Biology subjects

Hansen, J. E.

Publications and source records attributed to Hansen, J. E..

4 recordsLinked to original sources

bioRxiv2023

The ontogeny of individual specialization

Individual dietary specialization, where individuals occupy a subset of a populations wider dietary niche, is a key factor determining a species resilience against environmental change. However, the ontogeny of individual specialization, as well as associated underlying social learning, genetic, and environmental drivers, remain poorly understood. Using a multigenerational dataset of female European brown bears (Ursus arctos) followed since birth, we discerned the relative contributions of environmental similarity, genetic heritability, maternal effects, and offspring social learning from the mother to individual specialization. Individual specialization accounted for 43% of phenotypic variation and spanned half a trophic position, with individual diets ranging from omnivorous to carnivorous. The main determinants of dietary specialization were social learning during rearing (13%), environmental similarity (9%), maternal effects (11%), and permanent between-individual effects (8%), whereas the contribution of genetic heritability was negligible. The trophic position of offspring closely resembled the trophic position of their mothers during the first 3-4 years of independence, but this relationship ceased with increasing time since separation. Our study shows that social learning and maternal effects are as important for individual dietary specialization as environmental composition. We propose a tighter integration of social effects into future studies of range expansion and habitat selection under global change that, to date, are mostly explained by environmental drivers.

ecology↗

bioRxiv2023

DNA-targeting and cell-penetrating antibody-drug conjugate

DNA released by dying cancer cells offers a tumor targeting strategy that is independent of specific cell surface antigens. Anti-DNA antibodies preferentially localize to tumor microenvironments enriched in extracellular DNA and can penetrate live tumor cells through nucleoside salvage pathways. Nuclear-localizing variants of anti-DNA antibodies cause DNA damage and selectively kill cancer cells with defects in DNA repair. Here we show that an optimized full-length IgG1 anti-DNA antibody penetrates live cells and is synthetically lethal to BRCA2-deficient tumors but has minimal effect of DNA repair-proficient tumors. Linkage of the antibody to the anti-mitotic drug monomethyl auristatin E yields a DNA-targeting and cell-penetrating anti-DNA antibody-drug conjugate (ADC) that is well tolerated in mice and highly toxic to tumors with intact DNA repair. This work provides proof-of-concept for the novel use of an anti-DNA antibody as the backbone of a DNA-targeting, cell-penetrating ADC that can impact tumors that otherwise lack specifically targetable surface antigens. Statement of significanceA strategy for targeting tumors that lack specific surface antigens is revealed by an anti-DNA antibody-drug conjugate that localizes to tumor microenvironments enriched in DNA and penetrates cells through nucleoside salvage pathways.

immunology↗

bioRxiv2023

Cellular protection from H2O2 toxicity by Fv-Hsp70 and mutants of Fv-Hsp70. Protection via catalase and gamma-glutamyl cysteine synthase.

Heat shock proteins (HSPs), especially Hsp70 (HSPA1), have been associated with cellular protection from various cellular stresses including heat, hypoxia-ischemia, neurodegeneration, toxins, and trauma. Endogenous HSPs are often synthesized in direct response to these stresses but in many situations are inadequate in protecting cells. The present study addresses the transduction of Hsp70 into cells providing protection from acute oxidative stress by H2O2. The recombinant Fv-Hsp70 protein and two mutant Fv-Hsp70 proteins minus the ATPase domain, and minus the ATPase and terminal lid domains were tested at 0.5 and 1.0 uM concentrations after two different concentrations of H2O2 treatment. All three recombinant proteins protected SH-SY5Y cells from acute H2O2 toxicity. This data indicated that the protein binding domain was responsible for cellular protection. In addition, experiments pretreating cells with inhibitors of antioxidant proteins catalase and gamma-glutamylcysteine synthase (GGCS) before H2O2 resulted in cell death despite treatment with Fv-Hsp70, implying that both enzymes were protected from acute oxidative stress after treatment with Fv-Hsp70. This study demonstrates that Fv-Hsp70 is protective in our experiments primarily by the protein-binding domain. The Hsp70 terminal lid domain was also not necessary for protection. Cellular protection was protective via the antioxidant proteins catalase and GGCS.

cell biology↗

bioRxiv2023

cGAS-activating lupus autoantibody for cancer immunotherapy

Cytoplasmic DNA triggers a cGAS-mediated signaling cascade that promotes an innate immune response and is potentially actionable in cancer immunotherapy. Here we show that a cytoplasmic-localizing lupus anti-DNA autoantibody activates cGAS and facilitates an immune-mediated prolongation of survival in orthotopic models of glioblastoma (GBM). Mechanistically, cellular penetration and blood-brain barrier crossing by the anti-DNA autoantibody is linked to nucleoside transport. Pulldown, knockdown, signaling, and cytotoxicity assays demonstrate autoantibody association with and activation of cGAS. In orthotopic GBM models, the autoantibody localizes to brain tumor, increases tumor CD8+ T cell content, and prolongs survival in immunocompetent but not immunodeficient mice. This work introduces the new concept of a cGAS-activating anti-DNA autoantibody, which impacts theories on mechanisms of autoimmunity and has translational applications in cancer immunotherapy.

immunology↗