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Biology subjects

Edgar, C.

Publications and source records attributed to Edgar, C..

3 recordsLinked to original sources

Behavioral metabolic suppression confounds thermal performance estimates and climate vulnerability assessments in a marine ectotherm

O_LIThermal performance curves (TPCs) predict species vulnerability to climate change, but standard respirometry assumes that measured oxygen consumption reflects physiological state. Sessile invertebrates that retract their tentacles and contract under thermal stress violate this assumption, with unmeasured consequences for thermal limit estimates. C_LIO_LIWe tested this behavioral confound in an undescribed cold-water intertidal anemone (Urticina sp.) in the Northwest Atlantic by integrating a negative binomial encounter-rate regression, a maximum entropy species distribution model (both from effort-corrected iNaturalist data), and closed-chamber respirometry across seven temperatures (1-30{degrees}C). C_LIO_LIThe strongest distributional predictors were cloud cover and coastal urbanization, with a weaker association with winter minimum SST; direct evidence for warm-edge thermal limitation came from the experiment. Anemone expansion state was variable and without a clear trend across the coldest treatments, declining above 20{degrees}C, and collapsing at the 30{degrees}C treatment, which proved lethal. C_LIO_LIStandard TPC models extrapolated the thermal maximum far beyond the lethal bracket. A Bayesian multiplicative model that separated physiology from behavior showed that physiology continued to track temperature while expansion state declined above 20{degrees}C; a fully expanded anemone respired about twice as fast as a fully closed one at the same temperature. The decline in measured respiration is therefore both behavioral and physiological, and disentangling the two requires recording expansion state alongside oxygen consumption. C_LIO_LIBecause a closed anemone cannot feed or exchange gases, the ecologically relevant thermal limit is the temperature at which the animal can no longer maintain its normal expanded posture, not a curve-fitted thermal maximum. That behavioral threshold leaves warm-edge populations within a few degrees of functional thermal failure. C_LIO_LIFuture thermal physiology studies of organisms capable of modulating oxygen consumption through behavior should incorporate quantitative behavioral covariates to separate physiological from behavioral components of the metabolic response. C_LI ResumeO_LILes courbes de performance thermique (CPT) predisent la vulnerabilite des especes au changement climatique, mais la respirometrie classique postule que la consommation doxygene mesuree reflete letat physiologique. Les invertebres sessiles qui retractent leurs tentacules et se contractent sous stress thermique ne satisfont pas cette hypothese, avec des consequences non quantifiees sur lestimation des limites thermiques. C_LIO_LINous avons teste ce facteur de confusion comportemental chez une anemone intertidale deau froide non decrite (Urticina sp.) de lAtlantique Nord-Ouest, en combinant une regression binomiale negative du taux de rencontre, un modele de distribution despeces a maximum dentropie (tous deux sur donnees iNaturalist corrigees de leffort) et une respirometrie en chambre close a sept temperatures (1 a 30 {degrees}C). C_LIO_LILes principaux predicteurs etaient la couverture nuageuse et lurbanisation cotiere, lassociation au minimum hivernal de temperature de surface de la mer etant plus faible. La preuve directe dune limitation thermique en bordure chaude provient de lexperience. Letat dexpansion variait sans tendance nette aux traitements les plus froids, diminuait au-dela de 20 {degrees}C et seffondrait a 30 {degrees}C, traitement qui sest revele letal. C_LIO_LILes CPT classiques ont extrapole le maximum thermique bien au-dela de lintervalle letal. Un modele bayesien multiplicatif separant physiologie et comportement a montre que la physiologie suivait toujours la temperature alors que letat dexpansion diminuait au-dela de 20 {degrees}C; a temperature egale, une anemone pleinement epanouie respirait environ deux fois plus quune anemone pleinement fermee. La baisse mesuree est donc a la fois comportementale et physiologique, et les dissocier exige denregistrer letat dexpansion avec la consommation doxygene. C_LIO_LIUne anemone fermee ne pouvant ni se nourrir ni assurer ses echanges gazeux, la limite thermique ecologiquement pertinente est la temperature a laquelle lanimal ne peut plus maintenir son expansion normale, et non un maximum issu dun ajustement de courbe. Ce seuil comportemental place les populations de bordure chaude a quelques degres de la defaillance thermique fonctionnelle. C_LIO_LILes futures etudes de physiologie thermique sur des organismes capables de moduler leur consommation doxygene par leur comportement devraient integrer des covariables comportementales quantitatives pour separer les composantes physiologique et comportementale de la reponse metabolique. C_LI

ecology↗

Overexpression of Ssd1 and calorie restriction extend yeast replicative lifespan by preventing deleterious age-dependent iron uptake

Overexpression of the mRNA binding protein Ssd1 extends the yeast replicative lifespan. Using microfluidics to trap and image single cells throughout their lifespans, we find that lifespan extension by Ssd1 overexpression is accompanied by formation of cytoplasmic Ssd1 foci. The age-dependent Ssd1 foci are condensates that appear dynamically in a cell cycle-dependent manner and their failure to resolve during mitosis coincided with the end of lifespan. Ssd1 overexpression was epistatic with calorie restriction (CR) for lifespan extension and yeast overexpressing Ssd1 or undergoing CR were resistant to iron supplementation-induced lifespan shortening while their lifespans were reduced by iron chelation. The nuclear translocation of the Aft1 transcriptional regulator of the iron regulon occurred during aging in a manner that predicted remaining lifespan, but was prevented by CR. Accordingly, age-dependent induction of the Fit2 and Arn1 high-affinity iron transporters within the iron regulon was reduced by CR and Ssd1 overexpression. Consistent with age-dependent activation of the iron regulon, intracellular iron accumulated during aging but was prevented by CR and Ssd1 overexpression. Moreover, lifespan extension by Ssd1 overexpression or CR was epistatic to inactivation of the iron regulon. These studies reveal that CR and Ssd1 overexpression extend the yeast replicative lifespan by blocking deleterious age-dependent iron uptake, identifying novel therapeutic targets for lifespan extension and providing insight into how CR may extend the lifespan and healthspan in humans.

cell biology↗

Lack of blocking activity in anti-CTLA-4 antibodies reduces toxicity, but not anti-tumor efficacy

Anti-CTLA-4 antibodies such as ipilimumab were among the first immune-oncology agents to show significantly improved outcomes for patients. However, existing anti-CTLA-4 therapies fail to induce a response in a majority of patients and can induce severe, immune-related adverse events. It has been assumed that checkpoint inhibition, i.e., blocking the interaction between CTLA-4 and its ligands, is the primary mechanism of action for ipilimumab. In this study we present evidence that checkpoint inhibition is not a primary mechanism of action for efficacy of anti-CTLA-4 antibodies. Instead, the primary mechanism for efficacy is FcR-mediated Treg depletion in the tumor microenvironment. First, we identified a monoclonal antibody (mAb) that binds to CTLA-4 at an epitope that differs from ipilimumabs by only a few amino acids, yet has limited checkpoint inhibitor activity. Surprisingly, the weak checkpoint inhibitor has superior anti-tumor activity compared to ipilimumab in a murine model. The weak checkpoint inhibitor also induces less Treg proliferation and has increased ability to induce in vitro FcR signaling and in vivo depletion of intratumoral Tregs. Further experiments showed that the enhanced FcR activity of the weak checkpoint inhibitor likely contributes to its enhanced anti-tumor activity. Importantly, we also showed that weak checkpoint inhibition was associated with lower toxicity in murine models. Our work suggests that new anti-CTLA-4 drugs should be optimized for Treg depletion rather than checkpoint inhibition.

immunology↗