Sustained release drug delivery systems remain a major clinical need for small molecule therapeutics in oncology. Here, mechanisms of small molecule interactions with silk protein films were studied with cationic oncology drugs, vincristine and doxorubicin, with a focus on hydrophobicity (non-ionic surfactant) and charge (pH and ionic strength). Interactions were primarily driven by charge interactions between the positively charged drugs and the negatively charged groups within the silk films. Exploiting chemical modifications of silk further modulated the drug interactions in a controlled fashion. Increasing anionic side groups via carboxylate- and sulfonate-modifications of tyrosine side chains in the silk protein using diazonium coupling chemistry, increased drug binding and altered drug release. The effects of silk film protein crystallinity, beta sheet content, on drug binding and release was also explored. Lower crystallinity supported more rapid drug binding when compared to higher crystalline silk films. The drug release kinetics were governed by the protonation state of vincristine and doxorubicin and were tunable based on silk crystallinity and chemistry. These studies depict an approach to characterize small molecule-silk protein interactions and methods to tune drug binding and release kinetics from this protein delivery matrix.

Eskine, Kacinik, and Prinz's (2011) influential experiment demonstrated that gustatory disgust triggers a heightened sense of moral wrongness. We report a large-scale multi-site direct replication of this study conducted by participants in the Collaborative Replications and Education Project. Participants in each sample were randomly assigned to one of three beverage conditions: bitter/disgusting, control, or sweet. Then, participants made a series of judgments indicating the moral wrongness of the behavior depicted in each of six vignettes.In the original study (N = 57), drinking the bitter beverage led to higher ratings of moral wrongness than drinking the control and sweet beverages; a beverage contrast was significant among conservative (N = 19) but not liberal (N = 25) participants. In this report, random effects meta-analyses across all participants (N = 1,137 in k = 11 studies), conservative participants (N = 142, k = 5), and liberal participants (N = 635, k = 9) revealed standardized effect sizes that were smaller than reported in the original study. Some were in the opposite of the predicted direction, all had 95% confidence intervals containing zero, and most were smaller than the effect size the original authors could meaningfully detect. In linear mixed-effects regressions, drinking the bitter beverage led to higher ratings of moral wrongness than drinking the control beverage but not the sweet beverage. Bayes Factor tests reveal greater relative support for the null hypothesis. The overall pattern provides little to no support for the theory that physical disgust via taste perception harshens judgments of moral wrongness.

Alveolar macrophage remodeling after pneumonia resolution results from replacement plus retraining.

During bacterial pneumonia, alveolar epithelial cells are critical for maintaining gas exchange and providing antimicrobial as well as pro-immune properties. We previously demonstrated that leukemia inhibitory factor (LIF), an IL-6 family cytokine, is produced by type II alveolar epithelial cells (ATII) and is critical for tissue protection during bacterial pneumonia. However, the target cells and mechanisms of LIF-mediated protection remain unknown. Here, we demonstrate that antibody-induced LIF blockade remodels the lung epithelial transcriptome in association with increased apoptosis. Based on these data, we performed pneumonia studies using a novel mouse model in which LIFR (the unique receptor for LIF) is absent in lung epithelium. While LIFR is expressed on the surface of epithelial cells, its absence only minimally contributed to tissue protection during pneumonia. Single-cell RNA-sequencing (scRNAseq) was conducted to identify adult murine lung cell types most prominently expressing Lifr, revealing endothelial cells, mesenchymal cells, and ATIIs as major sources of Lifr. Sequencing data indicated that ATII cells were significantly impacted by pneumonia, with additional differences observed in response to LIF neutralization, including but not limited to gene programs related to cell death, injury, and inflammation. Overall, our data suggest that LIF signaling on epithelial cells alters responses in this cell type during pneumonia. However, our results also suggest separate and perhaps more prominent roles of LIFR in other cell types, such as endothelial cells or mesenchymal cells, which provide grounds for future investigation.

Identifying host factors that contribute to pneumonia incidence and severity are of utmost importance to guiding the development of more effective therapies. Lectin-like oxidized lowdensity lipoprotein receptor-1 (LOX-1) is a scavenger receptor known to promote vascular injury and inflammation, but it is unknown whether and how LOX-1 functions in the lung. Here, we provide evidence of substantial accumulation of LOX-1 in the lungs of ARDS patients and in mice with pneumonia. Unlike previously described injurious contributions of LOX-1, we found that LOX-1 is uniquely protective in the pulmonary airspaces, limiting proteinaceous edema and inflammation. We also identified alveolar macrophages and recruited neutrophils as two prominent sites of LOX-1 expression in the lungs, whereby macrophages are capable of further induction during pneumonia and neutrophils exhibit a rapid, but heterogenous elevation of LOX-1 in the infected lung. Blockade of LOX-1 led to dysregulated immune signaling in alveolar macrophages, marked by alterations in activation markers and a concomitant elevation of inflammatory gene networks. However, bone marrow chimeras also suggested a prominent role for neutrophils in LOX-1-mediated lung protection, further supported by LOX-1+ neutrophils exhibiting transcriptional changes consistent with reparative processes. Taken together, this work establishes LOX-1 as a tissue-protective factor in the lungs during pneumonia, possibly mediated by its influence on immune signaling in alveolar macrophages (AMs) and LOX-1+ airspace neutrophils.