Biology subjects

Knight, C.

Publications and source records attributed to Knight, C..

7 recordsLinked to original sources

bioRxiv2026

Species-specific WNT requirements shape somite morphogenesis in mammalian embryo models

Somitogenesis establishes the metameric body plan of the vertebrate embryo and can be recapitulated in vitro using stem cell-based embryo models. Although these systems are well established in individual species, they have rarely been compared across species, leaving unresolved how conserved developmental programmes generate species-specific tissue organisation. Here, we compare somitogenesis in embryo models derived from human, pig, sheep and cow pluripotent stem cells and investigate how WNT signalling and the extracellular matrix regulate axis segmentation. Under identical induction conditions, human and pig models diverge in cell-type composition and morphology, revealing distinct modes of axial elongation. Increasing WNT stimulation restores somite formation in pig models but fails to restore ordered segmentation. Furthermore, each of the four mammalian species requires a different level of WNT stimulation and matrix embedding time for somite formation. Finally, comparative analyses identify species-specific differences in progenitor dynamics. Human models, showing ordered segmentation, retain a posterior mesoderm-producing domain, whereas pig models show rapid depletion of this domain, associated with simultaneous somite formation. Together, these findings reveal species-specific requirements for mammalian somitogenesis in stem cell-derived embryo models and suggest that maintenance of a posterior axial domain contributes to ordered segmentation.

developmental biology↗

bioRxiv2025

A preclinical pig model of Angelman syndrome mirrors the early developmental trajectory of the human condition

Angelman syndrome is a neurodevelopmental disorder characterized by severe motor and cognitive deficits. It is caused by the loss of the maternally inherited allele of the imprinted ubiquitin-protein ligase E3A (UBE3A) gene. Rodent models of Angelman syndrome do not fully recapitulate all the symptoms associated with the condition and are limited as a preclinical model for therapeutic development. Here, we show that pigs (Sus scrofa) with a maternally inherited deletion of UBE3A (UBE3A-/+) have altered postnatal behaviors, impaired vocalizations, reduced brain growth, motor incoordination, and ataxia. Neonatal UBE3A-/+ pigs exhibited several symptoms observed in infants with Angelman syndrome, including hypotonia, suckling deficits, and failure to thrive. Collectively, these findings are consistent with the pathophysiology and developmental trajectory observed in individuals with Angelman syndrome. We anticipate that this pig model will advance our understanding of the pathophysiology of Angelman syndrome and be used as a preclinical large animal model for therapeutic development.

genetics↗

bioRxiv2024

Inflammation-like environments limit the loss of quorum sensing in Pseudomonas aeruginosa

Within-host environments are complex and multidimensional, making it challenging to link evolutionary responses of colonizing pathogens to causal selective drivers. Loss of quorum sensing (QS) via mutation of the master regulator, lasR, is a common adaptation of Pseudomonas aeruginosa during chronic infections. Here, we use experimental evolution in host-mimicking media to show that loss of QS is constrained by environmental factors associated with host inflammation. Specifically, environments combining oxidative stress and abundant free amino acids limited loss of QS, whereas QS loss was rapid in the absence of oxidative stress regardless of amino acids. Under oxidative stress, lasR mutations were contingent upon first decoupling regulation of oxidative stress responses from QS via mutations in the promoter region of the primary catalase, katA, or in the oxidative stress regulator, oxyR, enabling maintenance of oxidative stress tolerance. Together, our findings suggest that host inflammatory responses likely delay the loss of QS whilst colonizers undergo stepwise evolution, first adapting to survive lethal stressors before responding to other nutritional selective drivers that favour loss of QS.

evolutionary biology↗

bioRxiv2024

Multiplicity of Type 6 Secretion System toxins limits the evolution of resistance

The bacterial Type 6 Secretion System (T6SS) is a toxin-injecting nanoweapon that mediates competition in plant- and animal-associated microbial communities. Bacteria can evolve de novo resistance against T6SS attacks, but resistance is far from universal in natural communities, suggesting key features of T6SS weaponry may act to limit its evolution. Here, we combine eco-evolutionary modelling and experimental evolution to examine how toxin type and multiplicity in Acinetobacter baylyi attackers shape resistance evolution in susceptible Escherichia coli competitors. In both our models and experiments, we find that combinations of multiple distinct toxins limit resistance evolution by creating genetic bottlenecks, driving resistant lineages extinct before they can reach high frequency. We also show that, paradoxically, single-toxin attackers often drive the evolution of cross-resistance, protecting bacteria against unfamiliar toxin combinations, even though such evolutionary pathways were inaccessible against multi-toxin attackers. Our findings indicate that, comparable to antimicrobial and anticancer combination therapies, multi-toxin T6SS arsenals function to limit resistance evolution in competing microbes. This helps us to understand why T6SSs remain widespread and effective weapons in microbial communities, and why many bacteria T6SS-armed encode functionally diverse anti-competitor toxins. SignificanceToxin secretion systems, such as T6SSs, are widely used by bacteria to inhibit competing microorganisms. Here, we show that the secretion of multiple toxins in combination can suppress the evolution of resistance to the T6SS, rationalising its continued widespread use across diverse communities. Our work shows that principles of combination therapy--well known in the context of antimicrobial, antiviral and anticancer therapies--also apply in the context of microbial warfare, helping to explain why many bacteria maintain diverse T6SS toxin arsenals. Resistance suppression is also a technologically useful property of T6SS toxin cocktails, which could be harnessed as part of future biocontrol or biotherapeutic applications, using live T6SS-armed bacteria to limit the growth of problem microorganisms.

microbiology↗

bioRxiv2021

Remote sensing reveals multi-decadal losses of tree cover in California driven by increasing fire disturbance and climate stress

Forests provide natural climate solutions for sequestering carbon and mitigating climate change yet are threatened by increasing temperatures and disturbance. Accurate information on vegetation dynamics is lacking in some regions with forest carbon offset programs and dense forests like California. To address this, we combined remote sensing observations with geospatial databases to develop annual maps of vegetation cover (tree, shrub, herbaceous) and disturbance type (fires, harvest, and forest die-off) in California at 30 m resolution from 1985 to 2021. California lost 3783 km2 of its tree cover area (5.5% relative to initial cover). Early gains in tree cover area were more than offset by fire-driven declines, resulting in greater shrub and herbaceous cover area. Fires and tree cover area loss occurred where temperatures were high or increasing, whereas tree cover gain occurred in cooler areas. Disturbance and warming are threatening the integrity of Californias forests and its carbon offsets program. TeaserClimate and disturbance-driven tree cover loss challenges the viability of forests as natural climate solutions in California

ecology↗

bioRxiv2019

Distinct microbial communities in the murine gut are revealed by taxonomy-independent phylogenetic random forests

Gut microbiome analysis using 16S rRNA frequently focuses on summary statistics (e.g. diversity) or single taxonomic scales (e.g. Operational Taxonomic units, OTUs). This approach risks misinterpreting the phylogenetic or abundance scales of community differences (e.g. over-emphasising the role of single strains). We therefore constructed a 16S phylogenetic tree from mouse stool and colonic mucus communities. Random forest models, of all 428,234 clades, tested community differences among niches (stool versus mucus), host ages (6 versus 18 weeks), genotypes (wildtype versus colitis prone-mdr1a-/-) and social groups (co-housed siblings). Models discriminated all criteria except host genotype, where no community differences were found. Host social groups differed in abundant, low-level, taxa whereas intermediate phylogenetic and abundance scales distinguished ages and niches. Thus, treating evolutionary clades of microbes equivalently without reference to OTUs or taxonomy, clearly identifies whether and how gut microbial communities are distinct and provides a novel way to define functionally important bacteria.

microbiology↗

bioRxiv2018

Whole genome sequencing, de novo assembly and phenotypic profiling for the new budding yeast species Saccharomyces jurei

Saccharomyces sensu stricto complex consist of yeast species, which are not only important in the fermentation industry but are also model systems for genomic and ecological analysis. Here, we present the complete genome assemblies of Saccharomyces jurei, a newly discovered Saccharomyces sensu stricto species from high altitude oaks. Phylogenetic and phenotypic analysis revealed that S. jurei is a sister-species to S. mikatae, than S. cerevisiae, and S. paradoxus. The karyotype of S. jurei presents two reciprocal chromosomal translocations between chromosome VI/VII and I/XIII when compared to S. cerevisiae genome. Interestingly, while the rearrangement I/XIII is unique to S. jurei, the other is in common with S. mikatae strain IFO1815, suggesting shared evolutionary history of this species after the split between S. cerevisiae and S. mikatae. The number of Ty elements differed in the new species, with a higher number of Ty elements present in S. jurei than in S. cerevisiae. Phenotypically, the S. jurei strain NCYC 3962 has relatively higher fitness than the other strain NCYC 3947T under most of the environmental stress conditions tested and showed remarkably increased fitness in higher concentration of acetic acid compared to the other sensu stricto species. Both strains were found to be better adapted to lower temperatures compared to S. cerevisiae.

genomics↗