Selectivity of mass extinctions: Patterns, processes, and future directions

A central question in the study of mass extinction is whether these events simply intensify background extinction processes and patterns versus change the driving mechanisms and associated patterns of selectivity. Over the past two decades, aided by the development of new fossil occurrence databases, selectivity patterns associated with mass extinction have become increasingly well quantified and their differences from background patterns established. In general, differences in geographic range matter less during mass extinction than during background intervals, while differences in respiratory and circulatory anatomy that may correlate with tolerance to rapid change in oxygen availability, temperature, and pH show greater evidence of selectivity during mass extinction. The recent expansion of physiological experiments on living representatives of diverse clades and the development of simple, quantitative theories linking temperature and oxygen availability to the extent of viable habitat in the oceans have enabled the use of Earth system models to link geochemical proxy constraints on environmental change with quantitative predictions of the amount and biogeography of habitat loss. Early indications are that the interaction between physiological traits and environmental change can explain substantial proportions of observed extinction selectivity for at least some mass extinction events. A remaining challenge is quantifying the effects of primary extinction resulting from the limits of physiological tolerance versus secondary extinction resulting from the loss of taxa on which a given species depended ecologically. The calibration of physiology-based models to past extinction events will enhance their value in prediction and mitigation efforts related to the current biodiversity crisis

Identification of a β-Arrestin-Biased Negative Allosteric Modulator for the β2-Adrenergic Receptor

Catecholamine-stimulated β2-adrenergic receptor (β2AR) signaling via the canonical Gs–adenylyl cyclase–cAMP–PKA pathway regulates numerous physiological functions, including the therapeutic effects of exogenous β-agonists in the treatment of airway disease. β2AR signaling is tightly regulated by GRKs and β-arrestins, which together promote β2AR desensitization and internalization as well as downstream signaling, often antithetical to the canonical pathway. Thus, the ability to bias β2AR signaling toward the Gs pathway while avoiding β-arrestin-mediated effects may provide a strategy to improve the functional consequences of β2AR activation. Since attempts to develop Gs-biased agonists and allosteric modulators for the β2AR have been largely unsuccessful, here we screened small molecule libraries for allosteric modulators that selectively inhibit β-arrestin recruitment to the receptor. This screen identified several compounds that met this profile, and, of these, a difluorophenyl quinazoline (DFPQ) derivative was found to be a selective negative allosteric modulator of β-arrestin recruitment to the β2AR while having no effect on β2AR coupling to Gs. DFPQ effectively inhibits agonist-promoted phosphorylation and internalization of the β2AR and protects against the functional desensitization of β-agonist mediated regulation in cell and tissue models. The effects of DFPQ were also specific to the β2AR with minimal effects on the β1AR. Modeling, mutagenesis, and medicinal chemistry studies support DFPQ derivatives binding to an intracellular membrane-facing region of the β2AR, including residues within transmembrane domains 3 and 4 and intracellular loop 2. DFPQ thus represents a class of biased allosteric modulators that targets an allosteric site of the β2AR

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials

Metabolic Trait Diversity Shapes Marine Biogeography

Climate and physiology shape biogeography, yet the range limits of species can rarely be ascribed to the quantitative traits of organisms1,2,3. Here we evaluate whether the geographical range boundaries of species coincide with ecophysiological limits to acquisition of aerobic energy4 for a global cross-section of the biodiversity of marine animals. We observe a tight correlation between the metabolic rate and the efficacy of oxygen supply, and between the temperature sensitivities of these traits, which suggests that marine animals are under strong selection for the tolerance of low O2 (hypoxia)5. The breadth of the resulting physiological tolerances of marine animals predicts a variety of geographical niches—from the tropics to high latitudes and from shallow to deep water—which better align with species distributions than do models based on either temperature or oxygen alone. For all studied species, thermal and hypoxic limits are substantially reduced by the energetic demands of ecological activity, a trait that varies similarly among marine and terrestrial taxa. Active temperature-dependent hypoxia thus links the biogeography of diverse marine species to fundamental energetic requirements that are shared across the animal kingdom

Impact of warming on aquatic body sizes explained by metabolic scaling from microbes to macrofauna

Rising temperatures are associated with reduced body size in many marine species, but the biological cause and generality of the phenomenon is debated. We derive a predictive model for body size responses to temperature and oxygen (O2) changes based on thermal and geometric constraints on organismal O2 supply and demand across the size spectrum. The model reproduces three key aspects of the observed patterns of intergenerational size reductions measured in laboratory warming experiments of diverse aquatic ectotherms (i.e., the “temperature-size rule” [TSR]). First, the interspecific mean and variability of the TSR is predicted from species\u27 temperature sensitivities of hypoxia tolerance, whose nonlinearity with temperature also explains the second TSR pattern-its amplification as temperatures rise. Third, as body size increases across the tree of life, the impact of growth on O2 demand declines while its benefit to O2 supply rises, decreasing the size dependence of hypoxia tolerance and requiring larger animals to contract by a larger fraction to compensate for a thermally driven rise in metabolism. Together our results support O2 limitation as the mechanism underlying the TSR, and they provide a physiological basis for projecting ectotherm body size responses to climate change from microbes to macrofauna. For small species unable to rapidly migrate or evolve greater hypoxia tolerance, ocean warming and O2 loss in this century are projected to induce \u3e20% reductions in body mass. Size reductions at higher trophic levels could be even stronger and more variable, compounding the direct impact of human harvesting on size-structured ocean food webs

Thermal optima in the hypoxia tolerance of marine ectotherms: Physiological causes and biogeographic consequences.

The minimum O2 needed to fuel the demand of aquatic animals is commonly observed to increase with temperature, driven by accelerating metabolism. However, recent measurements of critical O2 thresholds ("Pcrit") reveal more complex patterns, including those with a minimum at an intermediate thermal "optimum". To discern the prevalence, physiological drivers, and biogeographic manifestations of such curves, we analyze new experimental and biogeographic data using a general dynamic model of aquatic water breathers. The model simulates the transfer of oxygen from ambient water through a boundary layer and into animal tissues driven by temperature-dependent rates of metabolism, diffusive gas exchange, and ventilatory and circulatory systems with O2-protein binding. We find that a thermal optimum in Pcrit can arise even when all physiological rates increase steadily with temperature. This occurs when O2 supply at low temperatures is limited by a process that is more temperature sensitive than metabolism, but becomes limited by a less sensitive process at warmer temperatures. Analysis of published species respiratory traits suggests that this scenario is not uncommon in marine biota, with ventilation and circulation limiting supply under cold conditions and diffusion limiting supply at high temperatures. Using occurrence data, we show that species with these physiological traits inhabit lowest O2 waters near the optimal temperature for hypoxia tolerance and are restricted to higher O2 at temperatures above and below this optimum. Our results imply that hypoxia tolerance can decline under both cold and warm conditions and thus may influence both poleward and equatorward species range limits