Biology subjects

Smith, K. E.

Publications and source records attributed to Smith, K. E..

11 recordsLinked to original sources

bioRxiv2026

Estrogen-related receptor gamma is required for normal auditory innervation and is essential for hearing.

Estrogen-related receptor gamma (ESRRG), an orphan nuclear receptor with structural homology to the classical estrogen receptors, is widely recognised as a key metabolic regulator involved in mitochondrial, synaptic, and ion-homeostatic pathways. Previous clinical studies suggest a link between ESRRG and auditory function; for example, ESRRG has been associated with susceptibility to age-related hearing loss in women and implicated in congenital hearing loss. However, the biological mechanisms by which ESRRG may mediate hearing function remain largely unknown. Here, using a combination of in vivo auditory physiological recordings, immunofluorescence analyses, single hair-cell electrophysiology, and transcriptomic approaches, we characterise the phenotype of a new inner-ear conditional Esrrg knockout (Esrrg-cKO) to investigate the role of Esrrg in the auditory system. We found that Esrrg-cKO mice of both sexes develop early-onset hearing loss, as evidenced by elevated auditory brainstem response thresholds and reduced wave 1 amplitudes from two weeks of age. These auditory deficits arise from a combination of early-onset cochlear neuronal and innervation malformations, together with inner hair cell synaptic defects and delayed myelination that persist into adulthood. Furthermore, distortion product otoacoustic emissions and endocochlear potential recordings are normal in Esrrg-cKO mice, and although sensory hair cells are preserved, IHCs retain immature biophysical properties. These findings are consistent with auditory neuropathy, and together with our comparative transcriptome analyses, indicate that Esrrg is an essential molecular driver of normal cochlear innervation and maturation.

neuroscience↗

bioRxiv2025

Functional heterogeneity and plasticity in naive CD8 T cells drive superior effector and memory responses

While significant progress has been made in defining subsets among antigen-experienced CD8 T cells, the heterogeneity of naive CD8 T cells remains poorly understood. Here, we identify naive CD8 T cell subsets with superior persistence and an enhanced capacity to generate effector and memory cells, leading to more effective protection. These high-quality naive CD8 T cells are marked by IL-18R, CD73, and CXCR3, and functionally less potent naive CD8 T cells can convert into these superior subsets. Their enhanced response to infections is driven by better survival of the progeny effector cells during the T cell expansion phase. This improved survival is mediated by increased Ly6C2 expression on effector cells derived from these high-quality naive cells. Collectively, our findings reveal functional heterogeneity and plasticity among naive CD8 T cells and uncover a mechanism by which high-quality naive subsets drive robust CD8 T cell responses, providing a previously unrecognized layer of immune regulation. SUMMARYOur study reveals functional heterogeneity and plasticity within naive CD8 T cells, identifying high-quality subsets that can emerge from less potent cells and drive superior immune responses through enhanced survival of effector progeny.

immunology↗

bioRxiv2025

Von Willebrand Factor Deficiency Impairs Vascular Morphogenesis via Angiopoietin-2: Relevance for Gut Angiodysplasia

Management of recurrent gastrointestinal (GI) bleeding is a clinical unmet need for patients with Von Willebrand disease (VWD) and is linked to the presence of gut vascular malformations (angiodysplasia). We previously demonstrated that von Willebrand factor (VWF) regulates angiogenesis and vascular integrity, the likely mechanism underlying angiodysplasia. VWF controls the storage of the angiogenesis regulator Angiopoietin-2 (Angpt-2) in endothelial cells (EC), suggesting a candidate for the genesis of angiodysplasia; however, no direct evidence of the role of Angpt-2 in VWF-dependent angiogenesis is available. Here we use VWF-deficient HUVEC, and endothelial colony forming cells (ECFCs) from severe VWD patients and find that loss of VWF in EC results in increased Angpt-2 expression through a positive feedback loop via the Angpt-2-TIE2-AKT-FOXO1 pathway. We also show an imbalance of the Angpt/Tie2 pathway in vivo. In the gut of VWF-deficient mice, Angpt-2 expression is increased whilst Angpt-1 expression is decreased; this correlates with reduced expression of the pericyte marker NG2. These data suggest that VWF regulates the Angpt/Tie2 balance in the gut. To investigate the functional defects caused by loss of VWF, we use a fibrin bead assay and show that VWF-deficient HUVEC present increased sprouting. We develop a microfluidic model of 3D vasculogenesis/angiogenesis and find that ECFCs from VWD patients exhibit defective remodeling and abnormal lumen formation compared to healthy controls. Importantly, inhibition of Angpt-2 reduces sprouting in VWF-deficient HUVEC and normalises vascular networks in ECFCs from severe VWD, suggesting Angpt-2 inhibitors may be effective in VWD patients with GI bleeding and angiodysplasia. Key pointsO_LIEndothelial VWF regulates multiple steps of angiogenesis, including sprouting and lumen formation. C_LIO_LIVWF regulates Angpt-2 storage and expression, and Angpt-2 blockade normalises defective angiogenesis in VWD ECFCs. C_LI Visual Abstract O_FIG O_LINKSMALLFIG WIDTH=170 HEIGHT=200 SRC="FIGDIR/small/675051v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@150eb15org.highwire.dtl.DTLVardef@179e6beorg.highwire.dtl.DTLVardef@1bcadborg.highwire.dtl.DTLVardef@a30fb8_HPS_FORMAT_FIGEXP M_FIG VWF deficiency in HUVECs results in increased Angpt-2 release and expression via the Tie2-Akt-FOXO1 pathway. A. Model pathway for the regulation of Angpt-2 levels by VWF. Loss of VWF results in increased Angpt-2 release from endothelial cells; Angpt-2 binds to and inhibits the Tie2 receptor, decreasing its phosphorylation as well as the downstream phosphorylation of Akt and FOXO1; this leads to FOXO1 activation and an increase expression of Angpt-2, generating a feedback loop. B. Model for the pathogenesis of angiodysplasia in VWD. In the absence of VWF, the increase in Angpt-2 disrupts vascular morphogenesis through multiple mechanisms: increased sprouting, impaired vascular remodelling and an imbalance between Angpt-1 and Angpt-2 in the gut. Figure generated with Biorender. C_FIG

cell biology↗

bioRxiv2024

Reliable sensory processing of superficial cortical interneurons is modulated by behavioral state

The GABAergic interneurons within cortical layer 1 (L1) integrate sensory and top-down inputs to modulate network activity and induce the plasticity underlying learning. However, little is known about how sensory inputs drive L1 interneuron activity. We used two-photon calcium imaging to measure the sound-evoked responses of two L1 interneuron populations expressing VIP (vasoactive intestinal peptide) or NDNF (neuron-derived neurotrophic factor) in mouse auditory cortex. We find that L1 interneurons respond to both simple and complex sounds with high trial-to-trial variability. However, these interneurons respond reliably to just a narrow range of stimuli, reflecting selectivity to spectrotemporal sound features. This response reliability is modulated by behavioral state and predicted by the activity of neighboring interneurons. Our data reveal that L1 interneurons exhibit sensory tuning and identify the modulation of response reliability as a potential mechanism by which L1 relays state-dependent cues to shape sensory representations.

neuroscience↗

bioRxiv2024

An ecological, phenotypic and genomic survey of duckweeds with their associated aquatic environments in the United Kingdom

The duckweeds feature global distributions and diverse applications in phytoremediation and nutrition, as well as use in fundamental studies of development. Existing collections have minimal environmental data linked to natural habitats. Thus, there is a lack of understanding of natural variation in the context of native habitats. Here, a novel collection of 124 duckweed accessions from 115 sites across the United Kingdom were characterised by genome sequencing and ionomics. In nutrient-replete conditions all accessions hyperaccumulated P, K, Mg and Ca. Local but not large-scale associations were revealed between elemental composition of duckweed in common, replete conditions and native water profiles. Lemna minor was the most prevalent species in the UK, with a closely related hybrid L. japonica frequently found in waters with higher micronutrient concentrations. Invasive L. minuta was common in the southern and midland regions, but restricted in Scotland. Lemna accessions accumulated heavy metal contaminants typically together with macronutrients, suggesting phytoremediation potential, but some limitations as food. Furthermore, monitoring the ecological interactions between native, hybrid and invasive Lemna species should be ongoing in the interest of biodiversity.

ecology↗

bioRxiv2023

The evolution of the duckweed ionome mirrors losses in structural complexity

Background and AimsThe duckweeds consist of 36 species exhibiting impressive phenotypic variation, including the progressive evolutionary loss of a fundamental plant organ, the root. Loss of roots and reduction of vascular tissues in recently derived taxa occur in concert with genome expansions of up to 14-fold. Given the paired loss of roots and reduction in structural complexity in derived taxa, we focus on the evolution of the ionome (whole-plant elemental contents) in the context of these fundamental body plan changes. We expect that progressive vestigiality and eventual loss of roots may have both adaptive and maladaptive consequences which are hitherto unknown. MethodsWe quantify the ionomes of 34 accessions in 21 species across all duckweed genera, spanning 70 million years in this rapid cycling plant (doubling times are as low as 24 hours). We relate both micro- and macroevolutionary ionome contrasts to body plan remodelling and show nimble microevolutionary shifts in elemental accumulation and exclusion in novel accessions. Key ResultsWe observe a robust directional trend in calcium and magnesium levels decreasing from the ancestral representative Spirodela genus towards the derived rootless Wolffia, with the latter also accumulating cadmium. We also identify abundant within-species variation and hyperaccumulators of specific elements, with this extensive variation at the fine- as opposed to broad-scale. ConclusionsThese data underscore the impact of root loss, and reveal the very fine scale of microevolutionary variation in hyperaccumulation and exclusion of a wide range of elements. Broadly, they may point to trade-offs not well recognized in ionomes.

plant biology↗

bioRxiv2023

Physiological adaptation to high irradiance in duckweeds depends on light habitat niche and is ecotype and species-specific.

Duckweeds are free-floating aquatic organisms with species ranging from 2 mm-10 mm, where each plant is a single leaflike structure. Recognized as an emerging food crop, their fast growth rates offer potential for cultivation in closed systemsHowever the majority of available duckweed clones lack information regarding habitat origin and physiology. We describe a novel UK collection derived from low light (dLL) or high light (dHL) habitats and profiled for growth, photosynthesis and photoprotection (Non Photochemical Quenching, NPQ) responses. Multiple ecotypes of three Lemna species and one ecotype of Spirodela polyrhiza, were grown under low light (LL:100 mol m-2 s-1) and high light (HL:350 mol m-2 s-1). We found species and ecotypic variation in photosynthesis acclimation. Duckweeds grown under HL exhibited lower growth rate, biomass, chlorophyll and quantum yield of photosynthesis. In HL-compared to LL, carotenoid de-epoxidation state and NPQ were higher whilst photosystem II efficiency ({phi}PSII) and chla:b ratios were unchanged. Interestingly dLL plants showed relatively stronger acclimation to HL compared to dHL plants: These ecotypes achieved faster growth in HL: by area and colony gain, higher carotenoid levels and less degradation of chlorophyll. We conclude that adaptation to local habitat among ecotypes strongly affects performance under controlled conditions.

physiology↗

bioRxiv2022

Correlations across timing cues in natural vocalizations predict judging synthetic sound burst durations.

It is well known that animals rely on multiple sources of information in order to successfully identify sounds in natural environments, to make decisions that are optimal for their survival. For example, rats use duration and pitch cues to respond appropriately to prosocial and distress vocalizations (Saito et al., 2019). Vocalization duration cues are known to co-vary with other temporal cues (Khatami et al., 2018), yet little is known about whether animals rely upon such co-variations to successfully discriminate sounds. In the current study, we find natural alarm vocalizations in rats have onset and offset slopes that are correlated with their duration. Accordingly, vocalizations with faster onset slopes are more likely to have shorter durations. Given that vocalization slopes begin and end within milliseconds, they could provide rapid perceptual cues for predicting and discriminating vocalization duration. To examine this possibility, we train rodents to discriminate duration differences in sequences of synthetic vocalizations and examine how artificially changing the slope impacts duration judgments. We find animals are biased to misjudge a range of synthetic vocalizations as being shorter in duration when the onset and offset slopes are artificially fast. Moreover, this bias is reduced when rats are exposed to multiple synthetic vocalization bursts. The observed perceptual bias is accurately captured by a Bayesian decision-theoretic model that utilizes the empirical joint distribution of duration and onset slopes in natural vocalizations as a prior during duration judgements of synthetic vocalizations. This model also explains why the bias is reduced when more evidence is accumulated across multiple bursts, reducing the priors influence. These results support the theory that animals are sensitive to fine-grained statistical co-variations in auditory timing cues and integrate this information optimally with incoming sensory evidence to guide their decisions.

animal behavior and cognition↗

bioRxiv2022

Duckweed roots are dispensable and are on a trajectory toward vestigiality

Duckweeds are morphologically simplified, free floating aquatic monocots comprising both rooted and rootless genera. This has led to the idea that roots in these species may be vestigial, but empirical evidence supporting this is lacking. Here we show that duckweed roots are no longer required for their ancestral role of nutrient uptake. Comparative analyses of nearly all rooted duckweed species revealed a highly reduced anatomy, with greater simplification in the more recently diverged genus Lemna. A series of root excision experiments demonstrated that roots are dispensable for normal growth in Spirodela polyrhiza and Lemna minor. Furthermore, ionomic analyses of fronds in these two species showed little difference in the elemental composition of plants in rooted versus root-excised samples. In comparison, another free-floating member of the Araceae, Pistia stratiotes, which colonized the aquatic environment independently of duckweeds, has retained a more complex root anatomy. Whilst Pistia roots were not absolutely required for growth, their removal inhibited plant growth and resulted in a broad change in the mineral profile of aerial tissues. Collectively, these observations suggest that duckweeds and Pistia may be different stages along a trajectory towards root vestigialization Given this, along with the striking diversity of root phenotypes, culminating in total loss in the most derived species, we propose that duckweed roots are a powerful system with which to understand organ loss and vestigiality. One sentence summaryThrough their adaption to the aquatic environment, duckweed roots have progressively become structurally reduced making them an ideal plant model with which to study vestigiality.

evolutionary biology↗

bioRxiv2020

Composite modeling of leaf shape across shoots discriminates Vitis species better than individual leaves

Premise of studyLeaf morphology is dynamic, continuously deforming during leaf expansion and among leaves within a shoot. We measured leaf morphology from over 200 vines over four years, and modeled changes in leaf shape along the shoot to determine if a composite "shape of shapes" can better capture variation and predict species identity compared to individual leaves. MethodsUsing homologous universal landmarks found in grapevine leaves, we modeled various morphological features as a polynomial function of leaf node. The resulting functions are used to reconstruct modeled leaf shapes across shoots, generating composite leaves that comprehensively capture the spectrum of possible leaf morphologies. ResultsWe found that composite leaves are better predictors of species identity than individual leaves from the same plant. We were able to use composite leaves to predict species identity of previously unassigned vines, which were verified with genotyping. DiscussionObservations of individual leaf shape fail to capture the true diversity between species. Composite leaf shape--an assemblage of modeled leaf snapshots across the shoot--is a better representation of the dynamic and essential shapes of leaves, as well as serving as a better predictor of species identity than individual leaves.

plant biology↗

bioRxiv2019

Olfactory ensheathing cells from the nasal mucosa and olfactory bulb have distinct membrane properties

Transplantation of Olfactory Ensheathing Cells (OECs) is a potential therapy for the regeneration of damaged neurons. While they maintain tissue homeostasis in the olfactory mucosa (OM) and olfactory bulb (OB), their regenerative properties also support the normal sense of smell by enabling continual turnover and axonal regrowth of olfactory sensory neurons (OSNs). However, the molecular physiology of OECs is not fully understood, especially that of OECs from the mucosa. Here, we carried out whole-cell patch clamp recordings from individual OECs cultured from the OM and OB of the adult rat, and from the human OM. A subset of OECs from the rat OM cultured 1-3 days in vitro (DIV) had large weakly rectifying K+ currents, which were sensitive to Ba2+ and desipramine, blockers of Kir4-family channels. Kir4.1 immunofluorescence was detectable in OM cells co-labelled for the OEC marker S100, and found adjacent to axons of OSNs. OECs cultured from rat OB had distinct properties though, displaying strongly rectifying inward currents at hyperpolarized membrane potentials and strongly rectifying outward currents at depolarized potentials. Kir4.1 immunofluorescence was not evident in OECs adjacent to axons of OSNs in the OB. A subset of human OECs cultured from the OM of adults had membrane properties comparable to those of the rat OM, i.e. dominated by Ba2+-sensitive weak inwardly rectifying currents. The membrane properties of peripheral OECs are different to those in central OECs, suggesting they may play distinct roles during olfaction.\n\nTable of Contents Image\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=169 SRC=\"FIGDIR/small/640839v2_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (39K):\norg.highwire.dtl.DTLVardef@7bc4edorg.highwire.dtl.DTLVardef@1bdc7c1org.highwire.dtl.DTLVardef@85851corg.highwire.dtl.DTLVardef@1e620b8_HPS_FORMAT_FIGEXP M_FIG C_FIG Main pointsO_LIPeripheral and central OECs are functionally distinct\nC_LIO_LIPeripheral OECs have large weak inward rectifier currents\nC_LIO_LICentral OECs have strong inward and outward rectifier currents\nC_LI

physiology↗