SummarySenescent cells contribute to age‐related pathology and loss of function, and their selective removal improves physiological function and extends longevity. Rapamycin, an inhibitor of mTOR, inhibits cell senescence in vitro and increases longevity in several species. Nrf2 levels have been shown to decrease with aging and silencing Nrf2 gene induces premature senescence. Therefore, we explored whether Nrf2 is involved in the mechanism by which rapamycin delays cell senescence. In wild‐type (WT) mouse fibroblasts, rapamycin increased the levels of Nrf2, and this correlates with the activation of autophagy and a reduction in the induction of cell senescence, as measured by SA‐β‐galactosidase (β‐gal) staining, senescence‐associated secretory phenotype (SASP), and p16 and p21 molecular markers. In Nrf2KO fibroblasts, however, rapamycin still decreased β‐gal staining and the SASP, but rapamycin did not activate the autophagy pathway or decrease p16 and p21 levels. These observations were further confirmed in vivo using Nrf2KO mice, where rapamycin treatment led to a decrease in β‐gal staining and pro‐inflammatory cytokines in serum and fat tissue; however, p16 levels were not significantly decreased in fat tissue. Consistent with literature demonstrating that the Stat3 pathway is linked to the production of SASP, we found that rapamycin decreased activation of the Stat3 pathway in cells or tissue samples from both WT and Nrf2KO mice. Our data thus suggest that cell senescence is a complex process that involves at least two arms, and rapamycin uses Nrf2 to regulate cell cycle arrest, but not the production of SASP.

Predicting and disrupting transmission of human parasites from wildlife hosts or vectors remains challenging because ecological interactions can influence their epidemiological traits. Human schistosomes, parasitic flatworms that cycle between freshwater snails and humans, typify this challenge. Human exposure risk, given water contact, is driven by the production of free-living cercariae by snail populations. Conventional epidemiological models and management focus on the density of infected snails under the assumption that all snails are equally infectious. However, individual-level experiments contradict this assumption, showing increased production of schistosome cercariae with greater access to food resources. We built bioenergetics theory to predict how resource competition among snails drives the temporal dynamics of transmission potential to humans and tested these predictions with experimental epidemics and demonstrated consistency with field observations. This resource-explicit approach predicted an intense pulse of transmission potential when snail populations grow from low densities, i.e., when per capita access to resources is greatest, due to the resource-dependence of cercarial production. The experiment confirmed this prediction, identifying a strong effect of infected host size and the biomass of competitors on per capita cercarial production. A field survey of 109 waterbodies also found that per capita cercarial production decreased as competitor biomass increased. Further quantification of snail densities, sizes, cercarial production, and resources in diverse transmission sites is needed to assess the epidemiological importance of resource competition and support snail-based disruption of schistosome transmission. More broadly, this work illustrates how resource competition can sever the correspondence between infectious host density and transmission potential.

Fanconi Anemia (FA) is characterized by bone marrow failure, congenital abnormalities, and cancer. Of over 20 FA-linked genes, FANCJ uniquely encodes a DNA helicase and mutations are also associated with breast and ovarian cancer. fancj−/− cells are sensitive to DNA interstrand cross-linking (ICL) and replication fork stalling drugs. We delineated the molecular defects of two FA patient-derived FANCJ helicase domain mutations. FANCJ-R707C was compromised in dimerization and helicase processivity, whereas DNA unwinding by FANCJ-H396D was barely detectable. DNA binding and ATP hydrolysis was defective for both FANCJ-R707C and FANCJ-H396D, the latter showing greater reduction. Expression of FANCJ-R707C or FANCJ-H396D in fancj−/− cells failed to rescue cisplatin or mitomycin sensitivity. Live-cell imaging demonstrated a significantly compromised recruitment of FANCJ-R707C to laser-induced DNA damage. However, FANCJ-R707C expressed in fancj-/- cells conferred resistance to the DNA polymerase inhibitor aphidicolin, G-quadruplex ligand telomestatin, or DNA strand-breaker bleomycin, whereas FANCJ-H396D failed. Thus, a minimal threshold of FANCJ catalytic activity is required to overcome replication stress induced by aphidicolin or telomestatin, or to repair bleomycin-induced DNA breakage. These findings have implications for therapeutic strategies relying on DNA cross-link sensitivity or heightened replication stress characteristic of cancer cells.

The opportunity to participate in and contribute to emerging fields is increasingly prevalent in science. However, simply thinking about stepping outside of your academic silo can leave many students reeling from the uncertainty. Here, we describe 10 simple rules to successfully train yourself in an emerging field, based on our experience as students in the emerging field of ecological forecasting. Our advice begins with setting and revisiting specific goals to achieve your academic and career objectives and includes several useful rules for engaging with and contributing to an emerging field.