Biology subjects

York, A.

Publications and source records attributed to York, A..

13 recordsLinked to original sources

bioRxiv2026

The global evolutionary dynamics of natural capsule switching in a human-restricted bacterial pathogen

Exchange of genetic loci encoding extracellular capsular polysaccharides in bacteria can change capsular antigens or serotype, which, in turn, can lead to evasion of vaccines targeting the capsule. However, the evolutionary dynamics and drivers of bacterial capsule switching remain poorly understood. Here, we investigate the evolutionary dynamics and correlates of capsule switching in bacteria, using the human-restricted bacterial pathogen Streptococcus pneumoniae as an example, using 10,558 genetically and geographically diverse whole-genome sequences. Our phylogenomic and ancestral state reconstruction analysis revealed that the propensity for capsule switching varies by capsule type and genetic background. We found capsule switches only between ~4% of all possible capsule-type pairs, varying by specific pairs and switching direction. We also found associations between capsule switching patterns and genetic and ecological factors, including nasopharyngeal carriage duration, capsule biosynthesis locus size, and capsule thickness. Furthermore, the genetic similarity of the replacing and replaced capsule loci was primarily associated with the frequency of switching between specific capsule type pairs. Although a few specific non-capsule genomic loci were associated with the propensity for capsule switching across distinct lineages, the collective effect of the genetic background appears to influence capsule switching more strongly. These findings shed light on how bacterial capsule types and lineages undergo capsule switching influenced by genetic and ecological factors, informing our understanding of the emergence of novel capsule-genotype combinations that may impact the design of capsule-targeting glycoconjugate vaccines.

microbiology↗

bioRxiv2026

Ultra-high field fMRI reveals functional patterns consistent with columnar organisation in human somatosensory cortex

In animal models, the primary somatosensory cortex (S1) exhibits columnar organisation, where vertically arranged neurons share functional properties. In humans, however, the thinness and folding of S1 have limited non-invasive investigations of such columnar structures. In this study, we aimed to identify columns in human S1 by delivering alternating bursts of 3 Hz and 30 Hz fingertip vibration while acquiring functional MRI time series at 7 Tesla. Using cortical surface modelling, we identified functional patterns in S1 that showed higher reliability, stronger differential responses, and greater statistical sensitivity than those observed in a frontal cortex control region (p = .001-.012 for reliability; p < .001 for differential signal; p = .004-.011 for sensitivity). Laminar analyses revealed depth-consistent frequency preferences in approximately 20-45% of S1 nodes, a pattern compatible with vertically organised functional structure. Although the relative signal difference between 3 Hz and 30 Hz was small (0.14% signal change), frequency tuning was reliably observed. Taken together, these findings reveal functional patterns in human S1 consistent with aspects of columnar-like organisation, providing non-invasive evidence of fine-scale functional architecture. TeaserfMRI reveals highly reliable but modestly selective responses in human S1, consistent with column-like functional organisation.

neuroscience↗

bioRxiv2025

Storage stability of non-encapsulated pneumococci in saliva is dependent on null-capsule clade, with strains carrying aliC and aliD showing a competitive disadvantage during culture enrichment

BackgroundNon-encapsulated Streptococcus pneumoniae (NESp) represent up to 19% of circulating pneumococci and exhibit high rates of antimicrobial resistance. Saliva is increasingly used as a pneumococcal carriage study specimen, and we recently developed a qPCR assay to enhance carriage surveillance and characterization of NESpn in saliva. Previous work has established that pneumococci remain viable in unsupplemented saliva for extended periods under various conditions, however these findings may not be applicable to NESp. Therefore, to ensure the robustness of NESp detection in saliva-based carriage studies we evaluated the impact of transport and storage conditions of saliva samples on NESp detection. MethodsSix NESp strains from two clinically relevant NESp null capsule clades (NCC), NCC1 (carrying pspK) and NCC2 (carrying aliC and aliD), were spiked into lytA-negative saliva and incubated through various temperatures and freeze-thaw conditions. Endpoints were processed using either culture-enrichment and DNA extraction (CE-DNA), or an extraction-free method without CE, before testing for lytA using qPCR. Detection stability was assessed using regression modelling over temperature, time and freeze-thaws. ResultsFollowing CE-DNA, detection of NESp remained stable for [≤]24 or [≤]72 hours when stored at room temperature or 4{degrees}C, respectively, and over 2 freeze-thaw cycles (-80{degrees}C), with glycerol-supplementation providing slight benefits. Stability of detection when using CE-DNA depended on NCC; detection of NCC2 strains was lower, and less stable than NCC1. Compared to CE-DNA, extraction-free detection was more stable, with no significant loss over 72 hours at room temperature and over 3 freeze-thaw cycles. With extraction-free detection, there were also negligible diderences in detection between NCC1 and NCC2. Additionally, extraction-free detection of NCC1, and less so NCC2, increased over the first 24 hours when stored at 20-30{degrees}C, suggesting growth in saliva. Testing of{Delta} aliCaliD and{Delta} pspK mutants revealed these genes increased in vitro viability of NCC2 and NCC1, respectively, but did not significantly alter competitive fitness during CE. ConclusionNCC1 NESp strains exhibit similar stability patterns in unsupplemented saliva as encapsulated pneumococci. NCC2 strains, however, are less resilient during CE, likely due to competition with other oral microbes. Therefore, recovery of NCC2 NESp may be impacted by transport and storage conditions, leading to an underestimation of carriage prevalence when tested using CE-based methods. For the reliable carriage surveillance of NESp, samples should be stored at 4{degrees}C soon after collection and at -80{degrees}C within 72 hours. Methods which directly detect DNA without CE may provide a less biased accounting of NCC2 strains.

microbiology↗

bioRxiv2024

The capsule and genetic background, rather than specific loci, strongly influence pneumococcal growth kinetics

Bacterial growth characteristics intrinsic to each strain can impact and influence gene expression, antibiotic susceptibility, and disease pathogenesis. However, little is known about specific genomic variations that influence these bacterial growth features. Here, we investigate the impact of Streptococcus pneumoniae genetics on its in vitro growth features to shed light on genes that may be important targets in the development of vaccines and therapeutics. We use statistical models to estimate growth features and demonstrate that they varied significantly across capsular serotypes and lineages, were strongly correlated with phylogeny, and showed high heritability, highlighting a strong genetic basis. Despite this, genome-wide association studies revealed no specific genomic loci statistically associated with the growth features independently of the genetic background, including those in the locus responsible for capsular polysaccharide synthesis. Our findings suggest that the serotype and lineage, as well as a combination of genomic loci, influence intrinsic pneumococcal growth kinetics, which may have implications for pneumococcal disease pathogenesis.

microbiology↗

bioRxiv2024

Neural correlates of phonetic categorization under auditory (phoneme) and visual (grapheme) modalities

We tested whether the neural mechanisms of phonetic categorization are specific to speech sounds or generalize to graphemes (i.e., visual letters) of the same phonetic label. Given that linguistic experience shapes categorical processing, and letter-speech sound matching plays a crucial role during early reading acquisition, we hypothesized sound phoneme and visual grapheme tokens representing the same linguistic identity might recruit common neural substrates, despite originating from different sensory modalities. Behavioral and neuroelectric brain responses (ERPs) were acquired as participants categorized stimuli from sound (phoneme) and homologous letter (grapheme) continua each spanning a /da/ - /ga/ gradient. Behaviorally, listeners were faster and showed stronger categorization of phoneme compared to graphemes. At the neural level, multidimensional scaling of the EEG revealed responses self-organized in a categorial fashion such that tokens clustered within their respective modality beginning [~]150-250 ms after stimulus onset. Source-resolved ERPs further revealed modality-specific and overlapping brain regions supporting phonetic categorization. Left inferior frontal gyrus and auditory cortex showed stronger responses for sound category members compared to phonetically ambiguous tokens, whereas early visual cortices paralleled this categorical organization for graphemes. Auditory and visual categorization also recruited common visual association areas in extrastriate cortex but in opposite hemispheres (auditory = left; visual=right). Our findings reveal both auditory and visual sensory cortex supports categorical organization for phonetic labels within their respective modalities. However, a partial overlap in phoneme and grapheme processing among occipital brain areas implies the presence of an isomorphic, domain-general mapping for phonetic categories in dorsal visual system.

neuroscience↗

bioRxiv2022

Variability of visual field maps in human early extrastriate cortex challenges the canonical model of organization of V2 and V3

Visual field maps in human early extrastriate areas (V2 and V3) are traditionally thought to form mirror-image representations which surround the primary visual cortex (V1). According to this scheme, V2 and V3 form nearly symmetrical halves with respect to the calcarine sulcus, with the dorsal halves representing lower contralateral quadrants, and the ventral halves representing upper contralateral quadrants. This arrangement is considered to be consistent across individuals, and thus predictable with reasonable accuracy using templates. However, data that deviate from this expected pattern have been observed, but mainly treated as artifactual. Here we systematically investigate individual variability in the visual field maps of human early visual cortex using the 7T Human Connectome Project (HCP) retinotopy dataset. Our results demonstrate substantial and principled inter-individual variability. Visual field representation in the dorsal portions of V2 and V3 was more variable than in their ventral counterparts, including substantial departures from the expected mirror-symmetrical patterns. In addition, left hemisphere retinotopic maps were more variable than those in the right hemisphere. Surprisingly, only one-third of individuals had maps that conformed to the expected pattern in the left hemisphere. Visual field sign analysis further revealed that in many individuals the area conventionally identified as dorsal V3 shows a discontinuity in the mirror-image representation of the retina, associated with a Y-shaped lower vertical representation. Our findings challenge the current view that inter-individual variability in early extrastriate cortex is negligible, and that the dorsal portions of V2 and V3 are roughly mirror images of their ventral counterparts.

neuroscience↗

bioRxiv2022

Increasing the Field-of-View in Oblique Plane Microscopy via optical tiling

Fast volumetric imaging of large fluorescent samples with high-resolution is required for many biological applications. Oblique plane microscopy (OPM) provides high spatiotemporal resolution, but the field of view is typically limited by its optical train and the pixel number of the camera. Mechanically scanning the sample or decreasing the overall magnification of the imaging system can partially address this challenge, albeit by reducing the volumetric imaging speed or spatial sampling, respectively. In this Letter, we introduce a novel dual-axis scan unit for OPM that enables rapid and high-resolution volumetric imaging throughout a volume of 800 x 500 x 200 microns. This enables imaging of model organisms, such as zebrafish embryos, with subcellular resolution. Furthermore, we combined this microscope with a real-time and multi-perspective projection imaging technique to increase the volumetric interrogation rate to more than 10 Hz.

bioengineering↗

bioRxiv2021

Highly accurate retinotopic maps of the physiological blind spot in human visual cortex

The physiological blind spot is a naturally occurring scotoma corresponding with the optic disc in the retina of each eye. Even during monocular viewing, observers are usually oblivious to the scotoma, in part because the visual system extrapolates information from the surrounding area. Unfortunately, studying this visual field region with neuroimaging has proven difficult, as it occupies only a small part of retinotopic cortex. Here we used functional magnetic resonance imaging and a novel data-driven method for mapping the retinotopic organization in and around the blind spot representation in V1. Our approach allowed for highly accurate reconstructions of the extent of an observers blind spot, and out-performed conventional model-based analyses. This method opens exciting opportunities to study the plasticity of receptive fields after visual field loss, and our data add to evidence suggesting that the neural circuitry responsible for impressions of perceptual completion across the physiological blind spot most likely involves regions of extrastriate cortex - beyond V1.

neuroscience↗

bioRxiv2021

Magnetic Bead-Based Separation (MBS) of Pneumococcal Serotypes

The separation of pneumococcal serotypes from a complex polymicrobial mixture may be required for different applications. For instance, a minority strain could be present at a low frequency in a clinical sample, making it difficult to identify and isolate by traditional culture-based methods. We therefore developed an assay to separate mixed pneumococcal samples using serotype-specific antiserum and a magnetic bead-based separation method. Using qPCR and colony counting methods, we first show that serotypes (12F, 23F, 3, 14, 19A and 15A) present at [~]0.1% of a dual serotype mixture can be enriched to between 10% and 90% of the final sample. We demonstrate two applications for this method: extraction of a known pneumococcal serotype from saliva samples and efficient purification of capsule switch variants from experimental transformation experiments. Moreover, this method may have further laboratory or clinical applications when the selection of specific serotypes is required.

microbiology↗

bioRxiv2020

High-Resolution, Large Field-of-View, and Multi-View Single Objective Light-Sheet Microscopy

Recent developments in Oblique Plane Microscopy (OPM) have shown that it can achieve high spatio-temporal resolution. Here we describe a single objective light-sheet microscope based on oblique plane illumination that achieves: (i) large field of view and high-resolution imaging via a custom remote focusing objective; (ii) fast volumetric imaging by means of light-sheet stabilised stage scanning - a novel scanning modality that extends the imaging volume without compromising imaging speed nor quality; (iii) multi-view imaging by alternating the orientation of light-sheet illumination and detection to improve the image quality on large samples; (iv) simpler design and ergonomics by remote placement of coverslips to allow inverted imaging, enabling imaging across scales in a high-throughput format. Overall, we achieved a resolution of 450 nm laterally and 2 m axially and a field of view of 3000 m x 800 m x 300 m. We demonstrate the speed, field of view, resolution and versatility of our novel instrument by imaging various systems, including zebrafish whole brain activity, Drosophila egg chamber development, and zebrafish development - up to nine embryos simultaneously.

developmental biology↗

bioRxiv2020

Structure-based modelling and dynamics of MurM, a Streptococcus pneumoniae penicillin resistance determinant that functions at the cytoplasmic membrane interface

MurM is an aminoacyl-tRNA dependant ligase that aminoacylates the Lipid II peptidoglycan precursor, in the human pathogen Streptococcus pneumoniae. MurM is required for the generation of branched peptidoglycan precursors enabling indirect cross-links in the peptidoglycan and is found to be essential for penicillin resistance. In this study we have solved the X-ray crystal structure of Staphylococcus aureus FemX, an isofunctional homologue of MurM, and used this as a template to generate a homology model of MurM. Using this model, we perform molecular docking and molecular dynamics to examine the interaction of the protein with the phospholipid bilayer and the membrane embedded Lipid II substrate of MurM. Our model suggests that MurM is associated with the major membrane phospholipid cardiolipin, and we confirm this with experimental evidence that the activity of MurM is enhanced by this phospholipid and inhibited by its direct precursor phosphatidylglycerol. This suggests that the spatial association of pneumococcal membrane phospholipids and their impact on MurM activity may be a critical to the final architecture of the peptidoglycan and the expression of clinically relevant penicillin resistance in this pathogen.

biochemistry↗

bioRxiv2020

Development of an Ocean Protein Portal for Interactive Discovery and Education

Proteins are critical in catalyzing chemical reactions, forming key cellular structures, and in regulating cellular processes. Investigation of marine microbial proteins by metaproteomics methods enables the discovery of numerous aspects of microbial biogeochemistry processes. However, these datasets present big-data challenges as they often involve many samples collected across broad geospatial and temporal scales, resulting in thousands of protein identifications, abundances, and corresponding annotation information. The Ocean Protein Portal (OPP) was created to enable data sharing and discovery among multiple scientific domains and serve both research and education functions. The portal focuses on three use case questions: "Where is my protein of interest?", "Who makes it?", and "How much is there?", and provides profile and section visualizations, real-time taxonomic analysis, and links to metadata, sequence analysis, and other external resources to enabling connections to be made between biogeochemical and proteomics datasets.

systems biology↗

bioRxiv2019

Longitudinal Automatic Segmentation of Hippocampal Subfields (LASHiS) using Multi-Contrast MRI

The volumetric and morphometric examination of hippocampus formation subfields in a longitudinal manner using in vivo MRI could lead to more sensitive biomarkers for neuropsychiatric disorders and diseases including Alzheimers disease, as the anatomical subregions are functionally specialised. Longitudinal processing allows for increased sensitivity due to reduced confounds of inter-subject variability and higher effect-sensitivity than cross-sectional designs. We examined the performance of a new longitudinal pipeline (Longitudinal Automatic Segmentation of Hippocampus Subfields [LASHiS]) against three freely available, published approaches. LASHiS automatically segments hippocampus formation subfields by propagating labels from cross-sectionally labelled time point scans using joint-label fusion to a non-linearly realigned single subject template, where image segmentation occurs free of bias to any individual time point. Our pipeline measures tissue characteristics available in in vivo high-resolution MRI scans, at both clinical (3 Tesla) and ultra-high field strength (7 Tesla) and differs from previous longitudinal segmentation pipelines in that it leverages multi-contrast information in the segmentation process. LASHiS produces robust and reliable automatic multi-contrast segmentations of hippocampus formation subfields, as measured by higher volume similarity coefficients and Dice coefficients for test-retest reliability and robust longitudinal Bayesian Linear Mixed Effects results at 7 T, while showing sound results at 3 T. All code for this project including the automatic pipeline is available at https://github.com/CAIsr/LASHiS

neuroscience↗