Biology subjects

Gibbons, A.

Publications and source records attributed to Gibbons, A..

7 recordsLinked to original sources

bioRxiv2026

Provisional extracellular matrix signaling network regulates tumor lymphoneogenesis and response to immunotherapy

Tertiary lymphoid structures (TLS) predict response to checkpoint inhibition, and conventional dendritic cells (cDC) are required to build and maintain them. What renders a niche permissive for their assembly is unknown: chemokines recruit the cellular constituents but do not specify how they organize. Here we show that the organizing signal is a matrix fragment. Proteolysis of the proteoglycan versican (VCAN) releases the matrikine versikine, constitutively in germinal center light zones and inducibly in tumor stroma. Versikine activates CD11b+ cDC and expands cDC1 to assemble TLS-archetypal triads, apposed DC: CD4+ T: CD8+ T units. Versikine-conditioned DC engage progenitor-exhausted CD8+ T cells (Tpex) and Th1-polarized follicular helper CD4+ T cells. Excess unproteolyzed VCAN inverts this toward DC-Treg crosstalk and Tpex loss. Versikine supplied as mRNA or recombinant protein sensitizes refractory tumors to PD-L1 blockade. VCAN proteolysis prospectively predicted outcomes after PD-1 blockade in metastatic colorectal cancer. Matrikines organize chemokine-recruited cells into functional immune niches.

immunology↗

bioRxiv2026

Acoustic detection of a rarely vocalising invasive mammal from sparse data

O_LIMonitoring and limiting the spread of invasive species on islands requires efficient detection and population estimation methods. However, elusive species can be difficult to monitor using traditional methods, making autonomous approaches such as camera trapping and acoustic monitoring increasingly valuable. C_LIO_LIOn the island of Okinawa, Japan, the small Indian mongoose ( Urva auropunctata) threatens many native species since its introduction in 1910. Listed among the worlds worst invasive species, effective monitoring of U. auropunctata in Okinawa is critical. The Okinawa Environmental Observation Network (OKEON) uses camera traps to detect U. auropunctata, but success depends on precise placement. Though OKEON also includes a high-resolution acoustic monitoring programme, no audio classification model currently exists for U. auropunctata. Developing such a model could improve substantially our capacity to detect and manage the species. C_LIO_LIUsing sparse U. auropunctata vocalisations collected from camera trap videos, we built a lightweight Convolutional Neural Network distilled from a more complex model for classifying contact calls and alarm calls of U. auropunctata. Our distilled model performed similarly to the full model at detecting vocalisations from training data, but was considerably faster. C_LIO_LIWe applied the distilled classifier to [~]486 hrs of audio collected over eight years from southern Okinawa, where we successfully detected U. auropunctata a handful of times in each year of recording. In spite of strong model performance on test data, our model did not transfer well to unseen data, perhaps owing to the rarity of U. auropunctata calls and consequent small training dataset size, limiting its utility for ecological monitoring. C_LIO_LIPractical implication. The use of sparse audio data from camera trap videos to train an acoustic classifier had limited utility to detect the rarely vocalising U. auropunctata from passive acoustic monitoring data. We provide several recommendations for enhancing classifier performance to provide robust actionable insights into the distribution and spread of U. auropunctata, and aid targeted conservation efforts for Okinawas threatened biodiversity. C_LI

ecology↗

bioRxiv2025

LPC 18:2-Driven Apoptosis In Neutrophils Is Non-Inflammatory and Lipid Raft Dependent

Lysophosphatidylcholines (LPCs) are potent bioactive lipids whose fatty acid compositions dictate their immunomodulatory effects. Here, we delineate how unsaturated LPC 18:2 and saturated LPC 16:0 differentially regulate neutrophil survival and inflammatory programs. LPC 18:2 markedly increased reactive oxygen species (ROS) generation and caspase-3/7 activation, mitochondrial membrane depolarization, and cytochrome c release, features consistent with intrinsic apoptosis. In contrast, LPC 16:0 induced robust LDH and HMGB-1 release, indicating membrane rupture and pyroptosis-like death. Bulk RNA sequencing revealed that LPC 16:0 strongly upregulated inflammatory and cytokine gene expression. Disruption of lipid-raft integrity abolished LPC 18:2-induced ROS and apoptosis, underscoring the dependence of these effects on membrane organization. Collectively, these results identify LPC 18:2 as a non-inflammatory, mitochondria-dependent inducer of neutrophil apoptosis, whereas LPC 16:0 promotes inflammatory, lytic death programs. These findings highlight how lipid saturation determines neutrophil fate and immune tone, providing mechanistic insight into how distinct LPC species shape inflammation and tissue injury.

immunology↗

bioRxiv2025

Deoxyguanosine Kinase Deficiency Couples Purine Metabolism to Innate Immune Activation and Lipid Accumulation in Hepatocytes

Mitochondrial DNA depletion syndromes (MDS) encompass a heterogeneous set of metabolic disorders caused by defects in enzymes responsible for maintaining mitochondrial nucleotide pools and genome integrity. Among these, deoxyguanosine kinase (DGUOK) acts within the mitochondrial purine-salvage pathway and loss-of-function mutations give rise to DGUOK deficiency, a severe hepatocerebral form of MDS marked by liver failure, neurodevelopmental impairment, and systemic metabolic inflammation. Although the clinical manifestations of DGUOK deficiency have been primarily ascribed to defective mitochondrial DNA (mtDNA) replication, some patients exhibit hepatic steatosis and inflammation despite preserved mtDNA content, suggesting that DGUOK deficiency may deregulate additional metabolic and immune pathways. Here we show that DGUOK depletion reprograms hepatocellular metabolism and innate immune signaling through a purine-dependent mechanism operating independently of mtDNA depletion. In human hepatocellular carcinoma hepatocytes (HEPG2) subjected to siRNA-mediated DGUOK silencing, mitochondrial architecture and respiration remained intact but cells exhibited pronounced lipid droplet accumulation and a robust cell-intrinsic innate immune type I interferon response. Bulk RNA sequencing revealed widespread transcriptional reprogramming, including upregulation of human endogenous retroviruses (HERVs) and interferon-stimulated genes (ISGs), suppression of lipid metabolic pathways, and changes in purine, methionine, and methylation-associated gene networks. Perturbing purine homeostasis through deoxyadenosine (dAdo) supplementation in wild-type cells phenocopied DGUOK disruption, causing global DNA hypomethylation and activation of viral mimicry pathways. Together, these findings identify DGUOK as a central regulator of the purine-regulated lipid-immune axis in hepatocytes, demonstrating that mitochondrial nucleotide salvage preserves hepatic immune and metabolic homeostasis beyond its canonical role in mtDNA synthesis. By linking purine imbalances to steatosis and type I interferon activation, this study establishes a mechanistic framework for immunometabolic pathology in DGUOK deficiency.

immunology↗

bioRxiv2025

Unmasking Early Microglial Remodeling in an Alzheimer's Disease Mouse Model

Early neuroimmune remodeling is a critical yet understudied component of Alzheimers disease (AD) pathogenesis. To investigate microglial contributions to AD development prior to overt plaque deposition, we developed an open-source morphometric pipeline to systematically quantify hippocampal microglial structure and activation states in pre-plaque 5xFAD mice. Across [~]11,000 cells, we extracted multidimensional parameters including area, circularity, convex hull, branch points, nearest-neighbor distance, and nuclear features, alongside Iba1 and CD68 intensity measurements. While no significant overt gliosis was observed at this early stage, microglia from 5xFAD mice exhibited subtle trends toward increased structural complexity compared to wild-type controls. Importantly, significant sex-specific differences were detected within the CA1 subregion: male 5xFAD microglia displayed hyper-ramified morphologies consistent with enhanced surveillance states, whereas female microglia demonstrated greater density and a more reactive phenotype. Correlation analyses revealed a conserved association between microglial complexity and Iba1/CD68 expression, independent of sex or genotype, underscoring a fundamental link between cytoskeletal remodeling and phagolysosomal activity. These findings highlight the capacity of morphometric profiling to sensitively detect early, region-specific, and sex-dependent shifts in microglial phenotype before amyloid deposition. By integrating quantitative morphology with canonical molecular markers, this framework provides a robust and unbiased approach for characterizing microglial activation trajectories. Such early readouts may inform biomarker discovery and therapeutic strategies aimed at modulating microglial responses to delay or prevent AD progression.

neuroscience↗

bioRxiv2025

Generation of two Betacellulin CRISPR-Cas9 knockout hiPSC lines to study affected EGF system paradigm in Schizophrenia

Several members of the epidermal growth factor (EGF) family have been implicated in the biology of schizophrenia (Ketharanathan et al., 2024). The EGF-related ligand, Betacellulin (BTC), plays an important role in the proliferation and differentiation of neural stem cells and our group found markedly reduced BTC levels in patients with schizophrenia. Nevertheless, the interplay of affected BTC and its participation in neural specification and neurodevelopment remains elusive. We generated Knockout (KO) - BTC clones from an existing hiPSC line through CRISPR/Cas9-mediated modification. Furthermore, we validated BTC-KO through genotyping/sequencing, FACS and Western Blot. Finally, we demonstrated trilineage differentiation potential in vitro.

neuroscience↗

bioRxiv2020

Validation of a SARS-CoV-2 spike ELISA for use in contact investigations and serosurveillance

Since emergence of SARS-CoV-2 in late 2019, there has been a critical need to understand prevalence, transmission patterns, to calculate the burden of disease and case fatality rates. Molecular diagnostics, the gold standard for identifying viremic cases, are not ideal for determining true case counts and rates of asymptomatic infection. Serological detection of SARS-CoV-2 specific antibodies can contribute to filling these knowledge gaps. In this study, we describe optimization and validation of a SARS-CoV-2-specific-enzyme linked immunosorbent assay (ELISA) using the prefusion-stabilized form of the spike protein [1]. We performed receiver operator characteristic (ROC) analyses to define the specificities and sensitivities of the optimized assay and examined cross reactivity with immune sera from persons confirmed to have had infections with other coronaviruses. These assays will be used to perform contact investigations and to conduct large-scale, cross sectional surveillance to define disease burden in the population.

immunology↗