Biology subjects

Carey, M.

Publications and source records attributed to Carey, M..

6 recordsLinked to original sources

bioRxiv2026

Tumor-Derived SPP1 Drives Immunosuppressive Macrophage Reprogramming in Gastric Peritoneal Carcinomatosis

Peritoneal carcinomatosis is a major cause of death in gastric cancer, yet effective therapies remain limited. Tumor-derived soluble factors are increasingly recognized as key regulators of the peritumoral microenvironment. Here, we nominate osteopontin (SPP1) as a tumor-derived mediator that orchestrates macrophage-driven immunoregulation in gastric peritoneal carcinomatosis. Using integrated analyses of human clinical datasets and murine models, we demonstrate that tumor-secreted SPP1 promotes macrophage recruitment and induces tolerogenic IL-10 production. Clinically, SPP1 correlated with inferior overall survival and progression-free survival in gastric cancer. In syngeneic murine models of gastric peritoneal carcinomatosis, intracavitary pharmacologic inhibition of SPP1 restricted peritoneal dissemination, impaired macrophage infiltration and suppressed IL-10 production. Consistent with these findings, macrophage depletion phenocopied antitumor effects of SPP1 inhibition, resulting in decreased metastatic burden. Collectively, these findings define a mechanism of tumor-macrophage crosstalk that promotes peritoneal dissemination and provide a rationale for therapeutic targeting of SPP1 in gastric peritoneal carcinomatosis.

Cancer Biology↗

bioRxiv2024

A robust unsupervised clustering approach for high-dimensional biological imaging data reveals shared drug-induced morphological signatures

Modern biology increasingly relies on large-scale screening to generate high dimensional datasets with potential to accelerate discovery. However, analysing these complex datasets remains challenging, particularly in applications where the underlying structure and groupings are unknown, and high dimensionality introduces noise and artifacts that make follow up studies difficult to prioritise. Here, we present an unsupervised consensus clustering tool that quantifies biologically meaningful patterns based on multi-scale data organisation to guide decision-making in high-throughput screening. Using large-scale drug screening data in cancer cell lines and bacterium model, we demonstrate its ability to use diverse data inputs to prioritize robust drug clusters with shared biological mechanisms and conserved drug responses. This method addresses key limitations associated with prioritising robust, actionable hits from scalable screening data.

bioinformatics↗

bioRxiv2020

The genetic signatures of Salmonella Typhi carriage in the human gallbladder

Despite recent gains in typhoid fever control, asymptomatic carriage of Salmonella Typhi in the gallbladder remains an enigma. Aiming to understand if S. Typhi in the gallbladder are vital for transmission and/or adapted for long-term colonisation we performed whole genome sequencing on a collection of S. Typhi isolated from the gallbladders of typhoid carriers. These sequences were compared to contemporaneous sequences from organisms isolated from the blood of acute patients.S. Typhi carriage was not restricted to any particular genotype or conformation of antimicrobial resistance genes but reflective of the general population. However, gallbladder isolates had a higher genetic variability than acute isolates, with median pairwise SNP distances of 21 and 13 SNPs (p=2.8x10-9), respectively. This variation was associated with a higher prevalence of nonsense mutations in the gallbladder isolates in the predominant genotype. Notably, gallbladder isolates displayed a higher frequency of non-synonymous mutations in genes encoding hypothetical proteins, membrane lipoproteins, transport/binding proteins, surface antigens, and carbohydrate degradation. Particularly, we identified several gallbladder-specific non-synonymous mutations involved in LPS synthesis and modification, with some isolates lacking the Vi capsular polysaccharide vaccine target due to a 134Kb deletion. Long-term gallbladder carriage of S. Typhi results in atypically long branch lengths that can distinguish between carriage and acute infection. Our data strongly suggests typhoid carriers are unlikely to play a principal role in disease transmission in endemic settings, but that the hostile environment of the human gallbladder may generate new antigenic variants through immune selection.

microbiology↗

bioRxiv2019

Orthogonal Drug Pooling Enhances Phenotype-based Discovery of Ocular Anti-angiogenic Drugs in Zebrafish Larvae

Unbiased screening of large randomized chemical libraries in vivo is a powerful tool to find new drugs and targets. However, forward chemical screens in zebrafish can be time consuming and usually >99% of test compounds have no significant effect on the desired phenotype. Here, we sought to find bioactive drugs more efficiently and to comply with the 3R principles of replacement, reduction and refinement of animals in research. We investigated if pooling of drugs to simultaneously test 8-10 compounds in zebrafish larvae can increase the screening efficiency of an established assay that identifies drugs inhibiting developmental angiogenesis in the eye. In a phenotype-based screen, we tested 1760 small molecule compounds from the ChemBridge DIVERSet chemical library for their ability to inhibit the formation of distinct primary hyaloid vessels in the eye. Applying orthogonal pooling of the chemical library, we treated zebrafish embryos from 3 to 5 days post fertilization with pools of 8 or 10 compounds at 10 M each. This reduced the number of tests from 1760 to 396. In 63% of cases, treatment showed sub-threshold effects of <40% reduction of primary hyaloid vessels. From 18 pool hits, we identified 8 compounds that reduce hyaloid vessels in the larval zebrafish eye by at least 40%. Compound 4-[4-(1H-benzimidazol-2-yl)phenoxy]aniline ranked as the most promising candidate with reproducible and dose-dependent effects. To our knowledge, this is the first report of a self-deconvoluting matrix strategy applied to drug screening in zebrafish. We conclude that the orthogonal drug pooling strategy is a cost-effective, time-saving and unbiased approach to discover novel inhibitors of developmental angiogenesis in the eye. Ultimately, this approach may identify new drugs or targets to mitigate disease caused by pathological angiogenesis in the eye e.g. diabetic retinopathy or age-related macular degeneration wherein blood vessel growth and leaky vessels lead to vision impairment or clinical blindness.

pharmacology and toxicology↗

bioRxiv2018

The Effect of Visual Capture Towards Subjective Embodiment Within the Full Body Illusion

Typically, multisensory illusion paradigms emphasise the importance of synchronous visuotactile integration to induce subjective embodiment towards another body. However, the extent to which embodiment is due to the visual capture of congruent visuoproprioceptive information alone remains unclear. Thus, across two experiments (total N = 80), we investigated how mere visual observation of a mannequin body, viewed from a first-person perspective, influenced subjective embodiment independently from concomitant visuotactile integration. Moreover, we investigated whether slow, affective touch on participants own, unseen body (without concomitant touch on the seen mannequin) disrupted visual capture effects to a greater degree than fast, non-affective touch. In total, 40% of participants experienced subjective embodiment towards the mannequin body following mere visual observation, and this effect was significantly higher than conditions which included touch to participants own, unseen body. The velocity of the touch that participants received (affective/non-affective) did not differ in modulating visual capture effects. Furthermore, the effects of visual capture and perceived pleasantness of touch was not modulated by subthreshold eating disorder psychopathology. Overall, this study suggests that congruent visuoproprioceptive cues can be sufficient to induce subjective embodiment of a whole body, in the absence of visuotactile integration and beyond mere confabulatory responses.

neuroscience↗

bioRxiv2017

Scopoletin 8-hydroxylase: a novel enzyme involved in coumarin biosynthesis and iron-deficiency responses in Arabidopsis

HighlightA strongly iron-responsive gene of previously unknown function, At3g12900, encodes a scopoletin 8-hydroxylase involved in coumarin biosynthesis and plays an important role in the iron uptake strategy in Arabidopsis.\n\nAbstractIron (Fe) deficiency represents a serious agricultural problem, particularly in alkaline soils. Secretion of coumarins by Arabidopsis thaliana roots is induced under Fe-deficiency. An essential enzyme for the biosynthesis of major Arabidopsis coumarins, scopoletin and its derivatives, is Feruloyl-CoA 6-Hydroxylase1 (F6'H1) that belongs to a large enzyme family of the 2-oxoglutarate and Fe(II)-dependent dioxygenases. Another member of this family that is a close homologue of F6H1 and is encoded by a strongly Fe-responsive gene, At3g12900, is functionally characterized in the presented work. We purified the At3g12900 protein heterologously expressed in Escherichia coli and demonstrated that it is involved in the conversion of scopoletin into fraxetin via hydroxylation at the C8-position. Consequently, it was named scopoletin 8-hydroxylase (S8H). Its function in plant cells was confirmed by the transient expression of S8H protein in Nicotiana benthamiana leaves followed by the metabolite profiling and the biochemical and ionomic characterization of Arabidopsis s8h knockout lines grown under various regimes of Fe availability. Our results indicate that S8H is involved in coumarin biosynthesis as part of the Fe acquisition machinery.

plant biology↗