Solving the conundrum of intra-specific variation in metabolic rate: A multidisciplinary conceptual and methodological toolkit: New technical developments are opening the door to an understanding of why metabolic rate varies among individual animals of a species: New technical developments are opening the door to an understanding of why metabolic rate varies among individual animals of a species.

Researchers from diverse disciplines, including organismal and cellular physiology, sports science, human nutrition, evolution and ecology, have sought to understand the causes and consequences of the surprising variation in metabolic rate found among and within individual animals of the same species. Research in this area has been hampered by differences in approach, terminology and methodology, and the context in which measurements are made. Recent advances provide important opportunities to identify and address the key questions in the field. By bringing together researchers from different areas of biology and biomedicine, we describe and evaluate these developments and the insights they could yield, highlighting the need for more standardisation across disciplines. We conclude with a list of important questions that can now be addressed by developing a common conceptual and methodological toolkit for studies on metabolic variation in animals.

Island restoration to rebuild seabird populations and amplify coral reef functioning.

Mobile organisms like seabirds can provide important nutrient flows between ecosystems, but this connectivity has been interrupted by the degradation of island ecosystems. Island restoration (via invasive species eradications and the restoration of native vegetation) can reestablish seabird populations and their nutrient transfers between their foraging areas, breeding colonies, and adjacent nearshore habitats. Its diverse benefits are making island restoration increasingly common and scalable to larger islands and whole archipelagos. We identified the factors that influence breeding seabird abundances throughout the Chagos Archipelago in the Indian Ocean and conducted predictive modeling to estimate the abundances of seabirds that the archipelago could support under invasive predator eradication and native vegetation restoration scenarios. We explored whether the prey base exists to support restored seabird populations across the archipelago, calculated the nitrogen that restored populations of seabirds might produce via their guano, and modeled the cascading conservation gains that island restoration could provide. Restoration was predicted to increase breeding pairs of seabirds to over 280,000, and prey was predicted to be ample to support the revived seabird populations. Restored nutrient fluxes were predicted to result in increases in coral growth rates, reef fish biomasses, and parrotfish grazing and bioerosion rates. Given these potential cross-ecosystem benefits, our results support island restoration as a conservation priority that could enhance resilience to climatic change effects, such as sea-level rise and coral bleaching. We encourage the incorporation of our estimates of cross-ecosystem benefits in prioritization exercises for island restoration.

Restauración en islas para reconstruir las poblaciones de aves marinas y amplificar la funcionalidad de los arrecifes de coral Resumen Los organismos móviles como las aves marinas pueden proporcionar flujos importantes de nutrientes entre los ecosistemas, aunque esta conectividad ha sido interrumpida por la degradación de los ecosistemas isleñas. La restauración de islas (por medio de la erradicación de especies invasoras y la restauración de la vegetación nativa) puede reestablecer las poblaciones de aves marinas y su transferencia de nutrientes entre las áreas de forrajeo, las colonias reproductoras y los hábitats adyacentes a la costa. Los diferentes beneficios de la restauración de islas hacen que sea cada vez más común y escalable a islas más grandes y archipiélagos completos. Identificamos los factores que influyen sobre la abundancia de aves reproductoras en todo el archipiélago de Chagos en el Océano Índico y realizamos un modelo predictivo para estimar la abundancia de aves que podría soportar el archipiélago bajo escenarios de la erradicación de un depredador invasor y la restauración de la vegetación nativa. Exploramos si existe la base de presas para soportar las poblaciones restauradas de aves marinas en el archipiélago, calculamos el nitrógeno que las poblaciones restauradas podrían producir mediante el guano y modelamos la conservación en cascada que podría proporcionar la restauración de la isla. Se pronosticó que la restauración incrementaría las parejas reproductoras a más de 280,000 y que las presas serían las suficientes para soportar las poblaciones restauradas de aves marinas. También se pronosticó que los flujos restaurados de nutrientes resultarían en un incremento de la tasa de crecimiento de los corales, la biomasa de los peces del arrecife y las tasas de bio­erosión y de alimentación de los peces loro. Dados estos beneficios potenciales entre los ecosistemas, nuestros resultados respaldan a la restauración de islas como una prioridad de conservación que podría incrementar la resiliencia a los efectos del cambio climático, como el incremento en el nivel del mar y el blanqueamiento de los corales. Promovemos que se incorporen nuestras estimaciones de los beneficios transecosistémicos dentro de los ejercicios de priorización para la restauración de islas.

Evaluating the delivery of care by telemedicine for incarcerated people living with HIV: a cohort study.

BACKGROUND: The use of telemedicine has grown significantly since the COVID-19 pandemic and has the potential to improve access to specialized care for otherwise underserved populations. Incarcerated people living with HIV (PLWH) could potentially benefit from expanded access to HIV care through telemedicine. METHODS: All PLWH who were incarcerated within the Tennessee Department of Corrections and received care through the HIV telemedicine clinic at Regional One Hospital between 5/1/2019 through 2/28/2022 were identified from the electronic health records (EHR). Demographics, laboratory data, vaccine history, and treatment outcomes were abstracted from the EHR. Retention in care and viral suppression were defined using Centers for Disease Control and Prevention definitions. RESULTS: Of the 283 incarcerated PLWH receiving care from this telemedicine clinic, 78% remained retained in care and 94% achieved or maintaining viral suppression at 12 months. Many preventative care measures remained unperformed or undocumented, including vaccinations and testing for concurrent sexually transmitted infections. There were 56 patients (20%) found to have chronic hepatitis C in this population, with 71% either cured or still on treatment in this study period. CONCLUSIONS: Retention in care and viral suppression rates were excellent among incarcerated PLWH receiving telemedicine care for their HIV. HIV related primary health care screenings and vaccinations, however, were less consistently documented and represent areas for improvement.

A framework to unlock marine bird energetics.

Energetics can provide novel insights into the roles of animals, but employing an energetics approach has traditionally required extensive empirical physiological data on the focal species, something that can be challenging for those that inhabit marine environments. There is therefore a demand for a framework through which to estimate energy expenditure from readily available data. We present the energetic costs associated with important time- and energy-intensive behaviours across nine families of marine bird (including seabirds, ducks, divers and grebes) and nine ecological guilds. We demonstrate a worked example, calculating the year-round energetic expenditure of the great auk, Pinguinus impennis, under three migration scenarios, thereby illustrating the capacity of this approach to make predictions for data-deficient species. We provide a comprehensive framework through which to model marine bird energetics and demonstrate the power of this approach to provide novel, quantitative insights into the influence of marine birds within their ecosystems.

An ethanolic extract of Artemisia scoparia inhibits lipolysis in vivo and has antilipolytic effects on murine adipocytes in vitro.

An ethanolic extract of Artemisia scoparia (SCO) has metabolically favorable effects on adipocyte development and function in vitro and in vivo. In diet-induced obese mice, SCO supplementation significantly reduced fasting glucose and insulin levels. Given the importance of adipocyte lipolysis in metabolic health, we hypothesized that SCO modulates lipolysis in vitro and in vivo. Free fatty acids and glycerol were measured in the sera of mice fed a high-fat diet with or without SCO supplementation. In cultured 3T3-L1 adipocytes, the effects of SCO on lipolysis were assessed by measuring glycerol and free fatty acid release. Microarray analysis, qPCR, and immunoblotting were used to assess gene expression and protein abundance. We found that SCO supplementation of a high-fat diet in mice substantially reduces circulating glycerol and free fatty acid levels, and we observed a cell-autonomous effect of SCO to significantly attenuate tumor necrosis factor-α (TNFα)-induced lipolysis in cultured adipocytes. Although several prolipolytic and antilipolytic genes were identified by microarray analysis of subcutaneous and visceral adipose tissue from SCO-fed mice, regulation of these genes did not consistently correlate with SCO's ability to reduce lipolytic metabolites in sera or cell culture media. However, in the presence of TNFα in cultured adipocytes, SCO induced antilipolytic changes in phosphorylation of hormone-sensitive lipase and perilipin. Together, these data suggest that the antilipolytic effects of SCO on adipose tissue play a role in the ability of this botanical extract to improve whole body metabolic parameters and support its use as a dietary supplement to promote metabolic resiliency.

A model to estimate seabird field metabolic rates.

For free-ranging animals, field metabolic rate (FMR) is the sum of their energy expenditure over a specified period. This quantity is a key component of ecological processes at every biological level. We applied a phylogenetically informed meta-analytical approach to identify the large-scale determinants of FMR in seabirds during the breeding season. Using data from 64 studies of energetics in 47 species, we created a model to estimate FMR for any seabird population. We found that FMR was positively influenced by body mass and colony latitude and that it increased throughout the breeding season from incubation to brood to crèche. FMR was not impacted by colony-relative predation pressure or species average brood size. Based on this model, we present an app through which users can generate estimates of FMR for any population of breeding seabird. We encourage the use of this app to complement behavioural studies and increase understanding of how energetic demands influence the role of seabirds as driving components of marine systems.

Extraordinary transgressive phenotypes of hybrid tomato are influenced by epigenetics and small silencing RNAs.

Hybrid organisms may fail to develop, be sterile or they may be more vigorous than either of the parents. Examples of hybrid vigour or hybrid necrosis in the F1 are often not inherited stably in subsequent generations if they are associated with overdominance. There can also be transgressive phenotypes that are inherited stably in these later generations, but the underlying mechanisms are not well understood. Here we have investigated the possibility that stable transgressive phenotypes in the progeny of crosses between cultivated tomato (Solanum lycopersicum cv. M82) and a wild relative (Solanum pennellii, accession LA716) are associated with micro or small interfering(si) RNAs. We identified loci from which these small(s)RNAs were more abundant in hybrids than in either parent and we show that accumulation of such transgressive sRNAs correlated with suppression of the corresponding target genes. In one instance this effect was associated with hypermethylation of the corresponding genomic DNA. Our results illustrate a potential role of transgressive sRNAs in plant breeding and in natural evolution with wild plants.

Retinal Toxicity Induced by a Novel ß-secretase Inhibitor in the Sprague-Dawley Rat.

ß-Secretase 1 (BACE1) represents an attractive target for the treatment of Alzheimer's disease. In the course of development of a novel small molecule BACE1 inhibitor (AMG-8718), retinal thinning was observed in a 1-month toxicity study in the rat. To further understand the lesion, an investigational study was conducted whereby rats were treated daily with AMG-8718 for 1 month followed by a 2-month treatment-free phase. The earliest detectable change in the retina was an increase in autofluorescent granules in the retinal pigment epithelium (RPE) on day 5; however, there were no treatment-related light microscopic changes observed in the neuroretina and no changes observed by fundus autofluorescence or routine ophthalmoscopic examination after 28 days of dosing. Following 2 months of recovery, there was significant retinal thinning attributed to loss of photoreceptor nuclei from the outer nuclear layer. Electroretinographic changes were observed as early as day 14, before any microscopic evidence of photoreceptor loss. BACE1 knockout rats were generated and found to have normal retinal morphology indicating that the retinal toxicity induced by AMG-8718 was likely off-target. These results suggest that AMG-8718 impairs phagolysosomal function in the rat RPE, which leads to photoreceptor dysfunction and ultimately loss of photoreceptors.

Uniparental expression of PolIV-dependent siRNAs in developing endosperm of Arabidopsis.

Most eukaryotes produce small RNA (sRNA) mediators of gene silencing that bind to Argonaute proteins and guide them, by base pairing, to an RNA target. MicroRNAs (miRNAs) that normally target messenger RNAs for degradation or translational arrest are the best-understood class of sRNAs. However, in Arabidopsis thaliana flowers, miRNAs account for only 5% of the sRNA mass and less than 0.1% of the sequence complexity. The remaining sRNAs form a complex population of more than 100,000 different small interfering RNAs (siRNAs) transcribed from thousands of loci. The biogenesis of most of the siRNAs in Arabidopsis are dependent on RNA polymerase IV (PolIV), a homologue of DNA-dependent RNA polymerase II. A subset of these PolIV-dependent (p4)-siRNAs are involved in stress responses, and others are associated with epigenetic modifications to DNA or chromatin; however, the biological role is not known for most of them. Here we show that the predominant phase of p4-siRNA accumulation is initiated in the maternal gametophyte and continues during seed development. Expression of p4-siRNAs in developing endosperm is specifically from maternal chromosomes. Our results provide the first evidence for a link between genomic imprinting and RNA silencing in plants.

High hematocrit resulting from administration of erythropoiesis-stimulating agents is not fully predictive of mortality or toxicities in preclinical species.

We conducted a retrospective analysis of publicly available preclinical toxicology studies with erythropoiesis-stimulating agents (ESAs) to examine common adverse events in rats, Beagle dogs, and cynomolgus monkeys. Mortality and/or thrombotic events were reported sporadically in a subset of studies and attributed to the high hematocrit (HCT) achieved in the animals. However, similarly high HCT was achieved in both high-dose and low-dose groups, but there were no reported adverse events in the low-dose group suggesting HCT was not the sole contributing factor leading to toxicity. Our analysis indicated that increased dose, dose frequency, and dosing duration in addition to high HCT contributed to mortality and thrombosis. To further evaluate this relationship, the incidence of toxicities was compared in rats administered an experimental hyperglycosylated analog of recombinant human erythropoietin (AMG 114) at varying dosing schedules in 1-month toxicity studies. The incidence of mortality and thrombotic events increased in higher dose groups and when dosed more frequently, despite a similarly high HCT in all animals. The results from the investigative study and retrospective analysis demonstrate that ESA-related toxicities in preclinical species are associated with dose level, dose frequency, and dosing duration, and not solely dependent upon a high HCT.

Dose-related differences in the pharmacodynamic and toxicologic response to a novel hyperglycosylated analog of recombinant human erythropoietin in Sprague-Dawley rats with similarly high hematocrit.

We recently reported results that erythropoiesis-stimulating agent (ESA)-related thrombotic toxicities in preclinical species were not solely dependent on a high hematocrit (HCT) but also associated with increased ESA dose level, dose frequency, and dosing duration. In this article, we conclude that sequelae of an increased magnitude of ESA-stimulated erythropoiesis potentially contributed to thrombosis in the highest ESA dose groups. The results were obtained from two investigative studies we conducted in Sprague-Dawley rats administered a low (no thrombotic toxicities) or high (with thrombotic toxicities) dose level of a hyperglycosylated analog of recombinant human erythropoietin (AMG 114), 3 times weekly for up to 9 days or for 1 month. Despite similarly increased HCT at both dose levels, animals in the high-dose group had an increased magnitude of erythropoiesis measured by spleen weights, splenic erythropoiesis, and circulating reticulocytes. Resulting prothrombotic risk factors identified predominantly or uniquely in the high-dose group were higher numbers of immature reticulocytes and nucleated red blood cells in circulation, severe functional iron deficiency, and increased intravascular destruction of iron-deficient reticulocyte/red blood cells. No thrombotic events were detected in rats dosed up to 9 days suggesting a sustained high HCT is a requisite cofactor for development of ESA-related thrombotic toxicities.

Cytokines associated with increased erythropoiesis in Sprague-Dawley rats administered a novel hyperglycosylated analog of recombinant human erythropoietin.

We previously reported an increased incidence of thrombotic toxicities in Sprague-Dawley rats administered the highest dose level of a hyperglycosylated analog of recombinant human erythropoietin (AMG 114) for 1 month as not solely dependent on high hematocrit (HCT). Thereafter, we identified increased erythropoiesis as a prothrombotic risk factor increased in the AMG 114 high-dose group with thrombotic toxicities, compared to a low-dose group with no toxicities but similar HCT. Here, we identified pleiotropic cytokines as prothrombotic factors associated with AMG 114 dose level. Before a high HCT was achieved, rats in the AMG 114 high, but not the low-dose group, had imbalanced hemostasis (increased von Willebrand factor and prothrombin time, decreased antithrombin III) coexistent with cytokines implicated in thrombosis: monocyte chemotactic protein 1 (MCP-1), MCP-3, tissue inhibitor of metalloproteinases 1, macrophage inhibitory protein-2, oncostatin M, T-cell-specific protein, stem cell factor, vascular endothelial growth factor, and interleukin-11. While no unique pathway to erythropoiesis stimulating agent-related thrombosis was identified, cytokines associated with increased erythropoiesis contributed to a prothrombotic intravascular environment in the AMG 114 high-dose group, but not in lower dose groups with a similar high HCT.

Ecological roles and importance of sharks in the Anthropocene Ocean.

In ecosystems, sharks can be predators, competitors, facilitators, nutrient transporters, and food. However, overfishing and other threats have greatly reduced shark populations, altering their roles and effects on ecosystems. We review these changes and implications for ecosystem function and management. Macropredatory sharks are often disproportionately affected by humans but can influence prey and coastal ecosystems, including facilitating carbon sequestration. Like terrestrial predators, sharks may be crucial to ecosystem functioning under climate change. However, large ecosystem effects of sharks are not ubiquitous. Increasing human uses of oceans are changing shark roles, necessitating management consideration. Rebuilding key populations and incorporating shark ecological roles, including less obvious ones, into management efforts are critical for retaining sharks' functional value. Coupled social-ecological frameworks can facilitate these efforts.

The Arabidopsis RNA-directed DNA methylation argonautes functionally diverge based on their expression and interaction with target loci.

Argonaute (AGO) effectors of RNA silencing bind small RNA (sRNA) molecules and mediate mRNA cleavage, translational repression, or epigenetic DNA modification. In many organisms, these targeting mechanisms are devolved to different products of AGO multigene families. To investigate the basis of AGO functional diversification, we characterized three closely related Arabidopsis thaliana AGOs (AGO4, AGO6, and AGO9) implicated in RNA-directed DNA methylation. All three AGOs bound 5' adenosine 24-nucleotide sRNAs, but each exhibited different preferences for sRNAs from different heterochromatin-associated loci. This difference was reduced when AGO6 and AGO9 were expressed from the AGO4 promoter, indicating that the functional diversification was partially due to differential expression of the corresponding genes. However, the AGO4-directed pattern of sRNA accumulation and DNA methylation was not fully recapitulated with AGO6 or AGO9 expressed from the AGO4 promoter. Here, we show that sRNA length and 5' nucleotide do not account for the observed functional diversification of these AGOs. Instead, the selectivity of sRNA binding is determined by the coincident expression of the AGO and sRNA-generating loci, and epigenetic modification is influenced by interactions between the AGO protein and the different target loci. These findings highlight the importance of tissue specificity and AGO-associated proteins in influencing epigenetic modifications.

Seabirds boost coral reef resilience.

Global climate change threatens tropical coral reefs, yet local management can influence resilience. While increasing anthropogenic nutrients reduce coral resistance and recovery, it is unknown how the loss, or restoration, of natural nutrient flows affects reef recovery. Here, we test how natural seabird-derived nutrient subsidies, which are threatened by invasive rats, influence the mechanisms and patterns of reef recovery following an extreme marine heatwave using multiyear field experiments, repeated surveys, and Bayesian modeling. Corals transplanted from rat to seabird islands quickly assimilated seabird-derived nutrients, fully acclimating to new nutrient conditions within 3 years. Increased seabird-derived nutrients, in turn, caused a doubling of coral growth rates both within individuals and across entire reefs. Seabirds were also associated with faster recovery time of Acropora coral cover (<4 years) and more dynamic recovery trajectories of entire benthic communities. We conclude that restoring seabird populations and associated nutrient pathways may foster greater coral reef resilience through enhanced growth and recovery rates of corals.

Conservation implications of forage base requirements of a marine predator population at carrying capacity.

Prey depletion may contribute to marine predator declines, yet the forage base required to sustain an unfished population of predatory fish at carrying capacity is unknown. We integrated demographic and physiological data within a Bayesian bioenergetic model to estimate annual consumption of a gray reef shark (Carcharhinus amblyrhynchos) population at a remote Pacific atoll (Palmyra Atoll) that are at carrying capacity. Furthermore, we estimated the proportion of the atoll's reef fish biomass production consumed by the gray reef sharks, assuming sharks either partially foraged pelagically (mean 7%), or solely within the reef environment (mean 52%). We then predicted the gray reef shark population potential of other, less remote Pacific Ocean coral reef islands, illustrating that current populations are substantially smaller than could be supported by their forage base. Our research highlights the utility of modeling how far predator population sizes are from their expected carrying capacity in informing marine conservation.

Survey results on the use of the tissue cross-reactivity immunohistochemistry assay.

A multinational pharmaceutical and biotechnology company survey was conducted to gain a better understanding of the use and value of the tissue cross-reactivity (TCR) assay in the development of biotherapeutic molecules. The majority of the molecules did not use TCR data as the only basis for determining species selection for toxicity studies (73%). For 95% of the molecules, the TCR data had no impact on the development strategy. For 2% of the molecules (1/56), TCR data was the sole source of information indicating a potential risk to patients. Unexpected or off-target binding was seen with 35% of the molecules, with the majority of this binding occurring in the CNS and reproductive organs. Tissues that were known or presumed to contain the target stained positively in 22% and 10% of molecules tested in non-human primate and human tissues, respectively. Tissues that were known or presumed to lack the target were negative for staining in 39% and 50% of molecules for non-human primate and human tissue, respectively. For 5% (6/110) of all the molecules, companies stated that toxicities would have been missed in animal studies or the clinic (i.e., not identified by clinical signs, histopathology, etc.) if the TCR studies had not been performed.

Effects of Gender-Affirming Hormone Therapy on Progression Along the HIV Care Continuum in Transgender Women.

BACKGROUND: Progression along the HIV care continuum has been a key focus for improving outcomes for people with HIV (PWH). Transgender women with HIV (TGWWH) have not made the same progress as their cisgender counterparts. METHODS: All PWH identifying as transgender women receiving care at our clinic from 1/1/2015 to 12/31/2019 were identified from the electronic health records (EHRs) using International Classification of Diseases (ICD) codes. Demographics, laboratory data, prescription of gender-affirming hormone therapy (GAHT), and visit history were abstracted from the EHR. Retention in care and viral suppression were defined using Centers for Disease Control and Prevention definitions. The proportions of TGWWH who were consistently retained in care or virally suppressed over time were calculated using a binary response generalized mixed model including random effects and correlated errors. RESULTS: Of the 76 PWH identified by ICD codes, 2 were excluded for identifying as cisgender and 15 for insufficient records, leaving 59 TGWWH included for analysis. Patients were on average 35 years old and Black (86%), with a median CD4 count of 464 cells/µL. There were 13 patients on GAHT at study entry and 31 receiving GAHT at any point during the study period. Fifty-five percent were virally suppressed at study entry and 86% at GAHT initiation. The proportion of TGWWH who were consistently virally suppressed over time was greater among those receiving GAHT compared with those who were not (P = .04). CONCLUSIONS: Rates of viral suppression were significantly greater among TGWWH receiving GAHT when compared with those who were not. More research to evaluate the reasons behind this effect is needed.

A year in the life of a North Atlantic seabird: behavioural and energetic adjustments during the annual cycle.

During their annual cycles, animals face a series of energetic challenges as they prioritise different life history events by engaging in temporally and potentially spatially segregated reproductive and non-breeding periods. Investigating behaviour and energy use across these periods is fundamental to understanding how animals survive the changing conditions associated with annual cycles. We estimated year-round activity budgets, energy expenditure, location, colony attendance and foraging behaviour for surviving individuals from a population of common guillemots Uria aalge. Despite the potential constraints of reduced day lengths and sea surface temperatures in winter, guillemots managed their energy expenditure throughout the year. Values were high prior to and during the breeding season, driven by a combination of high thermoregulatory costs, diving activity, colony attendance and associated flight. Guillemots also exhibited partial colony attendance outside the breeding season, likely supported by local resources. Additionally, there was a mismatch in the timing of peaks in dive effort and a peak in nocturnal foraging activity, indicating that guillemots adapted their foraging behaviour to the availability of prey rather than daylight. Our study identifies adaptations in foraging behaviour and flexibility in activity budgets as mechanisms that enable guillemots to manage their energy expenditure and survive the annual cycle.