Our invisible poor

https://stars.library.ucf.edu/prism/1078/thumbnail.jp

Enantiomer Discrimination Illustrated by the High Resolution Crystal Structures of Type 4 Phosphodiesterase †

Type 4 phosphodiesterase (PDE4) inhibitors are emerging new treatment for a number of disorders including asthma and chronic obstructive pulmonary disease. Here we report the biochemical characterization on the second generation inhibitor (+)-1 (L-869298, IC50 = 0.4 nM) and its enantiomer (−)-1 (L-869299, IC50 = 43 nM), and their co-crystal structures with PDE4D at 2.0 Å resolution. In spite of the 107-fold affinity difference, both enantiomers interact with the same sets of residues in the rigid active site. The weaker (−)-1 adopts an unfavorable conformation in order to preserve the pivotal interactions between the Mg-bound waters and N-oxide of pyridine. These structures support a model in which inhibitors are anchored by the invariant glutamine at one end and the metal-pocket residues at another end. This model provides explanation for most of the observed structure-activity relationship and the metal ion dependency of the catechol-ether based inhibitors and should facilitate their further design

“A General Separation of Colored and White”: the WWII riots, military segregation, and racism(s) beyond the White/Nonwhite binary

This article uses archival research to explore important differences in the discursive and institutional positioning of Mexican American and African American men during World War II. Through the focal point of the riots which erupted in Los Angeles and other major cities in the summer of 1943, I examine the ways in which black and Mexican ‘rioters’ were imagined in official and popular discourses. Though both groups of youth were often constructed as deviant and subversive, there were also divergences in the ways in which their supposed racial difference was discursively configured. I also consider the experiences of each group in the WWII military, a subject that has received little attention in previous work on the riots. Though both groups were subject to discrimination and brutality on the home front, only African Americans were segregated in the military - a fact that profoundly influenced the 1943 riots. Examining the very different conditions under which these men served, as well as the distinct ways in which their presence within the military and on the home front was interpreted and given meaning by press, law enforcement and military officials helps to illuminate the uneven and complex workings of racism in America, disrupting the common conceptualization of a definitive white/nonwhite color line

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

Ernest Hemingway

Negative assessment of Hemingway’s creative output after 1930. Previously published in Encounter 18 (Jan. 1962): 179-84

Macdonald, James B., and Dwight Clark, Critical Value Questions and the Analysis of Objectives and Curricula, pp. 405-412 in R. M. W. Travers, ed., Second Handbook of Research on Teaching . Chicago: Rand McNally & Co., 1973.*

Discusses the value-laden issues behind the formulation of curriculum objectives and behind choices in instructional materials and media; laments the lack of research on these matters