Alkaloids from the Sponge Stylissa carteri Present Prospective Scaffolds for the Inhibition of Human Immunodeficiency Virus 1 (HIV-1).

The sponge Stylissa carteri is known to produce a number of secondary metabolites displaying anti-fouling, anti-inflammatory, and anti-cancer activity. However, the anti-viral potential of metabolites produced by S. carteri has not been extensively explored. In this study, an S. carteri extract was HPLC fractionated and a cell based assay was used to evaluate the effects of HPLC fractions on parameters of Human Immunodeficiency Virus (HIV-1) infection and cell viability. Candidate HIV-1 inhibitory fractions were then analyzed for the presence of potential HIV-1 inhibitory compounds by mass spectrometry, leading to the identification of three previously characterized compounds, i.e., debromohymenialdisine (DBH), hymenialdisine (HD), and oroidin. Commercially available purified versions of these molecules were re-tested to assess their antiviral potential in greater detail. Specifically, DBH and HD exhibit a 30%-40% inhibition of HIV-1 at 3.1 μM and 13 μM, respectively; however, both exhibited cytotoxicity. Conversely, oroidin displayed a 50% inhibition of viral replication at 50 μM with no associated toxicity. Additional experimentation using a biochemical assay revealed that oroidin inhibited the activity of the HIV-1 Reverse Transcriptase up to 90% at 25 μM. Taken together, the chemical search space was narrowed and previously isolated compounds with an unexplored anti-viral potential were found. Our results support exploration of marine natural products for anti-viral drug discovery

Transition from initiation to promoter proximal pausing requires the CTD of RNA polymerase II

The C-terminal domain (CTD) of mammalian RNA polymerase II consists of 52 repeats of the consensus hepta-peptide YSPTSPS, and links transcription to the processing of pre-mRNA. Although Pol II with a CTD shortened to five repeats (Pol II Δ5) is transcriptionally inactive on chromatin templates, it is not clear whether CTD is required for promoter recognition in vivo. Here, we demonstrate that in the context of chromatin, Pol II Δ5 can bind to the c-myc promoter with the same efficiency as wild type Pol II. However, Pol II Δ5 does not form a stable initiation complex, and does not transcribe promoter proximal sequences. Fluorescence recovery after photobleaching (FRAP) experiments with cells expressing enhanced green fluorescent protein (EGFP)-tagged Δ5 or wildtype Pol II revealed a single, highly mobile Pol II Δ5 fraction whereas wildtype Pol II yielded less mobile fractions. These data suggest that CTD is not required for promoter recognition, but rather for subsequent formation of a stable initiation complex and isomerization to an elongation competent complex

Mean-field description of ground-state properties of drip-line nuclei. (I) Shell-correction method

A shell-correction method is applied to nuclei far from the beta stability line and its suitability to describe effects of the particle continuum is discussed. The sensitivity of predicted locations of one- and two-particle drip lines to details of the macroscopic-microscopic model is analyzed.Comment: 22 REVTeX pages, 13 uuencoded postscript figures available upon reques

Shell structure and orbit bifurcations in finite fermion systems

We first give an overview of the shell-correction method which was developed by V. M. Strutinsky as a practicable and efficient approximation to the general selfconsistent theory of finite fermion systems suggested by A. B. Migdal and collaborators. Then we present in more detail a semiclassical theory of shell effects, also developed by Strutinsky following original ideas of M. Gutzwiller. We emphasize, in particular, the influence of orbit bifurcations on shell structure. We first give a short overview of semiclassical trace formulae, which connect the shell oscillations of a quantum system with a sum over periodic orbits of the corresponding classical system, in what is usually called the "periodic orbit theory". We then present a case study in which the gross features of a typical double-humped nuclear fission barrier, including the effects of mass asymmetry, can be obtained in terms of the shortest periodic orbits of a cavity model with realistic deformations relevant for nuclear fission. Next we investigate shell structures in a spheroidal cavity model which is integrable and allows for far-going analytical computation. We show, in particular, how period-doubling bifurcations are closely connected to the existence of the so-called "superdeformed" energy minimum which corresponds to the fission isomer of actinide nuclei. Finally, we present a general class of radial power-law potentials which approximate well the shape of a Woods-Saxon potential in the bound region, give analytical trace formulae for it and discuss various limits (including the harmonic oscillator and the spherical box potentials).Comment: LaTeX, 67 pp., 30 figures; revised version (missing part at end of 3.1 implemented; order of references corrected

Shape Coexistence and the Effective Nucleon-Nucleon Interaction

The phenomenon of shape coexistence is discussed within the self-consistent Hartree-Fock method and the nuclear shell model. The occurrence of the coexisting configurations with different intrinsic shapes is traced back to the properties of the effective Hamiltonian.Comment: 40 pages (16 text, 24 figures). The file may also be retrieved at http://csep2.phy.ornl.gov/theory_group/people/dean/shape_coex/shapes.htm

Shell structure of superheavy nuclei in self-consistent mean-field models

We study the extrapolation of nuclear shell structure to the region of superheavy nuclei in self-consistent mean-field models -- the Skyrme-Hartree-Fock approach and the relativistic mean-field model -- using a large number of parameterizations. Results obtained with the Folded-Yukawa potential are shown for comparison. We focus on differences in the isospin dependence of the spin-orbit interaction and the effective mass between the models and their influence on single-particle spectra. While all relativistic models give a reasonable description of spin-orbit splittings, all non-relativistic models show a wrong trend with mass number. The spin-orbit splitting of heavy nuclei might be overestimated by 40%-80%. Spherical doubly-magic superheavy nuclei are found at (Z=114,N=184), (Z=120,N=172) or (Z=126,N=184) depending on the parameterization. The Z=114 proton shell closure, which is related to a large spin-orbit splitting of proton 2f states, is predicted only by forces which by far overestimate the proton spin-orbit splitting in Pb208. The Z=120 and N=172 shell closures predicted by the relativistic models and some Skyrme interactions are found to be related to a central depression of the nuclear density distribution. This effect cannot appear in macroscopic-microscopic models which have a limited freedom for the density distribution only. In summary, our findings give a strong argument for (Z=120,N=172) to be the next spherical doubly-magic superheavy nucleus.Comment: 22 pages REVTeX, 16 eps figures, accepted for publication in Phys. Rev.

Highlights from the Pierre Auger Observatory

The Pierre Auger Observatory is the world's largest cosmic ray observatory. Our current exposure reaches nearly 40,000 km$^2$ str and provides us with an unprecedented quality data set. The performance and stability of the detectors and their enhancements are described. Data analyses have led to a number of major breakthroughs. Among these we discuss the energy spectrum and the searches for large-scale anisotropies. We present analyses of our X$_{max}$ data and show how it can be interpreted in terms of mass composition. We also describe some new analyses that extract mass sensitive parameters from the 100% duty cycle SD data. A coherent interpretation of all these recent results opens new directions. The consequences regarding the cosmic ray composition and the properties of UHECR sources are briefly discussed.Comment: 9 pages, 12 figures, talk given at the 33rd International Cosmic Ray Conference, Rio de Janeiro 201

Peptides Derived from HIV-1 Integrase that Bind Rev Stimulate Viral Genome Integration

The human immunodeficiency virus type 1 (HIV-1) integrase protein (IN), catalyzes the integration of viral DNA into the host cell genome. IN catalyzes the first step of the integration process, namely the 3′-end processing in which IN removes a pGT dinucleotide from the 3′ end of each viral long terminal repeat (LTR). Following nuclear import of the viral preintegration complex, the host chromosomal DNA becomes accessible to the viral cDNA and the second step of the integration process, namely the strand-transfer step takes place. This ordered sequence of events, centered on integration, is mandatory for HIV replication. assay system, we show that INr-1 and INr-2 are able to abrogate the inhibitory effects exerted by Rev and Rev-derived peptides on integrase activity. Both INr-1 and INr-2 were found to be cell-permeable and nontoxic, allowing a study of their effect in HIV-1-infected cultured cells. Interestingly, both INr peptides stimulated virus infectivity as estimated by production of the viral P24 protein, as well as by determination of the appearance of newly formed virus particles. Furthermore, kinetics studies revealed that the cell-permeable INr peptides enhance the integration process, as was indeed confirmed by direct determination of viral DNA integration by real-time PCR.The results of the present study raise the possibility that in HIV-infected cells, the Rev protein may be involved in the integration of proviral DNA by controlling/regulating the activity of the integrase. Release from such inhibition leads to stimulation of IN activity and multiple viral DNA integration events

A search for point sources of EeV photons

Measurements of air showers made using the hybrid technique developed with the fluorescence and surface detectors of the Pierre Auger Observatory allow a sensitive search for point sources of EeV photons anywhere in the exposed sky. A multivariate analysis reduces the background of hadronic cosmic rays. The search is sensitive to a declination band from -85{\deg} to +20{\deg}, in an energy range from 10^17.3 eV to 10^18.5 eV. No photon point source has been detected. An upper limit on the photon flux has been derived for every direction. The mean value of the energy flux limit that results from this, assuming a photon spectral index of -2, is 0.06 eV cm^-2 s^-1, and no celestial direction exceeds 0.25 eV cm^-2 s^-1. These upper limits constrain scenarios in which EeV cosmic ray protons are emitted by non-transient sources in the Galaxy.Comment: 28 pages, 10 figures, accepted for publication in The Astrophysical Journa

Reconstruction of inclined air showers detected with the Pierre Auger Observatory

We describe the method devised to reconstruct inclined cosmic-ray air showers with zenith angles greater than $60^\circ$ detected with the surface array of the Pierre Auger Observatory. The measured signals at the ground level are fitted to muon density distributions predicted with atmospheric cascade models to obtain the relative shower size as an overall normalization parameter. The method is evaluated using simulated showers to test its performance. The energy of the cosmic rays is calibrated using a sub-sample of events reconstructed with both the fluorescence and surface array techniques. The reconstruction method described here provides the basis of complementary analyses including an independent measurement of the energy spectrum of ultra-high energy cosmic rays using very inclined events collected by the Pierre Auger Observatory.Comment: 27 pages, 19 figures, accepted for publication in Journal of Cosmology and Astroparticle Physics (JCAP