Biology subjects

Robinson, S. D.

Publications and source records attributed to Robinson, S. D..

At least 19 recordsLinked to original sources

bioRxiv2026

Bifidobacterium pseudocatenulatum extracellular vesicles promote Ly6G+ granulocyte infiltration to inhibit melanoma tumour progression

Harnessing the immunomodulatory capacity of commensal bacteria is an emerging avenue in cancer therapy. Bacterial extracellular vesicles (BEVs) provide a non-replicating, nanoscale alternative to live microbes with the potential for safer systemic delivery. Here, we investigated BEVs from a novel Gram-positive strain of Bifidobacterium pseudocatenulatum (Bif-210). Intravenous administration of Bif-210 BEVs reduced B16-F10 melanoma growth in C57BL/6J mice. Mechanistically, BEVs increased tumour-infiltrating Ly6G+ granulocytes in vivo, increased CD11b+Ly6G+ and ICAM-1+Ly6G+ bone marrow populations, and induced production of the neutrophil-attracting chemokines KC/CXCL1 (mouse) and IL-8 (human). Although Ly6G+ depletion independently inhibited tumour growth, it did not combine additively with BEVs, supporting a model in which Bif-210 BEVs alter Ly6G+ granulocyte function rather than simply expanding a conventional pro-tumour granulocyte pool. BEVs activated TLR2, did not activate TLR4, and upregulated TLR2 on Ly6G+ cells, while proxy assays provided no evidence of NETosis-associated activation. Repeated intravenous BEV administration produced no overt toxicity by tissue histology, body temperature, or body weight monitoring. These findings position B. pseudocatenulatum BEVs as a promising systemic immunotherapy that recruits and re-educates granulocytes via a TLR2-centred pathway to restrain melanoma progression. HIGHLIGHTSO_LIIntravenous Bif-210 BEVs reduce established B16-F10 melanoma growth in mice. C_LIO_LIBif-210 BEVs selectively increase tumour-associated Ly6G+ granulocytes. C_LIO_LIBEV treatment and Ly6G depletion are non-additive, linking BEV activity to granulocyte biology. C_LIO_LIBif-210 BEVs expand Ly6G+ bone marrow populations and induce granulocyte-recruiting chemokines. C_LIO_LIBif-210 BEVs engage TLR2 and enhance granulocyte fitness without NETosis-associated activation. C_LI

cancer biology↗

bioRxiv2026

Automated Segmentation of Prostatic Gold Fiducial Markers for MR-Only Radiotherapy Planning Using Multi-Modal Consensus Deep Learning

PurposeTo develop and evaluate a multi-model consensus deep learning approach for automated gold fiducial marker (FM) segmentation in T1-weighted prostate MRI. Materials and MethodsIn this retrospective study, T1-weighted MRI and CT-derived reference standard segmentations were collected from 127 prostate cancer patients (all male; mean age, 70 years {+/-} 7 [standard deviation]; age range, 50-88 years; collected between October 2020 and January 2026) who each had three implanted gold FMs. A 3D U-Net was trained on 93 subjects using four random seeds to produce an ensemble. At inference, marker-class probability maps were averaged across models and the top three connected components selected. Performance was evaluated on 34 temporally held-out subjects (9 tuning, 25 test) using marker-level sensitivity and precision with exact (Clopper-Pearson) 95% confidence intervals (CIs). A model count ablation study was performed. The pipeline was deployed for on-scanner processing on Siemens MRI systems via the OpenRecon framework and as a browser-based application using WebAssembly, executing entirely client-side. ResultsThe four-model consensus achieved 96% (70 of 73) sensitivity and 95% (70 of 74) precision on 25 test subjects, with 29 of 34 (85%) subjects achieving perfect marker detection. Single models had a mean sensitivity of 84% (SD, 9%), improving to 96% with four-model consensus (SD, <1%). ConclusionMulti-model consensus deep learning substantially improved FM segmentation reliability over individual models, achieving high sensitivity and precision using only routinely acquired T1-weighted MRI.

bioinformatics↗

bioRxiv2026

Maternal Gut Microbiota Regulates Neonatal Retinal Angiogenesis Through Lactational Metabolic Signalling

Early-life vascular development is a tightly regulated process that influences organ maturation and long-term cardiometabolic and neurovascular health. While the maternal microbiome is increasingly recognised as a determinant of neonatal immune, metabolic, and neurodevelopmental programming, its role in developmental angiogenesis remains poorly defined. Here, we investigated whether maternal gut microbiota regulates neonatal retinal vascular development through maternally derived metabolic signals. Using antibiotic-induced dysbiosis with a broad-spectrum antibiotic cocktail consisting of vancomycin, neomycin, metronidazole, amphotericin B, and ampicillin (VNMAA), together with germ-free animals, we assessed retinal angiogenesis at postnatal day 6 (P6) and P12. Maternal microbiome depletion significantly delayed retinal vascular extension at P6 and produced persistent abnormalities in P12 retinal vascular architecture, including reduced deep plexus vascular density, altered descending branch density, and reduced branching complexity after normalisation to vessel density. Whole-genome shotgun sequencing demonstrated pronounced remodelling of the maternal caecal microbiome following antibiotic treatment and reciprocal faecal microbiota transplantation (FMT), whereas P12 pup caecal communities were comparatively limited and did not mirror the dramatic restructuring observed in dams. Restoration of the maternal microbiome by FMT rescued neonatal vascular defects, supporting a causal role for maternal microbial state. Untargeted LC-MS metabolomics of maternal milk identified glycerophospholipid metabolism as a prominent microbiome-sensitive pathway. Choline and related lipid metabolites were prioritised as candidate mediators because of their position within this pathway and their biological relevance to membrane metabolism and endothelial function. In vitro endothelial assays demonstrated that choline modulates endothelial viability and promotes tubule formation. Together, these findings identify a maternal microbiota-milk metabolite-vascular axis regulating neonatal retinal angiogenesis and suggest that lactational metabolic signalling may represent an important mechanism through which maternal microbial ecology shapes offspring vascular development.

cell biology↗

bioRxiv2026

Systemically delivered Bacteroides thetaiotaomicron-derived bacterial extracellular vesicles inhibit primary and metastatic melanoma growth

The gut microbiome can contribute to anti-tumour immunity and cancer therapy responses, but translating live microbe-based interventions remains challenging due to safety, controllability, and delivery constraints. Bacterial extracellular vesicles (BEVs) are an attractive cell-free alternative, as they package bacterial cargo into a nanoscale format capable of host-cell engagement, immunological activation, and systemic distribution. Here, we investigated the anti-tumour potential of BEVs derived from the human gut commensal Bacteroides thetaiotaomicron (Bt). We show that delivery route is a major determinant of efficacy. Intravenous, but not intraperitoneal, administration produced robust anti-tumour activity in a B16F10 melanoma mouse model. Intravenously delivered Bt BEVs suppressed primary tumour growth in a dose-dependent manner and reduced metastatic outgrowth in the lung. Bt BEVs did not directly impair tumour-cell viability in vitro, but they activated NF-{kappa}B and Toll-like receptor signalling in innate immune reporter systems and localised to tumour tissue following systemic administration. Together, these data support a model in which Bt BEVs act via host immune modulation rather than direct tumour cytotoxicity. These findings identify naturally produced commensal-derived Bt BEVs as a potential microbial therapeutic modality and as an alternative to the use of live bacterial administration in cancer therapy.

cancer biology↗

bioRxiv2026

Mimics of the chordate gut-brain hormone neurotensin in parasitic intestinal hookworms

Hookworms of the family Ancylostomatidae are intestinal parasites that infect hundreds of millions of people worldwide, contributing to malnutrition, anemia, and impaired development. While hookworms are known to secrete immunomodulatory molecules to evade host defenses, it has been unclear whether they also exploit host hormonal signaling. Here, we identify a previously unrecognized family of hookworm peptides, which we term ancylotensins. Ancylotensins share strong sequence similarity with the chordate hormone neurotensin, a key regulator of metabolism, gut-brain communication, and intestinal function. In vitro pharmacological assays, ex vivo gut contractility studies, and cryo-electron microscopy demonstrate that ancylotensins closely replicate both the structural and functional properties of mammalian neurotensin to modulate gut function. Furthermore, ancylotensins do not share common ancestry with chordate neurotensin and instead evolved independently via convergent evolution. These findings reveal the existence of gut peptide mimicry as a mechanism by which intestinal parasites can manipulate host physiology.

biochemistry↗

bioRxiv2025

Quantifying brain-wide cerebrospinal fluid flow dynamics using slow-flow-sensitized phase-contrast MRI

Cerebrospinal fluid (CSF) flow is a key component of the brains waste clearance system. However, our understanding of CSF flow in the human brain, particularly within the brain-wide subarachnoid space (SAS), is limited due to a lack of non-invasive tools for measuring slow flow. Here, we propose a CSF flowmetry technique using phase-contrast MRI combined with a slow-flow-sensitized acquisition. It achieves high sensitivity in measuring slow CSF flow (e.g., 100 m/s), and enables quantitative measurement of the velocity and direction with whole-brain coverage, spanning from ventricles to SAS. Our proof-of-concept results demonstrate repeatable flow measurements and show that cardiac pulsation induces coherent CSF flow changes within the SAS. Our data also suggest that cardiac pulsation has a stronger driving effect on brain-wide CSF flow compared to respiration. This technique provides a valuable tool for investigating CSF dynamics and pathways to advance a holistic understanding of brain-wide CSF flow. TeaserA novel MR technique enables noninvasive, quantitative mapping of slow cerebrospinal fluid flow in the subarachnoid space across the human brain.

bioengineering↗

bioRxiv2025

Neuropilin 2 stabilises adherens junctions and protects against endothelial activation by promoting the interaction between VE cadherin and p120 catenin

The mechanosensing properties of endothelial cell-cell junctions are essential for vascular beds to respond to the mechanical forces exerted by blood flow. In states of disturbed flow, endothelial cells (ECs) become activated and transition to a pro-inflammatory, atheroprone phenotype. Here, we investigated the role of transmembrane glycoprotein neuropilin 2 (NRP2) in maintaining adherens junction integrity using cultured immortalised mouse ECs and a genetically modified mouse model to demonstrate the effects of an endothelial-specific deletion of Nrp2 in vivo. We reveal that, akin to its ortholog, Nrp1, Nrp2 exists as a constituent of adherens junctions, maintaining surface availability of VE cadherin by promoting its interaction with p120 catenin. As a consequence, endothelial knockout mice (Nrp2flfl.ECKO) display hyperpermeable retinal vasculature during development. Nrp2 depletion was subsequently found to activate key pro-inflammatory cytokines and adhesion molecules known to participate in the progression of atherogenesis, in addition to increased immune cell attachment aortic plaque development. These findings describe a role for Nrp2 in maintaining junctional signalling in ECs, protecting against endothelial activation during a state of vascular disease.

cell biology↗

bioRxiv2024

Bifidobacterium pseudocatenulatum capsular exopolysaccharide enhances systemic anti-tumour immunity in pre-clinical breast cancer

Gut microbes have merged as powerful regulators of cancer responses, with Bifidobacterium species and strains playing a key role in promoting anti-tumour immunity. While they represent promising candidates for cancer therapeutics, the specific underlying microbial mechanisms driving their efficacy remains poorly understood. In this study, we demonstrate the broad potential of Bifidobacterium species to inhibit breast cancer progression across multiple pre-clinical mouse models. We identify a novel strain, Bifidobacterium pseudocatenulatum 210, which induces systemic anti-tumour immunity and enhances responses to standard-of-care therapies via its cell surface capsular exopolysaccharide (EPS). B. pseudocatenulatum 210 EPS promotes dendritic cell activation and increases systemic cDC1 infiltration, leading to robust CD8+ T cell-mediated anti-tumour activity. Our findings position Bifidobacterium EPS as a novel class of therapeutic compounds with significant potential for cancer treatment.

cancer biology↗

bioRxiv2024

Adaptive trade-offs between vertebrate defense and insect predation drive ant venom evolution

Stinging ants have diversified into various ecological niches, and several evolutionary drivers may have contributed to shape the composition of their venom. To comprehend the drivers underlying venom variation in ants, we selected 15 Neotropical species and recorded a range of traits, including ecology, morphology, and venom bioactivity. Principal component analysis of both morphological and venom bioactivity traits revealed that stinging ants display two functional strategies. Additionally, phylogenetic comparative analysis indicated that venom function (predatory, defensive, or both) and mandible morphology significantly correlate with venom bioactivity and amount, while pain-inducing activity trades off with insect paralysis. Further analysis of the venom biochemistry of the 15 species revealed switches between cytotoxic and neurotoxic venom compositions in some species. This study highlights the fact that ant venoms are not homogenous, and for some species, there are major shifts in venom composition associated with the diversification of venom ecological functions. SignificanceVenoms are under severe evolutionary pressures, exerted either on the innovation of toxins or the reduction of the metabolic cost of production (1). To reduce the metabolic costs associated with venom secretion, some venomous animals can regulate venom expenditure by metering the amount of venom injected and by switching between offensive and defensive compositions (2-2). Many ants use venom for subduing a wide range of arthropod prey, as well as for defensive purposes against invertebrates and vertebrates, but are unable to adapt venom composition to stimuli (5, 6). Consequently, the expression of venom genes directly affects the ability of ants to interact with the biotic environment, and the venom composition may be fine-tuned to the ecology of each species. A previous study showed that defensive traits in ants exhibit an evolutionary trade-off in which the presence of a sting is negatively correlated with several other defensive traits, further supporting that trade-offs in defensive traits significantly constrain trait evolution and influence species diversification in ants (7). However, the sting is not used for the same purpose depending on the ant species. Our study supports an evolutionary trade-off between the ability of venom to deter vertebrates and to paralyze insects which are correlated with different life history strategies among Formicidae.

ecology↗

bioRxiv2024

Guidelines for QSM phantom production and evaluation ofcandidate phantom materials

PurposeTo measure magnetic susceptibility ({chi}) with Quantitative Susceptibility Mapping (QSM) and evaluate its repeatability using four phantom doping materials relevant to QSM applications. MethodsA cylindrical phantom was constructed containing vials of agarose gel doped with two paramagnetic materials (ferritin, USPIO) and two diamagnetic materials (CaCl2, CaCO3) at five concentrations each. Single orientation QSM measurements (MEDI+0) were carried out on the phantom at 3T and 7T. We measured molar susceptibility ({chi}mol) from QSM and evaluated the test-retest repeatability of {chi} using the standard error of the measurement (SEM). We evaluated material lifespan by conducting a t-test of {chi}mol at various timepoints. Results{chi}mol (ppm{middle dot}L{middle dot}mmol-1) were measured as 1.67 {+/-} 0.24 and 0.74 {+/-} 0.09 (USPIO: 3T and 7T, respectively), 10-2x(8.13 {+/-} 1.35; 8.13 {+/-} 1.19) (Ferritin: 3T; 7T), 10-4x(-2.68 {+/-} 0.24; -2.71 {+/-} 0.37) (CaCl2: 3T; 7T), and 10-5x(-9.52 {+/-} 1.44; -9.53 {+/-} 1.18) (CaCO3: 3T; 7T). The USPIO SEM (1.5 {+/-} 2.0; 5.1 {+/-} 2.0 ppb at 3T; 7T) was greater than the ferritin SEM (1.2 {+/-} 1.0; 2.2 {+/-} 1.3 ppb at 3T; 7T). The CaCl2 SEM (7.5 {+/-} 5.5; 1.2 {+/-} 0.6 ppb at 3T; 7T) was greater than the CaCO3 SEM (1.2 {+/-} 0.6; 0.9 {+/-} 0.7 ppb at 3T; 7T). We observed no significant changes in molar susceptibility for ferritin and CaCO3 over the measured timeframes (24 months and 15 months, respectively). ConclusionWe recommend using ferritin and CaCO3 in the construction of susceptibility phantoms, removing later echo times for CaCO3 QSM reconstructions.

biophysics↗

bioRxiv2023

Together, Neuropilin 1 and Neuropilin 2 direct α5 integrin trafficking through GTPase-activating-protein p120RasGAP in endothelial cells to promote fibronectin fibrillogenesis

Integrin trafficking to and from membrane adhesions is a crucial mechanism that dictates many aspects of a cells behaviour, including motility, polarisation, and invasion. In endothelial cells (ECs), the intracellular traffic of 5 integrin is regulated by both neuropilin 1 (NRP1) and neuropilin 2 (NRP2), yet the redundancies in function between these co-receptors remain unclear. Moreover, the endocytic complexes that participate in NRP-directed traffic remain poorly annotated. Using label-free quantitative mass spectrometry of 5 integrin associations in ECs we identify 5 trafficking pathways that depend on NRP1, NRP2, or both NRPs. We identify a trafficking pathway that depends on both NRPs: one that impinges on the GTPase-activating protein p120RasGAP. This pathway promotes the recycling of 5 integrin from early endosomes. Mechanistically, p120RasGAP enables transit of endocytosed 5 integrin-NRP1-NRP2 complexes to Rab11+ recycling endosomes, promoting cell polarisation and fibronectin (FN) fibrillogenesis. Silencing of both NRP receptors, or p120RasGAP, results in the accumulation of 5 integrin in early endosomes, a loss of 5 integrin from surface adhesions, and attenuated EC polarisation. Importantly, endothelial-specific deletion of both NRP1 and NRP2 in the postnatal retina recapitulated our in vitro findings, severely impairing FN fibrillogenesis and polarised sprouting. Our data assign an essential role for p120RasGAP during integrin traffic in ECs and support a hypothesis that NRP receptors can co-traffic internalised cargoes.

cell biology↗

bioRxiv2023

Deep-Learning-Enabled Differentiation between Intraprostatic Gold Fiducial Markers and Calcification in Quantitative Susceptibility Mapping

PurposeInterest is growing in MR-only radiotherapy (RT) planning for prostate cancer (PCa) due to the potential reductions in cost and patient exposure to radiation, and a more streamlined work-flow and patient imaging pathway. However, in MRI, the gold fiducial markers (FMs) used for target localization appear as signal voids, complicating differentiation from other void sources such as calcifications and bleeds. This work investigates using Quantitative Susceptibility Mapping (QSM), an MRI phase post-processing technique, to aid in the differentiation task. It also presents deep learning models that capture nuanced information and automate the segmentation task, facilitating a streamlined approach to MR-only RT. MethodsCT and MRI, including GRE and T1-weighted imaging, were acquired from 26 PCa patients, each with three implanted gold FMs. GRE data were post-processed into QSM, T 2*, and R2* maps using QSMxTs body imaging pipeline. Statistical analyses were conducted to investigate the quantitative differentiation of FMs and calcification in each contrast. 3D U-Nets were developed using fastMONAI to automate the segmentation task using various combinations of MR-derived contrasts, with a model trained on CT used as a baseline. Models were evaluated using precision and recall calculated using a leave-one-out cross-validation scheme. ResultsSignificant differences were observed between FM and calcification regions in CT, QSM and T 2*, though overlap was observed in QSM and T 2*. The baseline CT U-Net achieved an FM-level precision of {approx} 98% and perfect recall. The best-performing QSM-based model achieved precision and recall of 80% and 90%, respectively, while conventional MRI had values below 70% and 80%, respectively. The QSM-based model produced segmentations with good agreement with the ground truth, including a challenging FM that coincided with a bleed. ConclusionThe model performance highlights the value of using QSM over indirect measures in MRI, such as signal voids in magnitude-based contrasts. The results also indicate that a U-Net can capture more information about the presentation of FMs and other sources than would be possible using susceptibility quantification alone, which may be less reliable due to the diverse presentation of sources across a patient population. In our study, QSM was a reliable discriminator of FMs and other sources in the prostate, facilitating an accurate and streamlined approach to MR-only RT.

pathology↗

bioRxiv2022

Endothelial neuropilin-1 and neuropilin-2 are essential for tumour angiogenesis

Neuropilin (NRP) expression is highly correlated with poor outcome in multiple cancer subtypes. As known co-receptors for vascular endothelial growth factor receptors (VEGFRs), core drivers of angiogenesis, past investigations have alluded to their functional roles in facilitating tumorigenesis by promoting invasive vessel growth. Despite this, it remains unclear as to whether NRP1 and NRP2 act in a synergistic manner to enhance pathological angiogenesis. Here we demonstrate, using NRP1ECKO, NRP2ECKO and NRP1/NRP2ECKO mouse models, that maximum inhibition of primary tumour development and angiogenesis is only achieved when both endothelial NRP1 and NRP2 are targeted simultaneously. Metastasis and secondary site angiogenesis were also significantly inhibited in NRP1/NRP2ECKO animals. Mechanistic studies revealed that co-depleting NRP1 and NRP2 in mouse-microvascular endothelial cells (ECs) stimulates rapid shuttling of VEGFR-2 to Rab7+ endosomes for proteosomal degradation. Our results highlight the importance of targeting both NRP1 and NRP2 to modulate tumour angiogenesis.

cancer biology↗

bioRxiv2022

Unsupervised physiological noise correction of fMRI data using phase and magnitude information (PREPAIR)

Of the sources of noise which affect BOLD fMRI, respiration and cardiac fluctuations are responsible for the largest part of the variance, particularly at high and ultra-high field. Existing approaches to removing physiological noise either use external recordings, which can be unwieldy and unreliable, or attempt to identify physiological noise from the magnitude fMRI data. Data-driven approaches are limited by sensitivity, temporal aliasing and the need for user interaction. In the light of the sensitivity of the phase of the MR signal to local changes in the field stemming from physiological processes, we have developed an unsupervised physiological noise correction method which uses the information carried in both the phase and the magnitude of EPI data. Our technique, Physiological Regressor Estimation from Phase and mAgnItude, sub-tR (PREPAIR) derives time series signals which are sampled at the slice TR from both phase and magnitude images. It allows physiological noise to be captured without aliasing, and efficiently removes other sources of signal fluctuations which are not related to physiology, prior to regressor estimation. We demonstrate that the physiological signal time courses identified with PREPAIR not only agree well with those from external devices, but also retrieve challenging cardiac dynamics. The removal of physiological noise was as effective as that achieved with the most commonly used approach based on external recordings, RETROICOR. In comparison with widely used physiological noise correction tools which do not use external signals, PESTICA and FIX, PREPAIR removed more respiratory and cardiac noise and achieved a larger increase in tSNR at both 3 T and 7 T.

neuroscience↗

bioRxiv2021

Reciprocal interactions between the gut microbiome and mammary tissue mast cells promote metastatic dissemination of HR+ breast tumors

Establishing commensal dysbiosis, defined as an inflammatory gut microbiome with low biodiversity, prior to breast tumor initiation, enhances early dissemination of hormone-receptor positive (HR+) mammary tumor cells. Here, we sought to define mammary tissue mediators of dysbiosis-induced tumor dissemination. We found that commensal dysbiosis increased both the frequency and profibrogenicity of mast cells in the mammary tissue, a phenotypic change that persisted after tumor implantation. Fibroblast activation and tissue remodeling associate with enhanced breast tumor metastasis. We employed pharmacological and adoptive transfer approaches to demonstrate that mammary tissue mast cells from dysbiotic animals enhances dissemination of HR+ tumor cells. Collagen levels in mammary tissues from HR+ breast cancer patients correlated with mast cell abundance, suggesting clinical relevance of mast cell-mediated fibroblast activation. Together, these data demonstrate that a gut-mast cell axis exists that induces fibroblast activation and orchestrates early dissemination of HR+ breast tumors. SignificanceOur study defines the mechanism by which an inflammatory gut microbiome facilitates HR+ breast tumor cell dissemination. We establish that gut commensal dysbiosis triggers mammary tissue mast cells to facilitate early metastatic dissemination. These findings highlight a novel gut microbiome-innate immune cell axis involved in negative breast cancer outcomes.

cancer biology↗

bioRxiv2021

Endothelial NRP2 influences angiogenesis by regulating actin pattern development and α5-integrin-p-FAK complex recruitment to assembling adhesion sites

The ability to form a variety of cell-matrix connections is crucial for angiogenesis to take place. Without stable anchorage to the extracellular matrix (ECM), endothelial cells (ECs) are unable to sense, integrate and disseminate growth factor stimulated responses that drive growth of a vascular bed. Neuropilin-2 (NRP2) is a widely expressed membrane-bound multifunctional non-tyrosine kinase receptor, that has previously been implicated in influencing cell adhesion and migration by interacting with 5-integrin and regulating adhesion turnover. 5-integrin, and its ECM ligand fibronectin (FN) are both known to be upregulated during the formation of neo-vasculature. Despite being descriptively annotated as a candidate biomarker for aggressive cancer phenotypes, the EC-specific roles for NRP2 during developmental and pathological angiogenesis remain unexplored. The data reported here support a model whereby NRP2 actively promotes EC adhesion and migration by regulating dynamic cytoskeletal remodelling and by stimulating Rab11-dependent recycling of 5-integrin-p-FAK complexes to newly assembling adhesion sites. Furthermore, temporal depletion of EC-NRP2 in vivo impairs primary tumour growth by disrupting vessel formation. We also demonstrate that EC-NRP2 is required for normal postnatal retinal vascular development, specifically by regulating cell-matrix adhesion. Upon loss of endothelial NRP2, vascular outgrowth from the optic nerve during superficial plexus formation is disrupted, likely due to reduced FAK phosphorylation within sprouting tip cells.

cell biology↗

bioRxiv2020

Phase Unwrapping with a Rapid Opensource Minimum Spanning TreE AlgOrithm (ROMEO)

PurposeTo develop a rapid and accurate MRI phase unwrapping technique for challenging phase topographies encountered at high magnetic fields, around metal implants or post-operative cavities, that is sufficiently fast to be applied to large group studies including Quantitative Susceptibility Mapping and functional MRI (with phase-based distortion correction). MethodsThe proposed path-following phase unwrapping algorithm, ROMEO, estimates the coherence of the signal both in space - using MRI magnitude and phase information - and over time, assuming approximately linear temporal phase evolution. This information is combined to form a quality map that guides the unwrapping along a three-dimensional path through the object using a computationally efficient minimum spanning tree algorithm. ROMEO was tested against the two most commonly used exact phase unwrapping methods: PRELUDE and BEST PATH in simulated topographies and at several field strengths: in 3 T and 7 T in vivo human head images and 9.4 T ex vivo rat head images. ResultsROMEO was more reliable than PRELUDE and BEST PATH, yielding unwrapping results with excellent temporal stability for multi-echo or multi-time-point data. ROMEO does not require image masking and delivers results within seconds even in large, highly wrapped multi-echo datasets (e.g. 9 seconds for a 7 T head dataset with 31 echoes and a 208 x 208 x 96 matrix size). ConclusionOverall, ROMEO was both faster and more accurate than PRELUDE and BEST PATH delivering exact results within seconds, which is well below typical image acquisition times, enabling potential on-console application.

neuroscience↗

bioRxiv2020

Antibiotic-induced disturbances of the gut microbiota result in accelerated breast tumour growth via a mast cell-dependent pathway

The diverse community of commensal microbes that comprise the gut microbiota is known to play an integral role in human health, not least through its ability to regulate host immune responses and metabolic pathways. Alterations to the homeostasis of this community, including through the use of broad-spectrum antibiotics, have already been associated with the progression of several cancers, namely melanoma and liver. The aggressive nature of breast cancer (BrCa), largely due to its ability to metastasize early, has ranked the disease with the second highest mortality rate of all cancers globally. Yet the body of research into the complex relationship between the microbiota and BrCa is still limited. This study found that a depletion of the microbiota, through the administration of antibiotics, significantly increased the rate of primary tumour progression in mouse BrCa models. We show that antibiotic-induced microbiota disturbances lead to changes in behaviour of a relatively obscure tumour-immune cell population: mast cells. We observed increases in tumour stroma-associated mast cells in antibiotic treated animals. Moreover, inhibition of mast cell degranulation, via cromolyn, slowed tumour progression in antibiotic treated animals but not in control animals. Thus, it appears that a perturbed microbiota drives stroma-associated mast cell recruitment and activation, which in turn promotes primary tumour growth through an as yet unknown mechanism. One Sentence Summary: We show that breast cancer progression is accelerated through a unique/novel immune response involving mast cells as a result of an antibiotic induced perturbation of the gut microbiota in a mouse model.

cancer biology↗