Biology subjects

Sanford, E.

Publications and source records attributed to Sanford, E..

10 recordsLinked to original sources

bioRxiv2026

Revealing the abiotic and biotic drivers of past and future local adaptation in a coastal dogwhelk

Predicting whether populations can persist under rapid environmental change requires identifying the ecological drivers of local adaptation, uncovering their genetic bases, and understanding how adaptive variation will respond to future selection. Here, we combine landscape genomics, environmental data, and evolutionary simulations to identify the selective forces shaping adaptation across 1,500 km of the west coast of North America in the low-dispersing coastal dogwhelk Nucella canaliculata, determine their genomic bases, and forecast future evolutionary responses. We found strong associations of genome-wide variation with both abiotic (i.e., mean pH) and biotic variation (i.e., cross-sectional shell thickness of the mussel prey species, Mytilus californianus). These patterns are underlain by two large-effect loci, including a biomineralization gene associated with pH tolerance and a locus near a thiamine transporter associated with prey shell thickness. Genomic offset analyses and population genetic simulations further predict that ongoing ocean acidification will disrupt existing adaptive patterns and generate maladaptation in high latitude populations, with evolutionary outcomes strongly influenced by gene flow, which determines the rate at which adaptive alleles spread across the species range. Together, these findings reveal how biotic and abiotic selective pressures shape adaptive genomic variation and provide a framework for forecasting evolutionary responses to future global change.

evolutionary biology↗

bioRxiv2026

Ocean acidification changes diet effects and differentially impacts two populations of red abalone (Haliotis rufescens)

Absorption of CO2 by global oceans is decreasing pH resulting in ocean acidification (OA). Impacts on shellfish have been documented in ecologically and commercially important species. We examined the influence of diet and OA between two populations of red abalone (Haliotis rufescens) a species of aquaculture importance and declining wild populations. Populations experience different exposure histories: strong upwelling (Van Damme, California [VD]) historically exposed to low-pH conditions and weak-intermittent upwelling (Santa Barbara, California [SB]). Abalone were cultured under control-pH or OA-conditions and fed crustose coralline algae (CCA) or diatoms used in aquaculture. We tested treatment effects of population, settlement diet, and OA-exposure on survival as influenced by larval-energy stores. Survival in both populations was enhanced by CCA when cultured under both treatment conditions; however, by later stages, this effect remained only for SB. SB had reduced post-settlement survival when cultured under OA-conditions, whereas post-settlement survival of VD was not. Diet affected the relationship between larval-energy and post-settlement survival; a positive relationship when fed diatoms and a negative relationship with CCA. The relationship between larval energy and post-settlement survival was stronger in VD. CCA enhanced juvenile growth in SB cultured abalone at both three-months and one-year post-settlement. Settlement diets can reduce the impacts of OA on early-life stages of abalone, but population differences driven by underlying energetics affect the consistency of this outcome. These findings illuminate the impacts from OA, suggesting populations may be at risk, and inform strategies for developing and sustaining shellfish aquaculture in the face of changing ocean conditions.

physiology↗

bioRxiv2025

Spatial sorting and accelerated larval development in a range expanding fiddler crab

Although climate change has driven the widespread occurrence of species range shifts, the ecological and evolutionary processes that generate these patterns remain poorly understood. Here, we investigate spatial sorting and countergradient selection as evolutionary mechanisms contributing to range expansion. We focus on the rapid range expansion of a fiddler crab (Minuca pugnax) in the Gulf of Maine, an ocean warming hotspot. We use common garden experiments to quantify change in pelagic larval duration (PLD), a key determinant of dispersal ability, across edge and interior core populations, and between timepoints separated by 19 years. Consistent with spatial sorting, larvae from poleward, edge populations had shorter PLDs relative to equatorward, core populations, which is more dispersive in this system because it is characterized by equatorward flows. Compared to 19 years prior, PLDs were significantly shorter, consistent with genetic change over time. Analysis of sea surface temperatures reveal that the larval development window in the edge populations has doubled over the past twenty years, suggesting the combined influence of ocean warming, trait differentiation over time, and spatial sorting in promoting range expansion. While spatial sorting is known to aid in terrestrial range expansions, our results are the first to suggest that this process might be important in the coastal oceans.

ecology↗

bioRxiv2025

Biogeographic variation in reproductive strategy in a range-expanding marine gastropod

Although species geographic distributions are increasingly shifting poleward with climate change, the processes that facilitate or impede range shifts are poorly understood. More extreme environmental conditions near poleward range boundaries often impose reproductive constraints, which may limit fitness and future range expansion. However, few studies evaluate the extent to which adaptive evolution and/or phenotypic plasticity might mitigate the effects of reproductive constraints and contribute to successful range shifts. We examined reproductive trait variation across the geographic range of Acanthinucella spirata, an intertidal snail that has recently expanded poleward along the coast of California, USA. We found that, compared to the range core, A. spirata from cooler range-edge populations allocated approximately 16x more nurse eggs to each developing embryo and had larger offspring at hatching, which may lead to greater juvenile growth rates and survival. Furthermore, range-edge A. spirata populations had lower fecundity, highlighting a potential tradeoff between offspring size and number. Some trait differences between range-core and range-edge populations persisted in an 18-month common-garden experiment, consistent with the hypothesis that such traits may be under selection. This study suggests that life-history adaptations in range-edge populations are an important and understudied mechanism that may contribute to species range expansions.

ecology↗

bioRxiv2025

Naltrexone has variable and schedule-dependent effects on oral squamous cell carcinoma cells

Oral squamous cell carcinoma is marked by profound differences in survival between localized and disseminated disease. While at its site of origin, oral cancer is frequently treated with surgery and/or radiation, leading to approximately 70% five-year survival. In metastatic cases, chemotherapy is preferred, but drug resistance and therapy failure is common in this setting, leading to five-year survival below 40%. New therapeutic approaches are therefore needed to supplement existing chemotherapies and improve outcomes. Naltrexone, an opioid antagonist most well-known for treatment of substance abuse, has been evaluated at low doses in other contexts, including inflammation, autoimmunity, and other forms of cancer. In this study, we sought to determine if intermittent dosing of naltrexone would impact oral cancer cell survival, either as a single agent or in combination with traditional chemotherapy. We found that its effects alone were negligible, but that combination with cytotoxic drugs may have promise as a novel treatment strategy. Further study and optimization will be needed to determine if these findings will be of clinical benefit.

pharmacology and toxicology↗

bioRxiv2025

Geographic Divergence in Population Genomics and Shell Morphology Reveal History of Glacial Refugia in a Coastal Dogwhelk

Studying contemporaneous spatial patterns of genomic diversity can yield important insights into the evolutionary processes that structure populations and shape patterns of adaptation. In contrast to the large number of marine species with planktonic larvae, populations of marine taxa with low dispersal and deep evolutionary divergences offer an opportunity to reveal the phylogeographic histories of marine ecosystems. Here, we constructed a draft genome assembly for the low-dispersing marine dogwhelk, Nucella canaliculata, and studied patterns of genomic diversity and shell morphometrics in 19 populations distributed along [~]1,500 km of the west coast of North America. We observed significant population structure with a strong phylogeographic break at Monterey Bay, which was matched with divergence in shell morphology. Genomic patterns, concomitant with computer simulations, suggest that there were at least two refugial populations during the last glacial maximum that subsequently experienced post-glacial expansion and admixture. Lastly, linking genotype to phenotype, we identified candidate loci underlying variation in shell morphology. These findings demonstrate how high-resolution genomic data reveal the roles of demography, selection, and historical events in shaping the spatial distribution of genetic variation, offering key insights into the processes that structure modern coastal populations and their potential to respond to future climatic changes.

evolutionary biology↗

bioRxiv2024

Polystyrene nanoplastics promote neurodegeneration by catalyzing TDP43 hyperphosphorylation

The ubiquity of polystyrene nanoplastics (PS-NPs) in our environment raises substantial concerns about their potential impact on human health. Recent studies have shown that PS-NPs cross the blood-brain-barrier and accumulate in the central nervous system (CNS), raising the concerns on the causal role of PS-NP exposure and neurodegenerative diseases. In this study, we utilized human-induced pluripotent stem cell-derived neurons to examine the effects of PS-NPs on neuronal function and health. Our results revealed that PS-NPs penetrate neuronal cells in a size-dependent manner, and are bound by various cellular proteins, including TDP43, a key protein implicated in amyotrophic lateral sclerosis (ALS). Interestingly, CK1 and GSK3{beta} kinases that are known to phosphorylate TDP-43 were found to be associated with PS-NPs. This observation suggests that PS-NPs may play a role in facilitating conditions that lead to TDP43 phosphorylation. We further demonstrate that exposure to healthy motor neurons with PS-NPs resulted in ALS-like phenotypes, characterized by hyperphosphorylated TDP-43, disrupted neuronal morphology, impaired mitochondrial respiration, and accelerated motor neuron death. These findings suggest that PS-NPs contribute to the pathogenesis of neurodegenerative diseases such as ALS and highlight the urgent need for strategies to limit human exposure to nanoplastics.

neuroscience↗

bioRxiv2024

Sex-Specific Cardiac Remodeling in Aged Rats after Early-Life Chronic Stress: Associations with Endocrine and Metabolic Factors

BackgroundCardiovascular disease is a leading cause of death worldwide. Rates of cardiovascular disease vary both across the lifespan and between sexes. While multiple factors, including adverse life experiences, impact the development and progression of cardiovascular disease, the potential interactions of biological sex and stress history on the aged heart are unknown. To this end, we examined sex- and stress-specific impacts on left ventricular hypertrophy (VH) after aging. We hypothesized that early life chronic stress exposure impacts behavioral and physiologic responses that predict cardiac remodeling in a sex-specific manner. MethodsHistological analysis was conducted on hearts of male and female rats previously exposed to chronic variable stress during the late adolescent period (postnatal days 43-62). These animals were challenged with a forced swim test and a glucose tolerance test before aging to 15 months and again being challenged. Predictive analyses were then used to isolate factors that relate to cardiac remodeling among these groups. ResultsEarly-life chronic stress impacted cardiac remodeling in a sex-specific manner. Among rats with a history of chronic stress, females had increased inward VH. However, there were few associations within the female groups among individual behavioral and physiologic parameters and cardiac remodeling. While males as a group did not have VH after chronic stress, they exhibited multiple individual associations with cardiac susceptibility. Passive coping in young males and active coping in aged males related to VH in a stress history-dependent manner. Moreover, baseline corticosterone positively correlated with VH in unstressed males, while chronically-stressed males had positive correlations between VH and visceral adiposity. ConclusionsThese results indicate that females as a group are uniquely susceptible to the effects of early-life stress on cardiac remodeling later in life. Conversely, males have more individual differences in vulnerability, where susceptibility to cardiac remodeling relates to endocrine, metabolic, and behavioral measures depending on stress history. These results ultimately support a framework for accessing cardiovascular risk based on biological sex and prior adverse experiences. HighlightsO_LIAged female rats had greater left ventricular hypertrophy (VH) than males after early-life chronic variable stress. C_LIO_LITertile divisions based on susceptibility or resilience to inward VH indicated interactions between VH, sex, and stress on multiple behavioral and physiological measures. C_LIO_LIIn males, VH correlated with endocrine and metabolic parameters in a stress history-dependent manner. C_LIO_LIPrior adverse experience and biological sex interact across the lifespan to impact cardiovascular risk. C_LI Plain English SummaryCardiovascular disease is the leading cause of death worldwide. Multiple factors influence the incidence and severity of cardiovascular disease including adverse life experiences, biological sex, and age. Alterations of heart structure predict negative cardiovascular health by impacting blood circulation; however, the potential interactions of stress history and biological sex on the aged heart are unknown. In this study, we examined how chronic stress exposure impacts heart structure in male and female rats after aging. Adolescent male and female rats were chronically stressed and then acutely challenged to examine behavioral, endocrine, and metabolic parameters both immediately following chronic stress and after aging. Heart morphology was quantified to examine how behavioral and physiological responses related to cardiac remodeling. Our results indicate that, as a group, female rats previously exposed to chronic stress were uniquely susceptible to inward remodeling of the heart. Subjects were further divided into sub-groups based on the level of inward remodeling of the ventricle. While male rats did not exhibit group effects on heart structure, individual variability in male heart morphology related to endocrine and metabolic parameters in a stress history-dependent manner. Here, there were interactions with multiple systems including coping behavior, stress hormones, and body composition. Moreover, males without a prior history of chronic stress had correlations between stress hormones and the degree of heart remodeling. However, males that were exposed to chronic stress had correlations between heart structure and abdominal fat. Overall, our results indicate that biological sex and stress history interact to predict cardiovascular susceptibility.

physiology↗

bioRxiv2019

Gene networks with transcriptional bursting recapitulate rare transient coordinated expression states in cancer

SUMMARYNon-genetic transcriptional variability at the single-cell level is a potential mechanism for therapy resistance in melanoma. Specifically, rare subpopulations of melanoma cells occupy a transient pre-resistant state characterized by coordinated high expression of several genes. Importantly, these rare cells are able to survive drug treatment and develop resistance. How might these extremely rare states arise and disappear within the population? It is unclear whether the canonical stochastic models of probabilistic transcriptional pulsing can explain this behavior, or if it requires special, hitherto unidentified molecular mechanisms. Here we use mathematical modeling to show that a minimal network comprising of transcriptional bursting and interactions between genes can give rise to rare coordinated high states. We next show that although these states occur across networks of different sizes, they depend strongly on three (out of seven) model parameters and require network connectivity to be [≤] 6. Interestingly, we find that while entry into the rare coordinated high state is initiated by a long transcriptional burst that also triggers entry of other genes, the exit from it occurs through the independent inactivation of individual genes. Finally, our model predicts that increased network connectivity can lead to transcriptionally stable states, which we verify using network inference analysis of experimental data. In sum, we demonstrate that established principles of gene regulation are sufficient to describe this new class of rare cell variability and argue for its general existence in other biological contexts.

systems biology↗

bioRxiv2019

In-depth and 3-Dimensional Exploration of the Budding Yeast Phosphoproteome

Phosphorylation is one of the most dynamic and widespread post-translational modifications regulating virtually every aspect of eukaryotic cell biology. Here we present a comprehensive phosphoproteomic dataset for budding yeast, comprised of over 30,000 high confidence phosphorylation sites identified by mass spectrometry. This single dataset nearly doubles the size of the known phosphoproteome in budding yeast and defines a set of cell cycle-regulated phosphorylation events. With the goal of enhancing the identification of functional phosphorylation events, we performed computational positioning of phosphorylation sites on available 3D protein structures and systematically identified events predicted to regulate protein complex architecture. Results reveal a large number of phosphorylation sites mapping to or near protein interaction interfaces, many of which result in steric or electrostatic \"clashes\" predicted to disrupt the interaction. Phosphorylation site mutants experimentally validate our predictions and support a role for phosphorylation in negatively regulating protein-protein interactions. With the advancement of Cryo-EM and the increasing number of available structures, our approach should help drive the functional and spatial exploration of the phosphoproteome.

biochemistry↗