BMP-2 induces ATF4 phosphorylation in chondrocytes through a COX-2/PGE2 dependent signaling pathway

SummaryObjectiveBone morphogenic protein (BMP)-2 is approved for fracture non-union and spine fusion. We aimed to further dissect its downstream signaling events in chondrocytes with the ultimate goal to develop novel therapeutics that can mimic BMP-2 effect but have less complications.MethodsBMP-2 effect on cyclooxygenase (COX)-2 expression was examined using Real time quantitative PCR (RT-PCR) and Western blot analysis. Genetic approach was used to identify the signaling pathway mediating the BMP-2 effect. Similarly, the pathway transducing the PGE2 effect on ATF4 was investigated. Immunoprecipitation (IP) was performed to assess the complex formation after PGE2 binding.ResultsBMP-2 increased COX-2 expression in primary mouse costosternal chondrocytes (PMCSC). The results from the C9 Tet-off system demonstrated that endogenous BMP-2 also upregulated COX-2 expression. Genetic approaches using PMCSC from ALK2fx/fx, ALK3fx/fx, ALK6−/−, and Smad1fx/fx mice established that BMP-2 regulated COX-2 through activation of ALK3–Smad1 signaling. PGE-2 EIA showed that BMP-2 increased PGE2 production in PMCSC. ATF4 is a transcription factor that regulates bone formation. While PGE2 did not have significant effect on ATF4 expression, it induced ATF4 phosphorylation. In addition to stimulating COX-2 expression, BMP-2 also induced phosphorylation of ATF4. Using COX-2 deficient chondrocytes, we demonstrated that the BMP-2 effect on ATF4 was COX-2-dependent. Tibial fracture samples from COX-2−/− mice showed reduced phospho-ATF4 immunoreactivity compared to wild type (WT) ones. PGE2 mediated ATF4 phosphorylation involved signaling primarily through the EP2 and EP4 receptors and PGE2 induced an EP4-ERK1/2-RSK2 complex formation.ConclusionsBMP-2 regulates COX-2 expression through ALK3–Smad1 signaling, and PGE2 induces ATF4 phosphorylation via EP4-ERK1/2-RSK2 axis

Lensing at cosmological scales: a test of higher dimensional gravity

Recent developments in gravitational lensing astronomy have paved the way to genuine mappings of the gravitational potential at cosmological scales. We stress that comparing these data with traditional large scale structure surveys will provide us with a test of gravity at such scales. These constraints could be of great importance in the framework of higher dimensional cosmological models.Comment: 4 pages, latex, 3 figure

Time series irreversibility: a visibility graph approach

We propose a method to measure real-valued time series irreversibility which combines two differ- ent tools: the horizontal visibility algorithm and the Kullback-Leibler divergence. This method maps a time series to a directed network according to a geometric criterion. The degree of irreversibility of the series is then estimated by the Kullback-Leibler divergence (i.e. the distinguishability) between the in and out degree distributions of the associated graph. The method is computationally effi- cient, does not require any ad hoc symbolization process, and naturally takes into account multiple scales. We find that the method correctly distinguishes between reversible and irreversible station- ary time series, including analytical and numerical studies of its performance for: (i) reversible stochastic processes (uncorrelated and Gaussian linearly correlated), (ii) irreversible stochastic pro- cesses (a discrete flashing ratchet in an asymmetric potential), (iii) reversible (conservative) and irreversible (dissipative) chaotic maps, and (iv) dissipative chaotic maps in the presence of noise. Two alternative graph functionals, the degree and the degree-degree distributions, can be used as the Kullback-Leibler divergence argument. The former is simpler and more intuitive and can be used as a benchmark, but in the case of an irreversible process with null net current, the degree-degree distribution has to be considered to identifiy the irreversible nature of the series.Comment: submitted for publicatio

Nanofabrication by magnetic focusing of supersonic beams

We present a new method for nanoscale atom lithography. We propose the use of a supersonic atomic beam, which provides an extremely high-brightness and cold source of fast atoms. The atoms are to be focused onto a substrate using a thin magnetic film, into which apertures with widths on the order of 100 nm have been etched. Focused spot sizes near or below 10 nm, with focal lengths on the order of 10 microns, are predicted. This scheme is applicable both to precision patterning of surfaces with metastable atomic beams and to direct deposition of material.Comment: 4 pages, 3 figure

Holomorphic Functions on Bundles Over Annuli

We consider a family E_m(D,M) of holomorphic bundles constructed as follows: to any given M in GL_n(Z), we associate a "multiplicative automorphism" f of (C*)^n. Now let D be a f-invariant Stein Reinhardt domain in (C*)^n. Then E_m(D,M) is defined as the flat bundle over the annulus of modulus m>0, with fiber D, and monodromy f. We show that the function theory on E_m(D,M) depends nontrivially on the parameters m, M and D. Our main result is that E_m(D,M) is Stein if and only if m log(r(M)) <= 2 \pi^2, where r(M) denotes the max of the spectral radii of M and its inverse. As corollaries, we: -- obtain a classification result for Reinhardt domains in all dimensions; -- establish a similarity between two known counterexamples to a question of J.-P. Serre; -- suggest a potential reformulation of a disproved conjecture of Siu Y.-T

Running coupling: Does the coupling between dark energy and dark matter change sign during the cosmological evolution?

In this paper we put forward a running coupling scenario for describing the interaction between dark energy and dark matter. The dark sector interaction in our scenario is free of the assumption that the interaction term $Q$ is proportional to the Hubble expansion rate and the energy densities of dark sectors. We only use a time-variable coupling $b(a)$ (with $a$ the scale factor of the universe) to characterize the interaction $Q$. We propose a parametrization form for the running coupling $b(a)=b_0a+b_e(1-a)$ in which the early-time coupling is given by a constant $b_e$, while today the coupling is given by another constant, $b_0$. For investigating the feature of the running coupling, we employ three dark energy models, namely, the cosmological constant model ($w=-1$), the constant $w$ model ($w=w_0$), and the time-dependent $w$ model ($w(a)=w_0+w_1(1-a)$). We constrain the models with the current observational data, including the type Ia supernova, the baryon acoustic oscillation, the cosmic microwave background, the Hubble expansion rate, and the X-ray gas mass fraction data. The fitting results indicate that a time-varying vacuum scenario is favored, in which the coupling $b(z)$ crosses the noninteracting line ($b=0$) during the cosmological evolution and the sign changes from negative to positive. The crossing of the noninteracting line happens at around $z=0.2-0.3$, and the crossing behavior is favored at about 1$\sigma$ confidence level. Our work implies that we should pay more attention to the time-varying vacuum model and seriously consider the phenomenological construction of a sign-changeable or oscillatory interaction between dark sectors.Comment: 8 pages, 5 figures; refs added; to appear in EPJ

Hypothalamic Protein Kinase C Regulates Glucose Production

OBJECTIVE—A selective rise in hypothalamic lipid metabolism and the subsequent activation of SUR1/Kir6.2 ATP-sensitive K+ (KATP) channels inhibit hepatic glucose production. The mechanisms that link the ability of hypothalamic lipid metabolism to the activation of KATP channels remain unknown

An Oscillatory Contractile Pole-Force Component Dominates the Traction Forces Exerted by Migrating Amoeboid Cells

We used principal component analysis to dissect the mechanics of chemotaxis of amoeboid cells into a reduced set of dominant components of cellular traction forces and shape changes. The dominant traction force component in wild-type cells accounted for ~40% of the mechanical work performed by these cells, and consisted of the cell attaching at front and back contracting the substrate towards its centroid (pole-force). The time evolution of this pole-force component was responsible for the periodic variations of cell length and strain energy that the cells underwent during migration. We identified four additional canonical components, reproducible from cell to cell, overall accounting for an additional ~20% of mechanical work, and associated with events such as lateral protrusion of pseudopodia. We analyzed mutant strains with contractility defects to quantify the role that non-muscle Myosin II (MyoII) plays in amoeboid motility. In MyoII essential light chain null cells the polar-force component remained dominant. On the other hand, MyoII heavy chain null cells exhibited a different dominant traction force component, with a marked increase in lateral contractile forces, suggesting that cortical contractility and/or enhanced lateral adhesions are important for motility in this cell line. By compressing the mechanics of chemotaxing cells into a reduced set of temporally-resolved degrees of freedom, the present study may contribute to refined models of cell migration that incorporate cell-substrate interactions