Discovery of a small molecule probe that post-translationally stabilizes the survival motor neuron protein for the treatment of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is the leading genetic cause of infant death. We previously developed a high-throughput assay that employs an SMN2-luciferase reporter allowing identification of compounds that act transcriptionally, enhance exon recognition, or stabilize the SMN protein. We describe optimization and characterization of an analog suitable for in vivo testing. Initially, we identified analog 4m that had good in vitro properties but low plasma and brain exposure in a mouse PK experiment due to short plasma stability; this was overcome by reversing the amide bond and changing the heterocycle. Thiazole 27 showed excellent in vitro properties and a promising mouse PK profile, making it suitable for in vivo testing. This series post-translationally stabilizes the SMN protein, unrelated to global proteasome or autophagy inhibition, revealing a novel therapeutic mechanism that should complement other modalities for treatment of SMA

Deuteron and antideuteron production in Au+Au collisions at sqrt(s_NN)=200 GeV

The production of deuterons and antideuterons in the transverse momentum range 1.1 < p_T < 4.3 GeV/c at mid-rapidity in Au + Au collisions at sqrt(s_NN)=200 GeV has been studied by the PHENIX experiment at RHIC. A coalescence analysis comparing the deuteron and antideuteron spectra with those of protons and antiprotons, has been performed. The coalescence probability is equal for both deuterons and antideuterons and increases as a function of p_T, which is consistent with an expanding collision zone. Comparing (anti)proton yields p_bar/p = 0.73 +/- 0.01, with (anti)deuteron yields: d_bar/d = 0.47 +/- 0.03, we estimate that n_bar/n = 0.64 +/- 0.04.Comment: 326 authors, 6 pages text, 5 figures, 1 Table. Submitted to PRL. 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

Mid-Rapidity Direct-Photon Production in p+p Collisions at sqrt(s) = 200 GeV

A measurement of direct photons in p+p collisions at sqrt(s)=200 GeV is presented. A photon excess above background from pi^0 --> gamma+gamma, eta --> gamma+gamma, and other decays is observed in the transverse momentum range 5.5 < p_T < 7 GeV/c. The result is compared to a next-to-leading-order perturbative QCD calculation. Within errors, good agreement is found between the QCD calculation and the measured result.Comment: 330 authors, 7 pages text, RevTeX, 2 figures, 2 tables. Submitted to Physical Review D. 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

Autoimmunity conferred by chs3-2D relies on CSA1, its adjacent TIR-NB-LRR encoding neighbour

Plant innate immunity depends on the function of a large number of intracellular immune receptor proteins, the majority of which are structurally similar to mammalian nucleotidebinding oligomerization domain (NOD)-like receptor (NLR) proteins. CHILLING SENSITIVE 3 (CHS3) encodes an atypical Toll/Interleukin 1 Receptor (TIR)-type NLR protein with an additional Lin-11, Isl-1 and Mec-3 (LIM) domain at its C-terminus. The gain-of-function mutant allele chs3-2D exhibits severe dwarfism and constitutively activated defense responses, including enhanced resistance to virulent pathogens, high defence marker gene expression, and salicylic acid accumulation. To search for novel regulators involved in CHS3-mediated immune signaling, we conducted suppressor screens in the chs3-2D and chs3-2D pad4-1 genetic backgrounds. Alleles of sag101 and eds1-90 were isolated as complete suppressors of chs3-2D, and alleles of sgt1b were isolated as partial suppressors of chs3-2D pad4-1. These mutants suggest that SAG101, EDS1-90, and SGT1b are all positive regulators of CHS3-mediated defense signaling. Additionally, the TIR-type NLR-encoding CSA1 locus located genomically adjacent to CHS3 was found to be fully required for chs3-2D-mediated autoimmunity. CSA1 is located 3.9kb upstream of CHS3 and is transcribed in the opposite direction. Altogether, these data illustrate the distinct genetic requirements for CHS3-mediated defense signaling

Scaling properties of proton and anti-proton production in sqrt(s_NN) = 200 GeV Au + Au collisions

We report on the yield of protons and anti-protons, as a function of centrality and transverse momentum, in Au+Au collisions at sqrt(s_NN) = 200 GeV measured at mid-rapidity by the PHENIX experiment at RHIC. In central collisions at intermediate transverse momenta (1.5 < p_T < 4.5 GeV/c) a significant fraction of all produced particles are protons and anti-protons. They show a centrality-scaling behavior different from that of pions. The p-bar/pion and p/pion ratios are enhanced compared to peripheral Au+Au, p+p, and electron+positron collisions. This enhancement is limited to p_T < 5 GeV/c as deduced from the ratio of charged hadrons to pi^0 measured in the range 1.5 < p_T < 9 GeV/c.Comment: 325 authors, 6 pages text, 4 figures, RevTeX 4. Minor changes to text and figures to meet PRL length restrictions; no changes to figures; resubmitted to PRL. 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

Suppressed pi^0 Production at Large Transverse Momentum in Central Au+Au Collisions at sqrt(s_NN) = 200 GeV

Transverse momentum spectra of neutral pions in the range 1 < p_T < 10 GeV/c have been measured at mid-rapidity by the PHENIX experiment at RHIC in Au+Au collisions at sqrt(s_NN) = 200 GeV. The pi^0 multiplicity in central reactions is significantly below the yields measured at the same sqrt(s_NN) in peripheral Au+Au and p+p reactions scaled by the number of nucleon-nucleon collisions. For the most central bin, the suppression factor is ~2.5 at p_T = 2 GeV/c and increases to ~4-5 at p_T ~= 4 GeV/c. At larger p_T, the suppression remains constant within errors. The deficit is already apparent in semi-peripheral reactions and increases smoothly with centrality.Comment: 326 authors, 6 pages text, RevTeX, 3 figures, 2 tables. Submitted to PRL. 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

A Detailed Study of High-pT Neutral Pion Suppression and Azimuthal Anisotropy in Au+Au Collisions at \sqrt{s_{NN}} = 200 GeV

Measurements of neutral pion production at midrapidity in sqrt(s_NN) = 200 GeV Au+Au collisions as a function of transverse momentum, p_T, collision centrality, and angle with respect to reaction plane are presented. The data represent the final pi^0 results from the PHENIX experiment for the first RHIC Au+Au run at design center-of-mass-energy. They include additional data obtained using the PHENIX Level-2 trigger with more than a factor of three increase in statistics over previously published results for p_T > 6 GeV/c. We evaluate the suppression in the yield of high-p_T pi^0's relative to point-like scaling expectations using the nuclear modification factor R_AA. We present the p_T dependence of R_AA for nine bins in collision centrality. We separately integrate R_AA over larger p_T bins to show more precisely the centrality dependence of the high-p_T suppression. We then evaluate the dependence of the high-p_T suppression on the emission angle \Delta\phi of the pions with respect to event reaction plane for 7 bins in collision centrality. We show that the yields of high-p_T pi^0's vary strongly with \Delta\phi, consistent with prior measurements. We show that this variation persists in the most peripheral bin accessible in this analysis. For the peripheral bins we observe no suppression for neutral pions produced aligned with the reaction plane while the yield of pi^0's produced perpendicular to the reaction plane is suppressed by more than a factor of 2. We analyze the combined centrality and \Delta\phi dependence of the pi^0 suppression in different p_T bins using different possible descriptions of parton energy loss dependence on jet path-length averages to determine whether a single geometric picture can explain the observed suppression pattern.Comment: 330 authors, pages text, RevTeX4, figures, tables. 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

Measurement of Single Muons at Forward Rapidity in p+p Collisions at sqrt(s) = 200 GeV and Implications for Charm Production

Muon production at forward rapidity (1.5 < |\eta| < 1.8) has been measured by the PHENIX experiment over the transverse momentum range 1 < p_T \le 3 GeV/c in sqrt(s) = 200 GeV p+p collisions at the Relativistic Heavy Ion Collider. After statistically subtracting contributions from light hadron decays an excess remains which is attributed to the semileptonic decays of hadrons carrying heavy flavor, i.e. charm quarks or, at high p_T, bottom quarks. The resulting muon spectrum from heavy flavor decays is compared to PYTHIA and a next-to-leading order perturbative QCD calculation. PYTHIA is used to determine the charm quark spectrum that would produce the observed muon excess. The corresponding differential cross section for charm quark production at forward rapidity is determined to be d\sigma_(c c^bar)/dy|_(y=1.6)=0.243 +/- 0.013 (stat.) +/- 0.105 (data syst.) ^(+0.049)_(-0.087) (PYTHIA syst.) mb.Comment: 329 authors, pages text, 18 figures, tables. Submitted to Physical Review D. 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

J/Psi Production in Au-Au Collisions at sqrt(s_NN) = 200 GeV at the Relativistic Heavy Ion Collider

First results on charm quarkonia production in heavy ion collisions at the Relativistic Heavy Ion Collider (RHIC) are presented. The yield of J/Psi's measured in the PHENIX experiment via electron-positron decay pairs at mid-rapidity for Au-Au reactions at sqrt(s_NN) = 200 GeV are analyzed as a function of collision centrality. For this analysis we have studied 49.3 million minimum bias Au-Au reactions. We present the J/Psi invariant yield dN/dy for peripheral and mid-central reactions. For the most central collisions where we observe no signal above background, we quote 90% confidence level upper limits. We compare these results with our J/Psi measurement from proton-proton reactions at the same energy. We find that our measurements are not consistent with models that predict strong enhancement relative to binary collision scaling.Comment: 325 authors, 11 pages text, 6 figures, 4 tables, RevTeX 4. Accepted for publication as a regular article in Physical Review C. This version has minor changes to respond to referee suggestions. 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

Evidence for a long-range component in the pion emission source in Au+Au collisions at sqrt(s_NN) = 200 GeV

Emission source functions are extracted from correlation functions constructed from charged pions produced at mid-rapidity in Au+Au collisions at sqrt(s_NN)=200 GeV. The source parameters extracted from these functions at low k_T, give first indications of a long tail for the pion emission source. The source extension cannot be explained solely by simple kinematic considerations. The possible role of a halo of secondary pions from resonance emissions is explored.Comment: 334 authors, 6 pages, 3 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