Vaccinia virus protein A46R targets multiple Toll-like-interleukin-1 receptor adaptors and contributes to virulence

Viral immune evasion strategies target key aspects of the host antiviral response. Recently, it has been recognized that Toll-like receptors (TLRs) have a role in innate defense against viruses. Here, we define the function of the vaccinia virus (VV) protein A46R and show it inhibits intracellular signalling by a range of TLRs. TLR signalling is triggered by homotypic interactions between the Toll-like-interleukin-1 resistance (TIR) domains of the receptors and adaptor molecules. A46R contains a TIR domain and is the only viral TIR domain-containing protein identified to date. We demonstrate that A46R targets the host TIR adaptors myeloid differentiation factor 88 (MyD88), MyD88 adaptor-like, TIR domain-containing adaptor inducing IFN-beta (TRIF), and the TRIF-related adaptor molecule and thereby interferes with downstream activation of mitogen-activated protein kinases and nuclear factor kappaB. TRIF mediates activation of interferon (IFN) regulatory factor 3 (IRF3) and induction of IFN-beta by TLR3 and TLR4 and suppresses VV replication in macrophages. Here, A46R disrupted TRIF-induced IRF3 activation and induction of the TRIF-dependent gene regulated on activation, normal T cell expressed and secreted. Furthermore, we show that A46R is functionally distinct from another described VV TLR inhibitor, A52R. Importantly, VV lacking the A46R gene was attenuated in a murine intranasal model, demonstrating the importance of A46R for VV virulence

Ternatin and improved synthetic variants kill cancer cells by targeting the elongation factor-1A ternary complex.

Cyclic peptide natural products have evolved to exploit diverse protein targets, many of which control essential cellular processes. Inspired by a series of cyclic peptides with partially elucidated structures, we designed synthetic variants of ternatin, a cytotoxic and anti-adipogenic natural product whose molecular mode of action was unknown. The new ternatin variants are cytotoxic toward cancer cells, with up to 500-fold greater potency than ternatin itself. Using a ternatin photo-affinity probe, we identify the translation elongation factor-1A ternary complex (eEF1A·GTP·aminoacyl-tRNA) as a specific target and demonstrate competitive binding by the unrelated natural products, didemnin and cytotrienin. Mutations in domain III of eEF1A prevent ternatin binding and confer resistance to its cytotoxic effects, implicating the adjacent hydrophobic surface as a functional hot spot for eEF1A modulation. We conclude that the eukaryotic elongation factor-1A and its ternary complex with GTP and aminoacyl-tRNA are common targets for the evolution of cytotoxic natural products

The Role of Polycyclic Aromatic Hydrocarbons in Ultraviolet Extinction. I. Probing small molecular PAHs

We have obtained new STIS/HST spectra to search for structure in the ultraviolet interstellar extinction curve, with particular emphasis on a search for absorption features produced by polycyclic aromatic hydrocarbons (PAHs). The presence of these molecules in the interstellar medium has been postulated to explain the infrared emission features seen in the 3-13 $\mu$m spectra of numerous sources. UV spectra are uniquely capable of identifying specific PAH molecules. We obtained high S/N UV spectra of stars which are significantly more reddened than those observed in previous studies. These data put limits on the role of small (30-50 carbon atoms) PAHs in UV extinction and call for further observations to probe the role of larger PAHs. PAHs are of importance because of their ubiquity and high abundance inferred from the infrared data and also because they may link the molecular and dust phases of the interstellar medium. A presence or absence of ultraviolet absorption bands due to PAHs could be a definitive test of this hypothesis. We should be able to detect a 20 \AA wide feature down to a 3$\sigma$ limit of $\sim$0.02 A$_V$. No such absorption features are seen other than the well-known 2175 \AA bump.Comment: 16 pages, 3 figure, ApJ in pres

Dust Emission Features in NGC 7023 between 0.35 and 2.5 micron: Extended Red Emission (0.7 micron) and Two New Emission Features (1.15 and 1.5 micron)

We present 0.35 to 2.5 micron spectra of the south and northwest filaments in the reflection nebula NGC 7023. These spectra were used to test the theory of Seahra & Duley that carbon nanoparticles are responsible for Extended Red Emission (ERE). Our spectra fail to show their predicted second emission band at 1.0 micron even though both filaments exhibit strong emission in the familiar 0.7 micron ERE band. The northwest filament spectrum does show one, and possibly two, new dust emission features in the near-infrared. We clearly detect a strong emission band at 1.5 micron which we tentatively attribute to beta-FeSi_2 grains. We tentatively detect a weaker emission band at 1.15 micron which coincides with the location expected for transitions from the conduction band to mid-gap defect states of silicon nanoparticles. This is added evidence that silicon nanoparticles are responsible for ERE as they already can explain the observed behavior of the main visible ERE band.Comment: 9 pages, color figures, accepted to the ApJ, color and b/w versions available at http://dirty.as.arizona.edu/~kgordon/papers/ere_1um.htm

Interstellar Polarization in M31

The wavelength dependence of interstellar polarization due to dust in M31 has been observed along four sightlines. Only one sightline had been measured previously.The globular clusters, S78, S150, S233 and Baade 327 were used as point sources to probe the interstellar dust in M31. The Serkowski law produces good fits for all the sightlines although the relationship between K and lambda(max) may be different from that found in the Galaxy. The results of this study imply that the slope K/lambda(max) may be significantly larger in M31. The Serkowski curves are significantly narrower than those of the same lambda(max) in the Galaxy and may require extreme modifications to the size distributions of silicate particles. The fits for the four sightlines reveal values of lambda(max) ranging from 4800 to 5500 A. These are consistent with average values of lambda(max) measured in the Galaxy and the Magellanic Clouds. The range measured for M31 corresponds to R(V) values of 2.7 to 3.1. The range in R(V) seen in the Galaxy is 2.5 to 5.5 implying, for this small sample, that the average size ofinterstellar grains in M31 is typically smaller than that seen for Galactic grains if the nature of the grains is the same. Also, the polarization efficiency for these sightlines is large although some bias is expected since sightlines known to have significant interstellar polarization were selected for the sample.Comment: 13 pages, 2 figures, AJ in press (June