Biology subjects

Comer, E.

Publications and source records attributed to Comer, E..

5 recordsLinked to original sources

bioRxiv2025

Aging Leads to Altered Physiological Reactivity in Response to Repeated Social Separation Stress in a Nonhuman Primate Model

Social relationships are critical for maintaining physical health and psychological wellbeing. Since nearly 1 in 4 adults aged 65 years or older are socially isolated, there is a strong need to understand how repeated social stress negatively impacts health outcomes. Using a nonhuman primate model of social aging (i.e., marmosets), we examined whether individuals transitioning into old age ("peri-geri") or individuals who were already geriatric ("very-geri") showed differences in measures of hypothalamic-pituitary axis (HPA) activity, markers of metabolic and immune function, and reunion social behavior in response to repeated social separation challenges (SSC). We found female marmosets, especially peri-geri females, had higher HPA reactivity and better HPA recovery than male marmosets, but this difference diminished in older, very-geri marmosets. HPA activity was correlated with multiple outcomes including locomotive behavior and grooming, changes in blood glucose levels, and neutrophil counts. Moreover, marmosets who approached their partner more and were groomed less during reunions had higher cortisol levels the following day. Interestingly, we found two distinct HPA profiles among our marmosets with half showing strong HPA responses (reactors) and the other half showing little or no HPA response (non-reactors). Non-reactors had less weight gain/more weight loss; elevated levels of calcium, phosphorus, and white blood cells; and received less grooming and social contact time during reunion. Overall, old-aged marmosets who show attenuated HPA responses may have different vulnerabilities to negative health and behavioral outcomes during social stress, and male marmosets appear more likely to present with this HPA non-reactor phenotype earlier in aging.

physiology↗

bioRxiv2024

Bicyclic pyrrolidine inhibitors of Toxoplasma gondii phenylalanine t-RNA synthetase with antiparasitic potency in vitro and brain exposure

Previous studies have shown that bicyclic azetidines are potent and selective inhibitors of apicomplexan phenylalanine tRNA synthetase (PheRS), leading to parasite growth inhibition in vitro and in vivo, including in models of Toxoplasma infection. Despite these useful properties, additional optimization is required for the development of efficacious treatments of toxoplasmosis from this inhibitor series, in particular to achieve sufficient exposure in the brain. Here, we describe a series of PheRS inhibitors built on a new bicyclic pyrrolidine core scaffold designed to retain the exit-vector geometry of the isomeric bicyclic azetidine core scaffold while offering avenues to sample diverse chemical space. Relative to the parent series, bicyclic pyrrolidines retain reasonable potency and target selectivity for parasite PheRS vs. host. Further structure-activity relationship studies revealed that the introduction of aliphatic groups improved potency, ADME and PK properties, including brain exposure. The identification of this new scaffold provides potential opportunities to extend the analog series to further improve selectivity and potency and ultimately deliver a novel, efficacious treatment of toxoplasmosis. Lay abstractThe inhibition of protein synthesis in parasites has emerged as an attractive strategy to target parasitic diseases such as malaria, cryptosporidiosis, and toxoplasmosis. In this study, we report a new series of small molecules that inhibit the enzyme responsible for loading the amino acid phenylalanine onto its cognate tRNA in the parasite species Toxoplasma, directly upstream of protein synthesis. We show that small molecules in this new series inhibit Toxoplasma parasite growth at low concentrations, and that, orally administered to mice, these molecules achieve high concentrations in the brain, which hold promise for the treatment of forms of toxoplasmosis that result from parasitic brain infection.

microbiology↗

bioRxiv2022

Technical Report on Ancient DNA analysis of 27 African Americans from Catoctin Furnace, Maryland

Catoctin Furnace is an industrial site that functioned from 1776-1903 and was operated at least partially by an enslaved workforce until about 1850, when it shifted to paid European laborers. A cemetery including 35 graves from which the remains of 32 individuals identified with African ancestry were excavated in 1979-1980 during construction of a highway that impacted the site. Since then, the human remains have been under the stewardship of the Smithsonians National Museum of Natural History (NMNH). The goal of this report is to document the successful generation of ancient DNA from 27 individuals from the cemetery. The analysis of the Catoctin individuals is part of a long-term study dedicated to restoring knowledge of the identity, origins, and legacy of the enslaved and free African Americans who labored and were buried at Catoctin Furnace1.

genomics↗

bioRxiv2018

High throughput screen identifies IFN-γ-dependent inhibitors of Toxoplasma gondii growth

Toxoplasma gondii is an obligate intracellular parasite capable of causing severe disease due to congenital infection and in patients with compromised immune systems. Control of infection is dependent on a robust Th1 type immune response including production of interferon gamma (IFN-{gamma}), which is essential for control. IFN-{gamma} activates a variety of anti-microbial mechanisms in host cells, which are then able to control intracellular parasites such as T. gondii. Despite the effectiveness of these pathways in controlling acute infection, the immune system is unable to eradicate chronic infections that can persist for life. Similarly, while antibiotic treatment can control acute infection, it is unable to eliminate chronic infection. To identify compounds that would act synergistically with IFN-{gamma}, we performed a high-throughput screen of diverse small molecule libraries to identify inhibitors of T. gondii. We identified a number of compounds that inhibited parasite growth in vitro at low M concentrations and that demonstrated enhanced potency in the presence of low level of IFN-{gamma}. A subset of these compounds act by enhancing the recruitment of LC3 to the parasite-containing vacuole, suggesting they work by an autophagy-related process, while others were independent of this pathway. The pattern of IFN-{gamma}-dependence was shared among the majority of analogs from 6 priority scaffolds and analysis of structure activity relationships for one such class revealed specific stereochemistry associated with this feature. Identification of these IFN-{gamma}-dependent leads may lead to development of improved therapeutics due to their synergistic interactions with immune responses.

microbiology↗

bioRxiv2018

Tetracyclines Modify Translation By Targeting Key Human rRNA Substructures.

Apart from their antimicrobial properties, tetracyclines demonstrate clinically validated effects in the amelioration of pathological inflammation and human cancer. Delineation of the target(s) and mechanism(s) responsible for these effects, however, has remained elusive. Here, employing quantitative mass spectrometry-based proteomics, we identified human 80S ribosomes as targets of the tetracyclines Col-3 and doxycycline. We then developed in cell click selective crosslinking with RNA sequence profiling (icCL-Seq) to map binding sites for these tetracyclines on key human rRNA substructures at nucleotide resolution. Importantly, we found that structurally and phenotypically variant tetracycline analogs could chemically discriminate these rRNA binding sites. We also found that tetracyclines both subtly modify human ribosomal translation and selectively activate the cellular integrated stress response (ISR). Together, the data reveal that targeting of specific rRNA substructures, activation of the ISR, and inhibition of translation are correlated with the anti-proliferative properties of tetracyclines in human cancer cell lines.

cell biology↗