Biology subjects

Richardson, D. S.

Publications and source records attributed to Richardson, D. S..

15 recordsLinked to original sources

bioRxiv2026

Breast Cancer-derived PDGFB Remodels the CNS Vascular Niche to Promote Brain, Spinal and Leptomeningeal Metastasis

Background: Central nervous system (CNS) metastases are a major driver of breast cancer (BC) mortality. Recently, our group demonstrated that platelet-derived growth factor-B (PDGFB) and its receptor, platelet-derived growth factor receptor-beta (PDGFR{beta}), promote BC metastasis to the brain; however, the cellular/molecular mechanisms driving this process remain unclear. Here, we investigated tumor-derived PDGFB effects on the CNS vascular niche in regulating metastatic spread. Methods: Triple-negative BC cells were engineered to overexpress PDGFB and used to evaluate endothelial sprouting, blood-brain barrier (BBB) function, vascular permeability and experimental CNS metastasis. A novel retro-orbital (RO) injection model was used to study leptomeningeal/spinal experimental metastasis. Results: PDGFB enhanced human brain microvascular endothelial cell (HBMEC) sprouting, induced cell migration in BBB spheroids, increased permeability in 3D models, and disrupted tight junction proteins in HBMECs. Notably, alterations in vascular permeability were observed in both PDGFR{beta}-positive and PDGFR{beta}-negative endothelial systems, suggesting PDGFB can remodel the CNS vasculature through multiple mechanisms. In vivo, PDGFB increased CNS metastatic burden and altered tumor vasculature in xenograft and allograft models of BC. Furthermore, PDGFB promoted robust colonization of both spinal and leptomeningeal compartments, identifying a previously underappreciated role for this signaling pathway in a clinically devastating form of CNS metastasis. Analysis of patient transcriptomic datasets revealed enrichment of angiogenesis-related pathways in PDGFB-high tumors from patients who developed CNS metastases. Conclusions: Collectively, these findings identify tumor-derived PDGFB as a key regulator of CNS vascular remodeling and metastatic tropism, while introducing a new experimental framework to study spinal metastases and leptomeningeal disease in BC.

cancer biology↗

bioRxiv2026

Sexual selection purges mutation load, but not overall genetic diversity in populations, decreasing vulnerability to extinction

Theory suggests sexual selection will enhance population viability by purging deleterious alleles. However, direct genomic evidence for this fundamental idea is scarce and contradictory. We combined long-term experimental evolution with whole-genome re-sequencing to directly test how sexual selection affects mutation load, genomic divergence and extinction risk in Tribolium castaneum. After 156 generations, populations evolving under strong sexual selection carried substantially fewer deleterious alleles than populations under weak sexual selection, based on both individual-level estimates of missense and nonsense variants and population-level Rxy analyses, indicating more efficient purging of deleterious alleles. In contrast, nucleotide diversity and runs of homozygosity were similar across treatments, indicating that purging was targeted at deleterious variation, and that reduced mutation load in populations under strong sexual selection was not explained by demographic effects. Importantly, population-level mutation load estimates provided best explained extinction risk under inbreeding, directly linking sexual selection to purging and population viability for the first time. Genome scans of high and low sexual selection populations revealed peaks of divergence, enriched for genes involved in courtship, sex discrimination, and seminal fluid proteins. Our results provide direct genomic evidence that sexual selection can reduce mutation load without eroding standing genetic diversity and thus adaptive potential, while driving adaptive divergence in reproductive traits. This beneficial purging may help explain the widespread prevalence of sexual reproduction in nature despite inherent costs and have important ramifications as to how we manage populations of conservation concern. Significance StatementA long standing and unconfirmed prediction is that sexual selection can improve population health by biasing reproduction away from individuals with high deleterious mutation load. However, direct genomic evidence is lacking, and the indirect data available are scant and contradictory. Now, using whole-genome resequencing of experimental evolved beetle populations, we show that populations evolving under stronger sexual selection carry fewer deleterious mutations and, importantly, are less vulnerable to extinction. Our results provide the first direct genomic support for this long-debated evolutionary process that may help explain the widespread prevalence of sexual reproduction in nature. Our findings also highlight the importance of allowing sexual selection to act in populations of conservation concern.

evolutionary biology↗

bioRxiv2025

Life-history traits as predictors of expected genetic contributions 15 years later in a cooperatively breeding bird

An individuals life history plays an important role in how successful individuals are in passing on their genes to future generations. However, exactly which life-history traits best approximate an individuals long-term genetic contributions remains poorly studied, especially in cooperative breeders. Here, we use a genetic pedigree and long-term data of the closed population of the Seychelles warbler (Acrocephalus sechellensis) to calculate the expected individual genetic contributions (IGC) after 15 years (or [~]3 generations) across 11 cohorts. Using a Bayesian analysis we then quantified and compared how well six important life-history traits predict IGC in each sex of this cooperatively breeding species. The life-history traits compared were: acquisition of a dominant breeding position, age at first breeding attempt, tenure as a dominant breeder, lifespan, and LRS (measured as both the number of independent [surviving 3 months+] and recruited [surviving 1 year+] offspring produced over an individuals lifetime). An individuals lifetime reproductive success (LRS) was the strongest predictor of IGC and this predictive power did not differ across the different measurements used. However, this predictive power did differ between sexes, explaining [~]61-62% of IGC variation in males versus [~]47-49% in females owing to the larger variation among males in their annual reproductive success. Across other life-history traits the predictive power of IGC was similar across both sexes but differed between life-history traits considerably (2-37%). Comparing these predictive powers suggested that lifespan and the duration of a dominant breeding position are far more important in shaping long-term genetic contributions than if and when in their life they acquired dominance. Overall, these findings give insight into the individual and population-level processes influencing future gene pools and illustrate how life-history evolution is shaped by sex-specific reproductive patterns and cooperative breeding dynamics.

evolutionary biology↗

bioRxiv2025

Divergent selection on dispersal targets chemosensory and neuronal genes in Tribolium castaneum

Dispersal is key to the life history, ecology and evolution of many organisms, and important in pest invasiveness. However, the genetic architecture underlying variation in dispersal behaviour remains poorly understood outside of a few model species. We investigated the genomic basis of dispersal using artificial selection on replicated lines of Tribolium castaneum, a flour beetle, an emergent model system, and an economically important agricultural pest. Combining whole-genome resequencing with population-level genotype-phenotype association analysis, we identify genomic regions associated with selection on dispersal. Identified candidate genes were significantly enriched for functions related to neuronal structure and function, as well as chemosensory behaviour and mating, suggesting that variation in dispersal is mediated by neural and chemosensory pathways. Our results demonstrate that dispersal propensity has a polygenic basis and support an interaction between dispersal and mating ecology in this system. These findings contribute to a deeper understanding of the genetic mechanisms driving dispersal evolution of dispersal and its role in shaping eco-evolutionary dynamics.

evolutionary biology↗

bioRxiv2025

Does genetic rescue disrupt local adaptation? An experimental test using thermally adapted Tribolium castaneum lines

Anthropogenic drivers are restricting many species to small, genetically isolated populations. These are prone to inbreeding depression and are at an increased risk of extinction. Genetic rescue, the controlled introduction of genetic variation from another population, can alleviate inbreeding effects. A major conservation concern, restricting the use of this technique, is that such augmented gene flow may disrupt local adaptation crucial to a populations persistence. Using populations of the red flour beetle (Tribolium castaneum) experimentally adapted to reproduce at higher temperatures, we assess whether genetic rescue attempts disrupt thermal adaptation. Rescuers, drawn from populations adapted to either 30{degrees}C or 38{degrees}C, were introduced into populations adapted to 38{degrees}C, which had been inbred for two generations. We recorded population productivity for three generations post-rescue, in the adapted 38{degrees}C environment. Rescuers with and without local adaptation significantly increased the productivity of recipient inbred populations but, importantly, those sharing local adaptation to reproduction at 38{degrees}C provided greater increases in productivity. For the first time, we show that co-adaptation between rescuing individuals and rescuee population maybe an essential aspect of achieving desired conservation outcomes.

evolutionary biology↗

bioRxiv2025

Super-resolution microscopy reveals distinct epigenetic states regulated by estrogen receptor activity

Changes in gene expression regulated by ligand-dependent transcription factors such as estrogen receptor- (ER) involves the recruitment of coactivators including p300 that acetylates histone H3 at lysine 27 (H3K27ac). While H3K27ac marks active enhancers, the detailed chromatin architecture of enhancers remains unclear. Using super-resolution microscopy, we reveal distinct structural states of H3K27ac modified chromatin in response to ER activation. In estradiol (E2)-treated cells, H3K27ac modified chromatin adopts open, elongated structures, while ER inhibition induces compact, spherical H3K27ac modified chromatin conformations. Using MED1, a core subunit of the Mediator complex that bridges transcription factors with RNA polymerase II (Pol II), we demonstrate that larger H3K27ac structures are preferentially associated with active enhancers, whereas more compact structures show reduced MED1 association, consistent with a less active or inactive state. A constitutively active ER mutation linked to endocrine therapy resistance in breast cancer maintains open chromatin states independent of ligand, suggesting sustained transcriptional activity. Our findings provide the first direct visualization of H3K27ac associated chromatin structural dynamics, challenging the assumption that H3K27ac modification alone is sufficient to lead to enhancer activation. By demonstrating that H3K27ac architecture is dynamically regulated by ER, we establish a new paradigm for understanding epigenetic regulation and highlight potential therapeutic targets for endocrine therapy resistant cancers.

cancer biology↗

bioRxiv2024

Sexual selection matters in genetic rescue, but productivity benefits fade over time; a multi-generation experiment to inform conservation.

Globally, many species are threatened by population decline because of anthropogenic changes which leads to population fragmentation, genetic isolation, and inbreeding depression. Genetic rescue, the controlled introduction of genetic variation, is a method used to potentially relieve such effects in small populations. However, without understanding how the characteristics of rescuers impact rescue attempts interventions run the risk of being sub-optimal, or even counterproductive. We use the Red Flour Beetle (Tribolium castaneum) to test the impact of rescuer sex, and sexual selection background, on population productivity. We record the impact of genetic rescue on population productivity in 24/36 replicated populations for ten generations following intervention. We find little or no impact of rescuer sex on the efficacy of rescue but show that a background of elevated sexual selection makes individuals more effective rescuers. In both experiments, rescue effects diminish 6-10 generations after the rescue. Our results confirm that the efficacy of genetic rescue can be influenced by characteristics of the rescuers and that the level of sexual selection in the rescuing population is an important factor. We show that any increase in fitness associated with rescue may last for a limited number of generations, suggesting implications for conservation policy and practice.

evolutionary biology↗

bioRxiv2024

Craters on the melanoma surface facilitate tumor-immune interactions and demonstrate pathologic response to checkpoint blockade in humans

Immunotherapy leads to cancer eradication despite the tumors immunosuppressive environment. Here, we used extended long-term in-vivo imaging and high-resolution spatial transcriptomics of endogenous melanoma in zebrafish, and multiplex imaging of human melanoma, to identify domains that facilitate immune response during immunotherapy. We identified crater-shaped pockets at the margins of zebrafish and human melanoma, rich with beta-2 microglobulin (B2M) and antigen recognition molecules. The craters harbor the highest density of CD8+ T cells in the tumor. In zebrafish, CD8+ T cells formed prolonged interactions with melanoma cells within craters, characteristic of antigen recognition. Following immunostimulatory treatment, the craters enlarged and became the major site of activated CD8+ T cell accumulation and tumor killing that was B2M dependent. In humans, craters predicted immune response to ICB therapy, showing response better than high T cell infiltration. This marks craters as potential new diagnostic tool for immunotherapy success and targets to enhance ICB response.

cancer biology↗

bioRxiv2024

A path analysis disentangling determinants of natal dispersal in a cooperatively breeding bird

Delayed offspring dispersal is an important aspect of the evolution of cooperative breeding. By applying a path-analysis approach to the long-term Seychelles warbler (Acrocephalus sechellensis) dataset, we studied whether and how delayed dispersal is affected by territory quality, the presence of helpers and non-helping subordinates, maternal breeding status, age and fecundity, and offspring sex ratio. We found that offspring are more likely to disperse when their genetic mothers are co-breeders, helpers are absent and territory quality is high. In contrast to earlier findings, our analysis does not support the idea that offspring sex ratio is affected by territory quality and helper presence. Our findings suggest that a complex interplay of ecological and social factors shapes dispersal decisions. Our study underscores the importance of considering proximate factors in understanding cooperative breeding dynamics, and it shows that path analyses offer valuable insights into dissecting the intricate relationships influencing dispersal in wild populations.

ecology↗

bioRxiv2023

Loss of Tumour Suppressor TMEM127 Drives RET-mediated Transformation Through Disrupted Membrane Dynamics

Internalization from the cell membrane and endosomal trafficking of receptor tyrosine kinases (RTK) are important regulators of signaling in normal cells that can frequently be disrupted in cancer. The adrenal tumour pheochromocytoma (PCC) can be caused by activating mutations of the RET receptor tyrosine kinase, or inactivation of TMEM127, a transmembrane tumour suppressor implicated in trafficking of endosomal cargos. However, the role of aberrant receptor trafficking in PCC is not well understood. Here, we show that loss of TMEM127 causes wildtype RET protein accumulation on the cell surface, where increased receptor density facilitates constitutive ligand-independent activity and downstream signaling, driving cell proliferation. Loss of TMEM127 altered normal cell membrane organization and recruitment and stabilization of membrane protein complexes, impaired assembly, and maturation of clathrin coated pits, and reduced internalization and degradation of cell surface RET. In addition to RTKs, TMEM127 depletion also promoted surface accumulation of several other transmembrane proteins, suggesting it may cause global defects in surface protein activity and function. Together, our data identify TMEM127 as an important determinant of membrane organization including membrane protein diffusability, and protein complex assembly and provide a novel paradigm for oncogenesis in PCC where altered membrane dynamics promotes cell surface accumulation and constitutive activity of growth factor receptors to drive aberrant signaling and promote transformation.

cancer biology↗

bioRxiv2023

A major myna problem; invasive predator removal benefits female survival and population growth of a translocated island endemic

Invasive predators are a major driver of extinctions and continue to threaten native populations worldwide. Island eradications of (mostly mammalian) invasive predators have facilitated the (re)establishment of numerous island-endemic populations. Other invasive taxa, such as some predatory birds, could pose a more persistent threat due to their ability to fly and actively re-invade even remote and isolated islands. However, the impact of invasive predatory birds has been largely overlooked. We report on a novel sex-specific impact of an invasive-nest predator, the common myna (Acridotheres tristis), on a reintroduced population of Seychelles warblers (Acrocephalus sechellensis); translocated from Cousin Island to Denis Island in 2004. Regular post-translocation monitoring revealed that female mortality was 20% higher than males, leading to a 60-70% male-biased population sex-ratio between 2005-2015. This was attributed to mynas inflicting severe injuries to incubating female warblers while attempting to prey upon eggs in their nests. These effects likely contributed to the slower-than-expected population growth observed (relative to previous translocations of Seychelles warblers to other islands) over the same period. An eradication programme beginning in 2011 removed all mynas from Denis by 2015. Subsequently, we observed a balancing of sex-specific survival and the population sex-ratio of Seychelles warblers and, consequently, accelerated population growth. This study demonstrates the importance of assessing the threat posed by all invasive taxa (not just mammals) to island conservation. Furthermore, we show how extended monitoring is needed to identify problems, and develop solutions, post-translocation.

ecology↗

bioRxiv2022

Genetic structure and differentiation of the endemic Bolle's Laurel Pigeon (Columba bollii) in the Canary Islands

Island archipelagos are global biodiversity hotspots since they often foster high concentrations of diverse lineages and endemic species. Here, we examine the population genetics of the endemic Bolles Laurel Pigeon Columba bollii, a frugivorous bird inhabiting subtropical laurel forests. We genotyped ten microsatellite loci using DNA obtained from moulted tail feathers collected at eight sampling sites on the four western islands of the Canarian archipelago. Analyses including F-statistics, Bayesian clustering approaches, isolation by distance tests and population graph topologies, were used to infer the genetic diversity and the population differentiation within and among insular populations. Additionally, we evaluated the effect of null alleles on data analysis. Low genetic diversity was found in all populations of Bolles Laurel Pigeon, with no significant differences in diversity among them. However, significant genetic differentiation was detected among all populations, with pigeons from La Palma and El Hierro exhibiting the closest affinity. Bayesian clustering supported population separation between islands, and also detected fine-scale structure within the Tenerife and La Gomera populations. Present-day pigeon movements appear to occur between islands, however, this has not been sufficient to remove the signature of genetic divergence among the populations of Bolles Laurel Pigeon, which was moderately linked to geographical distance. According to metapopulation structure, this study suggests that the evolutionary history of C. bollii is closely related to the geological past of these oceanic islands and the distribution range of its habitat, the laurel forest. Finally, conservation implications for the species are discussed.

evolutionary biology↗

bioRxiv2022

Tissue libraries enable rapid determination of conditions that preserve antibody labeling in cleared mouse and human tissue

Difficulty achieving complete, specific, and homogenous staining is a major bottleneck preventing the widespread use of tissue clearing techniques to image large volumes of human tissue. In this manuscript, we describe a procedure to rapidly design immunostaining protocols for antibody labeling of cleared brain tissue. We prepared libraries of .5-1.0 mm thick tissue sections that are fixed, pre-treated, and cleared via similar, but different procedures to optimize staining conditions for a panel of antibodies. Results from a library of mouse tissue correlate well with results from a similarly prepared library of human brain tissue, suggesting mouse tissue is an adequate substitute for protocol optimization. These data show that procedural differences do not influence every antibody-antigen pair in the same way, and minor changes can have deleterious effects, therefore, optimization should be conducted for each target. The approach outlined here will help guide researchers to successfully label a variety of targets, thus removing a major hurdle to accessing the rich 3D information available in large, cleared human tissue volumes.

cell biology↗

bioRxiv2022

Putting life history theory to the test - the estimation of reproductive values from field data

Quantifying fitness is important to understand adaptive evolution. Reproductive values are useful for making fitness comparisons involving different categories of individuals, like males and females. By definition, the reproductive value of a category is the expected per capita contribution of the members of that category to the gene pool of future generations. Life history theory reveals how reproductive values can be determined via the estimation of life-history parameters, but this requires intricate algebraic calculations. Recently, a more intuitive, pedigree-based method has become popular, which estimates the genetic contributions of individuals to future generations by tracking their descendants down the pedigree. Here we compare both methods. We implement various life-history scenarios (for which the "true" reproductive values can be calculated) in individual-based simulations, use the simulation data to estimate reproductive values with both methods, and compare the results with the true target values. We show that the pedigree-based estimation of reproductive values is either systematically biased (and hence inaccurate), or very imprecise. This holds even for simple life histories and under idealized conditions. In contrast, the traditional algebraic method estimates reproductive values with high accuracy and precision. Lay SummaryTo study evolution in empirical systems it is important to accurately and precisely measure fitness. Here, using simulations, we compare two methods for estimating fitness and test their accuracy and precision. One estimates life-history parameters and calculates a fitness proxy using complex algebra. The other method estimates genetic contribution to future generations by tracking descendants down the pedigree. We conclude that the pedigree method is unreliable, while the algebraic method is accurate and precise.

evolutionary biology↗

bioRxiv2018

Compensatory and additive helper effects in the cooperatively breeding Seychelles warbler (Acrocephalus sechellensis).

O_LIIn cooperatively breeding species, helper aid may affect dominant breeders investment trade-offs between current and future reproduction. By compensating for the care provided by helpers, breeders can reduce the costs of reproduction and improve chances of survival. Also, helper care can be additive to that of dominants, resulting in higher success of the current brood.\nC_LIO_LIHowever, the influence of helpers on offspring care itself may be the by-product of group size and territory quality. Therefore to make conclusive inferences about causation of additive and compensatory care as a result of help per se requires disentangling the impact of helping from other factors determining parental investment.\nC_LIO_LIIn this study, we use 20 years of offspring provisioning data to investigate the effect of helping on breeder and overall offspring provisioning rates in the facultative cooperatively breeding Seychelles warbler (Acrocephalus sechellensis). Our extensive dataset allowed us to effectively control for the effects of living in a larger group and in territories with higher food availability.\nC_LIO_LIWe show compensatory and additive care in response to helper aid. Helpers lightened the provisioning load of the dominant male and female and increased the total provisioning to the nestlings. This was irrespective of group size or territory quality (food availability).\nC_LIO_LIOur results illustrate how multiple benefits of helping behaviour can simultaneously be fundamental to the evolutionary maintenance of cooperative behaviour.\nC_LI

animal behavior and cognition↗