Identification of methotrexate as a heterochromatin-promoting drug.

Heterochromatin is a tightly packed form of DNA involved in gene silencing, chromosome segregation, and protection of genome stability. Heterochromatin is becoming more recognized in tumor suppression and may thus serve as a potential target for cancer therapy. However, to date there are no drugs that are well established to specifically promote heterochromatin formation. Here, we describe a screening method using Drosophila to identify small molecule compounds that promote heterochromatin formation, with the purpose of developing epigenetic cancer therapeutics. We took advantage of a Drosophila strain with a variegated eye color phenotype that is sensitive to heterochromatin levels, and screened a library of 97 FDA approved oncology drugs. This screen identified methotrexate as the most potent small molecule drug, among the 97 oncology drugs screened, in promoting heterochromatin formation. Interestingly, methotrexate has been identified as a JAK/STAT inhibitor in a functional screen, causing reduced phosphorylation of STAT proteins. These findings are in line with our previous observation that unphosphorylated STAT (uSTAT) promotes heterochromatin formation in both Drosophila and human cells and suppresses tumor growth in mouse xenografts. Thus, Drosophila with variegated eye color phenotypes could be an effective tool for screening heterochromatin-promoting compounds that could be candidates as cancer therapeutics

Endogenous IL-33 and Its Autoamplification of IL-33/ST2 Pathway Play an Important Role in Asthma.

IL-33 and its receptor ST2 are contributing factors to airway inflammation and asthma exacerbation. The IL-33/ST2 signaling pathway is involved in both the onset and the acute exacerbations of asthma. In this study, we address the role of endogenous IL-33 and its autoamplification of the IL-33/ST2 pathway in Ag-dependent and Ag-independent asthma-like models. Wild-type, IL-33 knockout, ST2 knockout mice were either intratracheally administrated with 500 ng of rIL-33 per day for four consecutive days or were sensitized and challenged with OVA over 21 d. In wild-type mice, IL-33 or OVA induced similar airway hyperresponsiveness and eosinophilic airway inflammation. IL-33 induced its own mRNA and ST2L mRNA expression in the lung. IL-33 autoamplified itself and ST2 protein expression in airway epithelial cells. OVA also induced IL-33 and ST2 protein expression. In IL-33 knockout mice, the IL-33- and OVA-induced airway hyperresponsiveness and eosinophilic airway inflammation were both significantly attenuated, whereas IL-33-induced ST2L mRNA expression was preserved, although no autoamplification of IL-33/ST2 pathway was observed. In ST2 knockout mice, IL-33 and OVA induced airway hyperresponsiveness and eosinophilic airway inflammation were both completely diminished, and no IL-33/ST2 autoamplification was observed. These results suggest that endogenous IL-33 and its autoamplification of IL-33/ST2 pathway play an important role in the induction of asthma-like phenotype. Thus an intact IL-33/ST2 pathway is necessary for both Ag-dependent and Ag-independent asthma-like mouse models

PPAR? Downregulation by TGF in Fibroblast and Impaired Expression and Function in Systemic Sclerosis: A Novel Mechanism for Progressive Fibrogenesis

The nuclear orphan receptor peroxisome proliferator-activated receptor-gamma (PPAR-γ) is expressed in multiple cell types in addition to adipocytes. Upon its activation by natural ligands such as fatty acids and eicosanoids, or by synthetic agonists such as rosiglitazone, PPAR-γ regulates adipogenesis, glucose uptake and inflammatory responses. Recent studies establish a novel role for PPAR-γ signaling as an endogenous mechanism for regulating transforming growth factor-ß (TGF-ß)- dependent fibrogenesis. Here, we sought to characterize PPAR-γ function in the prototypic fibrosing disorder systemic sclerosis (SSc), and delineate the factors governing PPAR-γ expression. We report that PPAR-γ levels were markedly diminished in skin and lung biopsies from patients with SSc, and in fibroblasts explanted from the lesional skin. In normal fibroblasts, treatment with TGF-ß resulted in a time- and dose-dependent down-regulation of PPAR-γ expression. Inhibition occurred at the transcriptional level and was mediated via canonical Smad signal transduction. Genome-wide expression profiling of SSc skin biopsies revealed a marked attenuation of PPAR-γ levels and transcriptional activity in a subset of patients with diffuse cutaneous SSc, which was correlated with the presence of a ''TGF-ß responsive gene signature'' in these biopsies. Together, these results demonstrate that the expression and function of PPAR-γ are impaired in SSc, and reveal the existence of a reciprocal inhibitory cross-talk between TGF-ß activation and PPAR-γ signaling in the context of fibrogenesis. In light of the potent anti-fibrotic effects attributed to PPAR-γ, these observations lead us to propose that excessive TGF-ß activity in SSc accounts for impaired PPAR-γ function, which in turn contributes to unchecked fibroblast activation and progressive fibrosis. © 2010 Wei et al

Nuclear Modification Factors for Hadrons At Forward and Backward Rapidities in Deuteron-Gold Collisions at sqrt(s_NN) = 200 GeV

We report on charged hadron production in deuteron-gold reactions at sqrt(s_NN) = 200 GeV. Our measurements in the deuteron-direction cover 1.4 < eta < 2.2, referred to as forward rapidity, and in the gold-direction -2.0 < eta < -1.4, referred to as backward rapidity, and a transverse momentum range p_T = 0.5-4.0 GeV/c. We compare the relative yields for different deuteron-gold collision centrality classes. We observe a suppression relative to binary collision scaling at forward rapidity, sensitive to low momentum fraction (x) partons in the gold nucleus, and an enhancement at backward rapidity, sensitive to high momentum fraction partons in the gold nucleus.Comment: 330 authors, 6 pages text, 4 figures, REVTeX4. Published in Physical Review Letters. Minor changes over previous version in response to referee and editor comments, plus updating of references. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are publicly available at http://www.phenix.bnl.gov/papers.htm

Centrality dependence of charged hadron production in deuteron+gold and nucleon+gold collisions at sqrt(s_NN)=200 GeV

We present transverse momentum (p_T) spectra of charged hadrons measured in deuteron-gold and nucleon-gold collisions at \sqrts = 200 GeV for four centrality classes. Nucleon-gold collisions were selected by tagging events in which a spectator nucleon was observed in one of two forward rapidity detectors. The spectra and yields were investigated as a function of the number of binary nucleon-nucleon collisions, \nu, suffered by deuteron nucleons. A comparison of charged particle yields to those in p+p collisions show that the yield per nucleon-nucleon collision saturates with \nu for high momentum particles. We also present the charged hadron to neutral pion ratios as a function of p_T.Comment: 330 authors, 15 pages text, 16 figures, 3 tables. Submitted to Phys. Rev. Lett. v2 has minor changes to reflect revisions during review process. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Direct photon production in d+Au collisions at sqrt(s_NN)=200 GeV

Direct photons have been measured in sqrt(s_NN)=200 GeV d+Au collisions at midrapidity. A wide p_T range is covered by measurements of nearly-real virtual photons (1<p_T<6 GeV/c) and real photons (5<p_T<16 GeV/c). The invariant yield of the direct photons in d+Au collisions over the scaled p+p cross section is consistent with unity. Theoretical calculations assuming standard cold nuclear matter effects describe the data well for the entire p_T range. This indicates that the large enhancement of direct photons observed in Au+Au collisions for 1.0<p_T<2.5 GeV/c is due to a source other than the initial-state nuclear effects.Comment: 547 authors, 7 pages, 4 figures. Submitted to Phys. Rev. Lett.. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Energy Loss and Flow of Heavy Quarks in Au+Au Collisions at sqrt(s_NN) = 200 GeV

The PHENIX experiment at the Relativistic Heavy Ion Collider (RHIC) has measured electrons from heavy flavor (charm and bottom) decays for 0.3 < p_T < 9 GeV/c at midrapidity (|y| < 0.35) in Au+Au collisions at sqrt(s_NN) = 200 GeV. The nuclear modification factor R_AA relative to p+p collisions shows a strong suppression in central Au+Au collisions, indicating substantial energy loss of heavy quarks in the medium produced at RHIC. A large azimuthal anisotropy, v_2, with respect to the reaction plane is observed for 0.5 < p_T < 5 GeV/c indicating non-zero heavy flavor elliptic flow. Both R_AA and v_2 show a p_T dependence different from those of neutral pions. A comparison to transport models which simultaneously describe R_AA(p_T) and v_2(p_T) suggests that the viscosity to entropy density ratio is close to the conjectured quantum lower bound, i.e., near a perfect fluid.Comment: v2 replaced Fig. 3 to fix an error in using a wrong theory curve; v3 minor changes in review process, including last 2 sentences of abstract. 422 authors, 58 institutions, 6 pages text, 3 figures, REVTeX4. Submitted to Physical Review Letters. Plain text data tables for the points plotted in figures available at http://www.phenix.bnl.gov/papers.htm

Azimuthal Angle Correlations for Rapidity Separated Hadron Pairs in d+Au Collisions at sqrt(s_NN) = 200 GeV

We report on two-particle azimuthal angle correlations between charged hadrons at forward/backward (deuteron/gold going direction) rapidity and charged hadrons at mid-rapidity in deuteron-gold (d+Au) and proton-proton (p+p) collisions at sqrt(s_NN) = 200 GeV. Jet structures are observed in the correlations which we quantify in terms of the conditional yield and angular width of away side partners. The kinematic region studied here samples partons in the gold nucleus carrying nucleon momentum fraction x~0.1 to x~0.01. Within this range, we find no x dependence of the jet structure in d+Au collisions.Comment: 330 authors, 6 pages text, 4 figures, no tables. Submitted to Phys. Rev. Lett. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Charged hadron multiplicity fluctuations in Au+Au and Cu+Cu collisions from sqrt(s_NN) = 22.5 to 200 GeV

A comprehensive survey of event-by-event fluctuations of charged hadron multiplicity in relativistic heavy ions is presented. The survey covers Au+Au collisions at sqrt(s_NN) = 62.4 and 200 GeV, and Cu+Cu collisions sqrt(s_NN) = 22.5, 62.4, and 200 GeV. Fluctuations are measured as a function of collision centrality, transverse momentum range, and charge sign. After correcting for non-dynamical fluctuations due to fluctuations in the collision geometry within a centrality bin, the remaining dynamical fluctuations expressed as the variance normalized by the mean tend to decrease with increasing centrality. The dynamical fluctuations are consistent with or below the expectation from a superposition of participant nucleon-nucleon collisions based upon p+p data, indicating that this dataset does not exhibit evidence of critical behavior in terms of the compressibility of the system. An analysis of Negative Binomial Distribution fits to the multiplicity distributions demonstrates that the heavy ion data exhibit weak clustering properties.Comment: 464 authors from 60 institutions, 17 pages, 12 figures, 1 table. Submitted to Physical Review C. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm