Transforming Potential of Dbl Family Proteins Correlates with Transcription from the Cyclin D1 Promoter but Not with Activation of Jun NH 2 -terminal Kinase, p38/Mpk2, Serum Response Factor, or c-Jun

The dbl family of oncogenes encodes a large, structurally related, family of growth-regulatory molecules that possess guanine nucleotide exchange factor activity for specific members of the Rho family of Ras-related GTPases. We have evaluated matched sets of weakly and strongly transforming versions of five Dbl family proteins (Lfc, Lsc, Ect2, Dbl, and Dbs) to determine their ability to stimulate signaling pathways that are activated by Rho family proteins. We found that the transforming potential of this panel did not correlate directly with their ability to activate Jun NH2-terminal kinase, p38/Mpk2, serum response factor, or c-Jun. In contrast, transient stimulation of transcription from the cyclin D1 promoter provided a strong correlation with transforming potential, and we found constitutive up-regulation of cyclin D1 protein in Dbl family protein-transformed cells. In addition, we observed that at least two Dbl family members (Lfc and Ect2) induced changes in the actin cytoskeleton and exhibited nuclear signaling profiles that are consistent with a broader range of in vivo substrate utilization than is predicted from their in vitro exchange specificities. In summary, although Dbl family proteins exhibit signaling profiles that are consistent with their in vivo activation of Rho proteins, stimulation of cyclin D1 transcription is the only activity that correlates with transforming potential, thus suggesting that deregulated cell cycle progression may be important for Dbl family protein transformation

Radial Flow in Au+Au Collisions at E=0.25-1.15 A GeV

A systematic study of energy spectra for light particles emitted at midrapidity from Au+Au collisions at E=0.25-1.15 A GeV reveals a significant non-thermal component consistent with a collective radial flow. This component is evaluated as a function of bombarding energy and event centrality. Comparisons to Quantum Molecular Dynamics (QMD) and Boltzmann-Uehling-Uhlenbeck (BUU) models are made for different equations of state.Comment: 10 pages of text and 4 figures (all ps files in a uuencoded package)

A mechanism for the inhibition of DNA-PK-mediated DNA sensing by a virus

The innate immune system is critical in the response to infection by pathogens and it is activated by pattern recognition receptors (PRRs) binding to pathogen associated molecular patterns (PAMPs). During viral infection, the direct recognition of the viral nucleic acids, such as the genomes of DNA viruses, is very important for activation of innate immunity. Recently, DNA-dependent protein kinase (DNA-PK), a heterotrimeric complex consisting of the Ku70/Ku80 heterodimer and the catalytic subunit DNA-PKcs was identified as a cytoplasmic PRR for DNA that is important for the innate immune response to intracellular DNA and DNA virus infection. Here we show that vaccinia virus (VACV) has evolved to inhibit this function of DNA-PK by expression of a highly conserved protein called C16, which was known to contribute to virulence but by an unknown mechanism. Data presented show that C16 binds directly to the Ku heterodimer and thereby inhibits the innate immune response to DNA in fibroblasts, characterised by the decreased production of cytokines and chemokines. Mechanistically, C16 acts by blocking DNA-PK binding to DNA, which correlates with reduced DNA-PK-dependent DNA sensing. The C-terminal region of C16 is sufficient for binding Ku and this activity is conserved in the variola virus (VARV) orthologue of C16. In contrast, deletion of 5 amino acids in this domain is enough to knockout this function from the attenuated vaccine strain modified vaccinia virus Ankara (MVA). In vivo a VACV mutant lacking C16 induced higher levels of cytokines and chemokines early after infection compared to control viruses, confirming the role of this virulence factor in attenuating the innate immune response. Overall this study describes the inhibition of DNA-PK-dependent DNA sensing by a poxvirus protein, adding to the evidence that DNA-PK is a critical component of innate immunity to DNA viruses

Neurotoxicity with high dose disulfiram and vorinostat used for HIV latency reversal

OBJECTIVE: To examine whether administering both vorinostat and disulfiram to people with HIV (PWH) on antiretroviral therapy (ART) is safe and can enhance HIV latency reversal. DESIGN: Vorinostat and disulfiram, can increase HIV transcription in people with HIV (PWH) on antiretroviral therapy (ART). Together these agents may lead to significant HIV latency reversal. METHODS: Virologically suppressed PWH on ART received disulfiram 2000 mg daily for 28 days and vorinostat 400 mg daily on days 8-10 and 22-24. The primary endpoint was plasma HIV RNA on day 11 relative to baseline using a single copy assay. Assessments included cell-associated (CA) unspliced (US) RNA as a marker of latency reversal, HIV DNA in CD4+ T-cells, plasma HIV RNA and plasma concentrations of ART, vorinostat and disulfiram. RESULTS: The first two participants (P1 and P2) experienced grade 3 neurotoxicity leading to trial suspension. After 24 days, P1 presented with confusion, lethargy, and ataxia having stopped disulfiram and ART. Symptoms resolved by day 29. After 11 days, P2 presented with paranoia, emotional lability, lethargy, ataxia and study drugs were ceased. Symptoms resolved by day 23. CA-US RNA increased by 1.4- and 1.3-fold for P1 and P2 respectively. Plasma HIV RNA was detectable from day 8-37 (peak 81 copies/mL) for P2 but was not increased in P1 Antiretroviral levels were therapeutic and neuronal injury markers were elevated in P1. CONCLUSIONS: The combination of prolonged high dose disulfiram and vorinostat was not safe in PWH on ART and should not be pursued despite evidence of latency reversal

Statistical signatures of critical behavior in small systems

The cluster distributions of different systems are examined to search for signatures of a continuous phase transition. In a system known to possess such a phase transition, both sensitive and insensitive signatures are present; while in systems known not to possess such a phase transition, only insensitive signatures are present. It is shown that nuclear multifragmentation results in cluster distributions belonging to the former category, suggesting that the fragments are the result of a continuous phase transition.Comment: 31 pages, two columns with 30 figure

An Experimental Exploration of the QCD Phase Diagram: The Search for the Critical Point and the Onset of De-confinement

The QCD phase diagram lies at the heart of what the RHIC Physics Program is all about. While RHIC has been operating very successfully at or close to its maximum energy for almost a decade, it has become clear that this collider can also be operated at lower energies down to 5 GeV without extensive upgrades. An exploration of the full region of beam energies available at the RHIC facility is imperative. The STAR detector, due to its large uniform acceptance and excellent particle identification capabilities, is uniquely positioned to carry out this program in depth and detail. The first exploratory beam energy scan (BES) run at RHIC took place in 2010 (Run 10), since several STAR upgrades, most importantly a full barrel Time of Flight detector, are now completed which add new capabilities important for the interesting physics at BES energies. In this document we discuss current proposed measurements, with estimations of the accuracy of the measurements given an assumed event count at each beam energy.Comment: 59 pages, 78 figure

Observation of charge-dependent azimuthal correlations and possible local strong parity violation in heavy ion collisions

Parity-odd domains, corresponding to non-trivial topological solutions of the QCD vacuum, might be created during relativistic heavy-ion collisions. These domains are predicted to lead to charge separation of quarks along the orbital momentum of the system created in non-central collisions. To study this effect, we investigate a three particle mixed harmonics azimuthal correlator which is a \P-even observable, but directly sensitive to the charge separation effect. We report measurements of this observable using the STAR detector in Au+Au and Cu+Cu collisions at $\sqrt{s_{NN}}$=200 and 62~GeV. The results are presented as a function of collision centrality, particle separation in rapidity, and particle transverse momentum. A signal consistent with several of the theoretical expectations is detected in all four data sets. We compare our results to the predictions of existing event generators, and discuss in detail possible contributions from other effects that are not related to parity violation.Comment: 17 pages, 14 figures, as accepted for publication in Physical Review C