Globular Clusters as Testbeds for Type Ia Supernovae

Fundamental mysteries remain regarding the physics of Type Ia supernovae (SNIa) and their stellar progenitors. We argue here that important clues to these questions may emerge by the identification of those SNIa that occur in extragalactic globular clusters--stellar systems with well defined ages and metallicities. We estimate an all-sky rate of approximately 0.1 eta (D/100 Mpc)^3 per year for SNIa in globular clusters within a distance D, where eta is the rate enhancement per unit mass as a result of dynamical production channels that are inaccessible in the galactic field. If eta is approximately 2-10, as suggested by observations and theory, the combined efforts of accurate supernova astrometry and deep follow-up imaging should identify the > 1% of nearby (D < 100 Mpc) SNIa that occur in globular clusters.Comment: 9 pages, ApJL, in pres

The Effect of Diet and Opponent Size on Aggressive Interactions Involving Caribbean Crazy Ants (Nylanderia fulva)

Biotic interactions are often important in the establishment and spread of invasive species. In particular, competition between introduced and native species can strongly influence the distribution and spread of exotic species and in some cases competition among introduced species can be important. The Caribbean crazy ant, Nylanderia fulva, was recently introduced to the Gulf Coast of Texas, and appears to be spreading inland. It has been hypothesized that competition with the red imported fire ant, Solenopsis invicta, may be an important factor in the spread of crazy ants. We investigated the potential of interspecific competition among these two introduced ants by measuring interspecific aggression between Caribbean crazy ant workers and workers of Solenopsis invicta. Specifically, we examined the effect of body size and diet on individual-level aggressive interactions among crazy ant workers and fire ants. We found that differences in diet did not alter interactions between crazy ant workers from different nests, but carbohydrate level did play an important role in antagonistic interactions with fire ants: crazy ants on low sugar diets were more aggressive and less likely to be killed in aggressive encounters with fire ants. We found that large fire ants engaged in fewer fights with crazy ants than small fire ants, but fire ant size affected neither fire ant nor crazy ant mortality. Overall, crazy ants experienced higher mortality than fire ants after aggressive encounters. Our findings suggest that fire ant workers might outcompete crazy ant workers on an individual level, providing some biotic resistance to crazy ant range expansion. However, this resistance may be overcome by crazy ants that have a restricted sugar intake, which may occur when crazy ants are excluded from resources by fire ants

Basal LAT-diacylglycerol-RasGRP1 Signals in T Cells Maintain TCRα Gene Expression

In contrast to the well-characterized T cell receptor (TCR) signaling pathways that induce genes that drive T cell development or polarization of naïve CD4 T cells into the diverse TH1, TH2, TH17 and Treg lineages, it is unclear what signals maintain specific gene expression in mature resting T cells. Resting T cells residing in peripheral lymphoid organs exhibit low-level constitutive signaling. Whereas tonic signals in B cells are known to be critical for survival, the roles of tonic signals in peripheral T cells are unknown. Here we demonstrate that constitutive signals in Jurkat T cell lines are transduced via the adapter molecule LAT and the Ras exchange factor RasGRP1 to maintain expression of TCRα mRNA and surface expression of the TCR/CD3 complex. Independent approaches of reducing basal activity through the LAT-diacylglycerol-RasGRP pathway led to reduced constitutive Ras-MEK-ERK signals and decreased TCRα mRNA and surface TCR expression in Jurkat cells. However, loss of TCR expression takes several days in these cell line experiments. In agreement with these in vitro approaches, inducible deletion of Lat in vivo results in reduced TCRα mRNA- and surface TCR- expression in a delayed temporal manner as well. Lastly, we demonstrate that loss of basal LAT-RasGRP signals appears to lead to silencing or repression of TCRα transcription. We postulate that basal LAT-diacylglycerol-RasGRP signals fulfill a regulatory function in peripheral T lymphocytes by maintaining proper gene expression programs

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Basal LAT-diacylglycerol-RasGRP1 signals in T cells maintain TCRα gene expression.

In contrast to the well-characterized T cell receptor (TCR) signaling pathways that induce genes that drive T cell development or polarization of naïve CD4 T cells into the diverse T(H)1, T(H)2, T(H)17 and T(reg) lineages, it is unclear what signals maintain specific gene expression in mature resting T cells. Resting T cells residing in peripheral lymphoid organs exhibit low-level constitutive signaling. Whereas tonic signals in B cells are known to be critical for survival, the roles of tonic signals in peripheral T cells are unknown. Here we demonstrate that constitutive signals in Jurkat T cell lines are transduced via the adapter molecule LAT and the Ras exchange factor RasGRP1 to maintain expression of TCRα mRNA and surface expression of the TCR/CD3 complex. Independent approaches of reducing basal activity through the LAT-diacylglycerol-RasGRP pathway led to reduced constitutive Ras-MEK-ERK signals and decreased TCRα mRNA and surface TCR expression in Jurkat cells. However, loss of TCR expression takes several days in these cell line experiments. In agreement with these in vitro approaches, inducible deletion of Lat in vivo results in reduced TCRα mRNA- and surface TCR-expression in a delayed temporal manner as well. Lastly, we demonstrate that loss of basal LAT-RasGRP signals appears to lead to silencing or repression of TCRα transcription. We postulate that basal LAT-diacylglycerol-RasGRP signals fulfill a regulatory function in peripheral T lymphocytes by maintaining proper gene expression programs

Hepatitis C Screening Rate Among Underserved Adults With Serious Mental Illness Receiving Care in California Community Mental Health Centers.

Although HCV is more prevalent among people with severe mental illness (SMI; e.g., schizophrenia, bipolar disorder) than in the general population (17% vs 1%), no large previous studies have examined HCV screening in this population. In this cross-sectional study, we examined administrative data for 57 170 California Medicaid enrollees with SMI to identify prevalence and predictors of HCV screening from October 2010 through September 2011. Only 4.7% (2674 of 57 170) received HCV screening, with strongest predictors being nonpsychiatric health care utilization and comorbid substance abuse

Hepatitis C Screening Rate Among Underserved Adults With Serious Mental Illness Receiving Care in California Community Mental Health Centers.

Although HCV is more prevalent among people with severe mental illness (SMI; e.g., schizophrenia, bipolar disorder) than in the general population (17% vs 1%), no large previous studies have examined HCV screening in this population. In this cross-sectional study, we examined administrative data for 57 170 California Medicaid enrollees with SMI to identify prevalence and predictors of HCV screening from October 2010 through September 2011. Only 4.7% (2674 of 57 170) received HCV screening, with strongest predictors being nonpsychiatric health care utilization and comorbid substance abuse

Risk for Substance Use Disorders in young adulthood: Associations with developmental experiences of homelessness, foster care, and adverse childhood experiences

BackgroundMultiple developmental risk factors for Substance Use Disorders (SUDs) during young adulthood have been identified. In this investigation, we examined the impact of homelessness, foster care, and adverse childhood experiences (ACEs) prior to 12th grade on the development of three common SUDs during young adulthood-Alcohol Use Disorder (AUD), Tobacco Use Disorder (TUD) and Cannabis Use Disorder (CUD). Our hypothesis was that while both homelessness and ACEs are significant risk factors for young adult SUDs, foster care involvement might convey protection.MethodsUsing nationally representative data from the National Longitudinal Study of Adolescent to Adult Health, measures of ACEs were derived from the CDC-Kaiser ACE study, and DSM-V SUD diagnoses were derived from items originally based on DSM-IV. SUD diagnoses were binned into "mild", "moderate", and "severe" groupings. Survey-based logistic models were used to estimate risks of SUDs while controlling for demographics.ResultsThe results suggest that the experience of homelessness prior to 12th grade in addition to ACEs were significantly associated with the development in young adulthood of the most severe forms of AUD and TUD and all severity levels of CUD. Foster care was not associated with either risk or protection from SUDs.ConclusionsThe experience of homelessness during development may be viewed as another detrimental ACE that is a risk factor for the most common SUDs in young adulthood. Given the magnitude of the current epidemic of homelessness in the U.S., these results should raise substantial concern

Hepatitis C Screening Rate Among Underserved Adults With Serious Mental Illness Receiving Care in California Community Mental Health Centers

Although HCV is more prevalent among people with severe mental illness (SMI; e.g., schizophrenia, bipolar disorder) than in the general population (17% vs 1%), no large previous studies have examined HCV screening in this population. In this cross-sectional study, we examined administrative data for 57 170 California Medicaid enrollees with SMI to identify prevalence and predictors of HCV screening from October 2010 through September 2011. Only 4.7% (2674 of 57 170) received HCV screening, with strongest predictors being nonpsychiatric health care utilization and comorbid substance abuse