Biology subjects

Snyder-Mackler, N.

Publications and source records attributed to Snyder-Mackler, N..

49 records · Page 3Linked to original sources

bioRxiv2021

Subtype transcriptomic profiling of myeloid cells in Alzheimer Disease brain illustrates the diversity in active microglia phenotypes

Microglia contribute to Alzheimers Disease (AD) progression and are candidate therapeutic targets. Human microglia exhibit an array of transcriptional phenotypes implying that accurate manipulation of microglial function will require clarity of their molecular states and context dependent regulation. To increase the number of microglia analyzed per subject we employed fluorescence activated nuclei sorting prior to single-nucleus RNA-seq on human prefrontal cortices. We observed microglia phenotypes previously unrecognized in human brain gene expression studies and mapped their transcriptomic relationships by trajectory inference. Three clusters were enriched for endolysosomal pathways, one of which showed differential expression of AD GWAS genes in addition to genes implicated in nucleic acid detection and interferon signaling. Analysis of the "homeostatic" microglia cluster revealed a uniquely AD subcluster. Our study demonstrates the value of deeply profiling microglia to explore the biological implications of microglia transcriptomic diversity.

neuroscience↗

bioRxiv2021

Helminth infection is associated with dampened cytokine responses to viral and bacterial stimulations in Tsimane hunter-horticulturalists.

BackgroundSoil-transmitted helminth (STH) infections can catalyze immunological changes that affect the response to subsequent infections, particularly those that elicit strong inflammatory responses. As globalization heightens the risk that remote communities with high STH prevalence will encounter novel pathogens, understanding how STHs shape immune responses to these downstream infections becomes increasingly crucial. MethodologyWe worked with Tsimane forager-horticulturalists in the Bolivian Amazon, where STHs are prevalent. We tested whether STHs and eosinophil levels--most likely indicative of infection in this population--are associated with dampened immune responses to in vitro stimulation with H1N1 and lipopolysaccharide (LPS) antigens. Whole blood samples (n = 179) were treated with H1N1 vaccine and LPS and assayed for 13 cytokines (interferon gamma [INF-{gamma}], interleukin [IL]-1{beta}, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, Granulocyte-macrophage colony-stimulating factor [GM-CSF], and Tumor necrosis factor-alpha [TNF-]). We evaluated how STHs and eosinophil levels affected cytokine responses and T helper (Th) 1 and Th2-cytokine suite responses to stimulation. ResultsInfection with Ascaris lumbricoides was significantly (p [≤] 0.05) associated with lower response of some cytokines to H1N1 and LPS in women. Eosinophils were significantly negatively associated with some cytokine responses to H1N1 and LPS, with the strongest effects in women, and associated with a reduced Th1- and Th2-cytokine response to H1N1 and LPS in women and men. Conclusions and implicationsWe find that STHs were associated with dampened cytokine responses to certain viral and bacterial antigens, and suggest that this mitigation of host-induced damage may reduce the incidence of cytokine storms in populations with high STH prevalence.

immunology↗

bioRxiv2021

High-altitude adaptation and incipient speciation in geladas

Survival at high altitude requires adapting to extreme conditions such as environmental hypoxia. To understand high-altitude adaptations in a primate, we assembled the genome of the gelada (Theropithecus gelada), an endemic Ethiopian monkey, and complemented it with population resequencing, hematological, and morphometric data. Unexpectedly, we identified a novel karyotype that may contribute to reproductive isolation between gelada populations. We also identified genomic elements including protein-coding sequences and gene families that exhibit accelerated changes in geladas and may contribute to high-altitude adaptation. Our findings lend insight into mechanisms of speciation and adaptation while providing promising avenues for functional hypoxia research.

genomics↗

bioRxiv2021

Early life gut microbiome dynamics mediate maternal effects of infant growth in vervet monkeys

BackgroundMaternal parity is associated with variation in infant growth across mammals, but the mechanisms underlying this relationship are unclear. Given emerging links between growth and the microbiome, and the importance of maternal microbiota in establishing this community, the assembly of the infant gut microbiome may be a mediator of parity effects on infant growth. ResultsHere, we analyzed 118 fecal and milk samples from mother-infant vervet monkey dyads across the first 6 months postpartum in a population with high growth-associated infant mortality. Despite poorer milk production, infants born to low parity females were larger at 6 months of age than their counterparts and exhibited divergent patterns in gut microbiome assembly. Gut microbiome alpha diversity increased rapidly from the first days of life to 4 months old in all infants, but infants born to low parity females exhibited reduced gut microbiome alpha diversity during early life. At the taxonomic level, infants broadly exhibited a shift from Bacteroides fragilis to Prevotella dominance. Infants of low parity females housed more B. fragilis in their guts, and B. fragilis dominance drove reduced alpha diversity. Maternal vertical transmission to the infant gut was greater from milk than from the maternal gut, and was greatest among infants born to low parity females. B. fragilis was 15-fold more abundant in milk than in the maternal gut and was greater in the milk of low parity females, suggesting that milk may be the primary maternal reservoir of B. fragilis. Path analyses demonstrated that both infant gut alpha diversity and B. fragilis mediated parity effects on postnatal growth: infants were larger at 6 months old if they exhibited reduced alpha diversity and a greater relative abundance of B. fragilis during early life. ConclusionThe first days of life are a critical period of infant gut microbiome organization during which the establishment of a less diverse, milk-oriented microbial community abundant in B. fragilis promotes growth among infants born to reproductively inexperienced females.

physiology↗

bioRxiv2020

Mediterranean Diet, Stress Resilience, and Aging in Nonhuman Primates

Persistent psychological stress increases the risk of many chronic diseases of aging. Little progress has been made to effectively reduce stress responses or mitigate stress effects suggesting a need for better understanding of factors that influence stress responses. Limited evidence suggests that diet may be a factor in modifying the effects of stress. However, long-term studies of diet effects on stress reactive systems are not available, and controlled randomized clinical trials are difficult and costly. Here we report the outcomes of a controlled, randomized preclinical trial of the effects of long-term consumption (31 months, [~] equivalent to 9 human years) of Western versus Mediterranean - like diets on behavioral and physiological responses to acute (brief social separation) and chronic (social subordination) psychosocial stress in 38 adult, socially-housed, female cynomolgus macaques. Compared to animals fed a Western diet, those fed the Mediterranean diet exhibited enhanced stress resilience as indicated by lower sympathetic activity, brisker and more overt heart rate responses to acute stress, more rapid recovery, and lower cortisol responses to acute psychological stress and adrenocorticotropin (ACTH) challenge. Furthermore, age-related increases in sympathetic activity and cortisol responses to stress were delayed by the Mediterranean diet. Population level diet modification in humans has been shown to be feasible. Our findings suggest that population-wide adoption of a Mediterranean-like diet pattern may provide a cost-effective intervention on psychological stress and promote healthy aging with the potential for widespread efficacy. HighlightsO_LIThere is no population level treatment to reduce stress and associated disease. C_LIO_LIMediterranean diet reduced sympathetic activity. C_LIO_LIMediterranean diet reduced cortisol response to acute stress and to ACTH challenge. C_LIO_LIMediterranean diet delayed age-related increases in sympathetic activity and cortisol responses to stress. C_LIO_LIThese results suggest a dietary strategy to increase stress resilience. C_LI

physiology↗

bioRxiv2020

Rhesus macaques as a tractable physiological model of human ageing

Research in the basic biology of ageing is increasingly identifying mechanisms and modifiers of ageing in short-lived organisms such as worms and mice. The ultimate goal of such work is to improve human health, particularly in the growing segment of the population surviving into old age. Thus far, few interventions have robustly transcended species boundaries in the laboratory, suggesting that changes in approach are needed to avoid costly failures in translational human research. In this review, we discuss both well-established and alternative model organisms for ageing research and outline how research in nonhuman primates is sorely needed, first, to translate findings from shorter-lived organisms to humans, and second, to understand key aspects of ageing that are unique to primate biology. We focus on rhesus macaques as a particularly promising model organism for ageing research due to their social and physiological similarity to humans as well as the existence of key resources that have been developed for this species. As a case study, we compare gene regulatory signatures of ageing in the peripheral immune system between humans and rhesus macaques from a free-ranging study population in Cayo Santiago. We show that both mRNA expression and DNA methylation signatures of immune ageing are broadly shared between macaques and humans, indicating strong conservation of the trajectory of ageing in the immune system. We conclude with a review of key issues in the biology of ageing for which macaques and other nonhuman primates may uniquely contribute valuable insights, including the effects of social gradients on health and ageing. We anticipate that continuing research in rhesus macaques and other nonhuman primates will play a critical role in conjunction with model organism and human biodemographic research in ultimately improving translational outcomes and extending health and longevity in our ageing population.

genomics↗

bioRxiv2020

Male-mediated maturation in a wild primate

In humans, a controversial hypothesis suggests that father absence promotes early puberty in daughters. Data from rodents confirm females accelerate maturation with exposure to novel males (“Vandenbergh effect”) and delay it with exposure to male relatives. Here, we report the first case of male-mediated maturation in a wild primate, geladas (Theropithecus gelada). Females were more likely to mature after a change in the reproductive male: some matured earlier than expected (Vandenbergh effect) and some later (due to father presence). Novel males stimulated a surge in estrogens for all immature females - even females too young to mature. Although male-mediated puberty accelerated first births, the effect was modest, suggesting that alternative scenarios, such as co-evolution with the Bruce effect (male-mediated fetal loss) may explain this phenomenon.One Sentence Summary Novel males induce an estrogen surge, male-mediated puberty, and a head-start on reproduction for immature female geladas.Competing Interest StatementThe authors have declared no competing interest.View Full Text

zoology↗

bioRxiv2020

Divergent effects of Western and Mediterranean diets on behavior and monocyte polarization.

Dietary changes associated with industrialization substantially increase the prevalence of chronic diseases, such as obesity, type II diabetes, and cardiovascular disease, which are major contributors to the public health burden. The high prevalence of these chronic diseases is often attributed to an "evolutionary mismatch," between human physiology and modern nutritional environments. In support of this idea, Western diets enriched with foods that were scarce throughout human evolutionary history (e.g., simple sugars and saturated fats) promote inflammation and disease relative to diets more akin to hunter-gatherer diets, such as a Mediterranean diet; however, the mechanisms linking dietary mismatch to inflammation and chronic disease are poorly understood. We used a macaque model and whole diet manipulations to evaluate one possible mechanism - inflammatory polarization of monocytes - that potentially leads to this evolutionary mismatch. After consuming a Western- or Mediterranean-like diet for 15 months, monocytes from Western diet consumers exhibited a more proinflammatory phenotype, with 40% of their genes differentially expressed (FDR<0.05). Compared to the Mediterranean diet, the Western diet shifted the co-expression of 445 gene pairs, including small RNAs and transcription factors associated with metabolism and adiposity in humans, and dramatically altered animal behavior. For example, Western-fed individuals were more anxious and less socially integrated compared to the Mediterranean-fed subjects. These behavioral changes were also associated with some of the effects of diet on gene expression, suggesting an interaction between diet, central nervous system activity, and monocyte gene expression. The results of this study provide new insights into evolutionary mismatch at the molecular level and uncover new pathways through which Western diets generate inflammation and disease.

genomics↗

bioRxiv2019

Social history and exposure to pathogen signals modulate social status effects on gene regulation in rhesus macaques

Social experiences are an important predictor of disease susceptibility and survival in humans and other social mammals. Chronic social stress is thought to generate a pro-inflammatory state characterized by elevated antibacterial defenses and reduced investment in antiviral defense. Here, we manipulated long-term social status in female rhesus macaques to show that social subordination alters the gene expression response to ex vivo bacterial and viral challenge. As predicted by current models, bacterial lipopolysaccharide polarizes the immune response such that low status corresponds to higher expression of genes in NF-{kappa}B-dependent pro-inflammatory pathways and lower expression of genes involved in the antiviral response and type I interferon (IFN) signaling. Counter to predictions, however, low status drives more exaggerated expression of both NF-{kappa}B and IFN-associated genes after cells are exposed to the viral mimic Gardiquimod. Status-driven gene expression patterns are not only linked to social status at the time of sampling, but also to social history (i.e., past social status), especially in unstimulated cells. However, for a subset of genes, we observed interaction effects in which females who fell in rank were more strongly affected by current social status than those who climbed the social hierarchy. Together, our results indicate that the effects of social status on immune cell gene expression depend on pathogen exposure, pathogen type, and social history - in support of social experience-mediated biological embedding in adulthood, even in the conventionally memory-less innate immune system.

genomics↗

bioRxiv2019

Highly Heritable and Functionally Relevant Breed Differences in Dog Behavior

Variation across dog breeds presents a unique opportunity for investigating the evolution and biological basis of complex behavioral traits. We integrated behavioral data from more than 17,000 dogs from 101 breeds with breed-averaged genotypic data (N = 5,697 dogs) from over 100,000 loci in the dog genome. Across 14 traits, we found that breed differences in behavior are highly heritable, and that clustering of breeds based on behavior accurately recapitulates genetic relationships. We identify 131 single nucleotide polymorphisms associated with breed differences in behavior, which are found in genes that are highly expressed in the brain and enriched for neurobiological functions and developmental processes. Our results provide insight into the heritability and genetic architecture of complex behavioral traits, and suggest that dogs provide a powerful model for these questions.

animal behavior and cognition↗

bioRxiv2018

Social integration predicts mitochondrial DNA copy number in rhesus macaques

In many social mammals, social adversity predicts compromised health and reduced fitness. These effects are thought to be driven in part by chronic social stress, but their molecular underpinnings are not well understood. Recent work suggests that chronic stress can affect mitochondrial copy number, heteroplasmy rates, and function. Here, we tested the first two possibilities, for the first time in nonhuman primates. We manipulated dominance rank in captive female rhesus macaques (n=45), where low rank induces chronic social stress, and measured mitochondrial DNA copy number and heteroplasmy in five peripheral blood mononuclear cell types from each study subject. We found no effect of dominance rank on either mtDNA copy number or heteroplasmy rates. However, grooming rates, a measure of affiliative social behavior predicted by high social status, was positively associated with mtDNA copy number in B cells, cytotoxic T cells, and monocytes. Our results suggest that social interactions can influence mtDNA regulation in immune cells. Further, they indicate the importance of considering both affiliative and competitive interactions in investigating this relationship.

animal behavior and cognition↗

bioRxiv2018

Social status alters chromatin accessibility and the gene regulatory response to glucocorticoid stimulation in rhesus macaques

Low social status is an important predictor of disease susceptibility and mortality risk in humans and other social mammals. These effects are thought to stem in part from dysregulation of the glucocorticoid (GC)-mediated stress response. However, the molecular mechanisms that connect low social status and GC dysregulation to downstream health outcomes remain elusive. Here, we used an in vitro glucocorticoid challenge to investigate the consequences of experimentally manipulated social status (i.e., dominance rank) for immune cell gene regulation in female rhesus macaques, using paired control and GC-treated peripheral blood mononuclear cell samples. We show that social status not only influences immune cell gene expression, but also chromatin accessibility at hundreds of regions in the genome. Social status effects on gene expression were less pronounced following GC treatment than under control conditions. In contrast, social status effects on chromatin accessibility were stable across conditions, resulting in an attenuated relationship between social status, chromatin accessibility, and gene expression post-GC exposure. Regions that were more accessible in high status animals and regions that become more accessible following GC treatment were enriched for a highly concordant set of transcription factor binding motifs, including motifs for the glucocorticoid receptor co-factor AP-1. Together, our findings support the hypothesis that social status alters the dynamics of GC-mediated gene regulation, and identify chromatin accessibility as a mechanism involved in social stress-driven GC resistance. More broadly, they emphasize the context-dependent nature of social status effects on gene regulation and implicate epigenetic remodeling of chromatin accessibility as a contributing factor.

genomics↗

bioRxiv2018

The Goldilocks Effect: Female geladas in mid-sized groups have higher fitness

The cost-benefit ratio of group-living is thought to vary with group size: individuals in "optimally-sized" groups should have higher fitness than individuals in groups that are either too large or too small. However, the relationship between group size and individual fitness has been difficult to establish for long-lived species where the number of groups studied is typically quite low. Here we present evidence for optimal group size that maximizes female fitness in a population of geladas (Theropithecus gelada). Drawing on 14 years of demographic data, we found that females in small groups experienced the highest death rates, while females in mid-sized units exhibited the highest reproductive performance. This group-size effect on female reproductive performance was largely explained by variation in infant mortality (and, in particular, by infanticide from immigrant males) but not by variation in reproductive rates. Taken together, females in mid-sized units are projected to attain optimal fitness due to conspecific infanticide and, potentially, predation. Our findings provide insight into how and why group size shapes fitness in long-lived species.

evolutionary biology↗