Biology subjects

Dodd, R.

Publications and source records attributed to Dodd, R..

6 recordsLinked to original sources

bioRxiv2026

A role for heavy chain-modification in protecting hyaluronan from free radical fragmentation during inflammation

The glycosaminoglycan hyaluronan (HA) is an essential and ubiquitous component of human tissues and biofluids. The only known covalent modification of HA entails the attachment of heavy chains (HC) from the inter-alpha-inhibitor (II) family of proteoglycans, forming stable complexes (HC*HA) that arise during inflammation. In some contexts, HC*HA is thought to contribute to pathology, whereas in others it may form part of a protective pathway. However, its exact roles are not fully understood. Here, we report that HC modifications can protect HA from fragmentation by reactive oxygen species (ROS) produced during the inflammatory cascade. Using solid-state nanopore molecular size analysis, we show that HA is highly resistant to degradation from exogenous ROS in vitro when in the context of HC*HA complexes, while the unmodified HA polymer is fragmented rapidly under the same conditions. Experiments performed with admixtures of HA and unbound antioxidant proteins - including HC-bearing components - demonstrate the necessity of covalent HC attachment to the polysaccharide for the protection. Finally, we find that HA with high-HC content from inflammatory equine synovial fluid has increased resilience to ROS damage compared to low-HC HA from a healthy joint. Collectively, these results demonstrate that covalent HC modification is an effective biological strategy for preserving HA integrity against ROS fragmentation, including in inflammatory conditions.

molecular biology↗

bioRxiv2025

Exome Sequencing and Allele Dosage Analysis of Coast Redwood, a Hexaploid Conifer, Identifies a Major Population Break South of San Francisco Bay

1The coast redwood (Sequoia sempervirens) is a long-lived, hexaploid conifer of high ecological, cultural, and economic value whose range has been greatly reduced by historical logging [1]. Effective restoration and conservation depend on understanding patterns of genetic differentiation across the redwood range to delineate populations for management prioritization. Yet, past range-wide studies provided only a partial picture of population structure in coast redwood as they relied on a limited set of genetic markers [2, 3] or limited sampling, as sequencing was done on the same range-wide provenance collection [4, 5]. Here, we analyze 334,029 SNPs from a new range-wide set of 224 individuals using a dosage-based approach that accounts for polyploidy. Principal coordinates and clustering analyses reveal clear latitudinal structure, with a steeper break south of San Francisco Bay. Outlier SNP analysis identified new candidate loci involved in salinity tolerance, climate stress response, and nutrient uptake, suggesting potential local adaptation. These results point to the central role of geography in shaping genetic variation in coast redwood and give scientific basis for designing new conservation and management strategies aimed at preserving the species genetic diversity into the future.

ecology↗

bioRxiv2025

Migratory dermal gamma delta T cells determine the balance between lung immunity and tissue damage during Nippostrongylus brasiliensis infection

Many helminth parasites migrate through multiple host organs during infection but how immune responses are relayed across these tissues is still poorly understood. To investigate the cellular and molecular aspects of inter-tissue communication during infection we established a percutaneous infection model with the tissue-migrating nematode Nippostrongylus brasiliensis. High-dimension profiling of the initial cutaneous immune response revealed that dermal {gamma}{delta} T cells become activated via an IL-1R-dependent mechanism, engage cell motility-associated transcriptional pathways and leave the skin after parasite invasion. Chemical and genetic inhibition of leukocyte migration prevents the accumulation of IL-17-producing {gamma}{delta} T cells in the lungs. Notably, bypassing the skin phase of infection, and therefore preventing dermal {gamma}{delta} T cell migration, dampens the increase in early IL-17 production in the lungs, and, instead, leads to enhanced IFN-{gamma} responses together with increased lung damage. Collectively, our data highlights a critical skin-lung axis regulating host-parasite interactions and safeguarding lung health.

immunology↗

bioRxiv2024

Occurrence of Aneuploidy Across the Range of Coast Redwood (Sequoia sempervirens)

1Aneuploidy, a condition characterized by an abnormal number of chromosomes, can have significant consequences for fitness of an organism, often manifesting in reduced fertility and other developmental challenges. In plants, aneuploidy is particularly complex to study, especially in polyploid species such as coast redwood (Sequoia sempervirens), which is a hexaploid conifer (2n=6x=66). This study leverages a novel Markov Chain Monte Carlo (MCMC) method based on sequence depth to investigate the occurrence of aneuploidy across the range of coast redwood. We show that aneuploidy is prevalent in second-growth redwoods, predominantly as additional chromosomes, while tissue culture plants frequently experience chromosome loss. Although our study does not directly assess the fitness of aneuploids, the frequency of chromosomal instability observed in tissue culture plants compared to second-growth and old-growth trees raises questions about their long-term developmental viability and potential to become established trees. These findings have significant implications for redwood conservation and restoration strategies, especially as tissue culture becomes the primary mode of producing nursery stock plants used in reforestation.

plant biology↗

bioRxiv2021

Heritable Variation in Locomotion, Reward Sensitivity, and Impulsive Action, Choice, and Waiting in a Genetically Diverse Inbred Mouse Panel

Drugs of abuse, including alcohol and stimulants like cocaine, produce effects that are subject to individual variability, and genetic variation accounts for at least a portion of those differences. Notably, research in both animal models and human subjects point towards reward sensitivity and impulsivity as being trait characteristics that predict relatively greater positive subjective responses to stimulant drugs. Here we describe use of the eight Collaborative Cross (CC) founder strains and multiple CC strains to examine the heritability of reward sensitivity and impulsivity traits, as well as genetic correlations between these measures and existing addiction-related phenotypes. Methods. Strains were all tested for activity in an open field and reward sensitivity (intake of chocolate BOOST(R)). Mice were then divided into two counterbalanced groups and underwent reversal learning (impulsive action and waiting impulsivity) or delay discounting (impulsive choice). Results. CC and founder mice demonstrate significant heritability for impulsive action, impulsive choice, waiting impulsivity, locomotor activity, and reward sensitivity, with each impulsive phenotype determined to be non-correlating, independent traits. This research was conducted within the broader, inter-laboratory effort of the Center for Systems Neurogenetics of Addiction (CSNA) to characterize CC and DO mice for multiple, cocaine abuse related traits. These data will facilitate the discovery of genetic correlations between predictive traits, which will then guide discovery of genes and genetic variants that contribute to addictive behaviors.

neuroscience↗

bioRxiv2020

Genetic variation and sex differences are missed opportunities for addiction biology.

Concerns about external validity of rodent models and translation of findings across species are often based on narrow investigations of populations with limited diversity. Sources of individual variation - including genetics and sex - are only infrequently encompassed in model organism studies. As with most complex diseases, risk for cocaine use disorder is subject to considerable inter-individual variation. Explicit inclusion of individual differences in rodent research may reveal conserved phenotypes and molecular systems relevant to human addiction. We surveyed cocaine-related traits in both males and females of eight inbred mouse strains whose genomes collectively capture 90% of the genetic diversity of the mouse species. Across these strains, individual differences explained a substantial proportion of variance in cocaine-responsive or cocaine response-predictive behavioral and physiological phenotypes. Wild-derived mouse strains often extended the phenotypic ranges of these behaviors beyond what is observed in conventional laboratory strains. Striatum transcriptional responses to cocaine were also highly dependent upon strain and sex differences; most cocaine-responsive genes were differentially expressed in a manner moderated by strain, sex, or their combination. We compared the strain- and sex-mediated transcriptional responses to cocaine in mice to transcriptomic analysis of people with cocaine use disorder and found that mouse similarity to humans was highly dependent upon mouse genetic background and sex. Specifically, male WSB/EiJ mice and female NOD/ShiLtJ mice exhibited the greatest degree of neural transcriptional consilience with humans with cocaine use disorder. Model organism diversity thus represents a crucial source of biological information that can substantially improve external validity of neuropsychiatric research. Significance StatementLaboratory mice are widely used in research on neurobiological mechanisms of addiction, but most studies use a single strain and often sex of mice. To assess how individual differences in mice modulate addiction-related traits and how this impacts comparative analysis with humans, we studied cocaine-relevant behaviors and brain molecular correlates in both males and females of genetically diverse mouse strains. In this population, individual differences related to sex and/or genetics explain large proportions of differences in cocaine-related traits. Importantly, brain gene expression data demonstrated that some strains mimic human genomic states more readily than others. Individual differences thus represent a crucial and underdeveloped source of biological information about addiction mechanisms that may influence the translational utility of such studies.

neuroscience↗