Biology subjects

Foote, A.

Publications and source records attributed to Foote, A..

12 recordsLinked to original sources

bioRxiv2026

Differential Enhancer Activity and FOXF1 Levels Contribute to Higher Inflammatory Gene Expression of Fetal/Neonatal Versus Adult Fibroblasts in IR-induced Senescence

Some key inflammatory genes controlled by the RELA transcription factor are thought to be highly expressed in fibroblasts induced into senescence by ionizing radiation (IR) as part of the Senescent-Associated Secretory Phenotype (SASP). However, this view is based largely on studies of a limited number of fibroblast cell lines derived from fetal lung or neonatal foreskin. Here, we show that more than half of the primary adult fibroblast strains examined exhibit only weak induction of RELA-dependent inflammatory genes following IR-induced senescence. We define these fibroblasts as "low-responding" to distinguish them from fibroblasts that express high levels of inflammatory gene expression in response to IR. RNA-seq analysis indicated particularly weak IL1A and IL1B expression in low-responding fibroblasts. IL1-alpha and IL1-beta participate in a positive amplification loop for inflammatory gene expression in senescence. Addition of recombinant IL1-alpha or IL1-beta to these fibroblasts sufficed to induce high expression of inflammatory genes. Low-responding fibroblasts thus exhibit cell-autonomous defects in IL1A and IL1B gene activation in response to IR that explains their overall low expression of RELA-targeted inflammatory genes. This defect was correlated with reduced chromatin accessibility and H3-K27-acetylation at 2 putative enhancers in the intergenic region separating IL1A and IL1B, and deletion of either of these enhancers inhibited inflammatory gene expression in IR-induced senescence. Fibroblasts express distinct transcriptomes and we found that differential expression of the FOXF1 transcription factor gene in high-responding WI38 fetal lung fibroblasts contributes to inflammatory gene expression after IR. Our observations indicate that fibroblasts can be distinguished by their ability to manifest cell-autonomous induction of inflammatory genes under conditions of IR-induced senescence.

Cell Biology↗

bioRxiv2025

DNA Motors Powered by Exonuclease III for Autonomous Rolling Motion and Biosensing Applications

Nucleic acid-based synthetic motors emulate key behaviors of biological machines, enabling applications in biosensing and nanoscale actuation. Among the reported synthetic motors, RNase H-powered motors offer high speed and processivity with demonstrated applications in computation and viral sensing. However, these motors rely on RNA as "fuel" source, limiting their stability. Here, we report the development of a robust, RNA-free DNA motor powered by Exonuclease III. These motors exhibit self-avoiding rolling motion driven by enzymatic hydrolysis of surface-bound DNA fuel strands, consistent with a burnt-bridge Brownian ratchet mechanism of translocation. We systematically optimized motor performance by chemically tuning the fluorescence reporter, DNA sequence composition, and surface fuel density. Fluorescence and brightfield microscopy revealed super-diffusive and Levy-like stop-and-go dynamics under optimized conditions. Importantly, the established DNA-only architecture confers resistance to RNase degradation, and the system can be configured for motion-based biosensing via aptamer-functionalized components that selectively stall in response to viral targets. Beyond the significance of creating a chemically stable, tunable, and biosensing-compatible DNA motor platform, the work also establishes the modularity of the rolling motor platform and highlights how enzymatic diversity can expand their chemical and functional scope.

biophysics↗

bioRxiv2025

Complex patterns of hitchhiking mutation load among stickleback populations

Positive selection causes beneficial alleles to rapidly rise to high frequency in a population. This can cause linked genetic variation to "hitchhike", and thereby also rise in frequency. This linked variation may include deleterious recessive alleles, previously neutrally harbored at low frequency in heterozygous genotypes. Modeling studies have shown that local effective population size and reduced recombination rate should contribute to the probability of deleterious mutations being swept to high frequency by being linked to beneficial alleles in selective sweeps or inversions. Marine sticklebacks have repeatedly adapted to thousands of freshwater habitats that became available after the last ice age, resulting in the formation of distinct marine and freshwater ecotypes. Selection acts on ancient standing genetic variation present in marine populations, causing freshwater-adaptive alleles to increase rapidly over tens of generations. These genomic regions play a key role in the repeated freshwater adaptation of morphological, physiological, and behavioral traits, and evolve under strong selection. Thus, threespine stickleback are an ideal system for investigating the impact of hitchhiking mutation load. We estimate the mutation load in regions of low recombination, including inversions, and the Eda haplotype. We find little evidence for the accumulation of deleterious alleles among genomic regions and populations. Inversions deviated from Hardy-Weinberg equilibrium in several populations, exhibiting an excess of homozygotes. These observations are consistent with purging facilitated by recombination in inversion karyotypes. We conclude that adaptation in threespine stickleback is not limited by hitchhiking deleterious mutations. Significance statementHitchhiking is a ubiquitous force in population genetics, shaping genetic diversity across the genome. Threespine stickleback are a model system for studying parallel adaptation to ecological variation, with low recombination genomic regions known to drive ecological adaptation. A key question is whether a deleterious mutation load is associated with adaptation in this system. We find that hitchhiking mutation load patterns are complex and do not conform to simple model predictions, despite some widespread patterns shared among populations. Our findings suggest that purging in homozygous karyotypes may be critical in reducing deleterious mutation load.

evolutionary biology↗

bioRxiv2025

Ancient stickleback genomes reveal the chronology of parallel adaptation

Parallel evolution of traits and their underlying genetic basis is well-studied, however, studies of parallel chronology of adaptive genetic changes remain scarce. Threespine stickleback are a model system for studying parallel evolution. We present genomic data from nine subfossil stickleback bones dated to 14.8-0.7 KYR BP in age. Comparing the four highest coverage genomes, which represent different stages along the marine-freshwater continuum, we find that freshwater ancestry is often clustered rather than randomly distributed throughout the marine-freshwater divergent regions of the genome. We consistently find freshwater ancestry on chromosome IV at the early stages of freshwater adaptation. Regions of chromosome IV contain the greatest genetic differentiation between marine and freshwater ecotypes and among the highest density of quantitative trait loci. These include EDA, a large-effect pleiotropic locus associated with defensive armour and variation in neurosensory and behavioural traits. Freshwater ancestry is also found at inversions in the subfossils early in the adaptive process. Our findings add to the growing body of evidence that freshwater adaptation in threespine stickleback has a staggered but predictable temporal dynamic. The probability of parallel genetic change should be increased by the clustering of adaptive alleles in regions of suppressed recombination, particularly for genes that have a large phenotypic effect.

evolutionary biology↗

bioRxiv2025

A Single-Cell Atlas of the Upper Respiratory Epithelium Reveals Heterogeneity in Cell Types and Patterning Strategies

The upper respiratory tract, organized along the pharyngolaryngeal-to-tracheobronchial axis, is essential for homeostatic functions such as breathing and vocalization. The upper respiratory epithelium is frequently exposed to pollutants and pathogens, making this an area of first-line defense against respiratory injury and infection. The respiratory epithelium is composed of a rich array of specialized cell types, each with unique capabilities in immune defense and injury repair. However, the precise transcriptomic signature and spatial distribution of these cell populations, as well as potential cell subpopulations, have not been well defined. Here, using single cell RNAseq combined with spatial validation, we present a comprehensive atlas of the mouse upper respiratory epithelium. We systematically analyzed our rich RNAseq dataset of the upper respiratory epithelium to reveal 17 cell types, which we further organized into three spatially distinct compartments: the Tmprss11a+ pharyngolaryngeal, the Nkx2-1+ tracheobronchial, and the Dmbt1+ submucosal gland epithelium. We profiled/analyzed the pharyngolaryngeal epithelium, composed of stratified squamous epithelium, and identified distinct regional signatures, including a Keratin gene expression code. In profiling the tracheobronchial epithelium, which is composed of a pseudostratified epithelium-with the exception of the hillock structure-we identified that regional luminal cells, such as club cells and basal cells, show varying gradients of marker expression along the proximal-distal and/or dorsal-ventral axis. Lastly, our analysis of the submucosal gland epithelium, composed of an array of cell types, such as the unique myoepithelial cells, revealed the colorful diversity of between and within cell populations. Our single-cell atlas with spatial validation highlights the distinct transcriptional programs of the upper respiratory epithelium and serves as a valuable resource for future investigations to address how cells behave in homeostasis and pathogenesis. Highlights- Defined three spatially distinct epithelial compartments, Tmprss11a+ pharyngolaryngeal, Nkx2-1+ tracheobronchial, and Dmbt1+ submucosal gland, comprising 17 total cell types - Profiled Keratin gene expression code along proximal-distal and basal-luminal axes and highlighted "stress-induced" Keratins KRT6A and KRT17 at homeostasis - Demarcated expression gradients of Scgb1a1+ and Scgb3a2+ club cells along the proximal-distal axes - Specified submucosal gland cell heterogeneity including Nkx3-1+ mucin-producing cells, with ACTA2+ basal myoepithelial cells exhibiting gene profile for neuroimmune mediated signaling

genomics↗

bioRxiv2023

Climate change introduces threatened killer whale populations and conservation challenges to the Arctic

The Arctic is the fastest-warming region on the planet, and sea ice loss has opened new habitat for sub-Arctic species such as the killer whale (Orcinus orca). As apex predators, killer whales can cause significant ecosystem-scale changes, however, we know very little about killer whales in the Arctic. Setting conservation priorities for killer whales and their Arctic prey species requires knowledge of their evolutionary history and demography. We found that there are two highly genetically distinct, non-interbreeding populations of killer whales using the eastern Canadian Arctic--one population is newly identified as globally distinct. The effective sizes of both populations recently declined, and both are vulnerable to inbreeding and reduced adaptive potential. Furthermore, we present evidence that human-caused mortalities, particularly ongoing harvest, pose an ongoing threat to these populations. The certainty of substantial environmental change in the Arctic complicates conservation and management significantly. Killer whales bring top-down pressure to Arctic food webs, however, they also merit conservation concern. The opening of the Arctic to killer whales exemplifies the magnitude of complex decisions surrounding local peoples, wildlife conservation, and resource management as the effects of climate change are realized.

genomics↗

bioRxiv2023

Divergence and gene flow history at two large chromosomal inversions involved in long-snouted seahorse ecotype formation

Chromosomal inversions can play an important role in divergence and reproductive isolation by building and maintaining distinct allelic combinations between evolutionary lineages. Alternatively, they can take the form of balanced polymorphisms that segregate within populations over time until one arrangement becomes fixed. Many questions remain about how these different inversion polymorphisms arise, how the mechanisms responsible for their long-term maintenance interact, and ultimately how they contribute to speciation. The long-snouted seahorse (Hippocampus guttulatus) is known to be subdivided into partially isolated lineages and marine-lagoon ecotypes differentiated by structural variation. Here, we aim to characterise these differences along the entire genome, and to reconstruct their history and role in ecotype formation. We generated a near chromosome-level reference genome assembly and described genome-wide patterns of diversity and divergence through the analysis of 112 whole-genome sequences from Atlantic, Mediterranean, and Black Sea populations. Combined with linked-read sequencing data, we found evidence for two megabase-scale chromosomal inversions showing contrasted allele frequency patterns across the species range. We reveal that these inversions represent ancient intraspecific polymorphisms, one being likely maintained by divergent selection, and the other by associative overdominance. Haplotype combinations characterising Mediterranean ecotypes also suggest the existence of potential interactions between the two inversions, possibly driven by environment-dependent fitness effects. Lastly, we detected gene flux eroding divergence between inverted alleles at varying levels between the two inversions, with a likely impact on their long-term dynamics.

genomics↗

bioRxiv2023

Discrete Multiwalled Carbon Nanotubes for Versatile Intracellular Transport of Functional Biomolecular Complexes

In recent years, carbon nanotubes have emerged as a potentially revolutionary material with numerous uses in biomedical applications. Compared to other nanoparticles, discrete multi-walled carbon nanotubes (dMWCNTs) have been shown to exhibit advantageous characteristics such as high surface area to volume ratio, biocompatibility, and unique chemical and physical properties. dMWCNTs can be modified to load various molecules such as proteins and nucleic acids and are capable of crossing the cell membrane, making them attractive delivery vehicles for biomolecules. To investigate this, we measured the impact of dMWCNTs on cell proliferation. Furthermore, we used electron microscopy to demonstrate that dMWCNTs enter the cytoplasm of mammalian cells via an endocytosis-like process. And lastly, we employed various in vitro reporter and gene assays to demonstrate dMWCNT-mediated delivery of peptides, mRNA, siRNA, and dsRNA. Our work here has helped further characterize dMWCNTs as a versatile delivery platform for biomolecular cargo.

bioengineering↗

bioRxiv2023

Temporal progression of anaerobic fungal communities in dairy calves from birth to maturity

AbstractEstablishment of microbial communities in neonatal calves is vital for their growth and overall health. Feed type and associated gastrointestinal tract morphophysiological changes occurring during the pre-weaning, weaning, and post-weaning phases are known to induce shifts in microbial community diversity, structure, and function. However, while the process has received considerable attention for bacteria, our knowledge on temporal progression of anaerobic gut fungi (AGF) in calves is lacking. Here, we examined AGF communities in fecal samples from six dairy cattle collected at 24 different time points during the pre-weaning (day 1-48), weaning (day 49-60), and post-weaning (3-12 months) stages. Quantitative PCR (qPCR) indicated that AGF colonize the calves GIT within 24 hours after birth, with AGF loads slowly increasing during pre-weaning/weaning phases and drastically increasing post-weaning. Culture- independent amplicon surveys identified higher AGF alpha diversity during pre-weaning/ weaning phases, compared to post-weaning. Further, the AGF community structure underwent a drastic shift post-weaning, from a community enriched in the genera Khoyollomyces, Orpinomyces, AL3, and NY8 (some of which commonly encountered in hindgut fermenters) to one enriched in the genera Caecomyces, Piromyces, Pecoramyces, and Cyllamyces, commonly encountered in adult ruminants. Inter-calf community variability was low in the pre- weaning/weaning phases but increased post-weaning. Finally, pairwise comparison of AGF community between calves day 1 post-birth and their mothers suggest a major role for maternal transmission, with additional input from cohabitating subjects. The distinct pattern of AGF progression in calves could best be understood in-light of their narrower niche preferences, metabolic specialization, and physiological optima when compared to bacteria, hence eliciting a unique response to changes in feeding pattern and associated structural development in the GIT of calves during maturation.

microbiology↗

bioRxiv2022

Characterizing biofilm interactions between Ralstonia insidiosa and Chryseobacterium gleum

Ralstonia insidiosa and Chryseobacterium gleum are bacterial species commonly found in potable water systems and these two species contribute to the robustness of biofilm formation in a model six-species community from the International Space Station (ISS) potable water system. Here, we set about characterizing the interaction between these two ISS-derived strains and examining the extent to which this interaction extends to other strains and species in these two genera. The enhanced biofilm formation between the ISS strains of R. insidiosa and C. gleum is robust to starting inoculum and temperature, occurs in some but not all tested growth media, and evidence does not support a soluble mediator or co-aggregation mechanism. These findings shed light on the ISS R. insidiosa and C. gleum interaction, though such enhancement is not common between these species based on our examination of other R. insidiosa and C. gleum strains, as well as other species of Ralstonia and Chryseobacterium. Thus, while the findings presented here increase our understanding of the ISS potable water model system, not all our findings are broadly extrapolatable to strains found outside of the ISS. ImportanceBiofilms present in drinking water systems and terminal fixtures are important for human health, pipe corrosion, and water taste. Here we examine the enhanced biofilm of cu-cultures for two very common bacteria from potable water systems, Ralstonia insidiosa and Chryseobacterium gleum. While strains originally isolated on the International Space Station show enhanced dual-species biofilm formation, terrestrial strains do not show the same interaction properties. This study contributes to our understanding of these two species in both dual and mono-culture biofilm formation.

microbiology↗

bioRxiv2020

Runs of homozygosity in killer whale genomes provide a global record of demographic histories

Runs of homozygosity (ROH) occur when offspring receive the same ancestral haplotype from both parents, and, accordingly, reduce individual heterozygosity. Their distribution throughout the genome contains information on the probability of inbreeding mediated by mating system and population demography. Here, we investigate variation in killer whale demographic history as reflected in genome-wide heterozygosity, using a global dataset of 26 genomes. We find an overall pattern of lower heterozygosity in genomes sampled at high latitudes, with hundreds of short ROH (< 1Mbp) reflecting high background relatedness due to coalescence of haplotypes during bottlenecks associated with founder events during post-glacial range expansions. Across most of the species range, intermediate length ROH (1-10Mb) revealed long-term inbreeding in 22 of the 26 sampled killer whale genomes, consistent with the high social philopatry observed in all populations studied to date. Inbreeding coefficients (FROH) were comparable to those reported in other taxa with long-term low population size, such as bonobos and the Native American Karitiana of the Brazilian Amazon. The extreme outlier in this dataset, a Scottish killer whale, was homozygous over one-third of the autosomes (41.6%) with a distinct distribution of ROH length, indicating generations of inbreeding. This exceeds autozygosity in emblematic examples of long-term inbreeding, such as the Altai Neanderthal, and eastern lowland and mountain gorillas. The fate of this Scottish killer whale population, in which no calves have been born in over two decades, may be inextricably linked to its demographic history and consequential inbreeding depression.

evolutionary biology↗

bioRxiv2019

Proposal for a Global Adherence Scale for Acute Conditions (GASAC): a prospective cohort study in two Emergency Departments

BackgroundAdherence in the context of patients with acute conditions is a major public health issue. It is neglected by the research community and no clinically validated generic scale exists to measure it.\n\nObjectiveTo construct and validate a Global Adherence Scale usable in the context of Acute Conditions (GASAC) that takes into account adherence both to advice and to all types of prescriptions that the doctor may give. To measure adherence and to study its determinants.\n\nMaterials and methodWe based the construction of the GASAC questionnaire on a theoretical model and a literature search. Then, between 2013 and 2014, we validated it in a prospective observational study in two hospital emergency departments. Patients were contacted by phone about one week after their consultation to answer several questionnaires, including GASAC and the Girerd self-administered questionnaire about medication adherence as a control.\n\nResultsGASAC consists of four adherence subscales: drug prescriptions; blood test/ radiography prescriptions; lifestyle advice and follow-up instructions. An analysis of the 154 sets of answers from patients showed that the GASAC drug subscale had satisfactory internal coherence (Cronbachs alpha = 0.78) and was correlated with the Girerd score, as was GASAC as a whole (p<0.01)). The median score was 0.93 IQR [0.78-1] for a maximum value of 1 (n = 154). In multivariate analysis, infection was more conducive of good adherence (cut off at [≥] 0.8; n=115/154; 74.7% [67.0-81.3]) than trauma (OR 3.69; CI [1.60-8.52]). The Doctor-Patient Communication score (OR 1.06 by score point, CI [1.02-1.10]) also influenced adherence.\n\nConclusionsGASAC is a generic score to measure all dimensions of adherence in emergency departments for clinical research and the evaluation of clinical practice. The level of adherence was high for acute conditions and could be further improved by good Doctor-Patient Communication.

epidemiology↗