) to mediate CaMKII activation and downstream Kv4.3 channel mRNA destabilization by Ang II. In vitro experiments show that ONOO(-) oxidizes and modestly activates pure CaMKII in the absence of Ca(2+)/CaM. Remarkably, this apokinase stimulation persists after mutating known oxidation targets (M281, M282, C290), suggesting a novel mechanism for increasing baseline Ca(2+)-independent CaMKII activity. The role of ONOO(-) in cardiac and neuronal responses to Ang II was then tested by scavenging ONOO(-) and preventing its formation by inhibiting nitric oxide synthase. Both treatments blocked Ang II effects on Kv4.3, tyrosine nitration and CaMKIIδ oxidation and activation. Together, these data show that ONOO(-) participates in Ang II-CaMKII signaling. The requirement for ONOO(-) in transducing Ang II signaling identifies ONOO(-), which has been viewed as a reactive damaging byproduct of superoxide and nitric oxide, as a mediator of GPCR-CaMKII signaling

SUPPLEMENTARY INFORMATION Dislocation nucleation facilitated by atomic segregation DOI: 10.1038/NMAT5034

This is a set of supplementary data and information supporting the Journal Publication 'Dislocation nucleation facilitated by atomic segregation', DOI: 10.1038/NMAT5034, and available at Journal article in Nature Materials

Jamming II: Edwards' statistical mechanics of random packings of hard spheres

The problem of finding the most efficient way to pack spheres has an illustrious history, dating back to the crystalline arrays conjectured by Kepler and the random geometries explored by Bernal in the 60's. This problem finds applications spanning from the mathematician's pencil, the processing of granular materials, the jamming and glass transitions, all the way to fruit packing in every grocery. There are presently numerous experiments showing that the loosest way to pack spheres gives a density of ~55% (RLP) while filling all the loose voids results in a maximum density of ~63-64% (RCP). While those values seem robustly true, to this date there is no physical explanation or theoretical prediction for them. Here we show that random packings of monodisperse hard spheres in 3d can pack between the densities 4/(4 + 2 \sqrt 3) or 53.6% and 6/(6 + 2 \sqrt 3) or 63.4%, defining RLP and RCP, respectively. The reason for these limits arises from a statistical picture of jammed states in which the RCP can be interpreted as the ground state of the ensemble of jammed matter with zero compactivity, while the RLP arises in the infinite compactivity limit. We combine an extended statistical mechanics approach 'a la Edwards' (where the role traditionally played by the energy and temperature in thermal systems is substituted by the volume and compactivity) with a constraint on mechanical stability imposed by the isostatic condition. Ultimately, our results lead to a phase diagram that provides a unifying view of the disordered hard sphere packing problem.Comment: 55 pages, 19 figures, C. Song, P. Wang, H. A. Makse, A phase diagram for jammed matter, Nature 453, 629-632 (2008

Research on Control Methods of Planar Motors based on the Modal Forces

There is tight electromagnetic and mechanical coupling among planar motor (PM) 6- degree of freedom (DOF) motions for photolithography in semiconductor manufacturing. For the purpose of achieving decoupled control of the 6-DOF motions, this paper presents the current-controlled model of linear motor (LM) as the actuators, the concept of the actuator forces and the modal forces, and the decoupled dynamics model based on the modal forces. Under some reasonable assumptions on the prototype motor kinematics and structure parameters, the modal forces method successfully decouples the 6-DOF dynamics models and all the dynamics models become simple 2nd order linear systems which can be controlled with multiform linear controller. For the prototype motor, the transformation matrices between the modal forces and the actuator forces are derived and the current-controlled block diagram is presented

Investigating the effects of Pirfenidone on TGF-β1 stimulated non-SMAD signaling pathways in Dupuytren’s disease -derived fibroblasts

Abstract Background Dupuytren’s disease (DD) is a progressive, debilitating condition of the hand that can eventually cause contractures of the affected fingers. Transforming growth factor- β1 (TGF-β1) has been reported to play a key role in DD pathology. Increased expression of TGF-β1 has shown to be the main stimulator of myofibroblast activity and in DD contractures. Pirfenidone (PFD), a small active molecule possess the ability to inhibit TGF-β1-mediated action in various fibrotic disorders. Our recent published findings show that PFD reduced TGF-β1-mediated cellular functions implicated in DD through SMAD signaling pathways. In the present study, the effect of PFD on TGF-β1-mediated non-SMAD signaling pathways were investigated in both carpal tunnel (CT) - and DD-derived fibroblasts. Methods Fibroblasts harvested from Dupuytren’s disease (DD) and carpal tunnel (CT) tissues were cultured in the presence or absence of TGF-β1 (10 ng/ml) and/or PFD (800 μg/ml). Cell lysates were analyzed using Western blots. Equal amounts of proteins were loaded to determine the phosphorylation levels of phosphatidylinositol-3 kinase (PI3K/AKT), extracellular regulated kinases (ERK1/2), p38 mitogen-activated protein kinase and Rho family related myosin light chain (MLC). Results We show that the TGF-β1-induced phosphorylation of AKT was significantly decreased by the addition of PFD (800 μg/mL) in both CT- and DD-derived fibroblasts. Interestingly, there was no significant difference in the phosphorylation levels of both ERK and p38 on TGF-β1- induced cells in both CT-and DD-derived fibroblasts. But, PFD significantly decreased the TGF- β1-induced phosphorylation levels of ERK1/2 in both CT- and DD- cells. In contrast, PFD significantly decreased the basal and TGF- β1-induced phosphorylation levels of p38 in DD-derived fibroblasts. TGF- β1-induced phosphorylation levels of MLC was decreased by PFD in DD-derived fibroblasts. Conclusions These in-vitro results indicate for the first time that PFD has the potential to inhibit TGF-β1-induced non-SMAD signaling pathways in both CT- and DD-derived fibroblasts but pronounced statistically significant inhibition on all molecules was observed only in DD-derived fibroblasts. Our previous studies show that PFD can inhibit TGF-β1- induced SMAD signaling pathway proteins, namely p- SMAD2/SMAD3. These broad and complementary actions suggest PFD as a promising candidate to inhibit the TGF-β1- mediated molecular mechanisms leading to DD fibrosis