Biology subjects

Gray, E.

Publications and source records attributed to Gray, E..

8 recordsLinked to original sources

bioRxiv2026

White matter conduction in the human brain is mostly slow, with rare high velocity connections

White matter bundles play a crucial role in cognitive functions by rapidly transmitting information between brain regions. Inter-areal conduction guides the integration of information and conduction velocity is a fundamental parameter in theories and models of brain function. However, distributions of conduction velocity remain difficult to characterize in vivo in humans. In this work, we integrated diffusion magnetic resonance imaging (dMRI) tractography with intracranial electrical stimulation during clinical stereo-electroencephalography (sEEG) monitoring in 17 subjects to measure conduction velocity within four major white matter bundles. Our findings reveal that human brain conduction is characterized by high variability both within and between bundles, reflecting a predominance of slow connections alongside rare high-speed connections. Because conduction velocity in myelinated fibers follows an approximately linear relationship with axon diameter, we derive underlying axon diameter distributions and show that these estimates are comparable to previous post-mortem studies. These findings demonstrate a heavily skewed distribution of human neural conduction velocities and show that structural heterogeneity shapes the timing and integration of information in large-scale networks.

neuroscience↗

bioRxiv2026

Lake ecosystem responses to runoff variability across time and space

Inland waters in the Northern Hemisphere are experiencing increased annual runoff due to higher overall precipitation as well as intensified short-term events such as heavy rainfall, floods and storms. These events affect the total loading and variability of inputs of allochthonous, coloured dissolved organic matter (cDOM) and inorganic nutrients into lakes. Previous studies have shown that increased total cDOM and inorganic nutrient loads affect phytoplankton biomass and metabolic rates, but it is unknown how the effects of different cDOM and nutrient pulse scenarios are modified by spatial and seasonal differences in lake characteristics. Here, we conducted a coordinated, standardized mesocosm experiment across three lakes with different ambient cDOM and nutrient concentrations. In two of these lakes, the experiment was implemented in two seasons. The same total amounts of cDOM, nitrate and phosphate were added to all mesocosms, but in pulses that differed in intensity and frequency. We found that pulse intensity and frequency affected chlorophyll a and phycocyanin concentrations and metabolic rates, i.e. gross primary production and respiration, differently. Specifically, more pronounced effects were found in response to the extreme pulse scenario compared to those with more frequent, smaller pulse additions. Furthermore, the effects were mainly temporary and varied more among lakes than between seasons. The clearest differences between the extreme and more gradual runoff scenarios were found in the lake with the lowest background cDOM and nitrate concentrations, likely because lower light limitation and possibly stronger initial N-limitation caused a faster response to the nutrient addition. Our results highlight that both antecedent lake conditions and characteristics of runoff events can affect phytoplankton biomass and metabolic rates and that comparative experimental approaches are needed to reveal the complexity of the responses.

ecology↗

bioRxiv2025

StarTrace: A Multiplex Organoid Avatar Drug Testing Platform for Personalized Medicine

The goal of precision medicine is to improve clinical outcomes of cancer patients by choosing treatments most likely to work. One idea is to match tumor response to cancer-causing somatic mutations, but this strategy still faces limitations in colorectal cancer due to poorly understood genetic influences on drug resistance. We describe here a simple direct drug sensitivity assay platform applied to mixtures of patient-derived organoid avatars as a practical solution for choosing therapy, sidestepping the need for exhaustive knowledge of drug-genetic interactions. This approach rank orders individual patient organoid avatars responses to various drugs to be used to guide treatment choices. The platform multiplexes organoids using a clonal barcoding method, called StarTrace, which simultaneously tests pools of multiple patients organoid avatars for sensitivity or resistance to small molecule inhibitors. We utilized both quantitative real-time PCR-based and single-molecule sequencing assays to track the relative Darwinian fitness of each barcoded organoid within the pool. StarTrace offers a rapid, cost effective and sensitive testing platform that could be useful for either preclinical drug development or tailoring personalized therapy.

molecular biology↗

bioRxiv2022

Spatial transcriptomics reveals ovarian cancer subclones with distinct tumour microenvironments

High-grade serous ovarian carcinoma (HGSOC) is characterised by recurrence, chemotherapy resistance and overall poor prognosis. Genetic heterogeneity of tumour cells and the microenvironment of the tumour have been hypothesised as key determinants of treatment resistance and relapse. Here, using a combination of spatial and single cell transcriptomics (10x Visium and Chromium platforms), we examine tumour genetic heterogeneity and infiltrating populations of HGSOC samples from eight patients with variable response to neoadjuvant chemotherapy. By inferring gross copy number alterations (CNAs), we identified distinct tumour subclones co-existing within individual tumour sections. These tumour subclones have unique CNA profiles and spatial locations within each tumour section, which were further validated by ultra-low-pass whole genome sequencing. Differential expression analysis between subclones within the same section identified both tumour cell intrinsic expression differences and markers indicative of different infiltrating cell populations. The gene sets differentially expressed between subclones were significantly enriched for genes encoding plasma membrane and secreted proteins, indicative of subclone-specific microenvironments. Furthermore, we identified tumour derived ligands with variable expression levels between subclones that correlated or anticorrelated with various non-malignant cell infiltration patterns. We highlight several of these that are potentially direct tumour-stroma/immune cell relationships as the non-malignant cell type expresses a cognate receptor for the tumour derived ligand. These include predictions of CXCL10-CXCR3 mediated recruitment of T and B cells to associate with the subclones of one patient and CD47-SIRPA mediated exclusion of macrophages from association with subclones of another. Finally, we show that published HGSOC molecular subtype signatures associated with prognosis are heterogeneously expressed across tumour sections and that areas containing different tumour subclones with different infiltration patterns can match different subtypes. Our study highlights the high degree of intratumoural subclonal and infiltrative heterogeneity in HGSOC which will be critical to better understand resistance and relapse.

cancer biology↗

bioRxiv2021

Inside-out Signalling From Aminopeptidase N (CD13) To Complement Receptor 3 (CR3, CD11b/CD18)

Upon ligand engagement, certain receptors can activate an integrin through a mechanism called inside-out signalling. This phenomenon prepares the cell for the next steps of the process it will perform. CR3 (Complement receptor 3), the most abundant {beta}2 integrin in monocytes and macrophages, and CD13 (aminopeptidase N) are two immune receptors with overlapping activities: adhesion, phagocytosis of opsonized particles, and respiratory burst induction. They can be found together in functional signalling microdomains, or lipid rafts, on the surface of human leukocytes. Thus, given their common functions, shared physical location and the fact that some phagocytic and adhesion receptors activate a selection of integrins, we hypothesized that CD13 could activate CR3 through an inside-out signalling mechanism. To test this hypothesis, we first ascertained the activation of CR3 after CD13 crosslinking in human monocyte-derived macrophages. We used an integrated analysis of bioinformatics and experimental data to suggest two possible signalling cascades that could explain the phenomenon. Finally, we show that the non-receptor tyrosine kinase Syk is a key attenuator of this pathway. Our results demonstrated that, even in the absence of canonical signalling motifs, and despite having a noticeably short cytoplasmic tail (7-10 amino acids), CD13 was capable of triggering an inside-out signalling cascade, adding a new function to those already known for this moonlighting protein. One Sentence SummaryStimulation of CD13 activated the integrin CR3 via an inside-out signalling pathway, a mechanistic model is proposed.

immunology↗

bioRxiv2021

Known mechanisms account for less than half of antimicrobial resistance in a diverse collection of non-aureus staphylococci.

IntroductionNon-aureus staphylococci (NAS) are implicated in many healthcare-acquired infections and an understanding of the genetics of antimicrobial resistance in NAS is important in relation to both clinical intervention and the role of NAS as a reservoir of resistance genes. Gap statementThe burden of antimicrobial resistance in NAS, particularly to clinically relevant antimicrobials, is under recognised. MethodologyWe sourced 394 NAS isolates from clinical samples, healthy human volunteers, animals and type cultures and subjected them to agar dilution susceptibility testing against eight antimicrobials. Cefoxitin was used to screen for methicillin resistance in S. aureus, as it stimulates expression of mecA. We performed whole genome sequencing on 366 isolates and analysed these genotypically for the presence of genetic mechanisms responsible for the phenotypic levels of reduced antimicrobial susceptibility. ResultsWe observed 175 sequenced isolates with a minimum inhibitory concentration (MIC) of at least 4 g/ml to cefoxitin, of which 50% (87/175) did not harbour a known mec homologue. Eight clinical NAS isolates displayed high daptomycin MICs (>4 g/ml), with no known mechanism identified. Differences in MICs against erythromycin were attributable to the presence of different resistance genes (msrA and ermC). In total, 49% (193 /394) of isolates displayed reduced susceptibility to three or more of the antimicrobials tested. ConclusionsThe widespread presence of reduced antimicrobial susceptibility in NAS is a concern, with an increased likelihood of (1) harder to treat infections caused directly by NAS, and (2) resistance genes being passed on to other bacteria via horizontal gene transfer, both of which have clinical implications for treatment and management of patients.

microbiology↗

bioRxiv2020

Global RNA sequencing reveals enhanced photosynthetic activity and auxin response in Brassica napus treated with Pseudomonas chlororaphis PA23

Plant growth promoting bacteria (PGPB) are a growing subset of agricultural adjuncts which can be used to increase crop yield and plant productivity. Although substantial research has been conducted on the metabolites and active molecules secreted by PGPBs, relatively little is known about their effects on the global transcriptome of the host plant. The present study was carried out to investigate changes in the gene expression landscape of early vegetative Brassica napus following treatment with Pseudomonas chlororaphis PA23. This PGPB was isolated from the soybean rhizosphere and has been extensively studied as a biocontrol agent. However, little is known about its effects on plant growth and development. Using a combination of RNA-sequencing and physiological analyses, we identified increased abundance of mRNA transcripts associated with photosynthesis and phytohormone response. Phenotypically we observed increased photosynthetic rates and larger root and shoot systems in B. napus following P. chlororaphis PA23 treatment. Lastly, we identified auxin production by P. chlororaphis PA23 which likely contributes to changes in gene expression and the observed phenotypic differences in root and shoot structures. Together, the results of our study suggest that PA23 is a potent plant growth promoting agent with the potential for field applications as an agricultural adjunct.

plant biology↗

bioRxiv2018

Prognostic Relevance of CCDC88C (Daple) Transcripts in the Peripheral Blood of Patients with Malignant Melanoma

A loss of balance between G-protein activation and deactivation has been implicated in the initiation of melanomas, and non-canonical Wnt signaling via the Wnt5A/Frizzled (FZD) pathway has been shown to be critical for the switch to an invasive phenotype. Daple [CCDC88C gene], a cytosolic guanine nucleotide exchange factor (GEF) which enhances non-canonical Wnt5A/FZD signaling via activation of trimeric G protein, Gai has been shown to serve opposing roles-- as an inducer of EMT and invasiveness and a potent tumor suppressor -- via two isoforms, V1 (full-length) and V2, respectively. Here we report that the relative abundance of these isoforms in the peripheral circulation, presumably largely from circulating tumor cells (CTCs), is a prognostic marker of cutaneous melanomas. Expression of V1 is increased in both the early and late clinical stages (p<0.001, p=0.002, respectively); V2 is decreased exclusively in the late clinical stage (p=0.011). The two isoforms have opposing prognostic effects: high expression of V2 increases progression-free survival (PFS; p = 0.02), whereas high expression of V1 decreases PFS (p=0.013). Furthermore, these effects are additive, in that melanoma patients with a low V2-high V1 signature carry the highest risk of metastatic disease. We conclude that detection of Daple transcripts in the peripheral blood (i.e., liquid biopsies) of patients with melanoma may serve as a prognostic marker and an effective strategy for non-invasive long-term follow-up of patients with melanoma.

cancer biology↗