Biology subjects

Whelan, S.

Publications and source records attributed to Whelan, S..

13 recordsLinked to original sources

bioRxiv2025

Corticosterone elevation is associated with rapid, sex-specific increases in food-acquisition behaviors in free-living seabird chicks

Bidirectional relationships between hormones and behaviors are hypothesized: i.e. energetic consequences of behaviors may alter glucocorticoid levels, and elevated glucocorticoids may alter behavioral responses to stimuli in context-appropriate ways. We tested these relationships between the avian glucocorticoid corticosterone and behaviors related to food-acquisition in free-living seabird chicks (Black-legged kittiwakes, Rissa tridactyla) with robust HPA-axis activity. First, we tested the hypothesis that behavior affects HPA axis activity by quantifying chick behavior for 60 min, then taking a blood sample at baseline and 15-min post-restraint. Only feeding predicted subsequent corticosterone levels (fewer feeds = higher restraint-induced corticosterone). However, the hypothesis that increased corticosterone secretion alters behavior was supported: post-restraint corticosterone levels were positively correlated with increases in begging and aggression in the subsequent hour, primarily in males. In a second experiment, we isolated the role of corticosterone from other components of the stress response by administering exogenous topical corticosterone, which confirmed a positive relationship between subsequent corticosterone levels and changes in aggression, but not begging or feeding. Corticosterone:behavior relationships depended on nutritional context - they were eliminated in nests with experimental food supplementation. Finally, higher levels of corticosterone in response to restraint were associated with more rapid elimination of siblings, presumably increasing chick direct fitness by eliminating competition. We conclude that the magnitude of the endogenous corticosterone response to challenges is a) negatively correlated with recent feeding rates, b) subsequently associated with rapid, sex- and context-specific changes in chick behaviors, at least some of which are likely causally- driven by elevated corticosterone, and c) associated with fitness-relevant consequences.

animal behavior and cognition↗

bioRxiv2025

Tryptophan metabolism reprogramming contributes to the prothrombotic milieu in mice and humans infected with SARS-CoV-2

SARS-CoV-2 infection disturbs the coagulation balance in the blood, triggering thrombosis and contributing to organ failure. The role of prothrombotic metabolites in COVID-19-associated coagulopathy remains elusive. Leveraging K18-hACE2 mice infected with SARS-CoV-2, we observed higher levels of the tryptophan metabolite, kynurenine, compared to controls. SARS-CoV-2 infected mice showed a significant upregulation of enzymes controlling Kynurenine biogenesis, such as indoleamine 2,3-dioxygenase (IDO-1) and tryptophan 2,3-dioxygenase levels in kidneys and liver, respectively, as well as changes in the enzymes involved in kynurenine catabolism, including kynurenine monooxygenase and kynurinase. Consistent with the agonistic role of these metabolites in Aryl Hydrocarbon Receptor (AHR) signaling, AHR activation and its downstream mediator, tissue factor (TF), a highly potent procoagulant factor, was observed in endothelial cells (ECs) of lungs and kidneys of infected mice. These findings were validated in humans, where compared to controls, sera of COVID-19 patients showed increased levels of Kynurenine, kynurenic acid, anthranilic acid, and quinolinic acid. Activation of the AHR-TF axis was noted in the kidneys and lungs of COVID-19 patients, and COVID-19 sera showed higher IDO-1 activity than controls. Levels of Kyn in COVID-19 patients correlated strongly with the TF-inducing activity of COVID-19 sera on ECs. A specific IDO-1 inhibitor or AHR inhibitor separately or in combination suppressed COVID-19 sera-induced TF activity in ECs. Together, we identified IDO-1 as upregulated by SARS-CoV-2 infection, resulting in augmented Kyn and its prothrombotic catabolites, thereby suggesting the Kyn-AHR-TF axis as possibly a new diagnostic and/or therapeutic target. Key pointsO_LISARS-CoV-2-infection upregulates kynurenine biogenesis in the liver and diminishes kynurenine catabolism in the lungs and kidneys. C_LIO_LIAn increase in kynurenine stimulates the AHR-TF axis in the microvasculature in COVID-19 patients, which is inhibited by pharmacological manipulation. C_LI

systems biology↗

bioRxiv2024

Corticosterone in very young seabird chicks (Rissa tridactyla) is sensitive to environmental variability and responds rapidly and robustly to external challenges

In birds, patterns of development of the adrenocortical response to stressors vary among individuals, types of stressors, and species. Since there are benefits and costs of exposure to elevated glucocorticoids, this variation is presumably a product of selection such that animals modulate glucocorticoid secretion in contexts where doing so increases their fitness. In this study, we evaluated hypothalamic-pituitary-adrenal (HPA) activity in first-hatched free-living seabird nestlings that engage in intense sibling competition and facultative siblicide (black-legged kittiwakes, Rissa tridactlya). We sampled 5 day old chicks (of the [~]45 day nestling period), a critical early age when food availability drives establishment of important parent-offspring and intra-brood dynamics. We experimentally supplemented parents with food ("supplemented") and measured chick baseline corticosterone secretion and capacity to rapidly increase corticosterone in response to an acute challenge (handling and a 15 min restraint in a bag). We also used topical administration of corticosterone to evaluate the ability of chicks to downregulate physiologically relevant corticosterone levels on a short (minutes) time scale. We found that 5 day old chicks are not hypo-responsive but release corticosterone in proportion to the magnitude of the challenge, showing differences in baseline between parental feeding treatments (supplemented vs non-supplemented), moderate increases in response to handling, and a larger response to restraint (comparable to adults) that also differed between chicks from supplemented and control nests. Topical application of exogenous corticosterone increased circulating levels nearly to restraint-induced levels and induced downregulation of HPA responsiveness to the acute challenge of handling. Parental supplemental feeding did not affect absorbance/clearance or negative feedback. Thus, while endogenous secretion of corticosterone in young chicks is sensitive to environmental context, other aspects of the HPA function, such as rapid negative feedback and/or the ability to clear acute elevations in corticosterone, are not. We conclude that 5 day old kittiwake chicks are capable of robust adrenocortical responses to novel challenges, and are sensitive to parental food availability, which may be transduced behaviorally, nutritionally, or via maternal effects. Questions remain about the function of such rapid, large acute stress-induced increases in corticosterone in very young chicks.

physiology↗

bioRxiv2023

Glutathione supports lipid abundance in vivo

Cells rely on antioxidants to survive. The most abundant antioxidant is glutathione (GSH). The synthesis of GSH is non-redundantly controlled by the glutamate-cysteine ligase catalytic subunit (GCLC). GSH imbalance is implicated in many diseases, but the requirement for GSH in adult tissues is unclear. To interrogate this, we developed a series of in vivo models to induce Gclc deletion in adult animals. We find that GSH is essential to lipid abundance in vivo. GSH levels are reported to be highest in liver tissue, which is also a hub for lipid production. While the loss of GSH did not cause liver failure, it decreased lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we found that GSH promotes lipid abundance by repressing NRF2, a transcription factor induced by oxidative stress. These studies identify GSH as a fulcrum in the livers balance of redox buffering and triglyceride production.

biochemistry↗

bioRxiv2022

The role of wingbeat frequency and amplitude in flight power

Body-mounted accelerometers provide a new prospect for estimating power use in flying birds, as the signal varies with the two major kinematic determinants of aerodynamic power: wingbeat frequency and amplitude. Yet wingbeat frequency is sometimes used as a proxy for power output in isolation. There is therefore a need to understand which kinematic parameter birds vary and whether this is predicted by flight mode (e.g., accelerating, ascending/descending flight), speed or morphology. We investigate this using high-frequency acceleration data from (i) 14 species flying in the wild, (ii) two species flying in controlled conditions in a wind tunnel and (iii) a review of experimental and field studies. While wingbeat frequency and amplitude were positively correlated, R2 values were generally low, supporting the idea that parameters can vary independently. Indeed, birds were more likely to modulate wingbeat amplitude for more energy-demanding flight modes, including climbing and take-off. Nonetheless, the striking variability even within species and flight types, highlights the complexity of describing the kinematic relationships, which appear sensitive to both the biological and physical context. Notwithstanding this acceleration metrics that incorporate both kinematic parameters should be more robust proxies for power than wingbeat frequency alone.

biophysics↗

bioRxiv2022

Imprinted antibody responses against SARS-CoV-2 Omicron sublineages

SARS-CoV-2 Omicron sublineages carry distinct spike mutations and represent an antigenic shift resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity or vaccine boosters result in potent plasma neutralizing activity against Omicron BA.1 and BA.2 and that breakthrough infections, but not vaccination-only, induce neutralizing activity in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1 and BA.2 receptor-binding domains whereas Omicron primary infections elicit B cells of narrow specificity. While most clinical antibodies have reduced neutralization of Omicron, we identified an ultrapotent pan-variant antibody, that is unaffected by any Omicron lineage spike mutations and is a strong candidate for clinical development.

immunology↗

bioRxiv2021

Key Drivers of Ecological Assembly in the Hindgut of Atlantic Cod (Gadus morhua) when Fed with a Macroalgal Supplemented diet - How Robust Is the Gut to Taxonomic Perturbation?

The microbiota in the gastrointestinal tract of any species is shaped by internal and external cues in addition to random events which can be difficult to disentangle from a range of interacting variables. Estimating ecological assembly processes can help elucidate these factors. In our study, farmed Atlantic cod (Gadus morhua) were fed a diet of 10% macroalgae supplement (Ulva rigida species [ULVA] or Ascophyllum nodosum [ASCO] or a non-amended control diet [CTRL]) over a 12-week period and the ecological assembly processes quantified. The CTRL samples showed selection (variable selection - divergence in communities related to selective environmental conditions) as a key assembly process, while dispersal limitation (limited movement results in divergent communities through stochastic processes) was a driver of the gut microbiome for fish fed the macroalgae supplemented diet at Week 12 (i.e., ASCO and ULVA). Fish from the ASCO grouping diverged into ASCO_N (normal) and ASCO_LG (lower growth), where ASCO_LG individuals found the diet unpalatable. The recruitment of new taxa over time was altered in the ASCO_LG fish, with the gut microbiome showing phylogenetic under dispersion (nepotistic recruitment of species). Finally, the gut microbiome (CTRL and ULVA only) showed increasing robustness to taxonomic disturbance over time and an increase in functional redundancy. This study advances our understanding of the ecological assembly and succession in the hindgut of juvenile Atlantic cod across dietary regimes. Understanding the processes driving ecological assembly in the gut microbiome, in fish research specifically, could allow us to manipulate the microbiome for improved health or resilience to disease for improved aquaculture production.

microbiology↗

bioRxiv2021

Ecological inference using data from accelerometers needs careful protocols

O_LIAccelerometers in animal-attached tags have proven to be powerful tools in behavioural ecology, being used to determine behaviour and provide proxies for movement-based energy expenditure. Researchers are collecting and archiving data across systems, seasons and device types. However, in order to use data repositories to draw ecological inference, we need to establish the error introduced according to sensor type and position on the study animal and establish protocols for error assessment and minimization. C_LIO_LIUsing laboratory trials, we examine the absolute accuracy of tri-axial accelerometers and determine how inaccuracies impact measurements of dynamic body acceleration (DBA), as the main acceleration-based proxy for energy expenditure. We then examine how tag type and placement affect the acceleration signal in birds using (i) pigeons Columba livia flying in a wind tunnel, with tags mounted simultaneously in two positions, (ii) back- and tail-mounted tags deployed on wild kittiwakes Rissa tridactyla. Finally, we (iii) present a case study where two generations of tag were deployed using different attachment procedures on red-tailed tropicbirds Phaethon rubricauda foraging in different seasons. C_LIO_LIBench tests showed that individual acceleration axes required a two-level correction (representing up to 4.3% of the total value) to eliminate measurement error. This resulted in DBA differences of up to 5% between calibrated and uncalibrated tags for humans walking at different speeds. Device position was associated with greater variation in DBA, with upper- and lower back-mounted tags in pigeons varying by 9%, and tail- and back-mounted tags varying by 13% in kittiwakes. Finally, DBA varied by 25% in tropicbirds between seasons, which may be attributable to tag attachment procedures. C_LIO_LIAccelerometer accuracy, tag placement, and attachment details critically affect the signal amplitude and thereby the ability of the system to detect biologically meaningful phenomena. We propose a simple method to calibrate accelerometers that should be used prior to deployments and archived with resulting data, suggest a way that researchers can assess accuracy in previously collected data, and caution that variable tag placement and attachment can increase sensor noise and even generate trends that have no biological meaning. C_LI

animal behavior and cognition↗

bioRxiv2020

Temporal changes in the gut microbiota in farmed Atlantic cod (Gadus morhua) outweigh the response to diet supplementation with macroalgae.

BackgroundAquaculture successfully meets global food demands for many fish species. However, aquaculture production of Atlantic cod (Gadus morhua) is modest in comparison to market demand. For cod farming to be a viable economic venture specific challenges on how to increase growth, health and farming productivity need to be addressed. Feed ingredients play a key role here. Macroalgae (seaweeds) have been suggested as a functional feed supplement with both health and economic benefits for terrestrial farmed animals and fish. The impact of such dietary supplements to cod gut integrity and microbiota, which contribute to overall fish robustness is unknown. The objective of this study was to supplement the diet of juvenile Atlantic cod with macroalgae and determine the impacts on fish condition and growth, gut morphology and hindgut microbiota composition (16S rRNA amplicon sequencing). Fish were fed one of three diets: control (no macroalgal inclusion), 10% inclusion of either egg wrack (Ascophyllum nodosum) or sea lettuce (Ulva rigida) macroalgae in a 12-week trial. ResultsThe results demonstrated there was no significant difference in fish condition, gut morphology or hindgut microbiota between the U. rigida supplemented fish group and the control group at any time-point. This contrasts with the A. nodosum treatment. Fish within this group were further categorised as either Normal or Lower Growth. Lower Growth individuals found the diet unpalatable resulting in reduced weight and condition factor combined with an altered gut morphology and microbiome relative to the other treatments. Excluding this group, our results show that the hindgut microbiota was largely driven by temporal pressures with the microbial communities becoming more similar over time irrespective of dietary treatment. The core microbiome at the final time-point consisted of the orders Vibrionales (Vibrio and Photobacterium), Bacteroidales (Bacteroidetes and Macellibacteroides) and Clostridiales (Lachnoclostridium). ConclusionsOur study indicates that U. rigida macroalgae can be supplemented at 10% inclusion levels in the diet of juvenile farmed Atlantic cod without any impact on fish condition or hindgut microbial community structure. We also conclude that 10% dietary inclusion of A. nodosum is not a suitable feed supplement in a farmed cod diet.

microbiology↗

bioRxiv2020

Programmable gene regulation for metabolic engineering using decoy transcription factor binding sites

Transcription factor decoy binding sites are short DNA sequences that can serve as "sponges" to titrate a transcription factor away from its natural binding site, therefore regulating gene expression. In this study, we harness decoy sites to develop synthetic transcription factor sponge systems to regulate gene expression for metabolic pathways in Escherichia coli. We show that transcription factor sponges can effectively regulate expression of native and heterologous genes. Tunability of the sponge can be engineered via changes in copy number or modifications to the DNA decoy site sequence. Using arginine biosynthesis as a showcase, we observe a 16-fold increase in arginine production when we introduce the sponge system to steer metabolic flux towards increased arginine biosynthesis, with negligible growth differences compared to the wild type strain. The sponge-based production strain shows high genetic stability; in contrast to a gene knock-out approach where mutations were common, we detected no mutations in the production system using the sponge-based strain. We further show that transcription factor sponges are amenable to multiplexed library screening by demonstrating enhanced tolerance to pinene with a combinatorial sponge library. Our study shows that transcription factor sponges are a powerful and compact tool for metabolic engineering.

bioengineering↗

bioRxiv2019

Vesicular stomatitis virus transcription is inhibited by TRIM69 in the interferon-induced antiviral state

Interferons (IFNs) induce the expression of many interferon stimulated genes (ISGs), many of which are responsible for the cellular antiviral state in which the replication of numerous viruses is blocked. How the majority of individual ISGs inhibit the replication of particular viruses is unknown. We conducted a loss-of-function screen to identify genes required for the activity of IFN against vesicular stomatitis virus, Indiana serotype (VSVIND), a prototype negative strand RNA virus. Our screen revealed that TRIM69, a member of tripartite motif family of proteins, is a VSVIND inhibitor. TRIM69 potently inhibited VSVIND replication through a previously undescribed transcriptional inhibition mechanism. Specifically, TRIM69 physically associates with the VSVIND phosphoprotein (P), requiring a specific peptide target sequence encoded therein. P is a cofactor for the viral polymerase, and is required for viral RNA synthesis as well as the assembly of replication compartments. By targeting P, TRIM69 inhibits pioneer transcription of the incoming virion-associated minus strand RNA, thereby preventing the synthesis of viral mRNAs, and consequently impedes all downstream events in the VSVIND replication cycle. Unlike some TRIM proteins, TRIM69 does not inhibit viral replication by inducing degradation of target viral proteins. Rather, higher-order TRIM69 multimerization is required for its antiviral activity, suggesting that TRIM69 functions by sequestration or anatomical disruption of the viral machinery required for VSVIND RNA synthesis.\n\nSIGNIFICANCE STATEMENTInterferons are important antiviral cytokines that work by inducing hundreds of host genes whose products inhibit replication of many viruses. While the antiviral activity of interferon has long been known, the identities and mechanisms of action of most interferon-induced antiviral proteins remain to be discovered. We identified gene products that are important for the antiviral activity of interferon against vesicular stomatitis virus (VSV) a model virus that whose genome consists a single RNA molecule with negative sense polarity. We found that a particular antiviral protein, TRIM69, functions by a previously undescribed molecular mechanism. Specifically, TRIM69 interacts with, and inhibits the function, of a particular phosphoprotein (P) component the viral transcription machinery, preventing the synthesis of viral messenger RNAs.

microbiology↗

bioRxiv2018

Human, Nonhuman Primate, and Bat Cells Are Broadly Susceptible to Tibrovirus Particle Cell Entry

In 2012, the genome of a novel rhabdovirus, Bas-Congo virus, was discovered in the acute-phase serum of a Congolese patient with presumed viral hemorrhagic fever. In the absence of a replicating virus isolate, fulfilling Kochs postulates to determine whether Bas-Congo virus is indeed a human virus and/or pathogen has been impossible. However, experiments with vesiculoviral particles pseudotyped with Bas-Congo glycoprotein suggested that Bas-Congo virus particles can enter cells from multiple animals, including humans. In 2015, genomes of two related viruses, Ekpoma virus 1 and Ekpoma virus 2, were detected in human sera in Nigeria. Isolates could not be obtained. Phylogenetic analyses led to the classification of Bas-Congo virus, Ekpoma virus 1, and Ekpoma virus 2 in the same genus, Tibrovirus, together with five biting midge-borne rhabdoviruses (i.e., Beatrice Hill virus, Bivens Arm virus, Coastal Plains virus, Sweetwater Branch virus, and Tibrogargan virus) not known to infect humans. Using individual recombinant vesiculoviruses expressing the glycoproteins of all eight known tibroviruses and more than 75 cell lines representing different animal species, we demonstrate that the glycoproteins of all tibroviruses can mediate vesiculovirus particle entry into human, bat, nonhuman primate, cotton rat, boa constrictor, and Asian tiger mosquito cells. Using four of five isolated authentic tibroviruses (i.e., Bivens Arm virus, Coastal Plains virus, Sweetwater Branch virus, and Tibrogargan virus), our experiments indicate that many cell types may be partially resistant to tibrovirus replication after virion cell entry. Consequently, experimental data solely obtained from experiments using tibrovirus surrogate systems (e.g., vesiculoviral pseudotypes, recombinant vesiculoviruses) cannot be used to predict whether Bas-Congo virus, or any other tibrovirus, infects humans.

microbiology↗

bioRxiv2018

Physicochemical amino acid properties better describe substitution rates in large populations

Substitutions between chemically distant amino acids are known to occur less frequently than those between more similar amino acids. This knowledge, however, is not reflected in most codon substitution models, which treat all non-synonymous changes as if they were equivalent in terms of impact on the protein. A variety of methods for integrating chemical distances into models have been proposed, with a common approach being to divide substitutions into radical or conservative categories. Nevertheless, it remains unclear whether the resulting models describe sequence evolution better than their simpler counterparts.\n\nWe propose a parametric codon model that distinguishes between radical and conservative substitutions, allowing us to assess if radical substitutions are preferentially removed by selection. Applying our new model to a range of phylogenomic data, we find differentiating between radical and conservative substitutions provides significantly better fit for large populations, but see no equivalent improvement for smaller populations. Comparing codon- and amino acid models using these same data shows that alignments from large populations tend to select phylogenetic models containing information about amino acid exchangeabilities, whereas the structure of the genetic code is more important for smaller populations.\n\nOur results suggest selection against radical substitutions is, on average, more pronounced in large populations than smaller ones. The reduced observable effect of selection in smaller populations may be due to stronger genetic drift making it more challenging to detect preferences. Our results imply an important connection between the life history of a phylogenetic group and the model that best describes its evolution.

evolutionary biology↗