The Elemental Abundance Distributions of Milky Way Satellite Galaxies

The chemical compositions of the stars in Milky Way (MW) satellite galaxies reveals the history of gas flows and star formation (SF) intensity. This talk presented a Keck/DEIMOS spectroscopic survey of the Fe, Mg, Si, Ca, and Ti abundances of nearly 3000 red giants in eight MW dwarf satellites. The metallicity and alpha-to-iron ratio distributions obey the following trends: (1) The more luminous galaxies are more metal-rich, indicating that they retained gas more efficiently than the less luminous galaxies. (2) The shapes of the metallicity distributions of the more luminous galaxies require gas infall during their SF lifetimes. (3) At [Fe/H] < -1.5, [alpha/Fe] falls monotonically with increasing [Fe/H] in all MW satellites. One interpretation of these trends is that the SF timescale in any MW satellite is long enough that Type Ia supernovae exploded for nearly the entire SF lifetime.Comment: 6 pages, 4 figures, proceeding of oral contribution to A Universe of Dwarf Galaxies, Lyon, France, July 201

Identification of estrogen receptor modulators as inhibitors of flavivirus infection

Flaviviruses such as Zika virus (ZIKV), dengue virus (DENV) and West Nile virus (WNV) are major global pathogens for which safe and effective antiviral therapies are not currently available. To identify antiviral small molecules with well-characterized safety and bioavailability profiles we screened a library of 2,907 approved drugs and pharmacologically active compounds for inhibitors of ZIKV infection using a high-throughput cell-based immunofluorescence assay. Interestingly, estrogen receptor modulators raloxifene hydrochloride and quinestrol were amongst 15 compounds that significantly inhibited ZIKV infection in repeat screens. Subsequent validation studies revealed that these drugs effectively inhibit ZIKV, DENV and WNV (Kunjin strain) infection at low micromolar concentrations with minimal cytotoxicity in Huh-7.5 hepatoma cells and HTR-8 placental trophoblast cells. Since these cells lack detectable expression of estrogen receptors-α and -β (ER-α and ER-β) and similar antiviral effects were observed in the context of subgenomic DENV and ZIKV replicons, these compounds appear to inhibit viral RNA replication in a manner that is independent of their known effects on estrogen receptor signaling. Taken together, quinestrol, raloxifene hydrochloride and structurally related analogues warrant further investigation as potential therapeutics for treatment of flavivirus infections.Nicholas S. Eyre, Emily N. Kirby, Daniel R. Anfiteatro, Gustavo Bracho, Alice G. Russo, Peter A. White ... et al

The SPLASH Survey: Milky Way

We present the first systematic comparison of the detailed properties, including internal kinematics, chemical abundances, sizes, and dark matter masses, of Milky Way and M 31 dSphs as a part of the SPLASH Survey (Spectroscopic and Photometric Landscape of Andromeda’s Stellar Halo). Through Keck/DEIMOS spectroscopy of several hundred individual red giants in a half dozen M 31 galaxies, our results indicate both similarities and differences between the family of dSphs in the Milky Way and M 31. For example, we find that the luminosity-metallicity relation of dSphs in the two hosts is very similar between L = 105 and 107 L⊙, the size distribution of M 31 dSphs extends to larger values at the same luminosity compared to Milky Way counterparts (especially at the bright end), and that the dark matter masses of M 31 dSphs are slightly smaller than similar luminosity Milky Way galaxies

Genome-wide CRISPR screen identifies RACK1 as a critical host factor for flavivirus replication

ABSTRACT Cellular factors have important roles in all facets of the flavivirus replication cycle. Deciphering viral-host protein interactions is essential for understanding the flavivirus life cycle as well as development of effective antiviral strategies. To uncover novel host factors that are co-opted by multiple flaviviruses, a CRISPR/Cas9 genome wide knockout (KO) screen was employed to identify genes required for replication of Zika virus (ZIKV). Receptor for Activated Protein C Kinase 1 (RACK1) was identified as a novel host factor required for ZIKV replication, which was confirmed via complementary experiments. Depletion of RACK1 via siRNA demonstrated that RACK1 is important for replication of a wide range of mosquito- and tick-borne flaviviruses, including West Nile Virus (WNV), Dengue Virus (DENV), Powassan Virus (POWV) and Langat Virus (LGTV) as well as the coronavirus SARS-CoV-2, but not for YFV, EBOV, VSV or HSV. Notably, flavivirus replication was only abrogated when RACK1 expression was dampened prior to infection. Utilising a non-replicative flavivirus model, we show altered morphology of viral replication factories and reduced formation of vesicle packets (VPs) in cells lacking RACK1 expression. In addition, RACK1 interacted with NS1 protein from multiple flaviviruses; a key protein for replication complex formation. Overall, these findings reveal RACK1’s crucial role to the biogenesis of pan-flavivirus replication organelles. IMPORTANCE Cellular factors are critical in all facets of viral lifecycles, where overlapping interactions between the virus and host can be exploited as possible avenues for the development of antiviral therapeutics. Using a genome-wide CRISPR knockout screening approach to identify novel cellular factors important for flavivirus replication we identified RACK1 as a pro-viral host factor for both mosquito- and tick-borne flaviviruses in addition to SARS-CoV-2. Using an innovative flavivirus protein expression system, we demonstrate for the first time the impact of the loss of RACK1 on the formation of viral replication factories known as 'vesicle packets' (VPs). In addition, we show that RACK1 can interact with numerous flavivirus NS1 proteins as a potential mechanism by which VP formation can be induced by the former.Byron Shue, Abhilash I. Chiramel, Berati Cerikan, Thu-Hien To, Sonja Frölich, Stephen M. Pederson, Emily N. Kirby, Nicholas S. Eyre, Ralf F. W. Bartenschlager, Sonja M. Best, and Michael R. Bear