Biology subjects

Lawson, C.

Publications and source records attributed to Lawson, C..

11 recordsLinked to original sources

bioRxiv2026

Single-dose Efficacy of a Next-Generation Mpox Vaccine Harnessing an Immunomodulatory Peptide

Rapidly deployable, single-dose vaccines that maintain durability under operational constraints remain an unmet need in outbreak preparedness. Live viral vectors such as Modified Vaccinia Ankara (MVA) offer strong safety profiles, yet their suboptimal immunogenicity often requires multidose regimens, reducing flexibility during emergency response. To address these limitations, we developed a modular vaccine platform that leverages immune checkpoint modulation to enhance immune cell priming without compromising the established safety profile of MVA. This platform, exemplified by the recombinant virus MVA-X, was engineered to express a peptide-based PD-1 antagonist (LD10) that provides localized, transient checkpoint blockade during early antigen presentation. The approach requires no external adjuvants, is compatible with lyophilization and stockpiling, and is readily adaptable to diverse antigens and pathogens. A single immunization with MVA-X produced durable protection that matched or exceeded that of a conventional two-dose MVA regimen against the prototypic orthopoxvirus vaccinia virus. Despite modest and contracting antibody titers, single-dose MVA-X vaccination conferred complete survival following both lethal and high-dose viral challenge at early (Day 55), intermediate (Day 90), and long-term (Day 150) time points. MVA-X also restricted viral replication at the primary site of infection, reduced systemic dissemination, and preserved lung architecture during peak disease. Importantly, MVA-X maintained efficacy in the highly susceptible CAST/EiJ mouse model following challenge with highly pathogenic Clade I monkeypox virus (MPXV). Together, these findings demonstrate that vaccine-intrinsic checkpoint modulation provides a modular strategy for enhancing the potency and durability of attenuated viral vectors while preserving their favorable safety profile, supporting broader application to emerging infectious diseases beyond Mpox.

immunology↗

bioRxiv2025

Ovarian Tumor FAK Inhibition Releases Omega-3 Fatty Acids Stimulating GATA6 Peritoneal Macrophage CXCL13 Production Enhancing Immunotherapy

High grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy in the USA due to chemo- and immuno-therapy resistance. We show that focal adhesion kinase (FAK) inhibition with ifebemtinib or tumor genetic FAK knockout (KO) in syngeneic ovarian tumor models stimulated resident large peritoneal macrophages to express CXCL13 chemokine and promoted B cell infiltration. Macrophage GATA6 inactivation prevented CXCL13 expression and enhanced FAK-KO tumor growth. Combining ifebemtinib with pegylated doxorubicin chemotherapy and anti-TIGIT immune checkpoint antibody extended survival with tumor-associated tertiary lymphoid structure formation. Mechanistically, FAK-KO heat-treated conditioned media contained exosomes enriched with omega-3 fatty acids which stimulated macrophage CXCL13 production. Ifebemtinib-treated tumors, FAK-KO exosomes, and purified eicosapentaenoic acid enhanced murine and human HGSOC-associated tumor macrophage reprogramming and CXCL13 expression. Overall, our studies define a tumor to macrophage signaling linkage via omega-3 exosome lipids supporting B cell recruitment, survival, immunotherapy enhancement, and actionable via small molecule FAK inhibition. eTOC BlurbHigh-grade serous ovarian cancer remains difficult to treat due to therapy resistance. Chen et. al. reveal that tumor FAK inhibition educates macrophages to express CXCL13 associated with B cell infiltration - highlighting a new therapeutic pathway linking FAK inhibition, omega-3 fatty acid containing exosomes, and macrophage mediated anti-tumor activation. Bullet pointsO_LIGenetic or small molecule FAK inhibition enhances ovarian tumor B cell infiltration C_LIO_LITumor FAK inhibition stimulates GATA6+ macrophages to make CXCL13 C_LIO_LIFAKi, pegylated doxorubicin and anti-TIGIT promote tertiary lymphoid structures C_LIO_LIOmega-3 fatty acids stimulate human HGSOC ascites macrophages to make CXCL13 C_LI

cancer biology↗

bioRxiv2025

Targeting non-canonical NF-κB signalling in CYLD cutaneous syndrome by selective inhibition of IκB kinase alpha.

CYLD cutaneous syndrome (CCS) skin tumors develop from puberty onwards, can number in the hundreds and progressively grow over time. CCS patients lack medical therapies and require repeated surgery to control tumor burden. CYLD loss of heterozygosity (LOH) drives tumor growth, and CCS tumors have previously been shown to demonstrate increased canonical NF-{kappa}B and Wnt signalling. Here, we demonstrate evidence of non-canonical NF-{kappa}B signalling in CCS tumor keratinocytes, with increased p100 to p52 processing and RelB protein expression compared to normal skin. Utilizing complementary transcriptomics and proteomics on patient derived CCS tumor cell fractions, we identify I{kappa}B kinase alpha (IKK) as a candidate target in the non-canonical NF-{kappa}B signalling pathway. A novel, highly selective, IKK inhibitor (SU1644) used in patient derived CCS tumor spheroid cultures demonstrated that IKK inhibition reduced tumor spheroid viability. These data provide the pre-clinical rationale for the assessment of topical IKK inhibitors as a novel preventative treatment for CCS. TeaserTopical IKK inhibition emerges as a potential therapy for CYLD cutaneous syndrome by targeting non-canonical NF-{kappa}B signalling Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC="FIGDIR/small/635629v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@829218org.highwire.dtl.DTLVardef@459f5dorg.highwire.dtl.DTLVardef@e198f6org.highwire.dtl.DTLVardef@1015685_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Caspase-8 activity mediates TNFα production and restricts Coxiella burnetii replication during murine macrophage infection

Coxiella burnetii is an obligate intracellular bacteria which causes the global zoonotic disease Q Fever. Treatment options for infection are limited, and development of novel therapeutic strategies requires a greater understanding of how C. burnetii interacts with immune signaling. Cell death responses are known to be manipulated by C. burnetii, but the role of caspase-8, a central regulator of multiple cell death pathways, has not been investigated. In this research, we studied bacterial manipulation of caspase-8 signaling and the significance of caspase-8 to C. burnetii infection, examining bacterial replication, cell death induction, and cytokine signaling. We measured caspase, RIPK, and MLKL activation in C. burnetii-infected TNF/CHX-treated THP-1 macrophage-like cells and TNF/ZVAD-treated L929 cells to assess apoptosis and necroptosis signaling. Additionally, we measured C. burnetii replication, cell death, and TNF induction over 12 days in RIPK1-kinase-dead, RIPK3-kinase-dead, or RIPK3-kinase-dead-caspase-8-/- BMDMs to understand the significance of caspase-8 and RIPK1/3 during infection. We found that caspase-8 is inhibited by C. burnetii, coinciding with inhibition of apoptosis and increased susceptibility to necroptosis. Furthermore, C. burnetii replication was increased in BMDMs lacking caspase-8, but not in those lacking RIPK1/3 kinase activity, corresponding with decreased TNF production and reduced cell death. As TNF is associated with the control of C. burnetii, this lack of a TNF response may allow for the unchecked bacterial growth we saw in caspase-8-/- BMDMs. This research identifies and explores caspase-8 as a key regulator of C. burnetii infection, opening novel therapeutic doors.

microbiology↗

bioRxiv2023

The expression profile and tumorigenic mechanisms of CD97 (ADGRE5) in glioblastoma render it a targetable vulnerability

Glioblastoma (GBM) is the most common and aggressive primary brain malignancy. Adhesion G protein-coupled receptors (aGPCRs) have attracted interest for their functional role in gliomagenesis and their potential as treatment targets. To identify therapeutically targetable opportunities among aGPCR family members in unbiased fashion, we analyzed expression levels of all aGPCRs in GBM and non-neoplastic brain tissue. Using bulk and single cell transcriptomic and proteomic data, we show that CD97 (ADGRE5), an aGPCR previously implicated in GBM pathogenesis, is the most promising aGPCR target in GBM, by virtue of its abundance in all GBM tumors and its de novo expression profile in GBM compared to normal brain tissue and neural progenitors. CD97 knockdown or knockout significantly reduces the tumor initiation capacity of patient-derived GBM cultures (PDGC) in vitro and in vivo. Transcriptomic and metabolomic data from PDGCs suggest that CD97 promotes glycolytic metabolism. The oncogenic and metabolic effects of CD97 are mediated by the MAPK pathway. Activation of MAPK signaling depends on phosphorylation of the cytosolic C-terminus of CD97 and recruitment of {beta}-arrestin. Using single-cell RNA-sequencing and biochemical assays, we demonstrate that THY1/CD90 is the most likely CD97 ligand in GBM. Lastly, we show that targeting of PDGCs with an anti-CD97 antibody-drug conjugate in vitro selectively kills tumor cells but not human astrocytes or neural stem cells. Our studies identify CD97 as an important regulator of tumor metabolism in GBM, elucidate mechanisms of receptor activation and signaling, and provide strong scientific rationale for developing biologics to target it for therapeutic purposes.

cancer biology↗

bioRxiv2023

Bulk RNA-Sequencing of small airway cell cultures from IPF and post-COVID lung fibrosis patients illustrates disease signatures and differential responses to TGF-β1 treatment

IPF is a condition in which an injury to the lung leads to the accumulation of scar tissue. This fibrotic tissue reduces lung compliance and impairs gas exchange. Studies have shown that infection with COVID-19 significantly worsens the clinical outcomes of IPF patients. The exact etiology of IPF is unknown, but recent evidence suggests that the distal small airways, (those having a diameter less than 2 mm in adults), play a role in the early pathogenesis of IPF. TGF-{beta}1 is a main driver of fibrosis in a variety of tissues; the binding of TGF-{beta}1 to its receptor triggers a signaling cascade that results in inflammatory signaling, accumulation of collagen and other components of the extracellular matrix, and immune system activation. This study aimed to investigate possible mechanisms that contribute to worsening lung fibrosis in IPF patients after being diagnosed with COVID-19, with a particular focus on the role of TGF-{beta}1. Small airway cell cultures derived from IPF and post-COVID-19 IPF patient transplant tissues were submitted for RNA-sequencing and differential gene expression analysis. The genetic signatures for each disease state were determined by comparing the differentially expressed genes present in the cells cultured under control conditions to cells cultured with TGF-{beta}1. The genes shared between the culture conditions laid the framework for determining the genetic signatures of each disease. Our data found that genes associated with pulmonary fibrosis appeared to be more highly expressed in the post-COVID fibrosis samples, under both control and TGF-{beta}1-treated conditions. A similar trend was noted for genes involved in the TGF-{beta}1 signaling pathway; the post-COVID fibrosis cell cultures seemed to be more responsive to treatment with TGF-{beta}1. Gene expression analysis, RT-PCR, and immunohistochemistry confirmed increased levels of BMP signaling in the IPF small airway cell cultures. These findings suggest that TGF-{beta}1 signaling in IPF small airway cells could be inhibited by BMP signaling, leading to the differences in genetic signatures between IPF and post-COVID fibrosis.

cell biology↗

bioRxiv2023

Experimentally induced drought and growing season stage modulate community-level functional traits in a temperate grassland

O_LIExtreme precipitation events are expected to become more intense and frequent with climate change. This climatic shift may impact the structure and dynamics of natural communities and the key ecosystem services they provide. Changes in species abundance under these extreme conditions are thought to be driven by functional traits, morpho-physiological characteristics of an organism that impact its fitness. Future environmental conditions may, therefore, favour different functional traits to those in present-day communities. C_LIO_LIHere, we measure functional traits on 586 vascular plants in a temperate grassland where precipitation has been experimentally manipulated for six years. We calculated community-weighted means of five functional traits (plant height, leaf dry matter content, leaf thickness, specific leaf area, and leaf phosphorus concentration) and compared community-weighted means between three levels of precipitation: drought (-50%), irrigated (+50%), and control. Additionally, we contrasted treatments at two different timings along the growing season: mid-season and late-season. C_LIO_LIWe expected altered community-weighted means for traits associated with a conservative use of water that will result from increased summer stress-induced intraspecific variability in the mid-season and from community composition changes in the late-season, after the field is cut, a common management action across most European grasslands. C_LIO_LIIn the drought treatment, we found significantly lower community-weighted mean plant height and leaf dry matter content. However, we only observed these differences after the mid-season cut. We also observed an increase in leaf phosphorus concentration in the drought treatment before the mid-season cut. A combination of changes in community composition and intraspecific variation contributed to these differences, with community composition being more important after the cut. Species with higher height, leaf dry matter content, and lower leaf thickness showed a more pronounced abundance decline at the drought plots. We observed no changes in functional traits community-weighted means in the irrigated treatment compared to those in control and drought treatments. C_LIO_LISynthesis. Our results suggest how the functional trait composition of grassland communities may shift under climate change-induced drought, stressing the interacting effects with growing season stages. C_LI

ecology↗

bioRxiv2022

Targeting ATP12A, a non-gastric proton pump alpha subunit, for idiopathic pulmonary fibrosis treatment

Idiopathic Pulmonary Fibrosis (IPF) is a pathological condition of unknown etiology which results from injury to the lung and an ensuing fibrotic response that leads to thickening of the alveolar walls and obliteration of the alveolar space. The pathogenesis is not clear and there are currently no effective therapies for IPF. Small airway disease and mucus accumulation are prominent features in IPF lungs, similar to Cystic Fibrosis (CF) lung disease. The ATP12A gene encodes the alpha-subunit of the non-gastric H+, K+-ATPase, which functions to acidify the airway surface fluid and impairs mucociliary transport function in cystic fibrosis patients. We hypothesize that the ATP12A protein may play a role in the pathogenesis of IPF. Our studies demonstrate that ATP12A protein is overexpressed in distal small airways from IPF patient lungs compared to normal human lungs. In addition, overexpression of the ATP12A protein in mouse lungs worsened the bleomycin (BLEO)-induced experimental pulmonary fibrosis. This was prevented by a potassium-competitive proton pump blocker, vonoprazan (VON). This data supports the concept that the ATP12A protein plays an important role in the pathogenesis of lung fibrosis. Inhibition of the ATP12A protein has the potential as a novel therapeutic strategy in IPF.

cell biology↗

bioRxiv2020

A general approach to explore prokaryotic protein glycosylation reveals the unique surface layer modulation of an anammox bacterium.

The enormous chemical diversity and strain variability of prokaryotic protein glycosylation makes a large-scale exploration exceptionally challenging. Therefore, despite the universal relevance of protein glycosylation across all domains of life, the understanding of their biological significance and the evolutionary forces shaping oligosaccharide structures remains highly limited. Here, we report on a newly established mass binning glycoproteomics approach that establishes the chemical identity of the carbohydrate components and performs untargeted exploration of prokaryotic oligosaccharides from large-scale proteomics data directly. We demonstrate our approach by exploring an enrichment culture of the globally relevant anaerobic ammonium-oxidizing bacterium Ca. Kuenenia stuttgartiensis. By doing so we resolved a remarkable array of oligosaccharides, produced by two entirely unrelated glycosylation machineries targeting the same surface-layer protein (SLP) simultaneously. More intriguingly, the investigated strain also accomplished modulation of highly specialized sugars, supposedly in response to its energy metabolism--the anaerobic oxidation of ammonium --which depends on the acquisition of substrates of opposite charge. Ultimately, we provide a systematic approach for the compositional exploration of prokaryotic protein glycosylation, and reveal for the first time a remarkable balance between maximising cellular protection through a complex array of oligosaccharides and adhering to the requirements of the metabolic lifestyle.

systems biology↗

bioRxiv2020

U-Infuse: Democratization of Customizable AI for Object Detection

O_LIImage data is one of the primary sources of ecological data used in biodiversity conservation and management worldwide. However, classifying and interpreting large numbers of images is time and resource expensive, particularly in the context of camera trapping. Deep learning models have been used to achieve this task but are often not suited to specific applications due to their inability to generalise to new environments and inconsistent performance. Models need to be developed for specific species cohorts and environments, but the technical skills required to achieve this are a key barrier to the accessibility of this technology to ecologists. There is a strong need to democratise access to deep learning technologies by providing an easy to use software application allowing non-technical users to custom train custom object detectors. C_LIO_LIU-Infuse addresses this issue by putting the power of AI into the hands of ecologists. U-Infuse provides ecologists with the ability to train customised models using publicly available images and/or their own camera trap images, without the constraints of annotating and pre-processing large numbers of images, or specific technical expertise. U-Infuse is a free and open-source software solution that supports both multiclass and single class training and inference, allowing ecologists to access state of the art AI on their own device, customised to their application without sharing IP or sensitive data. C_LIO_LIU-Infuse provides ecological practitioners with the ability to (i) easily achieve camera trap object detection within a user-friendly GUI, generating a species distribution report, and other useful statistics, (ii) custom train deep learning models using publicly available and custom training data, (iii) achieve supervised auto-annotation of images for further training, with the benefit of editing annotations to ensure quality datasets. C_LIO_LIBroad adoption of U-Infuse by ecological practitioners will improve camera trap image analysis and processing by allowing significantly more image data to be processed with minimal expenditure of time and resources. Ease of training and reliance on transfer learning means domain-specific models can be trained rapidly, and frequently updated without the need for computer science expertise, or data sharing, protecting intellectual property and privacy. C_LI

ecology↗

bioRxiv2019

ClassifyMe: a field-scouting software for the identification of wildlife in camera trap images.

We present ClassifyMe a software tool for the automated identification of animal species from camera trap images. ClassifyMe is intended to be used by ecologists both in the field and in the office. Users can download a pre-trained model specific to their location of interest and then upload the images from a camera trap to a laptop or workstation. ClassifyMe will identify animals and other objects (e.g. vehicles) in images, provide a report file with the most likely species detections and automatically sort the images into sub-folders corresponding to these species categories. False Triggers (no visible object present) will also be filtered and sorted. Importantly, the ClassifyMe software operates on the users local machine (own laptop or workstation) not via internet connection. This allows users access to state-of-the-art camera trap computer vision software in situ, rather than only in the office. The software also incurs minimal cost on the end-user as there is no need for expensive data uploads to cloud services. Furthermore, processing the images locally on the users end-device allows them data control and resolves privacy issues surrounding transfer and third-party access to users datasets.

ecology↗