Duffy Antigen Receptor for Chemokines Mediates trans-Infection of HIV-1 from Red Blood Cells to Target Cells and Affects HIV-AIDS Susceptibility

Duffy antigen receptor for chemokines (DARC) expressed on red blood cells (RBCs) influences plasma levels of HIV-1-suppressive and proinflammatory chemokines such as CCL5/RANTES. DARC is also the RBC receptor for Plasmodium vivax. Africans with DARC -46C/C genotype, which confers a DARC negative phenotype, are resistant to vivax malaria. Here, we show that HIV-1 attaches to RBCs via DARC, effecting trans-infection of target cells. In African Americans, DARC -46C/C is associated with 40% increase in the odds of acquiring HIV-1. If extrapolated to Africans, ~11% of the HIV-1 burden in Africa may be linked to this genotype. After infection occurs, however, DARC-negative RBC status is associated with slower disease progression. Furthermore, the disease-accelerating effect of a previously described CCL5 polymorphism is evident only in DARC-expressing and not in DARC-negative HIV-infected individuals. Thus, DARC influences HIV/AIDS susceptibility by mediating trans-infection of HIV-1 and by affecting both chemokine-HIV interactions and chemokine-driven inflammation

Intracellular \u3cem\u3eSalmonella\u3c/em\u3e delivery of an exogenous immunization antigen refocuses CD8 T cells against cancer cells, eliminates pancreatic tumors and forms antitumor immunity

Introduction: Immunotherapies have shown great promise, but are not effective for all tumors types and are effective in less than 3% of patients with pancreatic ductal adenocarcinomas (PDAC). To make an immune treatment that is effective for more cancer patients and those with PDAC specifically, we genetically engineered Salmonella to deliver exogenous antigens directly into the cytoplasm of tumor cells. We hypothesized that intracellular delivery of an exogenous immunization antigen would activate antigen-specific CD8 T cells and reduce tumors in immunized mice. Methods: To test this hypothesis, we administered intracellular delivering (ID) Salmonella that deliver ovalbumin as a model antigen into tumor-bearing, ovalbumin-vaccinated mice. ID Salmonella delivers antigens by autonomously lysing in cells after the induction of cell invasion. Results: We showed that the delivered ovalbumin disperses throughout the cytoplasm of cells in culture and in tumors. This delivery into the cytoplasm is essential for antigen cross-presentation. We showed that co-culture of ovalbumin-recipient cancer cells with ovalbumin-specific CD8 T cells triggered a cytotoxic T cell response. After the adoptive transfer of OT-I CD8 T cells, intracellular delivery of ovalbumin reduced tumor growth and eliminated tumors. This effect was dependent on the presence of the ovalbumin-specific T cells. Following vaccination with the exogenous antigen in mice, intracellular delivery of the antigen cleared 43% of established KPC pancreatic tumors, increased survival, and prevented tumor re-implantation. Discussion: This response in the immunosuppressive KPC model demonstrates the potential to treat tumors that do not respond to checkpoint inhibitors, and the response to re-challenge indicates that new immunity was established against intrinsic tumor antigens. In the clinic, ID Salmonella could be used to deliver a protein antigen from a childhood immunization to refocus pre-existing T cell immunity against tumors. As an off-the-shelf immunotherapy, this bacterial system has the potential to be effective in a broad range of cancer patients

Early Radio and X-Ray Observations of the Youngest Nearby Type Ia Supernova PTF 11kly (SN 2011fe)

On 2011 August 24 (UT) the Palomar Transient Factory (PTF) discovered PTF11kly (SN 2011fe), the youngest and most nearby Type Ia supernova (SN Ia) in decades. We followed this event up in the radio (centimeter and millimeter bands) and X-ray bands, starting about a day after the estimated explosion time.We present our analysis of the radio and X-ray observations, yielding the tightest constraints yet placed on the pre-explosion mass-loss rate from the progenitor system of this supernova. We find a robust limit of Ṁ ≾ 10^(−8)(w/100 km s^(−1))M_☉ yr^(−1) from sensitive X-ray non-detections, as well as a similar limit from radio data, which depends, however, on assumptions about microphysical parameters. We discuss our results in the context of single-degenerate models for SNe Ia and find that our observations modestly disfavor symbiotic progenitor models involving a red giant donor, but cannot constrain systems accreting from main-sequence or sub-giant stars, including the popular supersoft channel. In view of the proximity of PTF11kly and the sensitivity of our prompt observations, we would have to wait for a long time (a decade or longer) in order to more meaningfully probe the circumstellar matter of SNe Ia

Neural origins of human sickness in interoceptive responses to inflammation

BACKGROUND: Inflammation is associated with psychological, emotional, and behavioral disturbance, known as sickness behavior. Inflammatory cytokines are implicated in coordinating this central motivational reorientation accompanying peripheral immunologic responses to pathogens. Studies in rodents suggest an afferent interoceptive neural mechanism, although comparable data in humans are lacking. METHODS: In a double-blind, randomized crossover study, 16 healthy male volunteers received typhoid vaccination or saline (placebo) injection in two experimental sessions. Profile of Mood State questionnaires were completed at baseline and at 2 and 3 hours. Two hours after injection, participants performed a high-demand color word Stroop task during functional magnetic resonance imaging. Blood samples were performed at baseline and immediately after scanning. RESULTS: Typhoid but not placebo injection produced a robust inflammatory response indexed by increased circulating interleukin-6 accompanied by a significant increase in fatigue, confusion, and impaired concentration at 3 hours. Performance of the Stroop task under inflammation activated brain regions encoding representations of internal bodily state. Spatial and temporal characteristics of this response are consistent with interoceptive information flow via afferent autonomic fibers. During performance of this task, activity within interoceptive brain regions also predicted individual differences in inflammation-associated but not placebo-associated fatigue and confusion. Maintenance of cognitive performance, despite inflammation-associated fatigue, led to recruitment of additional prefrontal cortical regions. CONCLUSIONS: These findings suggest that peripheral infection selectively influences central nervous system function to generate core symptoms of sickness and reorient basic motivational states. PMID:19409533[PubMed - indexed for MEDLINE] PMCID: PMC2885492Free PMC Articl

Real-Time Detection and Rapid Multiwavelength Follow-up Observations of a Highly Subluminous Type II-P Supernova from the Palomar Transient Factory Survey

The Palomar Transient Factory (PTF) is an optical wide-field variability survey carried out using a camera with a 7.8 square degree field of view mounted on the 48-in Oschin Schmidt telescope at Palomar Observatory. One of the key goals of this survey is to conduct high-cadence monitoring of the sky in order to detect optical transient sources shortly after they occur. Here, we describe the real-time capabilities of the PTF and our related rapid multiwavelength follow-up programs, extending from the radio to the gamma-ray bands. We present as a case study observations of the optical transient PTF10vdl (SN 2010id), revealed to be a very young core-collapse (Type II-P) supernova having a remarkably low luminosity. Our results demonstrate that the PTF now provides for optical transients the real-time discovery and rapid-response follow-up capabilities previously reserved only for high-energy transients like gamma-ray bursts.Comment: ApJ, in press; all spectroscopic data available from the Weizmann Institute of Science Experimental Astrophysics Spectroscopy System (WISEASS; http://www.weizmann.ac.il/astrophysics/wiseass/

PTF10fqs: A Luminous Red Nova in the Spiral Galaxy Messier 99

The Palomar Transient Factory (PTF) is systematically charting the optical transient and variable sky. A primary science driver of PTF is building a complete inventory of transients in the local Universe (distance less than 200 Mpc). Here, we report the discovery of PTF10fqs, a transient in the luminosity "gap" between novae and supernovae. Located on a spiral arm of Messier 99, PTF 10fqs has a peak luminosity of Mr = -12.3, red color (g-r = 1.0) and is slowly evolving (decayed by 1 mag in 68 days). It has a spectrum dominated by intermediate-width H (930 km/s) and narrow calcium emission lines. The explosion signature (the light curve and spectra) is overall similar to thatof M85OT2006-1, SN2008S, and NGC300OT. The origin of these events is shrouded in mystery and controversy (and in some cases, in dust). PTF10fqs shows some evidence of a broad feature (around 8600A) that may suggest very large velocities (10,000 km/s) in this explosion. Ongoing surveys can be expected to find a few such events per year. Sensitive spectroscopy, infrared monitoring and statistics (e.g. disk versus bulge) will eventually make it possible for astronomers to unravel the nature of these mysterious explosions.Comment: 12 pages, 12 figures, Replaced with published versio