Biology subjects

Gibson, J.

Publications and source records attributed to Gibson, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Beta-band dynamics during a naturalistic motor task: an OPM-MEG study

Beta oscillations are a fundamental feature of brain activity, linked to long-range connectivity within canonical networks, inhibition of sensorimotor cortices and the maintenance of a stable sensorimotor state in situations where the external world is predictable. The importance of beta oscillations in brain function is underscored by observations of their perturbation in neurological and psychiatric disorders. However, the precise role played by beta activity, particularly in mediating complex or skilful movements, remains incompletely understood. Here, we used a newly developed wearable optically pumped magnetometer-based magnetoencephalography (OPM-MEG) system to measure beta dynamics as participants learned to play a musical instrument. Twenty-two novice players took part in a study in which OPM-MEG data were recorded during two scanning sessions, while participants attempted to play a tune on a violin. Between the two sessions, participants received a violin lesson from an expert teacher. Results showed that robust data could be acquired during this naturalistic task, with beta oscillations decreasing in amplitude during movement and increasing upon movement cessation, as expected. Moreover, beta power whilst playing, in the motor and pre-motor areas, was significantly elevated after the lesson compared to before, and the movement-related modulation of beta amplitude was more pronounced after the lesson. These findings align with predictive coding models which suggest that beta amplitude should increase when individuals have greater certainty over the movements they carry out. Our study adds to an expanding literature on the role of beta oscillations and provides further evidence for the utility of OPM-MEG in naturalistic neuroscience.

neuroscience↗

bioRxiv2026

SMART: A Somatic Mutation Annotation and Reporting Tool for cancer genomics

MotivationTranslational interpretation of somatic variants from targeted oncology panels is hampered by inconsistent transcript prioritisation and by the need for reproducible pipelines that natively integrate OncoKB-derived evidence for research purposes. ResultsWe present SMART (Somatic Mutation Annotation and Reporting Tool), a Dockerised pipeline that embeds OncoKB API-derived annotations, including therapeutic (L1-4), resistance (R1-R3), diagnostic (Dx1-3), prognostic (Px1-3) and FDA levels, directly into a VCF-based workflow. SMART combines this with VEP, CIViC, Cancer Hotspots, ClinVar, SpliceAI, REVEL, LOEUF and gnomAD, applies a unified three-tier transcript prioritisation (whitelist > MANE Select > VEP fallback), and produces three-tiered outputs for computational, bioinformatic and research interpretation. Validation against reference APIs showed full concordance across 804 field-level checks. Availability and ImplementationSource code and Docker image are freely available at https://github.com/WeTGI-colab/SMART under the MIT License. SMART is provided for research use only; use of SMART outputs for patient specific clinical reports, clinical decision-making, or other patient-facing purposes requires appropriate governance and all required third-party licensing, including any OncoKB licence required for patient report generation.

bioinformatics↗

bioRxiv2025

Mitochondrial membrane junction-mediated ATP channeling drives activity-dependent glucose metabolism

Neurons and brown adipocytes rely on rapid ATP production from accelerated glucose metabolism to sustain bursts of activity upon stimulation, a process known as activity-dependent glucose metabolism. The first committed step in this pathway, the hexokinase I (HK1)-catalyzed phosphorylation of glucose, consumes ATP, raising the question of how this reaction can be accelerated when cytosolic ATP becomes limiting during stimulation. We identify Cell Cycle Exit and Neuronal Differentiation protein 1 (CEND1), expressed in both cell types, as a critical regulator of this process. Loss of CEND1 impairs activity-dependent glucose utilization, ATP generation, and stimulation-evoked activity both in vitro and in vivo. Mechanistically, CEND1 assembles a complex with HK1, voltage-dependent anion channel 1 (VDAC1), and adenine nucleotide translocase 1 (ANT1) at hemifusion-like membrane junction between the outer/inner mitochondrial membrane, channeling mitochondrially derived ATP directly to HK1. These findings uncover a previously unrecognized mechanism that sustains activity-dependent glucose metabolism, with broad implications for energy homeostasis in specialized cell types.

physiology↗

bioRxiv2024

Identification of molecular and functional subtypes using chronic pancreatitis patient-derived organoid models

Chronic pancreatitis (CP) affects [~]3 million people worldwide, yet altering the course of disease is challenging. We developed a patient-derived organoid (PDO) platform to investigate the molecular pathogenesis of this disease and identify therapeutic strategies. We generated 36 PDOs from patients with idiopathic, hereditary, and alcohol-related CP with high genetic concordance. PDOs retained inflammation-associated transcriptional and proteomic features. Transcriptomic profiling revealed three molecular subtypes of CP independent of etiology. We discovered widespread dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) in half of the CP PDOs, including those with wildtype CFTR. Clinically available CFTR modulators stabilized mutant or wildtype CFTR, restored CFTR function, and decreased mitogenic and inflammatory signaling. This work provides the first comprehensive PDO platform for modeling CP. We demonstrate the utility of this platform for precision therapeutic investigations. Our findings reveal CFTR modulators as a broadly applicable and effective therapeutic strategy.

cell biology↗

bioRxiv2024

Flexible use of conserved motif vocabularies constrains genome access in cell type evolution

Cell types evolve into a hierarchy with related types grouped into families. How cell type diversification is constrained by the stable separation between families over vast evolutionary times remains unknown. Here, integrating single-nucleus multiomic sequencing and deep learning, we show that hundreds of sequence features (motifs) divide into distinct sets associated with accessible genomes of specific cell type families. This division is conserved across highly divergent, early-branching animals including flatworms and cnidarians. While specific interactions between motifs delineate cell type relationships within families, surprisingly, these interactions are not conserved between species. Consistently, while deep learning models trained on one species can predict accessibility of other species sequences, their predictions frequently rely on distinct, but synonymous, motif combinations. We propose that long-term stability of cell type families is maintained through genome access specified by conserved motif sets, or vocabularies, whereas cell types diversify through flexible use of motifs within each set.

evolutionary biology↗

bioRxiv2024

Human-like APOBEC3 gene expression and anti-viral responses following replacement of mouse Apobec3 with the 7-gene human APOBEC3 locus

The seven human APOBEC3 (hA3) genes encode polynucleotide cytidine deaminases that play vital roles in restricting replication of viruses and retrotransposons. However, off-target A3 deamination of the cellular genome is a major source of somatic mutations in human cancer. The ability to study A3 biology in vivo is hindered by the fact that the solitary murine Apobec3 gene (mA3) encodes a cytoplasmic enzyme, with no apparent mutagenic activity. Transgenic expression of individual hA3 genes in mice has helped to confirm their oncogenic potential but important questions including which hA3 genes are active in different tissue contexts and how they function in concert when under control of their cognate promoters cannot be addressed using these models. Here we describe humanization of the mouse mA3 locus by integration of a modified BAC clone encompassing the entire 7-gene hA3 locus from human chromosome 22 replacing mA3 on mouse chromosome 15. APOBEC3 mice are viable and fertile and hA3 gene expression in cells and tissues correlates strongly with expression in corresponding human cells and tissues, indicating human-like regulation of hA3 gene expression in the mice. Splenocytes from this line display a functional human A3 response to Friend Murine Leukaemia Virus (F-MLV) infection. We propose that the Hs-APOBEC3 mouse will uniquely model the function of the complete hA3 locus in a living organism and that it will serve as a useful background upon which to model human cancer, as well as assisting drug discovery efforts.

cancer biology↗

bioRxiv2024

A genetic and microscopy toolkit for live imaging of whole-body regeneration in Macrostomum lignano

Live imaging of regenerative processes can reveal how animals restore their bodies after injury through a cascade of dynamic cellular events. Here, we present a comprehensive toolkit for live imaging of whole-body regeneration in the flatworm Macrostomum lignano, including a high throughput cloning pipeline, targeted cellular ablation, and advanced microscopy solutions. Using tissue-specific reporter expression, we examine how various structures regenerate. Enabled by a custom, low-cost luminescence/fluorescence microscope, we overcome intense stress-induced autofluorescence to demonstrate the first application of genetic cellular ablation in flatworms to reveal the limited regenerative capacity of neurons and their essential role during wound-healing. Finally, we build a novel open-source tracking microscope to continuously image moving animals throughout the week-long process of regeneration, quantifying kinetics of wound healing, nerve cord repair, body regeneration, growth, and behavioral recovery. Our findings suggest that nerve cord reconnection operates independently from primary body axis re-establishment and other downstream regenerative processes.

bioengineering↗

bioRxiv2023

Immune experience at time of circulation and time since virus circulation are predictors of HAI titre

Nearly everyone is infected with seasonal influenza viruses multiple times over the course of their lives due to the antigenic evolution of the virus to escape immunity induced by prior infections and vaccinations. Because antibody escape is usually partial, the antibody response to new infections depends on prior responses which wane and are boosted throughout life. We used serum antibody binding measurements of 864 individuals against a range of historical A/H3N2 viruses collected in previous studies in combination with statistical models to investigate how metrics of age and strain heterogeneities affect haemagglutination inhibition titres. We refine prior modelling of antigenic seniority by characterising immune experience as years of life since a (sub)types emergence at time of strain circulation, rather than age at time of circulation. Using Bayesian statistical modeling, we show that this variable, combined with time since circulation of the variant and an individuals age at circulation, yields the best model fit. Based on the best-fit model, we devised a novel parametric model, and use it to demonstrate and estimate how effects of antigenic seniority, individual age, strain age and strain effects act in concert to shape an individuals HAI titre.

immunology↗

bioRxiv2023

Compensation between FOXP transcription factors maintains proper striatal function

Spiny projection neurons (SPNs) of the striatum are critical in integrating neurochemical information to coordinate motor and reward-based behavior. Mutations in the regulatory transcription factors expressed in SPNs can result in neurodevelopmental disorders (NDDs). Paralogous transcription factors Foxp1 and Foxp2, which are both expressed in the dopamine receptor 1 (D1) expressing SPNs, are known to have variants implicated in NDDs. Utilizing mice with a D1-SPN specific loss of Foxp1, Foxp2, or both and a combination of behavior, electrophysiology, and cell-type specific genomic analysis, loss of both genes results in impaired motor and social behavior as well as increased firing of the D1-SPNs. Differential gene expression analysis implicates genes involved in autism risk, electrophysiological properties, and neuronal development and function. Viral mediated re-expression of Foxp1 into the double knockouts was sufficient to restore electrophysiological and behavioral deficits. These data indicate complementary roles between Foxp1 and Foxp2 in the D1-SPNs.

neuroscience↗

bioRxiv2023

Combination EZH2 inhibition and retinoic acid treatment promotes differentiation and apoptosis in rhabdomyosarcoma cells

Rhabdomyosarcomas (RMS) are predominantly pediatric sarcomas thought to originate from muscle precursor cells due to impaired myogenic differentiation. Despite intensive treatment, 5-year survival for patients with advanced disease remains low (<30%), highlighting a need for novel therapies to improve outcomes. Differentiation therapeutics are agents that induce differentiation of cancer cells from malignant to benign. The histone methyltransferase, Enhancer of Zeste Homolog 2 (EZH2) suppresses normal skeletal muscle differentiation and is highly expressed in RMS tumors. We demonstrate combining EZH2 inhibition with the differentiating agent retinoic acid (RA) is more effective at reducing cell proliferation in RMS cell lines than single agents alone. In PAX3 -FOXO1 positive RMS cells this is due to an RA-driven induction of the interferon pathway resulting in apoptosis. In fusion negative RMS, combination therapy led to an EZH2i-driven upregulation of myogenic signaling resulting in differentiation. These results provide insight into the mechanism that drives the anti-cancer effect of the EZH2/RA single agent and combination treatment and indicate that the reduction of EZH2 activity combined with the induction of RA signalling represents a potential novel therapeutic strategy to treat both subtypes of RMS. HighlightsO_LIEZH2 expression is upregulated fusion positive (FPRMS) and fusion negative (FNRMS) rhabdomyosarcomas C_LIO_LIEZH2 inhibition combined with retinoic acid treatment was investigated RMS cell models. C_LIO_LICombination treatment reduced cell proliferation and tumor spheroid volume. C_LIO_LICombination treatment in FPRMS resulted in apoptosis in FPRMS via interferon signaling. C_LIO_LIConversely, combination treatment in fusion negative RMS resulted in myogenic differentiation. C_LI

cancer biology↗

bioRxiv2022

Voltage-gated sodium channel activity mediates sea urchin larval skeletal patterning through spatial regulation of Wnt5 expression

Defining pattern formation mechanisms during embryonic development is important for understanding the etiology of birth defects and to inform tissue engineering approaches. In this study, we used tricaine, a voltage-gated sodium channel (VGSC) inhibitor, to show that VGSC activity is required for normal skeletal patterning in Lytechinus variegatus sea urchin larvae. We demonstrate that tricaine-mediated patterning defects are rescued by an anesthetic-insensitive version of the VGSC LvScn5a. Expression of this channel is enriched in the ventrolateral ectoderm where it spatially overlaps with posterolaterally expressed Wnt5. We show that VGSC activity is required to spatially restrict Wnt5 expression to this ectodermal region that is adjacent and instructive to clusters of primary mesenchymal cells that initiate secretion of the larval skeleton as triradiates. Tricaine-mediated Wnt5 spatial expansion correlates with the formation of ectopic PMC clusters and triradiates. These defects are rescued by Wnt5 knock down, indicating that the spatial expansion Wnt5 is responsible for the patterning defects induced by VGSC inhibition. These results demonstrate a novel connection between bioelectrical status and the spatial control of patterning cue expression during embryonic pattern formation. Summary statementInhibition of voltage-gated sodium channels perturbs Wnt5-mediated patterning of the sea urchin larval skeleton

developmental biology↗

bioRxiv2022

Extracellular ATP drives pancreatic cancer cell invasion via purinergic receptor-integrin interactions

Pancreatic ductal adenocarcinoma (PDAC) is a cancer of unmet clinical need. Given the elevated ATP levels seen in PDAC, the purinergic axis represents an attractive therapeutic target. Mediated in part by highly druggable extracellular proteins, it plays essential roles in fibrosis, inflammation response and immune function. We have analysed the PDAC purinome using publicly available databases to discern which members may impact patient survival. We identified P2RY2 to be the purinergic gene with the strongest association to hypoxia, the highest cancer cell specific expression and the strongest impact on overall survival. Invasion assays using a 3D spheroid model revealed P2Y2 to be critical in facilitating invasion driven by extracellular ATP. Using genetic modification or pharmacological strategies we identify the mechanism of this ATP-driven invasion to require direct protein-protein interactions between P2Y2 and V integrins. Using DNA-PAINT super-resolution fluorescence microscopy, we found that P2Y2 regulates the amount and distribution of integrin V in the plasma membrane. This work highlights a novel GPCR-integrin interaction in cancer invasion and its potential for therapeutic targeting.

cancer biology↗

bioRxiv2022

PD-L1 blockade restores CAR T cell activity through IFNγ-regulation of CD163+ macrophages

BackgroundThe immune suppressive tumor microenvironment (TME) that inhibits T cell infiltration, survival, and anti-tumor activity has posed a major challenge for developing effective immunotherapies for solid tumors. Chimeric antigen receptor (CAR)-engineered T cell therapy has shown unprecedented clinical response in treating patients with hematological malignancies, and intense investigation is underway to achieve similar responses with solid tumors. Immunologically cold tumors, including prostate cancers, are often infiltrated with abundant tumor-associated macrophages (TAMs), and infiltration of CD163+ M2 macrophages correlates with tumor progression and poor responses to immunotherapy. However, the impact of TAMs on CAR T cell activity alone and in combination with TME immunomodulators is unclear. MethodsTo model this in vitro, we utilized a novel co-culture system with tumor cells, CAR T cells, and polarized M1 or M2 macrophages from CD14+ PBMCs collected from healthy human donors. Tumor cell killing, T cell activation and proliferation, and macrophage phenotypes were evaluated by flow cytometry, cytokine production, RNA sequencing, and functional blockade of signaling pathways using antibodies and small molecule inhibitors. We also evaluated the TME in humanized mice following CAR T cell therapy for validation of our in vitro findings. ResultsWe observed inhibition of CAR T cell activity with the presence of M2 macrophages, but not M1 macrophages, coinciding with a robust induction of PD-L1 in M2 macrophages. We observed similar PD-L1 expression in TAMs following CAR T cell therapy in the TME of humanized mice. PD-L1, but not PD-1, blockade in combination with CAR T cell therapy altered phenotypes to more M1-like subsets and led to loss of CD163+ M2 macrophages via IFN{gamma} signaling, resulting in improved anti-tumor activity of CAR T cells. ConclusionThis study reveals an alternative mechanism by which the combination of CAR T cells and immune checkpoint blockade modulates the immune landscape of solid tumors to enhance therapeutic efficacy of CAR T cells.

immunology↗

bioRxiv2021

Mutational signature profiling classifies subtypes of clinically different mismatch repair deficient tumors with a differential immunogenic response potential

BackgroundMismatch repair (MMR) deficiency is the hallmark of tumors from Lynch syndrome (LS), sporadic MLH1 hypermethylated, and Lynch-like syndrome (LLS), but there is a lack of understanding of the variability in their mutational profiles based on clinical phenotypes. The aim of this study was to perform a molecular characterization to identify novel features that can impact tumor behavior and clinical management. MethodsWe tested 105 MMR-deficient colorectal cancer tumors (25 LS, 35 LLS, and 45 sporadic) for global exome microsatellite instability, cancer mutational signatures, mutational spectrum and neoepitope load. Results78% of tumors showed high contribution of MMR-deficient mutational signatures, high level of global exome microsatellite instability, loss of MLH1/PMS2 protein expression and included sporadic tumors. 22% of tumors showed weaker features of MMR deficiency, 73% lost MSH2/MSH6 expression and included half of LS and LLS tumors. Remarkably, 9% of all tumors lacked global exome microsatellite instability. Lastly, HLA-B07:02 could be triggering the neoantigen presentation in tumors that show the strongest contribution of MMR-deficient tumors. ConclusionsNext-generation sequencing approaches allow for a granular molecular characterization of MMR-deficient tumors, which can be essential to properly diagnose and treat patients with these tumors in the setting of personalized medicine.

genomics↗

bioRxiv2021

Genomic analysis of response to neoadjuvant chemotherapy in esophageal adenocarcinoma

Neoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal adenocarcinoma (EAC). Unfortunately, response to neoadjuvant chemotherapy (NAC) is poor (<20%), as is the overall survival benefit at 5 years (5%). The EAC genome is complex and heterogeneous between patients, and it is not yet understood whether specific mutational patterns may result in chemotherapy sensitivity or resistance. To identify associations between genomic events and response to NAC in EAC, a comparative genomic analysis was performed in 65 patients with extensive clinical and pathological annotation using whole-genome sequencing (WGS). We defined response using Mandard Tumor Regression Grade (TRG), with responders classified as TRG1-2 (n=27) and non-responders classified as TRG4-5 (n=38). We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs 1.70/Mb, P=0.036) and elevated copy number variation in non-responders (282 vs 136/patient, P<0.001). We identified copy number variants unique to each group in our cohort, with cell cycle (CDKN2A, CCND1), c-Myc (MYC), RTK/PIK3 (KRAS, EGFR) and gastrointestinal differentiation (GATA6) pathway genes being specifically altered in non-responders. Of note, NAV3 mutations were exclusively present in the non-responder group with a frequency of 22%. Thus, lower mutation burden, higher chromosomal instability and specific copy number alterations are associated with resistance to NAC.

genomics↗

bioRxiv2021

A burden-free gene overexpression system

Heterologous gene activation causes non-physiological burden on cellular resources that cells are unable to adjust to. Here, we introduce a feedforward controller that increases ribosome level upon activation of a gene of interest (GOI) to compensate for such a burden. The controller achieves this by activating a modified SpoT enzyme with sole hydrolysis activity, which lowers ppGpp level and thus de-represses ribosomes. Without the controller, activation of the GOI decreased growth rate by more than 50%. With the controller, we could activate the GOI to the same level without a growth rate decrease. A cell strain armed with the controller in co-culture enabled persistent population-level activation of a GOI, which could not be achieved by a strain devoid of the controller. The feedforward controller is a tunable, modular, and portable tool that for the first time allows dynamic gene activation without growth rate defects for bacterial synthetic biology applications.

synthetic biology↗

bioRxiv2020

Blood vessel occlusion by Cryptococcus neoformans is a mechanism for hemorrhagic dissemination of infection

Meningitis caused by infectious pathogens are associated with vessel damage and infarct formation, however the physiological cause is unknown. Cryptococcus neoformans, is a human fungal pathogen and causative agent of cryptococcal meningitis, where vascular events are observed in up to 30% of cases, predominantly in severe infection. Therefore, we aimed to investigate how infection may lead to vessel damage and associated pathogen dissemination using a zebrafish model for in vivo live imaging. We find that cryptococcal cells become trapped within the vasculature (dependent on there size) and proliferate there resulting in vasodilation. Localised cryptococcal growth, originating from a single or small number of cryptococcal cells in the vasculature was associated with sites of dissemination and simultaneously with loss of blood vessel integrity. Using a cell-cell junction tension reporter we identified dissemination from intact blood vessels and where vessel rupture occurred. Finally, we manipulated blood vessel stifness via cell junctions and found increased stiffness resulted in increased dissemination. Therefore, global vascular vasodilation occurs following infection, resulting in increased vessel tension which subsequently increases dissemination events, representing a positive feedback loop. Thus, we identify a mechanism for blood vessel damage during cryptococcal infection that may represent a cause of vascular damage and cortical infarction more generally in infective meningitis.

pathology↗

bioRxiv2019

Psychotic-like experiences, polygenic risk scores for schizophrenia and structural properties of the salience, default mode and central-executive networks in healthy participants from UK Biobank

Schizophrenia is a highly heritable disorder with considerable phenotypic heterogeneity. Hallmark psychotic symptoms can be considered as existing on a continuum from non-clinical to clinical populations. Assessing genetic risk and psychotic-like experiences (PLEs) in non-clinical populations and their associated neurobiological underpinnings can offer valuable insights into symptom-associated brain mechanisms without the potential confounds of the effects of schizophrenia and its treatment. We leveraged a large population-based cohort (UKBiobank) including information on PLEs, polygenic risk scores for schizophrenia (PRSSZ) and multi-modal brain imaging in combination with network neuroscience. Morphometric (cortical thickness, volume) and water diffusion (fractional anisotropy) properties of the regions and pathways belonging to the salience, default-mode and central-executive networks were computed. We hypothesized that these anatomical concomitants of functional dysconnectivity would be negatively associated with PRSSZ and PLEs. PRSSZ was significantly associated with a latent measure of cortical thickness across the salience network (r = -0.069, p = 0.010) and PLEs showed a number of significant associations with properties of the salience and default mode networks (involving the insular cortex, supramarginal gyrus and pars orbitalis, pFDR < 0.050); with the cortical thickness of the insula largely mediating the relationship between PRSSZ and auditory hallucinations. These results are consistent with the hypothesis that higher genetic liability for schizophrenia is related to subtle disruptions in brain structure and predisposes to PLEs even among healthy participants. In addition, our study suggests that networks engaged during auditory hallucinations show structural associations with PLEs in the general population.

neuroscience↗