Assessing Stress in Zoo-Housed Western Lowland Gorillas (<Emphasis Type="Italic">Gorilla gorilla gorilla</Emphasis>) Using Allostatic Load

Stress contributes to the development of chronic degenerative diseases in primates. Allostatic load is an estimate of stress-induced physiological dysregulation based on an index of multiple biomarkers. It has been applied to humans to measure effects of stress and predict health outcomes. Assessing allostatic load in nonhuman primates may aid in understanding factors promoting compromised health and longevity in captive populations, as well as risk assessment among wild populations following human activities. We applied an allostatic load index to gorillas housed at the Columbus Zoo and Aquarium (N = 27, 1956–2014) using data from medical records and biomarkers from banked serum. We estimated allostatic load using seven biomarkers (albumin, cortisol, corticotropin-releasing hormone, dehydroepiandrosterone sulfate, glucose, interleukin-6, and tumor necrosis factor alpha) and then examined this index for associations with age, sex, number of stressful events, parturition, physiological health measures, and age at death. Stressful events were defined as agonistic interactions with wounding, translocations, and anesthetizations. Allostatic load positively associated with age and total number of lifetime stressful events. Allostatic load was significantly higher in females than in males. Allostatic load was not associated with number of pregnancies and was not different between nulliparous and parous females. Allostatic load associated positively with serum creatinine and triglyceride levels, showed a nonsignificant negative association with cholesterol, and did not associate significantly with age at death. These results demonstrate the potential utility of allostatic load for exploring long-term stress and health risks, as well as for evaluating environmental stressors for gorillas and other nonhuman primates in captivity and in the wild.     

ALS-Linked Mutations Affect UBQLN2 Oligomerization and Phase Separation in a Position- and Amino Acid-Dependent Manner

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The Functional Proximal Proteome of Oncogenic Ras Includes mTORC2

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Resistance outside the substrate envelope: hepatitis C NS3/4A protease inhibitors

Direct acting antivirals have dramatically increased the efficacy and tolerability of hepatitis C treatment, but drug resistance has emerged with some of these inhibitors, including nonstructural protein 3/4?A protease inhibitors (PIs). Although many co-crystal structures of PIs with the NS3/4A protease have been reported, a systematic review of these crystal structures in the context of the rapidly emerging drug resistance especially for early PIs has not been performed. To provide a framework for designing better inhibitors with higher barriers to resistance, we performed a quantitative structural analysis using co-crystal structures and models of HCV NS3/4A protease in complex with natural substrates and inhibitors. By comparing substrate structural motifs and active site interactions with inhibitor recognition, we observed that the selection of drug resistance mutations correlates with how inhibitors deviate from viral substrates in molecular recognition. Based on this observation, we conclude that guiding the design process with native substrate recognition features is likely to lead to more robust small molecule inhibitors with decreased susceptibility to resistance.     

Evolutionary history predicts high‐impact invasions by herbivorous insects

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