Identifying Varicella-Zoster Virus Latent Genomes in an Alternative Neuronal Latency Model

Varicella zoster virus (VZV) is the etiologic agent of chickenpox (varicella) upon primary infection and shingles (herpes zoster, HZ) upon reactivation from neuronal latency. Shingles is a debilitating disease of the elderly and immune impaired that is frequently complicated. Reactivation of VZV causing HZ is painful and can result in a chronic pain state known as postherpetic neuralgia (PHN) that is difficult to alleviate. HZ has also been linked to encephalitis, meningitis, vasculopathies and increased risk of stroke, all of which emphasize the continued public health demand for better treatments and/or vaccines. VZV latency and reactivation has not been well characterized because it presents monumental difficulties studying it in a laboratory setting. Its human-specific restriction requires human neuronal platforms for modeling neurotropism, latency and reactivation. Importantly, VZV genomes are found not only in neurons of sensory ganglia, but in those of autonomic, enteric and cranial ganglia, and possibly even the CNS. These latent genomes are difficult to characterize and are usually found only by performing end-stage methods of analyses, when tissues/cells need to be fixed or extracted. One aspect of this research was to explore methods that would better enable the identification of VZV genomes in latently infected cells and whether they could be applied in a live-cell in vitro setting. We have previously established that sensory-like neurons derived from human embryonic stem cells (hESC) can host both a productive VZV infection and a model state of VZV latency that can be experimentally reactivated. However, the maintenance of hESCs and their differentiation into sensory neurons for larger scale applications is exceedingly demanding. The second goal of this research was to evaluate an alternative neuron-like system that is more easily expandable for large-scale applications. We evaluated the proliferative human neuronal precursor cell line Lund human mesencephalic (LUHMES) cells. Differentiated LUHMES can easily be scaled to large numbers and show biochemical, morphological, and functional features of mature neurons. While both undifferentiated and differentiated LUHMES cells are fully permissive to VZV infection, current studies are addressing the potential of this system to host a VZV latent state, and whether this is experimentally reactivatable

RCS043938-2904.9: A New Rich Cluster of Galaxies at z=0.951

We present deep I, J_s, K_s imaging and optical spectroscopy of the newly discovered Red-Sequence Cluster Survey cluster RCS043938-2904.9. This cluster, drawn from an extensive preliminary list, was selected for detailed study on the basis of its apparent optical richness. Spectroscopy of 11 members places the cluster at z=0.951 +- 0.006, and confirms the photometric redshift estimate from the (R-z) color-magnitude diagram. Analysis of the infrared imaging data demonstrates that the cluster is extremely rich, with excess counts in the Ks-band exceeding the expected background counts by 9 sigma. The properties of the galaxies in RCS043938-2904.9 are consistent with those seen in other clusters at similar redshifts. Specifically, the red-sequence color, slope and scatter, and the size-magnitude relation of these galaxies are all consistent with that seen in the few other high redshift clusters known, and indeed are consistent with appropriately evolved properties of local cluster galaxies. The apparent consistency of these systems implies that the rich, high-redshift RCS clusters are directly comparable to the few other systems known at z ~ 1, most of which have been selected on the basis of X-ray emission.Comment: 12 pages, 1 color figure. Accepted for publication on The ApJ Letter

Structure-based stabilization of insulin as a therapeutic protein assembly via enhanced aromatic-aromatic interactions

Key contributions to protein structure and stability are provided by weakly polar interactions, which arise from asymmetric electronic distributions within amino acids and peptide bonds. Of particular interest are aromatic side chains whose directional π-systems commonly stabilize protein interiors and interfaces. Here, we consider aromatic-aromatic interactions within a model protein assembly: the dimer interface of insulin. Semi-classical simulations of aromatic-aromatic interactions at this interface suggested that substitution of residue TyrB26 by Trp would preserve native structure while enhancing dimerization (and hence hexamer stability). The crystal structure of a [TrpB26]insulin analog (determined as a T3Rf3 zinc hexamer at a resolution of 2.25 Å) was observed to be essentially identical to that of WT insulin. Remarkably and yet in general accordance with theoretical expectations, spectroscopic studies demonstrated a 150-fold increase in the in vitro lifetime of the variant hexamer, a critical pharmacokinetic parameter influencing design of long-acting formulations. Functional studies in diabetic rats indeed revealed prolonged action following subcutaneous injection. The potency of the TrpB26-modified analog was equal to or greater than an unmodified control. Thus, exploiting a general quantum-chemical feature of protein structure and stability, our results exemplify a mechanism-based approach to the optimization of a therapeutic protein assembly

Theory of Abelian Projection

Analytic methods for Abelian projection are developed. A number of results are obtained related to string tension measurements. It is proven that even without gauge fixing, abelian projection yields string tensions of the underlying non-Abelian theory. Strong arguments are given for similar results in the case where gauge fixing is employed. The methods used emphasize that the projected theory is derived from the underlying non-Abelian theory rather than vice versa. In general, the choice of subgroup used for projection is not very important, and need not be Abelian. While gauge fixing is shown to be in principle unnecessary for the success of Abelian projection, it is computationally advantageous for the same reasons that improved operators, e.g., the use of fat links, are advantageous in Wilson loop measurements. Two other issues, Casimir scaling and the conflict between projection and critical universality, are also discussed.Comment: Minor corrections, new section added, 14 pages, 3 figures, RevTe

NASA ExoPAG Study Analysis Group 11: Preparing for the WFIRST Microlensing Survey

NASA's proposed WFIRST-AFTA mission will discover thousands of exoplanets with separations from the habitable zone out to unbound planets, using the technique of gravitational microlensing. The Study Analysis Group 11 of the NASA Exoplanet Program Analysis Group was convened to explore scientific programs that can be undertaken now, and in the years leading up to WFIRST's launch, in order to maximize the mission's scientific return and to reduce technical and scientific risk. This report presents those findings, which include suggested precursor Hubble Space Telescope observations, a ground-based, NIR microlensing survey, and other programs to develop and deepen community scientific expertise prior to the mission.Comment: 35 pages, 5 Figures. A brief overview of the findings is presented in the Executive Summary (2 pages

NICMOS and VLA Observations of the Gravitatonally Lensed Ultraluminous BAL Quasar APM~08279+5255: Detection of a Third Image

We present a suite of observations of the recently identified ultraluminous BAL quasar APM 08279+5255, taken both in the infra-red with the NICMOS high resolution camera on board the Hubble Space Telescope, and at 3.5cm with the Very Large Array. With an inferred luminosity of ~5x10^15 Solar luminosities, APM 08279+5255 is apparently the most luminous system known. Extant ground-based images show that APM 08279+5255 is not point-like, but is instead separated into two components, indicative of gravitational lensing. The much higher resolution images presented here also reveal two point sources, A and B, of almost equal brightness (f_B/f_A=0.782 +/- 0.010), separated by 0."378 +/- 0."001, as well as a third, previously unknown, fainter image, C, seen between the brighter images. While the nature of C is not fully determined, several lines of evidence point to it being a third gravitationally lensed image of the quasar, rather than being the lensing galaxy. Simple models which recover the relative image configuration and brightnesses are presented. While proving to be substantially amplified, APM 08279+5255 possesses an intrinsic bolometric luminosity of ~10^14 to 10^15 Solar luminosities and remains amongst the most luminous objects known.Comment: 21 pages, 5 figures (2 as GIF files); accepted for publication in the Astronomical Journa

The Multiplicity of M-Dwarfs in Young Moving Groups

We image 104 newly identified low-mass (mostly M-dwarf) pre-main sequence members of nearby young moving groups with Magellan Adaptive Optics (MagAO) and identify 27 binaries with instantaneous projected separation as small as 40 mas. 15 were previously unknown. The total number of multiple systems in this sample including spectroscopic and visual binaries from the literature is 36, giving a raw multiplicity rate of at least $35^{+5}_{-4}\%$ for this population. In the separation range of roughly 1 - 300 AU in which infrared AO imaging is most sensitive, the raw multiplicity rate is at least $24^{+5}_{-4}\%$ for binaries resolved by the MagAO infrared camera (Clio). The M-star sub-sample of 87 stars yields a raw multiplicity of at least $30^{+5}_{-4}\%$ over all separations, $21^{+5}_{-4}\%$ for secondary companions resolved by Clio from 1 to 300 AU ($23^{+5}_{-4}\%$ for all known binaries in this separation range). A combined analysis with binaries discovered by the Search for Associations Containing Young stars shows that multiplicity fraction as a function of mass and age over the range of 0.2 to 1.2 $M_\odot$ and 10 - 200 Myr appears to be linearly flat in both parameters and across YMGs. This suggests that multiplicity rates are largely set by 100 Myr without appreciable evolution thereafter. After bias corrections are applied, the multiplicity fraction of low-mass YMG members ($< 0.6 M_\odot$) is in excess of the field.Comment: 25 page

The Incidence of Strong-Lensing Clusters in the Red-Sequence Cluster Survey

The incidence of giant arcs due to strong-lensing clusters of galaxies is known to be discrepant with current theoretical expectations. This result derives from a comparison of several cluster samples to predictions in the framework of the currently favored $\Lambda$CDM cosmology, and one possible explanation for the discrepancy is that this cosmological model is not correct. In this paper we discuss the incidence of giant arcs in the Red-Sequence Cluster Survey (RCS), which again shows significant disagreement with theoretical predictions. We briefly describe a total of eight strong lens systems, seven of which are discussed here for the first time. Based on the details of these systems, in particular on the ratio of single to multiple arc systems, we argue that it may be possible to explain this discrepancy in the currently favored cosmology, by modifying the details of the lenses themselves. Specifically, the high incidence of multiple arc systems and their overall high redshift suggests that a sub-population of the global cluster population is responsible for much of the observed lensing. The lack of lensing clusters at $z<0.64$ in the RCS indicates that a property associated with clusters at early times results in the boosted lensing cross sections; likely a combination of ellipticity and elongation along the line of sight, substructure, and changes in the cluster mass profiles is responsible. Cluster mass, which should evolve to globally higher values toward lower redshifts, is clearly not the most significant consideration for the formation of giant arcs.Comment: ApJ, accepted version. Additions regarding surface brightness limits and seeing effects, and further modeling discussio

A bright, spatially extended lensed galaxy at z = 1.7 behind the cluster RCS2 032727-132623

We present the discovery of an extremely bright and extended lensed source from the second Red Sequence Cluster Survey (RCS2). RCSGA 032727-132609 is spectroscopically confirmed as a giant arc and counter-image of a background galaxy at $z=1.701$, strongly-lensed by the foreground galaxy cluster RCS2 032727-132623 at $z=0.564$. The giant arc extends over $\sim 38$\,\arcsec and has an integrated $g$-band magnitude of 19.15, making it $\sim 20$ times larger and $\sim 4$ times brighter than the prototypical lensed galaxy MS1512-cB58. This is the brightest distant lensed galaxy in the Universe known to date. Its location in the `redshift desert' provides unique opportunities to connect between the large samples of galaxies known at $z\sim3$ and $z\sim1$. We have collected photometry in 9 bands, ranging from $u$ to $K_s$, which densely sample the rest-frame UV and optical light, including the age-sensitive 4000\AA\ break. A lens model is constructed for the system, and results in a robust total magnification of $2.04 \pm 0.16$ for the counter-image; we estimate an average magnification of $17.2 \pm 1.4$ for the giant arc based on the relative physical scales of the arc and counter-image. Fits of single-component spectral energy distribution (SED) models to the photometry result in a moderately young age, $t = 115 \pm 65$\,Myr, small amounts of dust, $E(B-V) \le 0.035$, and an exponentially declining star formation history with \textit{e}-folding time $\tau = 10-100$\,Myr. After correcting for the lensing magnification, we find a stellar mass of $\log(\mathrm{M}/\mathrm{M}_\odot)=10.0 \pm 0.1$. Allowing for episodic star formation, an underlying old burst could contain up to twice the mass inferred from single-component modeling. This stellar mass estimate is consistent with the average stellar mass of a sample of `BM' galaxies ($1.4 < z < 2.0$) studied by Reddy et al. (2006).Comment: 13 pages, 8 figures, abstract abridge