Interferons (IFNs) were discovered as cytokines induced during and protecting from viral infection. They have been documented to play essential roles in numerous physiological processes beyond ...antiviral and antimicrobial defense, including immunomodulation, cell cycle regulation, cell survival, and cell differentiation. Recent data have also uncovered a potentially darker side to IFN, including roles in inflammatory diseases, such as autoimmunity and diabetes. IFN can have effects in the absence of acute infection, highlighting a physiologic role for constitutive IFN. Type I IFNs are constitutively produced at vanishingly low quantities and yet exert profound effects, mediated in part through modulation of signaling intermediates required for responses to diverse cytokines. We review evidence for a yin-yang of IFN function through its role in modulating crosstalk between multiple cytokines by both feedforward and feedback regulation of common signaling intermediates and postulate a homeostatic role for IFN through tonic signaling in the absence of acute infection.
Transcription induces a wave of DNA supercoiling, altering the binding affinity of RNA polymerases and reshaping the biochemical landscape of gene regulation. As supercoiling rapidly diffuses, ...transcription dynamically reshapes the regulation of proximal genes, forming a complex feedback loop. However, a theoretical framework is needed to integrate biophysical regulation with biochemical transcriptional regulation. To investigate the role of supercoiling-mediated feedback within multi-gene systems, we model transcriptional regulation under the influence of supercoiling-mediated polymerase dynamics, allowing us to identify patterns of expression that result from physical inter-gene coupling. We find that gene syntax—the relative ordering and orientation of genes—defines the expression profiles, variance, burst dynamics, and inter-gene correlation of two-gene systems. Furthermore, supercoiling can enhance or weaken biochemical regulation. Our results suggest that supercoiling couples behavior between neighboring genes, providing a regulatory mechanism that tunes transcriptional variance in engineered gene networks and explains the behavior of co-localized native circuits.
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•Supercoiling dynamics confer rapid, tunable coupling between adjacent genes•Syntax—the relative order and orientation of genes—alters expression levels•Supercoiling-dependent feedback tunes transcriptional variance and bursting•Supercoiling coordinates the dynamics of transcriptional networks and gene circuits
Supercoiling-mediated feedback couples the transcription of proximal genes. Here, Johnstone and Galloway provide a framework for integrating biochemical gene regulation with the biophysical effects of DNA supercoiling. This unified model provides design principles for improving the performance of gene networks, developing novel regulatory functions, and accessing previously inaccessible regulatory dynamics.
When vertebrate physiological ecologists use the terms ‘stress’ or ‘physiological stress’, they typically mean the level of hypothalamus–pituitary–adrenal (HPA-) axis activation. Measurements of ...stress hormone concentrations (e.g. glucocorticoids in blood, urine or faeces), leukocytes (e.g. the neutrophil–lymphocyte ratio or heterophil equivalent), immunofunction (e.g. innate, cell-mediated or humoral immunity measures) and regenerative anaemia (e.g. mean erythrocyte volume and red blood cell distribution width) have all been used to estimate HPA-axis activity in free-living vertebrates. Stress metrics have provided insights into aspects of autecology or population regulation that could not have been easily obtained using other indices of population wellbeing, such as body condition or relative abundance. However, short- and long-term stress (often problematically termed acute and chronic stress, respectively) can interact in unpredictable ways. When animals experience trapping and handling stress before blood, faeces and/or urine is sampled, the interaction of short- and long-term stress can confound interpretation of the data, a fact not always acknowledged in studies of stress in free-living vertebrates. This review examines how stress metrics can be confounded when estimates of HPA-axis activation are collected for free-living vertebrates and outlines some approaches that can be used to help circumvent the influence of potentially confounding factors.
Autocrine priming of cells by small quantities of constitutively produced type I interferon (IFN) is a well-known phenomenon. In the absence of type I IFN priming, cells display attenuated responses ...to other cytokines, such as anti-viral protection in response to IFNgamma. This phenomenon was proposed to be because IFNalpha/beta receptor1 (IFNAR1) is a component of the IFNgamma receptor (IFNGR), but our new data are more consistent with a previously proposed model indicating that regulated expression of STAT1 may also play a critical role in the priming process. Initially, we noticed that DNA binding activity of STAT1 was attenuated in c-Jun(-/-) fibroblasts because they expressed lower levels of STAT1 than wild-type cells. However, expression of STAT1 was rescued by culturing c-Jun(-/-) fibroblasts in media conditioned by wild-type fibroblasts suggesting they secreted a STAT1-inducing factor. The STAT1-inducing factor in fibroblast-conditioned media was IFNbeta, as it was inhibited by antibodies to IFNAR1, or when IFNbeta expression was knocked down in wild-type cells. IFNAR1(-/-) fibroblasts, which cannot respond to this priming, also expressed reduced levels of STAT1, which correlated with their poor responses to IFNgamma. The lack of priming in IFNAR1(-/-) fibroblasts was compensated by over-expression of STAT1, which rescued molecular responses to IFNgamma and restored the ability of IFNgamma to induce protective anti-viral immunity. This study provides a comprehensive description of the molecular events involved in priming by type I IFN. Adding to the previous working model that proposed an interaction between type I and II IFN receptors, our work and that of others demonstrates that type I IFN primes IFNgamma-mediated immune responses by regulating expression of STAT1. This may also explain how type I IFN can additionally prime cells to respond to a range of other cytokines that use STAT1 (e.g., IL-6, M-CSF, IL-10) and suggests a potential mechanism for the changing levels of STAT1 expression observed during viral infection.
ABSTRACT
We review evidence for and against the use of erythrocyte indicators of health status and condition, parasite infection level and physiological stress in free‐living vertebrates. The use of ...indicators that are measured directly from the blood, such as haemoglobin concentration, haematocrit and erythrocyte sedimentation rate, and parameters that are calculated from multiple measured metrics, such as mean cell volume, mean cell haemoglobin content or mean cell haemoglobin concentration is evaluated. The evidence for or against the use of any given metric is equivocal when the relevant research is considered in total, although there is sometimes strong support for using a particular metric in a particular taxon. Possibly the usefulness of these metrics is taxon, environment or condition specific. Alternatively, in an uncontrolled environment where multiple factors are influencing a metric, its response to environmental change will sometimes, but not always, be predictable. We suggest that (i) researchers should validate a metricfres utility before use, (ii) multiple metrics should be used to construct an overall erythrocyte profile for an individual or population, (iii) there is a need for researchers to compile reference ranges for free‐living species, and (iv) some metrics which are useful under controlled, clinical conditions may not have the same utility or applicability for free‐living vertebrates. Erythrocyte metrics provide useful information about health and condition that can be meaningfully interpreted in free‐living vertebrates, but their use requires careful forethought about confounding factors.
•Fluoxetine is one of the most widely prescribed psychoactive drugs in the world.•Short-term exposure altered the anti-predator behavior of freshwater fish.•Exposure to environmentally relevant ...levels of fluoxetine caused behavioural shifts.•Effects of fluoxetine exposure were sex-specific.
Chemical pollution from pharmaceuticals is increasingly recognised as a major threat to aquatic communities. One compound of great concern is fluoxetine, which is one of the most widely prescribed psychoactive drugs in the world and frequently detected in the environment. The aim of this study was to investigate the effects of 28-d fluoxetine exposure at two environmentally relevant levels (measured concentrations: 4ng/L and 16ng/L) on anti-predator behaviour in wild guppies (Poecilia reticulata). This was achieved by subjecting fluoxetine-exposed and unexposed guppies to a simulated bird strike and recording their subsequent behavioural responses. We found that exposure to fluoxetine affected the anti-predator behaviour of guppies, with exposed fish remaining stationary for longer (i.e. ‘freezing’ behaviour) after the simulated strike and also spending more time under plant cover. By contrast, control fish were significantly more active and explored the tank more, as indicated by the distance covered per minute over the period fish spent swimming. Furthermore, behavioural shifts were sex-dependent, with evidence of a non-monotonic dose-response among the fluoxetine-exposed fish. This is one of the first studies to show that exposure to environmentally relevant concentrations of fluoxetine can alter the anti-predator behaviour of adult fish. In addition to the obvious repercussions for survival, impaired anti-predator behaviour can have direct impacts on fitness and influence the overall population dynamics of species.
•We demonstrate the use of conditional inference trees in conservation biology.•We use this method to examine environmental affects on native small mammals.•We compare the relative importance of ...habitat loss, fragmentation and degradation.•Habitat loss is the most important of these drivers at a landscape scale.•Habitat loss is an understudied landscape-level driver of species decline.
Anthropogenic habitat loss, fragmentation and degradation often co-occur in a landscape and their relative influence on a native animals’ health and survival can be difficult to determine. We examined the influence of these environmental variables on the estimated relative abundance of some small mammal species in a large area (∼2500km2) of southeastern Australia. Using the agile antechinus (Antechinus agilis) as a model, we also examined the association between these variables and three population performance indices, mass-size residuals (MSR; indexing fat reserves), the neutrophil/lymphocyte ratio (N:L; indexing physiological stress) and red blood cell counts (RBC; indexing regenerative anaemia). Study sites were in either highly disturbed and fragmented, or relatively undisturbed, continuous Eucalyptus forest.
We generated conditional inference tree statistical models to identify the relative importance of up to 49 ecological variables in explaining variation in small mammal abundance and performance indices. Habitat loss was important in explaining small mammal abundance, as were the abundances of the same species in neighbouring study sites. The models also suggested that the habitat area required to support a ‘healthy’ population was greater in the larger species examined. Autocovariates of neighbouring site same-species abundances and habitat fragmentation were the next most important influences on small mammal relative abundance, implying that metapopulations may be important for population persistence, especially in bush rats (Rattus fuscipes). Habitat degradation, reflected in structural and floristic features, was less important, but explained some variance in relative abundances. For agile antechinus populations, time of year, degree of forest fragmentation and extent of native tree cover were important in explaining performance indices. Results indicated that habitat reduction per se was a significant threatening process for small mammals. Habitat loss requires at least the same research attention as that currently devoted to anthropogenic habitat fragmentation and degradation.
With the ability to resist biodegradation and exert therapeutic effects at low concentrations, pharmaceutical contaminants have become environmental stressors for wildlife. One such contaminant is ...the anxiolytic oxazepam, a psychoactive pharmaceutical that is frequently detected in surface waters globally. Despite growing interest in understanding how wildlife respond to anxiolytics, synergistic effects of pharmaceuticals and other abiotic (e.g. temperature) and biotic (e.g. predation risk) stressors remain unclear. Here, using a multi-stressor approach, we investigated effects of 7-day oxazepam exposure (6.5 μg/L) on anxiety-related behaviours in juvenile European perch (Perca fluviatilis). The multi-stressor approach was achieved by exposing perch to oxazepam at two temperatures (10 °C and 18 °C), and at two predation risk regimes—generated using chemical cues from the northern pike (Esox lucius). Our exposures resulted in a successful uptake of the drug from the water, i.e., oxazepam was measured in perch muscle tissue at 50 ± 17 ng/g (mean ± SD). We found significant oxazepam-induced effects on boldness, with 76.7% of the treated fish entering the white background (i.e. ‘exposed’ area where exposure to presumed risks are higher) within the first 5 min, compared to 66.6% of the control fish. We also found a significant effect of temperature on total time spent freezing (i.e. staying motionless). Specifically, fish in the low temperature treatments (oxazepam, predation) froze for longer than fish in high temperatures. Our multi-stressor study is the first to uncover how anxiety-related behaviours in wild juvenile fish are altered by changes in water temperature and perceived predation risk. Importantly, our findings highlight the need to focus on multiple stressors to improve understanding of how organisms not only survive, but adapt to, human-induced environmental change.
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•Juvenile European perch were exposed to oxazepam at two temperatures and under two predation risk regimes.•Exposure altered anxiety-related behaviour and boldness of fish.•Fish in the low temperature treatments froze for longer. Predator cue treatment affected perch risk-taking behaviour.•We found no interaction effects of oxazepam and temperature on the studied behaviours.•Highlights ecologically important sub-lethal effects of pharmaceutical contamination.
The capacity of pharmaceutical pollution to alter behaviour in wildlife is of increasing environmental concern. A major pathway of these pollutants into the environment is the treatment of livestock ...with hormonal growth promotants (HGPs), which are highly potent veterinary pharmaceuticals that enter aquatic ecosystems via effluent runoff. Hormonal growth promotants are designed to exert biological effects at low doses, can act on physiological pathways that are evolutionarily conserved across taxa, and have been detected in ecosystems worldwide. However, despite being shown to alter key fitness-related processes (e.g., development, reproduction) in various non-target species, relatively little is known about the potential for HGPs to alter ecologically important behaviours, especially across multiple contexts. Here, we investigated the effects of exposure to a field-realistic level of the androgenic HGP metabolite 17β-trenbolone—an endocrine-disrupting chemical that has repeatedly been detected in freshwater systems—on a suite of ecologically important behaviours in wild-caught female eastern mosquitofish (Gambusia holbrooki). First, we found that 17β-trenbolone-exposed fish were more active and exploratory in a novel environment (i.e., maze arena), while boldness (i.e., refuge use) was not significantly affected. Second, when tested for sociability, exposed fish spent less time in close proximity to a shoal of stimulus (i.e., unexposed) conspecific females and were, again, found to be more active. Third, when assayed for foraging behaviour, exposed fish were faster to reach a foraging zone containing prey items (chironomid larvae), quicker to commence feeding, spent more time foraging, and consumed a greater number of prey items, although the effect of exposure on certain foraging behaviours was dependent on fish size. Taken together, these findings highlight the potential for exposure to sub-lethal levels of veterinary pharmaceuticals to alter sensitive behavioural processes in wildlife across multiple contexts, with potential ecological and evolutionary implications for exposed populations.
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•Use of growth-promoting veterinary pharmaceuticals is widespread in global beef production.•The androgenic growth promotant metabolite 17β-trenbolone (17β-TB) is present in aquatic systems.•Adult female mosquitofish were exposed to 17β-TB at an environmentally realistic level.•Exposed females were more active and exploratory, less social, showed increased foraging behaviour.•Androgenic contaminant disrupts key fitness-related behaviours in female fish.
The androgenic endocrine disruptor 17β-trenbolone alters behaviour in female fish across multiple fitness-related contexts.
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