Environmental pathogens move from ecological niches to mammalian hosts, requiring adaptation to dramatically different environments. Microbes that disseminate farther, including the fungal meningitis pathogen Cryptococcus neoformans, require additional adaptation to diverse tissues. We demonstrate that formation of a small C. neoformans morphotype – called “seed” cells due to their colonizing ability – is critical for extrapulmonary organ entry. Seed cells exhibit changes in fungal cell size and surface expression that result in enhanced macrophage update. Seed cell formation is triggered by environmental factors, including C. neoformans’ environmental niche, pigeon guano with phosphate playing central roles. Seed cells show enhanced expression of phosphate acquisition genes and mutants unable to acquire phosphate fail to adopt the seed cell morphotype. Additionally, phosphate can be released by tissue damage, potentially establishing a feed-forward loop of seed cell formation and dissemination. Thus, C. neoformans’ size variation represent inducible morphotypes that change host interactions to facilitate microbe spread.

CAR T cells require optimization to be effective in patients with solid tumors. There are many barriers affecting their ability to succeed. One barrier is persistence, as to achieve an optimal antitumor response, infused CAR T cells must engraft and persist. This singular variable is impacted by a multitude of factors—the CAR T cell design, lymphodepletion regimen used, expansion method to generate the T cell product, and more. Additionally, external agents can be utilized to augment CAR T cells, such as the addition of novel cytokines, pharmaceutical drugs that bolster memory formation, or other agents during either the ex vivo expansion process or after CAR T cell infusion to support them in the oppressive tumor microenvironment. This review highlights many strategies being used to optimize T cell persistence as well as future directions for improving the persistence of infused cells.

In this Scholarly Perspectives Essay, a group of physician-scientist trainee leaders—all serving in the American Physician Scientists Association—describe our experiences in identifying and pursuing training in the social determinants of health (SDOH). Our experiences were variable, but can reliably be traced by beginning at our pre-medical institutions. Further, we describe the limited information for potential trainees about available opportunities in the United States. Finally, we describe a series of actionable steps that governmental and non-governmental leadership should take to improve the process for cultivating SDOH-minded physician-scientists of tomorrow.