Elastin-derived peptides potentiate atherosclerosis through the immune Neu1-PI3Kγ pathway

Aims Elastin is degraded during vascular ageing and its products, elastin-derived peptides (EP), are present in the human blood circulation. EP binds to the elastin receptor complex (ERC) at the cell surface, composed of elastin-binding protein (EBP), a cathepsin A and a neuraminidase 1. Some in vitro functions have clearly been attributed to this binding, but the in vivo implications for arterial diseases have never been clearly investigated. Methods and results Here, we demonstrate that chronic doses of EP injected into mouse models of atherosclerosis increase atherosclerotic plaque size formation. Similar effects were observed following an injection of a VGVAPG peptide, suggesting that the ERC mediates these effects. The absence of phosphoinositide 3-kinase γ (PI3Kγ) in bone marrow-derived cells prevented EP-induced atherosclerosis development, demonstrating that PI3Kγ drive EP-induced arterial lesions. Accordingly, in vitro studies showed that PI3Kγ was required for EP-induced monocyte migration and ROS production and that this effect was dependent upon neuraminidase activity. Finally, we showed that degradation of elastic lamellae in LDLR−/− mice fed an atherogenic diet correlated with atherosclerotic plaque formation. At the same time, the absence of the cathepsin A-neuraminidase 1 complex in cells of the haematopoietic lineage abolished atheroma plaque size progression and decreased leucocytes infiltration, clearly demonstrating the role of this complex in atherogenesis and suggesting the involvement of endogenous EP. Conclusion Altogether, this work identifies EP as an enhancer of atherogenesis and defines the Neuraminidase 1/PI3Kγ signalling pathway as a key mediator of this function in vitro and in viv

RNY-derived small RNAs as a signature of coronary artery disease

International audienceBackgroundData from next generation sequencing technologies uncovered the existence of many classes of small RNAs. Recent studies reported that small RNAs are released by cells and can be detected in the blood. In this report, we aimed to discover the occurrence of novel circulating small RNAs in coronary artery disease (CAD).MethodsWe used high-throughput sequencing of small RNAs from human and mouse apoptotic primary macrophages, and analyzed the data by empirical Bayes moderated t-statistics to assess differential expression and the Benjamini and Hochberg method to control the false discovery rate. Results were then confirmed by Northern blot and RT-qPCR in foam cells and in two animal models for atherosclerosis, namely ApoE −/− and Ldlr −/− mouse lines. Quantitative RT-PCR to detect identified small RNAs, the RNY-derived small RNAs, was performed using sera of 263 patients with CAD compared to 514 matched healthy controls; the Student t-test was applied to statistically assess differences. Associations of small RNAs with clinical characteristics and biological markers were tested using Spearman’s rank correlations, while multivariate logistic regressions were performed to test the statistical association of small RNA levels with CAD.ResultsHere, we report that, in macrophages stimulated with pro-apoptotic or pro-atherogenic stimuli, the Ro-associated non-coding RNAs, called RNYs or Y-RNAs, are processed into small RNAs (~24–34 nt) referred to as small-RNYs (s-RNYs), including s-RNY1-5p processed from RNY1. A significant upregulation of s-RNY expression was found in aortic arches and blood plasma from ApoE −/− and Ldlr −/− mice and in serum from CAD patients (P <0.001). Biostatistical analysis revealed a positive association of s-RNY1-5p with hs-CRP and ApoB levels; however, no statistical interaction was found between either of these two markers and s-RNY1-5p in relation to the CAD status. Levels of s-RNY1-5p were also independent from statin and fibrate therapies.ConclusionOur results position the s-RNY1-5p as a relevant novel independent diagnostic biomarker for atherosclerosis-related diseases. Measurement of circulating s-RNY expression would be a valuable companion diagnostic to monitor foam cell apoptosis during atherosclerosis pathogenesis and to evaluate patient’s responsiveness to future therapeutic strategies aiming to attenuate apoptosis in foam cells in advanced atherosclerotic lesions

Mutational Analysis of the Cyanobacterial Nitrogen Regulator PipX

PipX provides a functional link between the cyanobacterial global transcriptional regulator NtcA and the signal transduction protein PII, a protein found in all three domains of life as integrators of signals of the nitrogen and carbon balance. PipX, which is toxic in the absence of PII, can form alternative complexes with NtcA and PII and these interactions are respectively stimulated and inhibited by 2-oxoglutarate, providing a mechanism by which PII can modulate expression at the NtcA regulon. Structural information on PipX-NtcA complexes suggests that PipX coactivates NtcA controlled genes by stabilizing the active conformation of NtcA bound to 2-oxoglutarate and by possibly helping recruit RNA polymerase. To get insights into PipX functions, we perform here a mutational analysis of pipX informed by the structures of PipX-PII and PipX-NtcA complexes and evaluate the impact of point mutations on toxicity and gene expression. Two amino acid substitutions (Y32A and E4A) were of particular interest, since they increased PipX toxicity and activated NtcA dependent genes in vivo at lower 2-oxoglutarate levels than wild type PipX. While both mutations impaired complex formation with PII, only Y32A had a negative impact on PipX-NtcA interactions

Measurement of inclusive D*+- and associated dijet cross sections in photoproduction at HERA

Inclusive photoproduction of D*+- mesons has been measured for photon-proton centre-of-mass energies in the range 130 < W < 280 GeV and a photon virtuality Q^2 < 1 GeV^2. The data sample used corresponds to an integrated luminosity of 37 pb^-1. Total and differential cross sections as functions of the D* transverse momentum and pseudorapidity are presented in restricted kinematical regions and the data are compared with next-to-leading order (NLO) perturbative QCD calculations using the "massive charm" and "massless charm" schemes. The measured cross sections are generally above the NLO calculations, in particular in the forward (proton) direction. The large data sample also allows the study of dijet production associated with charm. A significant resolved as well as a direct photon component contribute to the cross section. Leading order QCD Monte Carlo calculations indicate that the resolved contribution arises from a significant charm component in the photon. A massive charm NLO parton level calculation yields lower cross sections compared to the measured results in a kinematic region where the resolved photon contribution is significant.Comment: 32 pages including 6 figure

Single Electrons from Heavy Flavor Decays in p+p Collisions at sqrt(s) = 200 GeV

The invariant differential cross section for inclusive electron production in p+p collisions at sqrt(s) = 200 GeV has been measured by the PHENIX experiment at the Relativistic Heavy Ion Collider over the transverse momentum range $0.4 <= p_T <= 5.0 GeV/c at midrapidity (eta <= 0.35). The contribution to the inclusive electron spectrum from semileptonic decays of hadrons carrying heavy flavor, i.e. charm quarks or, at high p_T, bottom quarks, is determined via three independent methods. The resulting electron spectrum from heavy flavor decays is compared to recent leading and next-to-leading order perturbative QCD calculations. The total cross section of charm quark-antiquark pair production is determined as sigma_(c c^bar) = 0.92 +/- 0.15 (stat.) +- 0.54 (sys.) mb.Comment: 329 authors, 6 pages text, 3 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

Nuclear Modification of Electron Spectra and Implications for Heavy Quark Energy Loss in Au+Au Collisions at sqrt(s_NN)=200 GeV

The PHENIX experiment has measured mid-rapidity transverse momentum spectra (0.4 < p_T < 5.0 GeV/c) of electrons as a function of centrality in Au+Au collisions at sqrt(s_NN)=200 GeV. Contributions from photon conversions and from light hadron decays, mainly Dalitz decays of pi^0 and eta mesons, were removed. The resulting non-photonic electron spectra are primarily due to the semi-leptonic decays of hadrons carrying heavy quarks. Nuclear modification factors were determined by comparison to non-photonic electrons in p+p collisions. A significant suppression of electrons at high p_T is observed in central Au+Au collisions, indicating substantial energy loss of heavy quarks.Comment: 330 authors, 6 pages text, 3 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

Angular and Current-Target Correlations in Deep Inelastic Scattering at HERA

Correlations between charged particles in deep inelastic ep scattering have been studied in the Breit frame with the ZEUS detector at HERA using an integrated luminosity of 6.4 pb-1. Short-range correlations are analysed in terms of the angular separation between current-region particles within a cone centred around the virtual photon axis. Long-range correlations between the current and target regions have also been measured. The data support predictions for the scaling behaviour of the angular correlations at high Q2 and for anti-correlations between the current and target regions over a large range in Q2 and in the Bjorken scaling variable x. Analytic QCD calculations and Monte Carlo models correctly describe the trends of the data at high Q2, but show quantitative discrepancies. The data show differences between the correlations in deep inelastic scattering and e+e- annihilation.Comment: 26 pages including 10 figures (submitted to Eur. J. Phys. C

System Size and Energy Dependence of Jet-Induced Hadron Pair Correlation Shapes in Cu+Cu and Au+Au Collisions at sqrt(s_NN) = 200 and 62.4 GeV

We present azimuthal angle correlations of intermediate transverse momentum (1-4 GeV/c) hadrons from {dijets} in Cu+Cu and Au+Au collisions at sqrt(s_NN) = 62.4 and 200 GeV. The away-side dijet induced azimuthal correlation is broadened, non-Gaussian, and peaked away from \Delta\phi=\pi in central and semi-central collisions in all the systems. The broadening and peak location are found to depend upon the number of participants in the collision, but not on the collision energy or beam nuclei. These results are consistent with sound or shock wave models, but pose challenges to Cherenkov gluon radiation models.Comment: 464 authors from 60 institutions, 6 pages, 3 figures, 2 tables. Submitted to Physical Review Letters. 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

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