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This paper studies the behaviour of the Elo rating system when the underlying modelling assumptions are not met. The Elo rating system is a popular statistical technique used to analyse pairwise comparison data. It is perhaps best known for rating chess players. The crucial assumption behind the Elo rating system is that the probability of which players wins a chess game depends primarily on a real-valued parameter, that quantifies the player’s “skill\". This implicitly assumes that the binary relation “more likely to win against\" is transitive. This paper studies how the Elo rating system behaves when this assumption is relaxed. First, we prove that once the assumption of transitivity is relaxed, the Elo ratings exhibits the undesirable property that estimated ratings are dependent on who plays who. Second, we prove that even when the assumption of transitivity is relaxed, for a given distribution with which players are selected, there is a unique point where the expected change of Elo ratings at that point is zero. This point represents the maximum likelihood estimator of the Elo ratings, given the observed data. Finally, we introduce a statistic that can be used to measure the intransitivity present in a game. We derive this measurement, and demonstrate on simulated data that it satisfies some useful sanity tests.

Parkinson’s disease is a synucleinopathy that is characterized by motor dysfunction, death of midbrain dopaminergic neurons and accumulation of α-synuclein (α-Syn) aggregates. Evidence suggests that α-Syn aggregation can originate in peripheral tissues and progress to the brain via autonomic fibers. We tested this by inoculating the duodenal wall of mice with α-Syn preformed fibrils. Following inoculation, we observed gastrointestinal deficits and physiological changes to the enteric nervous system. Using the AAV-PHP.S capsid to target the lysosomal enzyme glucocerebrosidase for peripheral gene transfer, we found that α-Syn pathology is reduced due to the increased expression of this protein. Lastly, inoculation of α-Syn fibrils in aged mice, but not younger mice, resulted in progression of α-Syn histopathology to the midbrain and subsequent motor defects. Our results characterize peripheral synucleinopathy in prodromal Parkinson’s disease and explore cellular mechanisms for the gut-to-brain progression of α-Syn pathology.Alpha-synuclein fibrils can disrupt the enteric nervous system, which is mitigated by peripheral GBA1 gene transfer via systemic AAVs. Aging increases susceptibility to α-synuclein pathology progression from the gut to the brain.

Individual variation in sociability is a central feature of every society. This includes honey bees, with some individuals well connected and sociable, and others at the periphery of their colony’s social network. However, the genetic and molecular bases of sociability are poorly understood. Trophallaxis—a behavior involving sharing liquid with nutritional and signaling properties—comprises a social interaction and a proxy for sociability in honey bee colonies: more sociable bees engage in more trophallaxis. Here, we identify genetic and molecular mechanisms of trophallaxis-based sociability by combining genome sequencing, brain transcriptomics, and automated behavioral tracking. A genome-wide association study (GWAS) identified 18 single nucleotide polymorphisms (SNPs) associated with variation in sociability. Several SNPs were localized to genes previously associated with sociability in other species, including in the context of human autism, suggesting shared molecular mechanisms of sociability. Variation in sociability also was linked to differential brain gene expression, particularly genes associated with neural signaling and development. Using comparative genomic and transcriptomic approaches, we also detected evidence for divergent mechanisms underpinning sociability across species, including those related to reward sensitivity and encounter probability. These results highlight both potential evolutionary conservation of the molecular roots of sociability and points of divergence.

Anthropogenic changes create evolutionarily novel environments that present opportunities for emerging diseases, potentially changing the balance between host and pathogen. Honey bees provide essential pollination services, but intensification and globalization of honey bee management has coincided with increased pathogen pressure, primarily due to a parasitic mite/virus complex. Here, we investigated how honey bee individual and group phenotypes are altered by a virus of concern, Israeli acute paralysis virus (IAPV). Using automated and manual behavioral monitoring of IAPV-inoculated individuals, we find evidence for pathogen manipulation of worker behavior by IAPV, and reveal that this effect depends on social context; that is, within versus between colony interactions. Experimental inoculation reduced social contacts between honey bee colony members, suggesting an adaptive host social immune response to diminish transmission. Parallel analyses with double-stranded RNA (dsRNA)-immunostimulated bees revealed these behaviors are part of a generalized social immune defensive response. Conversely, inoculated bees presented to groups of bees from other colonies experienced reduced aggression compared with dsRNA-immunostimulated bees, facilitating entry into susceptible colonies. This reduction was associated with a shift in cuticular hydrocarbons, the chemical signatures used by bees to discriminate colony members from intruders. These responses were specific to IAPV infection, suggestive of pathogen manipulation of the host. Emerging bee pathogens may thus shape host phenotypes to increase transmission, a strategy especially well-suited to the unnaturally high colony densities of modern apiculture. These findings demonstrate how anthropogenic changes could affect arms races between human-managed hosts and their pathogens to potentially affect global food security.

Crop pollination by the western honey bee Apis mellifera is vital to agriculture but threatened by alarmingly high levels of colony mortality, especially in Europe and North America. Colony loss is due, in part, to the high viral loads of Deformed wing virus (DWV), transmitted by the ectoparasitic mite Varroa destructor , especially throughout the overwintering period of a honey bee colony. Covert DWV infection is commonplace and has been causally linked to precocious foraging, which itself has been linked to colony loss. Taking advantage of four brain transcriptome studies that unexpectedly revealed evidence of covert DWV-A infection, we set out to explore whether this effect is due to DWV-A mimicking naturally occurring changes in brain gene expression that are associated with behavioral maturation. Consistent with this hypothesis, we found that brain gene expression profiles of DWV-A infected bees resembled those of foragers, even in individuals that were much younger than typical foragers. In addition, brain transcriptional regulatory network analysis revealed a positive association between DWV-A infection and transcription factors previously associated with honey bee foraging behavior. Surprisingly, single-cell RNA-Sequencing implicated glia, not neurons, in this effect; there are relatively few glial cells in the insect brain and they are rarely associated with behavioral plasticity. Covert DWV-A infection also has been linked to impaired learning, which together with precocious foraging can lead to increased occurrence of infected bees from one colony mistakenly entering another colony, especially under crowded modern apiary conditions. These findings provide new insights into the mechanisms by which DWV-A affects honey bee health and colony survival.

Yellow or Carolina jasmine/jessamine (Gelsemium sempervirens) is a flowering plant that serves as a model for the study of plant-pollinator interactions. During the early spring, it produces abundant flowers that are visited by generalist pollinators, such as honey bees (Apis mellifera), especially when other floral resources are scarce. Beekeepers in the Southeastern USA have observed signs of hive intoxication and weakening when yellow jessamine is in bloom, posing implications for hive and apiary management. The phytochemical gelsemine, which is a toxic indole alkaloid present in the plant’s pollen and nectar, may be linked to these observations. Few studies have looked at the effects of ecologically relevant concentrations of gelsemine on honey bee health at the colony level and on queen fecundity. We used Queen Monitoring Cages (QMCs), microcolonies composed of a queen and a small number of workers maintained under laboratory conditions to primarily investigate the impact of gelsemine exposure on queen fecundity, with additional measurements taken for worker mortality, number of workers in the brood area, and consumption of food resources. We exposed the workers to gelsemine by adding it to sucrose solution using field-relevant concentrations that ranged from 20 to 200 ppm for up to 15 days. We found that queen fecundity was significantly reduced in two of four experiments. Overall, worker mortality was low. In addition, when workers consumed sucrose solution containing higher doses of gelsemine, evidence of an aversion effect was observed. This study highlights one facet of yellow jessamine’s potential impact on honey bee colony health and promotes additional research looking at the behavioral and physiological mechanisms contributing to these responses.

The duration of interaction events in a society is a fundamental measure of its collective nature and potentially reflects variability in individual behavior. Here we performed a high-throughput measurement of trophallaxis and face-to-face event durations experienced by a colony of honeybees over their entire lifetimes. The interaction time distribution is heavy-tailed, as previously reported for human face-to-face interactions. We developed a theory of pair interactions that takes into account individual variability and predicts the scaling behavior for both bee and extant human datasets. The individual variability of worker honeybees was nonzero but less than that of humans, possibly reflecting their greater genetic relatedness. Our work shows how individual differences can lead to universal patterns of behavior that transcend species and specific mechanisms for social interactions.

Changes in neuroinflammatory tone have been shown to modulate neuroimmune responses to Alzheimer's disease (AD) pathology and shape disease outcomes, however, extrinsic factors that modify neuroimmune activation remain poorly understood. The gut microbiome is one such factor, with the ability to shape peripheral and central immune activation, as well as AD pathologies. AD patients display unique changes in microbiome composition, however, the link between specific AD-associated gut bacteria, neuroinflammatory tone, and AD outcomes remains to be elucidated. To identify AD-associated bacteria that modify neuroinflammatory tone, wildtype germ-free mice were mono-colonized with type strains of bacteria species of interest (Escherichia coli, Bacteroides thetaiotaomicron, Clostridium celatum, and Lactobacillus johnsonii) for 2 weeks. Further evaluation of the effect of E. coli-an identified neuroimmune modulatory bacteria-on AD outcomes was performed by exposing conventional 5xFAD mice to E. coli via oral gavage for one month. Neuroinflammatory outcomes were assessed by bulk and single cell RNA-seq and protein analysis. In addition, AD outcomes including cognitive and pathological markers were evaluated in E. coli exposed 5xFAD mice. AD-associated bacteria induced bacteria- and sex-specific changes in cytokine levels as well as myeloid cell gene expression within the brains of mono-colonized mice. In particular, E. coli was shown to induce a distinct, AD-associated neuroinflammatory phenotype that was characterized by increased MHC II antigen presentation and changes in boarder associated macrophage and endothelial cell gene expression. Further, E. coli-exposed 5xFAD mice displayed accelerated cognitive decline compared to vehicle controls. Neuroinflammatory and pathological markers in the brains of E. coli-exposed 5xFAD mice were also evaluated to further explore the effects of E. coli on AD pathophysiology. Together, these results highlight the neuroimmune modulatory potential of AD-associated gut bacteria. In particular, the present study demonstrates how increased intestinal exposure to non-pathogenic E. coli is sufficient to modify neuroinflammatory tone, cognition, and pathology in 5xFAD mice, highlighting the potential importance of this microbe for AD.

Spinal cord injury (SCI) results in numerous systemic dysfunctions, including intestinal dysmotility and enteric nervous system (ENS) atrophy. The ENS has capacity to recover following perturbation, yet intestinal pathologies persist. With emerging evidence demonstrating SCI-induced alterations to gut microbiome composition, we hypothesized that microbiome modulation contributes to post-injury enteric recovery. Here, we show that intervention with the dietary fiber, inulin, prevents SCI-induced ENS atrophy and dysmotility in mice. While SCI-associated microbiomes and specific injury-sensitive gut microbes are not sufficient to modulate intestinal dysmotility after injury, intervention with microbially-derived short-chain fatty acid (SCFA) metabolites prevents ENS dysfunctions in injured mice. Notably, inulin-mediated resilience is dependent on IL-10 signaling, highlighting a critical diet-microbiome-immune axis that promotes ENS resilience post-injury. Overall, we demonstrate that diet and microbially-derived signals distinctly impact ENS survival after traumatic spinal injury and represent a foundation to uncover etiological mechanisms and future therapeutics for SCI-induced neurogenic bowel.

Introduction: Increasing evidence indicates that neurodegenerative diseases, including Alzheimer’s disease (AD), are a product of gene-by-environment interplay. The immune system is a major contributor mediating these interactions. Signaling between peripheral immune cells and those within the microvasculature and meninges of the central nervous system (CNS), at the blood-brain barrier, and in the gut likely plays an important role in AD. The cytokine tumor necrosis factor (TNF) is elevated in AD patients, regulates brain and gut barrier permeability, and is produced by central and peripheral immune cells. Our group previously reported that soluble TNF (sTNF) modulates cytokine and chemokine cascades that regulate peripheral immune cell traffic to the brain in young 5xFAD female mice, and in separate studies that a diet high in fat and sugar (HFHS) dysregulates signaling pathways that trigger sTNF-dependent immune and metabolic responses that can result in metabolic syndrome, which is a risk factor for AD. We hypothesized that sTNF is a key mediator of peripheral immune cell contributions to gene-by-environment interactions to AD-like pathology, metabolic dysfunction, and diet-induced gut dysbiosis. Methods: Female 5xFAD mice were subjected to HFHS diet for 2 months and then given XPro1595 to inhibit sTNF for the last month or saline vehicle. We quantified immune cell profiles by multi-color flow cytometry on cells isolated from brain and blood; metabolic, immune, and inflammatory mRNA and protein marker biochemical and immunhistological analyses, gut microbiome, and electrophysiology in brain slices were also performed. Results: Here, we show that selective inhibition of sTNF signaling via the biologic XPro1595 modulates the effects of an HFHS diet in 5xFAD mice on peripheral and central immune profiles including CNS-associated CD8+ T cells, the composition of gut microbiota, and long-term potentiation deficits. Discussion: Obesogenic diet induces immune and neuronal dysfunction in 5xFAD mice and sTNF inhibition mitigates its effects. A clinical trial in subjects at risk for AD due to genetic predisposition and underlying inflammation associated with peripheral inflammatory co-morbidities will be needed to investigate the extent to which these findings translate to the clinic.