Community based complex interventions to sustain independence in older people: systematic review and network meta-analysis.

OBJECTIVE: To synthesise evidence of the effectiveness of community based complex interventions, grouped according to their intervention components, to sustain independence for older people. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Medline, Embase, CINAHL, PsycINFO, CENTRAL, clinicaltrials.gov, and International Clinical Trials Registry Platform from inception to 9 August 2021 and reference lists of included studies. ELIGIBILITY CRITERIA: Randomised controlled trials or cluster randomised controlled trials with ≥24 weeks' follow-up studying community based complex interventions for sustaining independence in older people (mean age ≥65 years) living at home, with usual care, placebo, or another complex intervention as comparators. MAIN OUTCOMES: Living at home, activities of daily living (personal/instrumental), care home placement, and service/economic outcomes at 12 months. DATA SYNTHESIS: Interventions were grouped according to a specifically developed typology. Random effects network meta-analysis estimated comparative effects; Cochrane's revised tool (RoB 2) structured risk of bias assessment. Grading of recommendations assessment, development and evaluation (GRADE) network meta-analysis structured certainty assessment. RESULTS: The review included 129 studies (74 946 participants). Nineteen intervention components, including "multifactorial action from individualised care planning" (a process of multidomain assessment and management leading to tailored actions), were identified in 63 combinations. For living at home, compared with no intervention/placebo, evidence favoured multifactorial action from individualised care planning including medication review and regular follow-ups (routine review) (odds ratio 1.22, 95% confidence interval 0.93 to 1.59; moderate certainty); multifactorial action from individualised care planning including medication review without regular follow-ups (2.55, 0.61 to 10.60; low certainty); combined cognitive training, medication review, nutritional support, and exercise (1.93, 0.79 to 4.77; low certainty); and combined activities of daily living training, nutritional support, and exercise (1.79, 0.67 to 4.76; low certainty). Risk screening or the addition of education and self-management strategies to multifactorial action from individualised care planning and routine review with medication review may reduce odds of living at home. For instrumental activities of daily living, evidence favoured multifactorial action from individualised care planning and routine review with medication review (standardised mean difference 0.11, 95% confidence interval 0.00 to 0.21; moderate certainty). Two interventions may reduce instrumental activities of daily living: combined activities of daily living training, aids, and exercise; and combined activities of daily living training, aids, education, exercise, and multifactorial action from individualised care planning and routine review with medication review and self-management strategies. For personal activities of daily living, evidence favoured combined exercise, multifactorial action from individualised care planning, and routine review with medication review and self-management strategies (0.16, -0.51 to 0.82; low certainty). For homecare recipients, evidence favoured addition of multifactorial action from individualised care planning and routine review with medication review (0.60, 0.32 to 0.88; low certainty). High risk of bias and imprecise estimates meant that most evidence was low or very low certainty. Few studies contributed to each comparison, impeding evaluation of inconsistency and frailty. CONCLUSIONS: The intervention most likely to sustain independence is individualised care planning including medicines optimisation and regular follow-up reviews resulting in multifactorial action. Homecare recipients may particularly benefit from this intervention. Unexpectedly, some combinations may reduce independence. Further research is needed to investigate which combinations of interventions work best for different participants and contexts. REGISTRATION: PROSPERO CRD42019162195.

Genomic evidence for domestication selection in three hatchery populations of Chinook salmon, Oncorhynchus tshawytscha.

Fish hatcheries are widely used to enhance fisheries and supplement declining wild populations. However, substantial evidence suggests that hatchery fish are subject to differential selection pressures compared to their wild counterparts. Domestication selection, or adaptation to the hatchery environment, poses a risk to wild populations if traits specific to success in the hatchery environment have a genetic component and there is subsequent introgression between hatchery and wild fish. Few studies have investigated domestication selection in hatcheries on a genomic level, and even fewer have done so in parallel across multiple hatchery-wild population pairs. In this study, we used low-coverage whole-genome sequencing to investigate signals of domestication selection in three separate hatchery populations of Chinook salmon, Oncorhynchus tshawytscha, after approximately seven generations of divergence from their corresponding wild progenitor populations. We sequenced 192 individuals from populations across Southeast Alaska and estimated genotype likelihoods at over six million loci. We discovered a total of 14 outlier peaks displaying high genetic differentiation (F ST) between hatchery-wild pairs, although no peaks were shared across the three comparisons. Peaks were small (53 kb on average) and often displayed elevated absolute genetic divergence (D xy) and linkage disequilibrium, suggesting some level of domestication selection has occurred. Our study provides evidence that domestication selection can lead to genetic differences between hatchery and wild populations in only a few generations. Additionally, our data suggest that population-specific adaptation to hatchery environments likely occurs through different genetic pathways, even for populations with similar standing genetic variation. These results highlight the need to collect paired genotype-phenotype data to understand how domestication may be affecting fitness and to identify potential management practices that may mitigate genetic risks despite multiple pathways of domestication.

Effects of testosterone on urogenital tract morphology and androgen receptor expression in immature Eastern Fence lizards (Sceloporus undulatus).

In non-avian reptiles, the onset of sexual dimorphism of the major structures of the urogenital tract varies temporally relative to gonadal differentiation, more so than in other amniote lineages. In the current study, we used tonic-release implants to investigate the effects of exogenous testosterone (T) on postnatal development of the urogenital tract in juvenile Eastern Fence Lizards (Sceloporus undulatus) to better understand the mechanisms underlying the ontogeny of sexual differentiation in reptiles. We examined gonads, mesonephric kidneys and ducts (male reproductive tract primordia), paramesonephric ducts (oviduct primordia), sexual segments of the kidneys (SSKs), and hemiphalluses to determine which structures were sexually dimorphic independent of T treatment and which structures exhibited sexually dimorphic responses to T. To better understand tissue-level responsiveness to T treatment, we also characterized androgen receptor (AR) expression by immunohistochemistry. At approximately 4 months after hatching in control animals, gonads were well differentiated but quiescent; paramesonephric ducts had fully degenerated in males; mesonephric kidneys, mesonephric ducts, and SSKs remained sexually undifferentiated; and hemiphalluses could not be everted in either sex. Exogenous T caused enlargement, regionalization, and secretory activity of the mesonephric ducts and SSKs in both sexes; enlargement and regionalization of the oviducts in females; and enlargement of male hemipenes. The most responsive tissues exhibited moderate but diffuse staining for AR in control lizards and intense nuclear staining in T-treated lizards, suggestive of autoregulation of AR. The similarity between sexes in the responsiveness of the mesonephric ducts and SSK to T indicates an absence of sexually dimorphic organizational effects in these structures prior to treatment, which was initiated approximately 2 months after hatching. In contrast, the sex-specific responses in oviducts and hemipenes indicate that significant organization and/or differentiation had taken place prior to treatment.

The Role of Dorsal Raphe Nucleus Serotonergic Systems in Emotional Learning and Memory in Male BALB/c Mice.

Selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacological treatment for a variety of anxiety-, trauma- and stressor-related disorders. Although they are efficacious, therapeutic improvements require several weeks of treatment and are often associated with an initial exacerbation of symptoms. The dorsal raphe nucleus (DR) has been proposed as an important target for the modulation of emotional responses and the therapeutic effects of SSRIs. Using a fear-conditioning paradigm we aimed to understand how SSRIs affect emotional learning and memory, and their effects on serotonergic circuitry. Adult male BALB/c mice were treated with vehicle (n = 16) or the SSRI fluoxetine (18 mg/kg/d) acutely (n = 16), or chronically (21d, n = 16), prior to fear conditioning. Treatment was stopped, and half of the mice (n = 8/treatment group) were exposed to cued fear memory recall 72 h later. Activation of DR serotonergic neurons during fear conditioning (Experiment 1) or fear memory recall (Experiment 2), was measured using dual-label immunohistochemistry for Tph2 and c-Fos. Acute and chronic fluoxetine treatment reduced associative fear learning without affecting memory recall and had opposite effects on anxiety-like behaviour. Acute fluoxetine decreased serotonergic activity in the DR, while chronic treatment led to serotonergic activity that was indistinguishable from that of control levels in DRD and DRV subpopulations. Chronic fluoxetine facilitated fear extinction, which was associated with rostral DRD inhibition. These findings provide further evidence that SSRIs can alter aspects of learning and memory processes and are consistent with a role for discrete populations of DR serotonergic neurons in regulating fear- and anxiety-related behaviours.

Association between dietary factors, symptoms, and psychological factors in adults with dyspepsia: A cross-sectional study.

BACKGROUND: Evidence-based dietary management approaches for symptoms of dyspepsia are lacking. This study aimed to compare dietary factors, symptoms, quality of life (QOL) and salivary cortisol in dyspepsia participants and healthy controls. METHODS: A cross-sectional survey was completed by adults with dyspepsia (n = 121) meeting Rome IV criteria and healthy controls (n = 52). Outcome measures included self-reported questionnaires about dietary habits, triggers, restrictions, dietary management approaches, nutritional intake, psychological variables, QOL, gastrointestinal symptoms, and optional cortisol awakening response (CAR) via saliva samples. Data were analyzed using Chi-square or Mann-Whitney U. Cortisol awakening response data was analyzed using moderated regression controlling for age, gender and distress. KEY RESULTS: Fermentable carbohydrates (FODMAPs) (55%) were the most reported trigger in adults with dyspepsia. The dyspepsia group (88%) followed special diets more than controls (47%; p < 0.001), with a low FODMAP diet being most common (69%). The dyspepsia group consumed less fiber (p = 0.014), calcium (p = 0.015), and total FODMAPs (p < 0.001) than controls. There was a greater prevalence of comorbid anxiety (41%) and depression (31%) in dyspepsia compared to controls (15% and 12%, respectively, p < 0.001 and p = 0.006). The dyspepsia group had poorer QOL and greater gastrointestinal symptom severity than controls (p < 0.001). There was a negative association between anxiety and CAR (p = 0.001) in dyspepsia but not in controls. CONCLUSIONS & INFERENCES: Adults with dyspepsia follow special diets more than controls and perceive FODMAPs as a key dietary trigger. These findings highlight the importance of monitoring nutritional adequacy and QOL, and emphasize mechanisms of depleted stress response in dyspepsia, warranting further exploration.

Practical hardware for evolvable robots.

The evolutionary robotics field offers the possibility of autonomously generating robots that are adapted to desired tasks by iteratively optimising across successive generations of robots with varying configurations until a high-performing candidate is found. The prohibitive time and cost of actually building this many robots means that most evolutionary robotics work is conducted in simulation, but to apply evolved robots to real-world problems, they must be implemented in hardware, which brings new challenges. This paper explores in detail the design of an example system for realising diverse evolved robot bodies, and specifically how this interacts with the evolutionary process. We discover that every aspect of the hardware implementation introduces constraints that change the evolutionary space, and exploring this interplay between hardware constraints and evolution is the key contribution of this paper. In simulation, any robot that can be defined by a suitable genetic representation can be implemented and evaluated, but in hardware, real-world limitations like manufacturing/assembly constraints and electrical power delivery mean that many of these robots cannot be built, or will malfunction in operation. This presents the novel challenge of how to constrain an evolutionary process within the space of evolvable phenotypes to only those regions that are practically feasible: the viable phenotype space. Methods of phenotype filtering and repair were introduced to address this, and found to degrade the diversity of the robot population and impede traversal of the exploration space. Furthermore, the degrees of freedom permitted by the hardware constraints were found to be poorly matched to the types of morphological variation that would be the most useful in the target environment. Consequently, the ability of the evolutionary process to generate robots with effective adaptations was greatly reduced. The conclusions from this are twofold. 1) Designing a hardware platform for evolving robots requires different thinking, in which all design decisions should be made with reference to their impact on the viable phenotype space. 2) It is insufficient to just evolve robots in simulation without detailed consideration of how they will be implemented in hardware, because the hardware constraints have a profound impact on the evolutionary space.

Species differences in hormonally mediated gene expression underlie the evolutionary loss of sexually dimorphic coloration in Sceloporus lizards.

Phenotypic sexual dimorphism often involves the hormonal regulation of sex-biased expression for underlying genes. However, it is generally unknown whether the evolution of hormonally mediated sexual dimorphism occurs through upstream changes in tissue sensitivity to hormone signals, downstream changes in responsiveness of target genes, or both. Here, we use comparative transcriptomics to explore these possibilities in 2 species of Sceloporus lizards exhibiting different patterns of sexual dichromatism. Sexually dimorphic S. undulatus develops blue and black ventral coloration in response to testosterone, while sexually monomorphic S. virgatus does not, despite exhibiting similar sex differences in circulating testosterone levels. We administered testosterone implants to juveniles of each species and used RNAseq to quantify gene expression in ventral skin. Transcriptome-wide responses to testosterone were stronger in S. undulatus than in S. virgatus, suggesting species differences in tissue sensitivity to this hormone signal. Species differences in the expression of genes for androgen metabolism and sex hormone-binding globulin were consistent with this idea, but expression of the androgen receptor gene was higher in S. virgatus, complicating this interpretation. Downstream of androgen signaling, we found clear species differences in hormonal responsiveness of genes related to melanin synthesis, which were upregulated by testosterone in S. undulatus, but not in S. virgatus. Collectively, our results indicate that hormonal regulation of melanin synthesis pathways contributes to the development of sexual dimorphism in S. undulatus, and that changes in the hormonal responsiveness of these genes in S. virgatus contribute to the evolutionary loss of ventral coloration.

Comparative genomics of rainbow trout (Oncorhynchus mykiss): Is the genetic architecture of migratory behavior conserved among populations?

Rainbow trout (Oncorhynchus mykiss) are a partially migratory species wherein some individuals undergo long-distance anadromous migrations, and others stay as residents in their native freshwater streams. The decision to migrate is known to be highly heritable, and yet, the underlying genes and alleles associated with migration are not fully characterized. Here we used a pooled approach of whole-genome sequence data from migratory and resident trout of two native populations-Sashin Creek, Alaska and Little Sheep Creek, Oregon-to obtain a genome-wide perspective of the genetic architecture of resident and migratory life history. We calculated estimates of genetic differentiation, genetic diversity, and selection between the two phenotypes to locate regions of interest and then compared these associations between populations. We identified numerous genes and alleles associated with life history development in the Sashin Creek population with a notable area on chromosome 8 that may play a critical role in the development of the migratory phenotype. However, very few alleles appeared to be associated with life history development in the Little Sheep Creek system, suggesting population-specific genetic effects are likely important in the development of anadromy. Our results indicate that a migratory life history is not controlled by a singular gene or region but supports the idea that there are many independent ways for a migratory phenotype to emerge in a population. Therefore, conserving and promoting genetic diversity in migratory individuals is paramount to conserving these populations. Ultimately, our data add to a growing body of literature that suggests that population-specific genetic effects, likely mediated through environmental variation, contribute to life history development in rainbow trout.

Genomics reveal the origins and current structure of a genetically depauperate freshwater species in its introduced Alaskan range.

Invasive species are a major threat to global biodiversity, yet also represent large-scale unplanned ecological and evolutionary experiments to address fundamental questions in nature. Here we analyzed both native and invasive populations of predatory northern pike (Esox lucius) to characterize landscape genetic variation, determine the most likely origins of introduced populations, and investigate a presumably postglacial population from Southeast Alaska of unclear provenance. Using a set of 4329 SNPs from 351 individual Alaskan northern pike representing the most widespread geographic sampling to date, our results confirm low levels of genetic diversity in native populations (average 𝝅 of 3.18 × 10-4) and even less in invasive populations (average 𝝅 of 2.68 × 10-4) consistent with bottleneck effects. Our analyses indicate that invasive northern pike likely came from multiple introductions from different native Alaskan populations and subsequently dispersed from original introduction sites. At the broadest scale, invasive populations appear to have been founded from two distinct regions of Alaska, indicative of two independent introduction events. Genetic admixture resulting from introductions from multiple source populations may have mitigated the negative effects associated with genetic bottlenecks in this species with naturally low levels of genetic diversity. Genomic signatures strongly suggest an excess of rare, population-specific alleles, pointing to a small number of founding individuals in both native and introduced populations consistent with a species' life history of limited dispersal and gene flow. Lastly, the results strongly suggest that a small isolated population of pike, located in Southeast Alaska, is native in origin rather than stemming from a contemporary introduction event. Although theory predicts that lack of genetic variation may limit colonization success of novel environments, we detected no evidence that a lack of standing variation limited the success of this genetically depauperate apex predator.

A Systematic Review and Revised Meta-analysis of the Effort-Reward Imbalance Model of Workplace Stress and Hypothalamic-Pituitary-Adrenal Axis Measures of Stress.

OBJECTIVE: Despite considerable research in the past 20 years into associations between the effort-reward imbalance (ERI) model and various health outcomes, the mechanisms responsible for the association remain unclear. Our meta-analysis assessed the associations of ERI and overcommitment (OC) in the workplace with measures from the hypothalamic-pituitary-adrenal (HPA) axis. METHODS: Electronic databases were searched with the phrase "effort * reward * imbalance," which yielded 319 studies leading to 56 full-text studies being screened. Thirty-two studies within 14 articles met the inclusion criteria and were meta-analyzed using mixed- and random-effects models. RESULTS: Greater ERI was associated with increased HPA axis activity (r = 0.05, p = .02, k = 14, n = 2461). The cortisol waking concentrations (r = 0.11, p = .02, k = 6, n = 493) were the only subgroup associated with ERI. Meta-regression revealed that studies that contained more men had stronger ERI to HPA marker associations. When all HPA markers were considered collectively, OC was not associated with greater HPA axis activity (r = 0.01, p = .70, k = 10, n = 1684), with only cortisol (pm) associated with OC (r = -0.24, p = .02, k = 2, n = 95). CONCLUSIONS: ERI and OC were associated with HPA responsivity. Although the cortisol waking concentrations and not the CAR were associated with ERI, this may be due to heterogeneity in the experience of stress between studies. Future studies should consider the concurrent assessment of burnout to better assist the interpretation of ERI with HPA responsivity.

DOMINO: Domain-aware loss for deep learning calibration.

Deep learning has achieved the state-of-the-art performance across medical imaging tasks; however, model calibration is often not considered. Uncalibrated models are potentially dangerous in high-risk applications since the user does not know when they will fail. Therefore, this paper proposes a novel domain-aware loss function to calibrate deep learning models. The proposed loss function applies a class-wise penalty based on the similarity between classes within a given target domain. Thus, the approach improves the calibration while also ensuring that the model makes less risky errors even when incorrect. The code for this software is available at https://github.com/lab-smile/DOMINO.

Clinical and Blood Biomarker Trajectories after Concussion: New Insights from a Longitudinal Pilot Study of Professional Flat-Track Jockeys.

There is a recognized need for objective tools for detecting and tracking clinical and neuropathological recovery after sports-related concussion (SRC). Although computerized neurocognitive testing has been shown to be sensitive to cognitive deficits after SRC, and some blood biomarkers have shown promise as indicators of axonal and glial damage, the potential utility of these measures in isolation and combination for assisting SRC diagnosis and tracking recovery is not well understood. To provide new insights, we conducted a prospective study of 64 male and female professional flat-track jockeys (49 non-SRC, 15 SRC), with each jockey undergoing symptom evaluation, cognitive testing using the CogSport battery, and serum biomarker quantification of glial fibrillary acidic protein (GFAP), tau, and neurofilament light (NfL) using a Simoa HD-X Analyzer. Measures were performed at baseline (i.e., pre-injury), and 2 and 7 days and 1 and 12 months after SRC. Symptoms were most pronounced at 2 days and had largely resolved by either 7 days or 1 month. CogSport testing at 2 days revealed cognitive impairments relative to both non-concussed peers and their own pre-injury baselines, with SRC classification utility found at 2 days, and to a slightly lesser extent, at 7 days. Relatively prolonged changes in serum NfL were observed, with elevated levels and classification utility persisting beyond the resolution of SRC symptoms and cognitive deficits. Finally, SRC classification performance throughout the 1st month after SRC was optimized through the combination of cognitive testing and serum biomarkers. Considered together, these findings provide further evidence for a role of computerized cognitive testing and fluid biomarkers of neuropathology as objective measures to assist in the identification of SRC and the monitoring of clinical and neuropathological recovery.

Engagement in research during specialist geriatric medicine training: results of a national trainee survey.

INTRODUCTION: Meaningful ageing research across the UK is dependent on a network of engaged geriatricians. The research in geriatric specialty training (RGST) survey aimed to establish current research opportunities available to geriatric medicine specialty trainees in the UK. METHODS: The RGST survey was disseminated to UK higher specialist trainees in geriatric medicine in 2019 via the Geriatric Medicine Research Collaborative network. RESULTS: Among the 36.9% (192/521) of respondents, 44% (83/188) reported previous research involvement and 7% (n=8) held a PhD or MD. Of the respondents with no research experience to date, 59.0% (n=49) reported a desire to undertake a period of research. One-third (31%) of geriatric registrars surveyed felt that they had gained sufficient research experience during their training. Perceived encouragement and support to undertake research was low (30.7%). Enablers and barriers to research engagement were identified. CONCLUSION: Research opportunity and engagement in geriatric medicine training is lacking. This could jeopardise the future workforce of research-active geriatricians in the UK and limit patient access to emerging research and innovation. Interventions to promote research engagement among geriatric medicine trainees are needed to facilitate integration of research into routine clinical practice to improve the health and care of older people.

Transcriptional networks underlying a primary ovarian insufficiency disorder in alligators naturally exposed to EDCs.

Interactions between the endocrine system and environmental contaminants are responsible for impairing reproductive development and function. Despite the taxonomic diversity of affected species and attendant complexity inherent to natural systems, the underlying signaling pathways and cellular consequences are mostly studied in lab models. To resolve the genetic and endocrine pathways that mediate affected ovarian function in organisms exposed to endocrine disrupting contaminants in their natural environments, we assessed broad-scale transcriptional and steroidogenic responses to exogenous gonadotropin stimulation in juvenile alligators (Alligator missippiensis) originating from a lake with well-documented pollution (Lake Apopka, FL) and a nearby reference site (Lake Woodruff, FL). We found that individuals from Lake Apopka are characterized by hyperandrogenism and display hyper-sensitive transcriptional responses to gonadotropin stimulation when compared to individuals from Lake Woodruff. Site-specific transcriptomic divergence appears to be driven by wholly distinct subsets of transcriptional regulators, indicating alterations to fundamental genetic pathways governing ovarian function. Consistent with broad-scale transcriptional differences, ovaries of Lake Apopka alligators displayed impediments to folliculogenesis, with larger germinal beds and decreased numbers of late-stage follicles. After resolving the ovarian transcriptome into clusters of co-expressed genes, most site-associated modules were correlated to ovarian follicule phenotypes across individuals. However, expression of two site-specific clusters were independent of ovarian cellular architecture and are hypothesized to represent alterations to cell-autonomous transcriptional programs. Collectively, our findings provide high resolution mapping of transcriptional patterns to specific reproductive function and advance our mechanistic understanding regarding impaired reproductive health in an established model of environmental endocrine disruption.

Evolution of hormone-phenotype couplings and hormone-genome interactions.

When selection favors a new relationship between a cue and a hormonally mediated response, adaptation can proceed by altering the hormonal signal that is produced or by altering the phenotypic response to the hormonal signal. The field of evolutionary endocrinology has made considerable progress toward understanding the evolution of hormonal signals, but we know much less about the evolution of hormone-phenotype couplings, particularly at the hormone-genome interface. We briefly review and classify the mechanisms through which these hormone-phenotype couplings likely evolve, using androgens and their receptors and genomic response elements to illustrate our view. We then present two empirical studies of hormone-phenotype couplings, one rooted in evolutionary quantitative genetics and another in comparative transcriptomics, each focused on the regulation of sexually dimorphic phenotypes by testosterone (T) in the brown anole lizard (Anolis sagrei). First, we illustrate the potential for hormone-phenotype couplings to evolve by showing that coloration of the dewlap (an ornament used in behavioral displays) exhibits significant heritability in its responsiveness to T, implying that anoles harbor genetic variance in the architecture of hormonal pleiotropy. Second, we combine T manipulations with analyses of the liver transcriptome to ask whether and how statistical methods for characterizing modules of co-expressed genes and in silico techniques for identifying androgen response elements (AREs) can improve our understanding of hormone-genome interactions. We conclude by emphasizing important avenues for future work at the hormone-genome interface, particularly those conducted in a comparative evolutionary framework.

Novel Antidepressant-Like Properties of the Iron Chelator Deferiprone in a Mouse Model of Depression.

Depressed individuals who carry the short allele for the serotonin-transporter-linked promotor region of the gene are more vulnerable to stress and have reduced response to first-line antidepressants such as selective serotonin reuptake inhibitors. Since depression severity has been reported to correlate with brain iron levels, the present study aimed to characterise the potential antidepressant properties of the iron chelator deferiprone. Using the serotonin transporter knock-out (5-HTT KO) mouse model, we assessed the behavioural effects of acute deferiprone on the Porsolt swim test (PST) and novelty-suppressed feeding test (NSFT). Brain and blood iron levels were also measured following acute deferiprone. To determine the relevant brain regions activated by deferiprone, we then measured c-Fos expression and applied network-based analyses. We found that deferiprone reduced immobility time in the PST in 5-HTT KO mice and reduced latency to feed in the NSFT in both genotypes, suggesting potential antidepressant-like effects. There was no effect on brain or blood iron levels following deferiprone treatment, potentially indicating an acute iron-independent mechanism. Deferiprone reversed the increase in c-Fos expression induced by swim stress in 5-HTT KO mice in the lateral amygdala. Functional network analyses suggest that hub regions of activity in mice treated with deferiprone include the caudate putamen and prefrontal cortex. The PST-induced increase in network modularity in wild-type mice was not observed in 5-HTT KO mice. Altogether, our data show that the antidepressant-like effects of deferiprone could be acting via an iron-independent mechanism and that these therapeutic effects are underpinned by changes in neuronal activity in the lateral amygdala.

Within subject rise in serum TNFα to IL-10 ratio is associated with poorer attention, decision-making and working memory in jockeys.

Jockeys work in high-risk environments that rely heavily on attention- and decision-making to perform well and safely. Workplace stress literature has often overlooked the impact of stress on cognition, and designs that include physiological measures are rare. This study assessed the prospective concurrent relationships between workplace stress, depression symptoms and low-grade inflammation with cognitive performance among professional jockeys. Professional jockeys (N = 35, Mage = 32.29) provided information on workplace stress and depression symptoms, with serum levels of inflammatory cytokines (IL-6, IL-10, TNFα) and cytokine balance (IL-6: IL-10, TNFα: IL-10) quantified with SIMOA, and cognitive performance with CogSport computer-based testing battery. These measures were repeated after a twelve-month interval. Increased workplace stress between testing intervals was associated to an increased cytokine imbalance (ß = 0.447, p = .015) after controlling for age and gender. Increases in cytokine imbalance occurred in unison with decreases in attention (ß = 0.516, p = .002), decision-making (ß = 0.452, p = .009) and working memory (ß = 0.492, p = .004). These preliminary findings suggest the underlying mechanisms linking workplace stress and reduced cognitive performance may be influenced by measures of low-grade inflammation and specifically a cytokine imbalance. Our findings suggest a measure of cytokine balance may explain the heterogenous findings in previous studies that have focussed solely on the association of workplace stress with pro-inflammatory cytokines. Future work is needed however, to provide a broader evidence-base for our claims to better inform designs to intervene in the higher workplace stress-poorer cognition relationship.

Ontogenetic Change in Male Expression of Testosterone-Responsive Genes Contributes to the Emergence of Sex-Biased Gene Expression in Anolis sagrei.

Sex differences in gene expression tend to increase with age across a variety of species, often coincident with the development of sexual dimorphism and maturational changes in hormone levels. However, because most transcriptome-wide characterizations of sexual divergence are framed as comparisons of sex-biased gene expression across ages, it can be difficult to determine the extent to which age-biased gene expression within each sex contributes to the emergence of sex-biased gene expression. Using RNAseq in the liver of the sexually dimorphic brown anole lizard (Anolis sagrei), we found that a pronounced increase in sex-biased gene expression with age was associated with a much greater degree of age-biased gene expression in males than in females. This pattern suggests that developmental changes in males, such as maturational increases in circulating testosterone, contribute disproportionately to the ontogenetic emergence of sex-biased gene expression. To test this hypothesis, we used four different experimental contrasts to independently characterize sets of genes whose expression differed as a function of castration and/or treatment with exogenous testosterone. We found that genes that were significantly male-biased in expression or upregulated as males matured tended to be upregulated by testosterone, whereas genes that were female-biased or downregulated as males matured tended to be downregulated by testosterone. Moreover, the first two principal components describing multivariate gene expression indicated that exogenous testosterone reversed many of the feminizing effects of castration on the liver transcriptome of maturing males. Collectively, our results suggest that developmental changes that occur in males contribute disproportionately to the emergence of sex-biased gene expression in the Anolis liver, and that many of these changes are orchestrated by androgens such as testosterone.

Neurotransmitters of sleep and wakefulness in flatworms.

STUDY OBJECTIVES: Sleep is a prominent behavioral and biochemical state observed in all animals studied, including platyhelminth flatworms. Investigations into the biochemical mechanisms associated with sleep-and wakefulness-are important for understanding how these states are regulated and how that regulation changed with the evolution of new types of animals. Unfortunately, beyond a handful of vertebrates, such studies on invertebrates are rare. METHODS: We investigated the effect of seven neurotransmitters, and one pharmacological compound, that modulate either sleep or wakefulness in mammals, on flatworms (Girardia tigrina). Flatworms were exposed via ingestion and diffusion to four neurotransmitters that promote wakefulness in vertebrates (acetylcholine, dopamine, glutamate, histamine), and three that induce sleep (adenosine, GABA, serotonin) along with the H1 histamine receptor antagonist pyrilamine. Compounds were administered over concentrations spanning three to five orders of magnitude. Flatworms were then transferred to fresh water and video recorded for analysis. RESULTS: Dopamine and histamine decreased the time spent inactive and increased distance traveled, consistent with their wake-promoting effect in vertebrates and fruit flies; pyrilamine increased restfulness and GABA showed a nonsignificant trend towards promoting restfulness in a dose-dependent manner, in agreement with their sleep-inducing effect in vertebrates, fruit flies, and Hydra. Similar to Hydra, acetylcholine, glutamate, and serotonin, but also adenosine, had no apparent effect on flatworm behavior. CONCLUSIONS: These data demonstrate the potential of neurotransmitters to regulate sleep and wakefulness in flatworms and highlight the conserved action of some neurotransmitters across species.