Biology subjects

Brown, J. L.

Publications and source records attributed to Brown, J. L..

16 recordsLinked to original sources

bioRxiv2026

Epigenetic Resilience to Early-Life Maternal Loss in African Savanna Elephants

Early-life trauma in humans, including maternal loss, is strongly associated with increased risk of chronic diseases, reduced life expectancy, and accelerated biological aging, as measured through epigenetic modifications, such as DNA methylation. Whether similar patterns occur in other long-lived, socially complex non-primate species, however, remains unknown. Elephants share key life-history traits with humans, including longevity, strong social bonds, and advanced cognitive abilities. Yet wild elephant populations face significant anthropogenic and environmental pressures, including poaching, habitat loss, and human-wildlife conflict that can result in maternal mortality and subsequent calf orphaning. We examined whether orphaning of elephant calves was associated with accelerated DNA methylation age and distinct epigenetic signatures. Contrary to our hypothesis and patterns observed in other species, orphaned African savanna elephants exhibited a younger DNA methylation age than non-orphans, no accelerated aging, and only limited differential methylation at CpG sites. At the genome-wide level, chronological age was not associated with differential CpG methylation after correcting for multiple testing. One interpretation of these findings is that elephants may have evolved mechanisms that buffer against epigenetic instability following stressful events. Investigating these protective mechanisms in elephants could inform strategies to mitigate the long-term health impacts of early-life trauma in humans. Significance StatementIn most mammals, early-life adversity, including maternal loss is associated with shorter lifespans and widespread epigenetic alterations. In contrast, we found that orphaned African savanna elephants exhibited a younger epigenetic age compared to non-orphans and showed only a weak distinct epigenetic signature. This unexpected pattern may reflect environmental influences, such as living under human care, or evolutionary adaptations that buffer against epigenetic instability. If the latter is confirmed, such mechanisms could confer resilience to the epigenetic consequences of early-life adversity.

genomics↗

bioRxiv2026

Overactive PDGFRα and PDGFRβ promote distinct yet overlapping phenotypes of skeletal muscle fibrosis and stiffness, with PDGFRβ also driving drastic muscle growth

Background: Fibrosis accumulates in skeletal muscle over time and leads to greater muscle rigidity, stiffness, and increased risk of injuries. However, investigations of experimental models to study the mechanisms through which muscle fibrosis occurs are often confounded by injury or disease. The contribution of platelet-derived growth factor receptors alpha and beta (PDGFR or PDGFR{beta}) to muscle fibrosis is yet to be clarified. We hypothesized that both receptors would promote ECM deposition and fibrosis, causing muscle stiffening and weakness, with sex-specific differences arising due to hormonal influences on receptors. Methods: To test this hypothesis, we used a mouse model with inducible overactive PDGFR or PDGFR{beta} signaling and assessed various indicators of muscle function, metabolism, motor coordination, exercise capacity, collagen deposition, and muscle stiffness. Results: Overactive PDGFR led to more collagen deposition, increased collagen crosslinking, and higher AGE/LOX protein levels, all of which correlated with greater muscle stiffness compared to CON. Overactive PDGFR{beta} resulted in greater muscle mass and lower fat mass, and had higher collagen deposition in female mice compared to CON. There were also sex-specific differences with fibrotic remodeling, muscle stiffness, and muscle size in response to overactive PDGFR and PDGFR{beta} signaling. Conclusion: These findings establish PDGFR and PDGFR{beta} signaling as distinct regulators of muscle remodeling and establish overactive PDGFR as a mouse model to study skeletal muscle fibrosis in the absence of other confounding variables.

physiology↗

bioRxiv2025

Genomic and Transcriptomic Characterization of Carbohydrate-Active Enzymes in the Anaerobic Fungus Neocallimastix cameroonii var. constans

Anaerobic gut fungi effectively degrade lignocellulose in the guts of large herbivores, but there remains a limited number of isolated, publicly available, and sequenced strains that impede our understanding of the role of anaerobic fungi within microbial communities. We isolated and characterized a new fungal isolate, Neocallimastix cameroonii var. constans, providing a transcriptomic and genomic understanding of its ability to degrade diverse carbohydrates. This anaerobic fungal strain was stably cultivated for multiple years in vitro among members of an initial enrichment microbial community derived from goat feces, and it demonstrated the ability to pair with other microbial members, namely archaeal methanogens to produce methane from lignocellulose. Genomic analysis revealed a higher number of predicted carbohydrate-active enzymes encoded in the N. cameroonii var. constans genome compared to most other sequenced anaerobic fungi. The carbohydrate-active enzyme profile for this isolate contained 660 glycoside hydrolases, 160 carbohydrate esterases, 194 glycosyltrasferases, and 85 polysaccharide lyases. Differential gene expression analysis showed the upregulation of thousands of genes (including predicted carbohydrate-active enzymes) when N. cameroonii var. constans was grown on lignocellulose (reed canary grass) compared to less complex substrates, such as cellulose (filter paper), cellobiose, and glucose. AlphaFold was used to predict functions of transcriptionally active yet poorly annotated genes, revealing feruloyl esterases that likely play an important role in lignocellulose degradation by anaerobic fungi. The combination of this strains genomic and transcriptomic characterization, omics-informed structural prediction, and robustness in microbial co-culture make it a well-suited platform to conduct future investigations into bioprocessing and enzyme discovery.

microbiology↗

bioRxiv2023

Polycomb protein binding and looping mediated by Polycomb Response Elements in the ON transcriptional state

Polycomb group proteins (PcG) mediate epigenetic silencing of important developmental genes and other targets. In Drosophila, canonical PcG-target genes contain Polycomb Response Elements (PREs) that recruit PcG protein complexes including PRC2 that tri- methylates H3K27 forming large H3K27me3 domains. In the OFF transcriptional state, PREs loop with each other and this looping strengthens silencing. Here we address the question of what PcG proteins bind to PREs when canonical PcG target genes are expressed, and whether PREs loop when these genes are ON. Our data show that the answer to this question is PRE-specific but general conclusions can be made. First, within a PcG-target gene, some regulatory DNA can remain covered with H3K27me3 and PcG proteins remain bound to PREs in these regions. Second, when PREs are within H3K27ac domains, PcG- binding decreases, however, this depends on the protein and PRE. The DNA binding protein GAF, and the PcG protein Ph remain at PREs even when other PcG proteins are greatly depleted. In the ON state, PREs can still loop with each other, but also form loops with presumptive enhancers. These data support the model that, in addition to their role in PcG silencing, PREs can act as "promoter-tethering elements" mediating interactions between promoter proximal PREs and distant enhancers.

genetics↗

bioRxiv2023

Genomic Resources for Asian (Elephas maximus) and African Savannah Elephant (Loxodonta africana) Conservation and Health Research

We provide novel genomic resources to help understand the genomic traits involved in elephant health and to aid conservation efforts. We sequence 11 elephant genomes (5 African savannah, 6 Asian) from North American zoos, including 9 de novo assemblies. We estimate elephant germline mutation rates and reconstruct demographic histories. Finally, we provide an in-solution capture assay to genotype Asian elephants. This assay is suitable for analyzing degraded museum and non-invasive samples, such as feces and hair. The elephant genomic resources we present here should allow for more detailed and uniform studies in the future to aid elephant conservation efforts and disease research.

genomics↗

bioRxiv2023

Liver Fibroblast Growth Factor 21 (FGF21) is Required for the Full Anorectic Effect of the Glucagon-Like Peptide-1 Receptor Agonist Liraglutide in Male Mice fed High Carbohydrate Diets

Glucagon-like peptide-1 receptor (GLP-1R) agonists and fibroblast growth factor 21 (FGF21) confer similar metabolic benefits. Studies report that GLP-1RA induce FGF21. Here, we investigated the mechanisms engaged by the GLP-1R agonist liraglutide to increase FGF21 levels and the metabolic relevance of liraglutide-induced FGF21. We show that liraglutide increases FGF21 levels via neuronal GLP-1R activation. We also demonstrate that lack of liver Fgf21 expression confers partial resistance to liraglutide-induced weight loss. Since FGF21 reduces carbohydrate intake, we tested whether the contribution of FGF21 to liraglutide-induced weight loss is dependent on dietary carbohydrate content. In control and liver Fgf21 knockout (LivFgf21-/-) mice fed calorically matched diets with low- (LC) or high-carbohydrate (HC) content, we found that only HC-fed LivFgf21-/- mice were resistant to liraglutide-induced weight loss. Similarly, liraglutide-induced weight loss was partially impaired in LivFgf21-/- mice fed a high-fat, high-sugar (HFHS) diet. Lastly, we show that loss of neuronal {beta}-klotho expression also diminishes liraglutide-induced weight loss in mice fed a HC or HFHS diet, indicating that FGF21 mediates liraglutide-induced weight loss via neuronal FGF21 action. Our findings support a novel role for a GLP-1R-FGF21 axis in regulating body weight in the presence of high dietary carbohydrate content.

physiology↗

bioRxiv2022

Senolytic Treatment Reduces Cell Senescence and Necroptosis in Sod1 Knockout Mice that is Associated with Reduced Inflammation and Hepatocellular Carcinoma

The goal of this study was to test the role cellular senescence plays in the increase in inflammation, chronic liver disease, and hepatocellular carcinoma, which are seen in mice null for Cu/Zn-Superoxide dismutase (Sod1KO). To inhibit senescence, six-month-old wildtype (WT) and Sod1KO mice were given the senolytics, dasatinib and quercetin (D+Q) for seven months. D+Q treatment reduced the expression of p16 in the livers of Sod1KO mice to WT levels as well as the expression of several SASP (senescence associated secretory phenotype) factors (IL-6, IL-1{beta}, CXCL-1, and GDF-15). D+Q treatment also reduced markers of inflammation in livers of the Sod1KO mice, e.g., cytokines, chemokines, macropthage levels, and Kupffer cell clusters. D+Q treatment had no effect on various markers of liver fibrosis in the Sod1KO mice but reduced the expression of genes involved in liver cancer (Myc, Tgfbr2, Socs3, and Cdkn2a) as well as dramatically reducing the incidence of hepatocellular carcinoma. Surprisingly, D+Q also reduced markers of necroptosis (phosphorylated and oligomerized MLKL) in the Sod1KO mice to WT levels. We also found that inhibiting necroptosis in the Sod1KO mice with necrostatin-1s reduced the markers of cellular senescence (p16, p21, and p53). The data from our study suggest that an interaction occurs between cellular senescence and necroptosis in the liver of Sod1KO mice. We propose that these two cell fates interact through a positive feedback loop resulting in a cycle amplifying both cellular senescence and necroptosis leading to inflammaging and age-associated pathology in the Sod1KO mice.

biochemistry↗

bioRxiv2021

Co-cultivation of the anaerobic fungus Caecomyces churrovis with Methanobacterium bryantii enhances transcription of carbohydrate binding modules

Anaerobic fungi and methanogenic archaea are two classes of microorganisms found in the rumen microbiome that metabolically interact during lignocellulose breakdown. Here, stable synthetic co-cultures of the anaerobic fungus Caecomyces churrovis and the methanogen Methanobacterium bryantii (not native to the rumen) were formed, demonstrating that microbes from different environments can be paired based on metabolic ties. Transcriptional and metabolic changes induced by methanogen co-culture were evaluated in C. churrovis across a variety of substrates to identify mechanisms that impact biomass breakdown and sugar uptake. A high-quality genome of C. churrovis was obtained and annotated, which is the first sequenced genome of a non-rhizoid forming anaerobic fungus. C. churrovis possess an abundance of CAZymes and carbohydrate binding modules and, in agreement with previous studies of early-diverging fungal lineages, N6-methyldeoxyadenine (6mA) was associated with transcriptionally active genes. Co-culture with the methanogen increased overall transcription of CAZymes, carbohydrate binding modules, and dockerin domains in co-cultures grown on both lignocellulose and cellulose and caused upregulation of genes coding associated enzymatic machinery including carbohydrate binding modules in family 18 and dockerin domains across multiple growth substrates relative to C. churrovis monoculture. Two other fungal strains grown on a reed canary grass substrate in co-culture with the same methanogen also exhibited high log2fold change values for upregulation of genes encoding carbohydrate binding modules in families 1 and 18. Transcriptional upregulation indicated that co-culture of the C. churrovis strain with a methanogen may enhance pyruvate formate lyase (PFL) function for growth on xylan and fructose and production of bottleneck enzymes in sugar utilization pathways, further supporting the hypothesis that co-culture with a methanogen may enhance certain fungal metabolic functions. Upregulation of CBM18 may play a role in fungal-methanogen physical associations and fungal cell wall development and remodeling.

microbiology↗

bioRxiv2021

Epigenetic predictors of maximum lifespan and other life history traits in mammals

Maximum lifespan of a species is the oldest that individuals can survive, reflecting the genetic limit of longevity in an ideal environment. Here we report methylation-based models that accurately predict maximum lifespan (r=0.89), gestational time (r=0.96), and age at sexual maturity (r=0.87), using cytosine methylation patterns collected from over 12,000 samples derived from 192 mammalian species. Our epigenetic maximum lifespan predictor corroborated the extended lifespan in growth hormone receptor knockout mice and rapamycin treated mice. Across dog breeds, epigenetic maximum lifespan correlates positively with breed lifespan but negatively with breed size. Lifespan-related cytosines are located in transcriptional regulatory regions, such as bivalent chromatin promoters and polycomb-repressed regions, which were hypomethylated in long-lived species. The epigenetic estimators of maximum lifespan and other life history traits will be useful for characterizing understudied species and for identifying interventions that extend lifespan.

evolutionary biology↗

bioRxiv2021

Universal DNA methylation age across mammalian tissues

Aging is often perceived as a degenerative process resulting from random accrual of cellular damage over time. Despite this, age can be accurately estimated by epigenetic clocks based on DNA methylation profiles from almost any tissue of the body. Since such pan-tissue epigenetic clocks have been successfully developed for several different species, we hypothesized that one can build pan-mammalian clocks that measure age in all mammalian species. To address this, we generated data using 11,754 methylation arrays, each profiling up to 36 thousand cytosines in highly-conserved stretches of DNA, from 59 tissue-types derived from 185 mammalian species. From these methylation profiles, we constructed three age predictors, each with a single mathematical formula, termed universal pan-mammalian clocks that are accurate in estimating the age (r>0.96) of any mammalian tissue. Deviations between epigenetic age and chronological age relate to mortality risk in humans, mutations that affect the somatotropic axis in mice, and caloric restriction. We characterized specific cytosines, whose methylation levels change with age across most mammalian species. These cytosines are greatly enriched in polycomb repressive complex 2-binding sites, are located in regions that gradually lose chromatin accessibility with age and are proximal to genes that play a role in mammalian development, cancer, human obesity, and human longevity. Collectively, these results support the notion that aging is indeed evolutionarily conserved and coupled to developmental processes across all mammalian species - a notion that was long-debated without the benefit of this new compelling evidence. SUMMARYThis study identifies and characterizes evolutionarily conserved cytosines implicated in the aging process across mammals and establishes pan mammalian epigenetic clocks.

developmental biology↗

bioRxiv2020

Epigenetic clock and methylation studies in elephants

Age-associated DNA-methylation profiles have been used successfully to develop highly accurate biomarkers of age ("epigenetic clocks") in humans, mice, dogs, and other species. Here we present epigenetic clocks for African and Asian elephants. These clocks were developed using novel DNA methylation profiles of 140 elephant blood samples of known age, at loci that are highly conserved between mammalian species, using a custom Infinium array (HorvathMammalMethylChip40). We present epigenetic clocks for Asian elephants (Elephas maximus), African elephants (Loxodonta africana), and both elephant species combined. Two additional human-elephant clocks were constructed by combing human and elephant samples. Epigenome-wide association studies identified elephant age-related CpGs and their proximal genes. The products of these genes play important roles in cellular differentiation, organismal development, metabolism, and circadian rhythms. Intracellular events observed to change with age included the methylation of bivalent chromatin domains, targets of polycomb repressive complexes, and TFAP2C binding sites. These readily available epigenetic clocks can be used for elephant conservation efforts where accurate estimates of age are needed to predict demographic trends.

developmental biology↗

bioRxiv2020

Candida auris phenotypic heterogeneity determines pathogenicity in vitro

Candida auris is an enigmatic yeast that provides substantial global risk in healthcare facilities and intensive care units. A unique phenotype exhibited by certain isolates of C. auris is their ability to form small clusters of cells known as aggregates, which have been to a limited extent described in the context of pathogenic traits. In this study, we screened several non-aggregative and aggregative C. auris isolates for biofilm formation, where we observed a level of heterogeneity amongst the different phenotypes. Next, we utilised an RNA-sequencing approach to investigate the transcriptional responses during biofilm formation of a non-aggregative and aggregative isolate of the initial pool. Observations from these analyses indicate unique transcriptional profiles in the two isolates, with several genes identified relating to proteins involved in adhesion and invasion of the host in other fungal species. From these findings we investigated for the first time the fungal recognition and inflammatory responses of a three-dimensional skin epithelial model to these isolates. In these models, a wound was induced to mimic a portal of entry for C. auris. We show both phenotypes elicited minimal response in the model minus induction of the wound, yet in the wounded tissue both phenotypes induced a greater response, with the aggregative isolate more pro-inflammatory. This capacity of aggregative C. auris biofilms to generate such responses in the wounded skin highlights how this opportunistic yeast is a high risk within the intensive care environment where susceptible patients have multiple indwelling lines. ImportanceCandida auris has recently emerged as an important cause of concern within healthcare environments due to its ability to persist and tolerate commonly used antiseptics and disinfectants, particularly when surface attached (biofilms). This yeast is able to colonise and subsequently infect patients, particularly those that are critically ill or immunosuppressed, which may result in death. We have undertaken analysis on two different types of this yeast, using molecular and immunological tools to determine whether either of these has a greater ability to cause serious infections. We describe that both isolates exhibit largely different transcriptional profiles during biofilm development. Finally, we show that the inability to form small aggregates (or clusters) of cells has an adverse effect on the organisms immuno-stimulatory properties, suggestive the non-aggregative phenotype may exhibit a certain level of immune evasion.

microbiology↗

bioRxiv2019

Short-term effects of GPS collars on the activity, behavior, and adrenal response of scimitar-horned oryx (Oryx dammah)

GPS collars have revolutionized the field of animal ecology, providing detailed information on animal movement and the habitats necessary for species survival. GPS collars also have the potential to cause adverse effects ranging from mild irritation to severe tissue damage, reduced fitness, and death. The impact of GPS collars on the behavior, stress, or activity, however, have rarely been tested on study species prior to release. The objective of our study was to provide a comprehensive assessment of the short-term effects of GPS collars fitted on scimitar-horned oryx (Oryx dammah), an extinct-in-the-wild antelope once widely distributed across Sahelian grasslands in North Africa. We conducted behavioral observations, assessed fecal glucocorticoid metabolites (FGM), and evaluated high-resolution data from tri-axial accelerometers. Using a series of non-standard regression models, we illustrate clear but short-term effects to animals fitted with GPS collars. Behavioral observations highlighted a significant increase in the amount of headshaking from pre-treatment levels, returning below baseline levels during the post-treatment period (>3 days post-collaring). Similarly, FGM concentrations (i.e., stress hormones) increased after GPS collars were fitted on animals but returned to pre-collaring levels within 5 days of collaring. Lastly, tri-axial accelerometers, collecting data at eight positions per second, indicated a > 480 percent increase in the amount of hourly headshaking immediately after collaring. This post-collaring increase in headshaking was estimated to decline in magnitude within 4 hours after GPS collar fitting. These effects constitute a handling and/or habituation response (model dependent), with animals showing short-term responses in activity, behavior, and stress that dissipated within several hours to several days of being fitted with GPS collars. Importantly, none of our analyses indicated any long-term effects that would have more pressing animal welfare concerns.

ecology↗

bioRxiv2019

Effects of arthropod prey turnover on the chemical traits of poison frogs: a landscape ecology approach to assess the phenotypic consequences of biotic interactions

Ecological studies of species pairs demonstrated that biotic interactions promote phenotypic change and eco-evolutionary feedbacks. However, we have a limited understanding of how phenotypes respond to interactions with multiple taxa. We investigate how interactions with a network of prey species contribute to spatially structured variation in the skin toxins of the Neotropical poison frog Oophaga pumilio. Specifically, we assess how beta-diversity of alkaloid-bearing arthropod prey assemblages (68 ant species) and evolutionary divergence among populations (from a neutral genetic marker) contribute to frog poison dissimilarity (toxin profiles composed of 230 different lipophilic alkaloids sampled from 934 frogs at 46 sites). We show that ant assemblage turnover predicts alkaloid turnover and unique toxin combinations across the range of O. pumilio. By contrast, evolutionary relatedness is barely correlated with toxin variation. We discuss how the analytical framework proposed here can be extended to other multi-trophic systems, coevolutionary mosaics, microbial assemblages, and ecosystem services.

ecology↗

bioRxiv2019

Environmental, social, management and health factors associated with within- and between-individual variability in fecal glucocorticoid metabolite concentrations in zoo-housed Asian and African elephants

Identifying links between environmental, social, management, and health factors as they relate to physiological stress in captive elephants is crucial for the improvement of welfare and husbandry practices in North American zoos. Studies have examined the effects of short-term and chronic elevations in glucocorticoids in small groups of elephants, but few have examined adrenal activity on a large scale. This study evaluated 106 Asian (Elephas maximus) and 131 African (Loxodonta africana) elephants housed at 64 accredited facilities across North America. Fecal samples were collected every other week for 12 months and analyzed for glucocorticoid metabolite (FGM) concentrations. Risk factors for mean and individual variability (CV) in FGM were subjected to univariate and multivariable analyses using epidemiological methods. Independent variables that included individual traits, social environment, housing and management factors were chosen based on their identification as risk factors in previously published models for the same North American population of elephants. Results indicate that African elephants are more responsive to social stressors than Asians, and that poor joint health is a stress-related welfare problem for Asian, but not African elephants. For both species, higher FGM concentrations were associated with zoos located at more northern latitudes and having free access to indoor/outdoor spaces, whereas spending more time in managed interactions with staff were associated with lower FGM concentrations. Also important for captive management, elephants having diverse enrichment options and belonging to compatible social groups exhibited lower mean and reduced intra-individual variability in FGM. Our findings show that aspects of the zoo environment can be potential sources of stress for captive elephants, and that there are management activities that can facilitate coping and adapting to zoo conditions. Given species differences in factors that affected FGM, targeted, species-specific management approaches likely are needed to ensure good welfare for all elephants.

zoology↗

bioRxiv2018

Influence of season, tourist activities and camp management on body condition, testicular and adrenal steroids, lipid profiles, and metabolic status in captive bull elephants in Thailand

We previously found relationships between body condition and physiological function affecting health and welfare of female tourist camp elephants in Thailand, and used that approach to conduct a similar study of bulls elephants in the same camps (n = 13). Elephants received a body condition score (BCS) every other month, and fecal glucocorticoid metabolite (FGM) concentrations were measured in twice monthly samples for 1 year. Effects of season, camp management and tourist activity on lipid profiles [total cholesterol (TC), low density lipoproteins (LDL), high density lipoproteins (HDL), triglycerides (TG)] and metabolic factors [insulin, glucose, fructosamine, glucose to insulin ratio (G:I)] were determined and correlated to measures of body condition, testosterone and adrenal function. Positive correlations were found between BCS and TG, between FGM and TG, HDL and glucose, and between testosterone and HDL (p<0.05), whereas BCS and testosterone were both negatively associated with the G:I (p<0.05). Elevated FGM concentrations were associated with altered lipid profiles and metabolic status and were higher in winter compared to summer and rainy seasons. Insulin and glucose levels were higher, while the G:I was lowest, in the winter season. Strong positive associations (p<0.001) were found between TC and HDL, LDL and HDL and glucose, and glucose and insulin. By contrast, negative relationships (p<0.001) were found between the G:I and HDL and glucose, and between insulin and G:I. Differences also were found between High and Low tourist season months for FGM, insulin, and G:I, which may be related to tourist activities. Last, there was notable variation among the camps in measured parameters, which together with the tourist season effect suggests camp management related to tourism may affect physiological function and welfare; some negatively like feeding high calorie treats, but others are positively, like exercise. Last, compared to females, bulls elephants appear to be in better physical health.

zoology↗