Hubble Space Telescope Observations of M32: The Color-Magnitude Diagram

We present a V-I color-magnitude diagram for a region 1'-2' from the center of M32 based on Hubble Space Telescope WFPC2 images. The broad color-luminosity distribution of red giants shows that the stellar population comprises stars with a wide range in metallicity. This distribution cannot be explained by a spread in age. The blue side of the giant branch rises to M_I ~ -4.0 and can be fitted with isochrones having [Fe/H] ~ -1.5. The red side consists of a heavily populated and dominant sequence that tops out at M_I ~ -3.2, and extends beyond V-I=4. This sequence can be fitted with isochrones with -0.2 < [Fe/H] < +0.1, for ages running from 15 Gyr to 5 Gyr respectively. We do not find the optically bright asymptotic giant branch stars seen in previous ground-based work and argue that the majority of them were artifacts of crowding. Our results are consistent with the presence of the infrared-luminous giants found in ground-based studies, though their existence cannot be directly confirmed by our data. There is little evidence for an extended or even a red horizontal branch, but we find a strong clump on the giant branch itself. If the age spread is not extreme, the distribution of metallicities in M32 is considerably narrower than that of the closed-box model of chemical evolution, and also appears somewhat narrower than that of the solar neighborhood. Overall, the M32 HST color-magnitude diagram is consistent with the average luminosity-weighted age of 8.5 Gyr and [Fe/H] = -0.25 inferred from integrated spectral indices.Comment: 22 pages, AASTeX, aaspp4 and flushrt style files included, 11 postscript figures, figures 1,2,5,7, and 8 available at ftp://bb3.jpl.nasa.gov/pub/m32 . Submitted to the Astronomical Journa

Recombinant Listeria promotes tumor rejection by CD8+ T cell-dependent remodeling of the tumor microenvironment.

Agents that remodel the tumor microenvironment (TME), prime functional tumor-specific T cells, and block inhibitory signaling pathways are essential components of effective immunotherapy. We are evaluating live-attenuated, double-deleted Listeria monocytogenes expressing tumor antigens (LADD-Ag) in the clinic. Here we show in numerous mouse models that while treatment with nonrecombinant LADD induced some changes in the TME, no antitumor efficacy was observed, even when combined with immune checkpoint blockade. In contrast, LADD-Ag promoted tumor rejection by priming tumor-specific KLRG1+PD1loCD62L- CD8+ T cells. These IFNγ-producing effector CD8+ T cells infiltrated the tumor and converted the tumor from an immunosuppressive to an inflamed microenvironment that was characterized by a decrease in regulatory T cells (Treg) levels, a proinflammatory cytokine milieu, and the shift of M2 macrophages to an inducible nitric oxide synthase (iNOS)+CD206- M1 phenotype. Remarkably, these LADD-Ag-induced tumor-specific T cells persisted for more than 2 months after primary tumor challenge and rapidly controlled secondary tumor challenge. Our results indicate that the striking antitumor efficacy observed in mice with LADD-based immunotherapy stems from TME remodeling which is a direct consequence of eliciting potent, systemic tumor-specific CD8+ T cells

A Potent and Effective Suicidal Listeria Vaccine Platform.

Live-attenuated Listeria monocytogenes has shown encouraging potential as an immunotherapy platform in preclinical and clinical settings. However, additional safety measures will enable application across malignant and infectious diseases. Here, we describe a new vaccine platform, termed Lm-RIID (L. monocytogenes recombinase-induced intracellular death), that induces the deletion of genes required for bacterial viability yet maintains potent T cell responses to encoded antigens. Lm-RIID grows normally in broth but commits suicide inside host cells by inducing Cre recombinase and deleting essential genes flanked by loxP sites, resulting in a self-limiting infection even in immunocompromised mice. Lm-RIID vaccination of mice induces potent CD8+ T cells and protects against virulent challenges, similar to live L. monocytogenes vaccines. When combined with α-PD-1, Lm-RIID is as effective as live-attenuated L. monocytogenes in a therapeutic tumor model. This impressive efficacy, together with the increased clearance rate, makes Lm-RIID ideal for prophylactic immunization against diseases that require T cells for protection

Inequitable distribution of plastic benefits and burdens on economies and public health

Plastic heterogeneously affects social systems – notably human health and local and global economies. Here we discuss illustrative examples of the benefits and burdens of each stage of the plastic lifecycle (e.g., macroplastic production, consumption, recycling). We find the benefits to communities and stakeholders are principally economic, whereas burdens fall largely on human health. Furthermore, the economic benefits of plastic are rarely applied to alleviate or mitigate the health burdens it creates, amplifying the disconnect between who benefits and who is burdened. In some instances, social enterprises in low-wealth areas collect and recycle waste, creating a market for upcycled goods. While such endeavors generate local socioeconomic benefits, they perpetuate a status quo in which the burden of responsibility for waste management falls on downstream communities, rather than on producers who have generated far greater economic benefits. While the traditional cost-benefit analyses that inform decision-making disproportionately weigh economic benefits over the indirect, and often unquantifiable, costs of health burdens, we stress the need to include the health burdens of plastic to all impacted stakeholders across all plastic life stages in policy design. We therefore urge the Intergovernmental Negotiating Committee to consider all available knowledge on the deleterious effects of plastic across the entire plastic lifecycle while drafting the upcoming international global plastic treaty.publishedVersio

X-ray Isophotes in a Rapidly Rotating Elliptical Galaxy: Evidence of Inflowing Gas

We describe two-dimensional gasdynamical computations of the X-ray emitting gas in the rotating elliptical galaxy NGC 4649 that indicate an inflow of about one solar mass per year at every radius. Such a large instantaneous inflow cannot have persisted over a Hubble time. The central constant-entropy temperature peak recently observed in the innermost 150 parsecs is explained by compressive heating as gas flows toward the central massive black hole. Since the cooling time of this gas is only a few million years, NGC 4649 provides the most acutely concentrated known example of the cooling flow problem in which the time-integrated apparent mass that has flowed into the galactic core exceeds the total mass observed there. This paradox can be resolved by intermittent outflows of energy or mass driven by accretion energy released near the black hole. Inflowing gas is also required at intermediate kpc radii to explain the ellipticity of X-ray isophotes due to spin-up by mass ejected by stars that rotate with the galaxy and to explain local density and temperature profiles. We provide evidence that many luminous elliptical galaxies undergo similar inflow spin-up. A small turbulent viscosity is required in NGC 4649 to avoid forming large X-ray luminous disks that are not observed, but the turbulent pressure is small and does not interfere with mass determinations that assume hydrostatic equilibrium.Comment: 21 pages, 9 figures, accepted for publication by Ap

A recombinant herpesviral vector containing a near-full-length SIVmac239 genome produces SIV particles and elicits immune responses to all nine SIV gene products

The properties of the human immunodeficiency virus (HIV) pose serious difficulties for the development of an effective prophylactic vaccine. Here we describe the construction and characterization of recombinant (r), replication-competent forms of rhesus monkey rhadinovirus (RRV), a gamma-2 herpesvirus, containing a near-full-length (nfl) genome of the simian immunodeficiency virus (SIV). A 306-nucleotide deletion in the pol gene rendered this nfl genome replication-incompetent as a consequence of deletion of the active site of the essential reverse transcriptase enzyme. Three variations were constructed to drive expression of the SIV proteins: one with SIV\u27s own promoter region, one with a cytomegalovirus (cmv) immediate-early promoter/enhancer region, and one with an RRV dual promoter (p26 plus PAN). Following infection of rhesus fibroblasts in culture with these rRRV vectors, synthesis of the early protein Nef and the late structural proteins Gag and Env could be demonstrated. Expression levels of the SIV proteins were highest with the rRRV-SIVcmv-nfl construct. Electron microscopic examination of rhesus fibroblasts infected with rRRV-SIVcmv-nfl revealed numerous budding and mature SIV particles and these infected cells released impressive levels of p27 Gag protein ( \u3e 150 ng/ml) into the cell-free supernatant. The released SIV particles were shown to be incompetent for replication. Monkeys inoculated with rRRV-SIVcmv-nfl became persistently infected, made readily-detectable antibodies against SIV, and developed T-cell responses against all nine SIV gene products. Thus, rRRV expressing a near-full-length SIV genome mimics live-attenuated strains of SIV in several important respects: the infection is persistent; \u3e 95% of the SIV proteome is naturally expressed; SIV particles are formed; and CD8+ T-cell responses are maintained indefinitely in an effector-differentiated state. Although the magnitude of anti-SIV immune responses in monkeys infected with rRRV-SIVcmv-nfl falls short of what is seen with live-attenuated SIV infection, further experimentation seems warranted

ADCC Develops Over Time during Persistent Infection with Live-Attenuated SIV and Is Associated with Complete Protection against SIVmac251SIV_{mac}251 Challenge

Live-attenuated strains of simian immunodeficiency virus (SIV) routinely confer apparent sterilizing immunity against pathogenic SIV challenge in rhesus macaques. Understanding the mechanisms of protection by live-attenuated SIV may provide important insights into the immune responses needed for protection against HIV-1. Here we investigated the development of antibodies that are functional against neutralization-resistant SIV challenge strains, and tested the hypothesis that these antibodies are associated with protection. In the absence of detectable neutralizing antibodies, Env-specific antibody-dependent cell-mediated cytotoxicity (ADCC) emerged by three weeks after inoculation with SIVΔnef, increased progressively over time, and was proportional to SIVΔnef replication. Persistent infection with SIVΔnef elicited significantly higher ADCC titers than immunization with a non-persistent SIV strain that is limited to a single cycle of infection. ADCC titers were higher against viruses matched to the vaccine strain in Env, but were measurable against viruses expressing heterologous Env proteins. In two separate experiments, which took advantage of either the strain-specificity or the time-dependent maturation of immunity to overcome complete protection against $SIV_{mac}251$ challenge, measures of ADCC activity were higher among the SIVΔnef-inoculated macaques that remained uninfected than among those that became infected. These observations show that features of the antibody response elicited by SIVΔnef are consistent with hallmarks of protection by live-attenuated SIV, and reveal an association between Env-specific antibodies that direct ADCC and apparent sterilizing protection by SIVΔnef

The core of the nearby S0 galaxy NGC 7457 imaged with the HST planetary camera

We have observed the nearby S0 galaxy NGC 7457 with the Planetary Camera of the Hubble Space Telescope. Spatial structure is observable at the diffraction-limited resolution of the 2.4 m HST primary despite the effects of spherical aberration. The central distribution of starlight appears consistent with a y ~ -1.0 power law for r 3 x 10^4 L_☉ pc^(-3) (V band). This is now the second densest core known after M32. From the ground, NGC 7457 resembles any number of unresolved elliptical galaxies, which suggests that compact dense cores may be common. The images of NGC 7457 demonstrate that HST can still provide unique and astrophysically interesting information on the central structure of galaxies