Biology subjects

Lawrence, T.

Publications and source records attributed to Lawrence, T..

14 recordsLinked to original sources

bioRxiv2026

OmniPath Metabo: chemical structures, interactions and mechanisms to study the metabolome

Mechanistic and functional analysis of omics data largely relies on the incorporation of prior knowledge; however, connecting metabolomics data and knowledge is a major methodological challenge. This is largely driven by the diverse prior knowledge being fragmented across many databases requiring the merging of different database records across chemical structures, identifiers, and varying levels of structural specificity. Hence, this limits mechanistic interpretation and functional characterisation of the metabolome. Here, we present OmniPath Metabo, a comprehensive, harmonized, metabolome-centric database covering metabolites, lipids, food-derived compounds, and small molecule drugs, along with their associated receptors, transporters, enzymes, reactions, allosteric regulators, and disease associations. OmniPath Metabo harmonizes attributes using controlled vocabularies and ontologies, structures and built-in cheminformatics to map identifiers and track ambiguity. OmniPath Metabo is built directly from 40+ original resources and is freely accessible via an interactive web app and API at metabo.omnipathdb.org. OmniPath Metabo enables dynamic, context-specific construction of subnetworks to serve dedicated purposes, such as cell-cell communication or integrated multi-omics metabolite-driven regulation, connecting reactions, allosteric regulation, metabolite-receptor and metabolite-transporter interactions. Combining it with the over 170 other resources in OmniPath, it can be used for integrated networks of signaling, gene regulation, and metabolism. We showcase the application of OmniPath Metabo by analysing publicly available metabolomics data of lung cancer cell lines and metabolic footprints to mutational patterns. In summary, OmniPath Metabo transforms fragmented resources into a harmonised prior knowledge framework for a mechanistic and functional analysis of the metabolome.

bioinformatics↗

bioRxiv2026

Eggerthella lenta evades bacteriophage through reversible megabase-scale inversions of capsular polysaccharide gene clusters

Bacteriophages are a promising tool for microbiome editing, yet their development has been constrained by limited insights into bacteriophage-host interactions within their shared mammalian body habitat. We isolated a lytic phage {Phi}KL11 that efficiently targets a disease-associated member of the human gut microbiota, Eggerthella lenta, during in vitro growth. However, {Phi}KL11 selects for a pre-existing and reversible bacteriophage-resistant sub-population in mice. Long-read sequencing revealed a massive genomic inversion event, representing >50% of the E. lenta genome, enriched in response to bacteriophage infection. Transcriptomics linked this inversion to the altered expression of three capsular polysaccharide synthesis (CPS) gene clusters and transmission electron microscopy confirmed differential capsule production. Finally, we show that {Phi}KL11 has a broad host range attributable to CPS and other strain-variable genes. These findings suggest a previously unrecognized strategy for phage evasion in the gut, involving megabase-scale genomic inversions and reversible capsule variation driving phage resistance.

microbiology↗

bioRxiv2025

OmniPath: integrated knowledgebase for multi-omics analysis

Analysis and interpretation of omics data largely benefit from the use of prior knowledge. However, this knowledge is fragmented across resources and often is not directly accessible for analytical methods. We developed OmniPath (https://omnipathdb.org/), a database combining diverse molecular knowledge from 168 resources. It covers causal protein-protein, gene regulatory, miRNA, and enzyme-PTM (post-translational modification) interactions, cell-cell communication, protein complexes, and information about the function, localization, structure, and many other aspects of biomolecules. It prioritizes literature curated data, and complements it with predictions and large scale databases. To enable interactive browsing of this large corpus of knowledge, we developed OmniPath Explorer, which also includes a large language model (LLM) agent that has direct access to the database. Python and R/Bioconductor client packages and a Cytoscape plugin create easy access to customized prior knowledge for omics analysis environments, such as scverse. OmniPath can be broadly used for the analysis of bulk, single-cell and spatial multi-omics data, especially for mechanistic and causal modeling. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/675512v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@17c2b6borg.highwire.dtl.DTLVardef@1069835org.highwire.dtl.DTLVardef@1f2ce76org.highwire.dtl.DTLVardef@1d0b34f_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2025

Xcr1+ type 1 conventional dendritic cells are essential mediators for atherosclerosis progression

BackgroundAtherosclerosis is characterized by lipid accumulation within plaques, leading to foam cell formation and an inflammatory response within the aortic lesions. Lipid disorders have been extensively investigated, however the cellular and molecular mechanisms that trigger the inflammatory response in atherosclerotic plaques remain far from being fully understood. Xcr1+ cDC1 cells are newly identified antigen-presenting cells in activating immune cells. However, the role of cDC1 cells in the development of atherosclerosis remains highly controversial. ResultsWe first confirmed the presence of cDC1 within human atherosclerotic plaques and discovered a significant association between the increasing cDC1 numbers and atherosclerosis progression in mice. Subsequently, we established Xcr1Cre-Gfp Rosa26LSL-DTA ApoE-/- mice, a novel and complex genetic model, in which cDC1 was constitutively depleted in vivo during atherosclerosis development. Intriguingly, we observed a notable reduction in atherosclerotic lesions in hyperlipidemic mice, alongside suppressed T cell activation of both CD4+ and CD8+ subsets in the aortic plaques. Notably, aortic macrophages and serum lipid levels were not significantly changed in the cDC1-depleted mice. Single-cell RNA sequencing revealed heterogeneity of Xcr1+ cDC1 cells across the aorta and lymphoid organs under hyperlipidemic conditions. As Xcr1 is the sole receptor for Xcl1, we next explored to target Xcr1+ cDC1 cells via Xcl1 by establishing Xcl1 and ApoE deficient mice. Xcl1 knockout mice exhibited decreased atherosclerotic plaque formation and reduced aortic cDC1 accumulation, indicating that Xcl1 contributes to cDC1-mediated atherosclerotic lesion development. ConclusionsOur results reveal crucial roles of cDC1 in atherosclerosis progression and provide insights into the development of immunotherapies by targeting cDC1 through Xcl1.

immunology↗

bioRxiv2025

A toolkit to characterize protein polymerization from cryo-electron tomography data

BackgroundCryogenic electron tomography (cryo-ET) is a powerful method to study protein structures and macromolecular complexes. These studies can provide structural information at the nanometer scale, allowing for the visualization of ultrastructures and access to subnanometer information through localized, subtomogram averaging (STA). STA alignments can provide analysts with an opportunity to quantify relationships between particles; however, the analytical tools to accomplish this are often lab or system specific. We offer a robust MATLAB script package that can be applied to a wide array of systems. MethodsMany tomographic analyses require extensive segmentation and image classification, which though useful can have poorly characterized error rates and user biases. We present a method for unbiased, numerical classification of head-to-tail polymerization in STA datasets with no outside information or user influence required. We provide this code in a modular MATLAB script package for ease of adaptation to other projects, with analyses including volumes, concentrations, binding, and fibril bundling. ResultsWe demonstrate the robust analysis possible with this script package using a model system of Rubisco in -carboxysomes (-CBs), showcasing the codes ability to evaluate global data such as volume and overall organization, polymerization data such as twist and bend, and lattice data such as lateral fibril distances and angles. DiscussionOur script package offers structural biologists a toolkit to conduct a robust biophysical analysis on STA data in an unbiased manner. The information generated will provide new insights into protein-protein interactions and the conditions favorable for larger ultrastructures. Particles can also be classified for further STA processing. This script package can be used for scientists studying proteins within isolated compartments or with clearly defined regions of interest.

biophysics↗

bioRxiv2025

Comprehensive analysis of myeloid reporter mice

Macrophages are a pivotal cell type within the synovial lining and sub-lining of the joint, playing a crucial role in maintaining homeostasis of synovium. Although fate-mapping techniques have been employed to differentiate synovial macrophages from other synovial myeloid cells, no comprehensive study has yet been conducted within the mouse synovial macrophage compartment. In this study, we present, for the first time, lineage tracing results from 18 myeloid-specific fate-mapping models in mouse peripheral blood (PB) and synovial tissue. The identification of synovial macrophages and monocyte-lineage cells through flow cytometry was further validated using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) datasets. These findings provide a valuable methodological tool for researchers to select appropriate models for studying the function of synovial myeloid cells and serve as a reference for investigations in other tissue types.

immunology↗

bioRxiv2024

Jagged-1+ Tregs Mediate Lymphatic Remodeling in Tumour-Draining Lymph Nodes

The tumour-draining lymph nodes (tdLNs) are crucial sites for early immune surveillance of tumours. During tumour development, tdLNs undergo significant stromal remodelling that impacts lymph node (LN) architecture. The reconstruction of tdLNs is dependent on the crosstalk between regulatory T cells (Tregs) and resident stromal cells. The Notch ligand Jagged1 (Jag1), highly expressed in skin Tregs, is critical for facilitating stem cell-mediated tissue regeneration. However, the role of Jag1pos Tregs in mediating the activity of tdLN-resident immune cells and stromal cells remains unexplored. Here, we used the B16-F10 tumour model to assess the role of Jag1pos Tregs during tdLN development. During tumor progression, late-stage tdLN Tregs expressed higher levels of Jag1 than early-stage tdLNs. Conditional deletion of Jag1 in Tregs markedly restrained tdLN expansion, without influencing effector T cell abundance or activation profile. Transcriptomic analysis of tdLNs revealed downregulation of lymphatic endothelial cell (LEC)-related markers in mice with Treg-specific Jag1 ablation. Disruption of lymphatic networks in the tdLN was further confirmed by flow cytometric profiling and histological analysis. In vivo permeability assessment by FITC-dextran demonstrated perturbed lymphatic drainage, likely due to suppressed LN lymphangiogenesis. Finally, we identify the presence of Jag1pos Tregs in tdLNs of human melanoma patients. Overall, our results highlight that crosstalk between Jag1pos Tregs and LECs is required for lymphatic sinus expansion, which is critical for the formation of the tdLN niche during melanoma progression.

immunology↗

bioRxiv2022

Mechanical Stimulation Shapes the Immunoregulatory Properties of Dendritic Cells

Motile cells such as immune and cancer cells experience large deformation events that result from the physical constraints they encounter while migrating within tissues or circulating between organs. It has become increasingly clear that these cells can survive and adapt to these changes in cell shape using dedicated shape sensing pathways. However, how shape sensing impacts their function and fate remains largely unknown. Here we identify a shape sensing mechanism that couples cell motility to expression of CCR7, the chemokine receptor that guides immune cells to lymph nodes. We found that this mechanism is controlled by the lipid metabolism enzyme cPLA2, requires an intact nuclear envelop and exhibits an exquisitely sensitive activation threshold tuned by ARP2/3 and its inhibitor Arpin. We further show that shape sensing through the ARP2/3-cPLA2 axis controls Ikk{beta}-NF{kappa}B-dependent transcriptional reprogramming of dendritic cells, which instructs them to migrate to lymph nodes in an immunoregulatory state compatible with their homeostatic tolerogenic function. These results highlight that the cell shape changes experienced by motile cells evolving within the complex environment of tissues can dictate their behavior and fate.

cell biology↗

bioRxiv2022

Targeting TRIP13 in Wilms Tumor with Nuclear Export Inhibitors

Wilms tumor (WT) is the most common renal malignancy of childhood. Despite improvements in the overall survival, relapse occurs in ~15% of patients with favorable histology WT (FHWT). Half of these patients will succumb to their disease. Identifying novel targeted therapies in a systematic manner remains challenging in part due to the lack of faithful preclinical in vitro models. We established ten short-term patient-derived WT cell lines and characterized these models using low-coverage whole genome sequencing, whole exome sequencing and RNA-sequencing, which demonstrated that these ex-vivo models faithfully recapitulate WT biology. We then performed targeted RNAi and CRISPR-Cas9 loss-of-function screens and identified the nuclear export genes (XPO1 and KPNB1) as strong vulnerabilities. We observed that these models are sensitive to nuclear export inhibition using the FDA approved therapeutic agent, selinexor (KPT-330). Selinexor treatment of FHWT suppressed TRIP13 expression, which was required for survival. We further identified in vitro and in vivo synergy between selinexor and doxorubicin, a chemotherapy used in high risk FHWT. Taken together, we identified XPO1 inhibition with selinexor as a potential therapeutic option to treat FHWTs and in combination with doxorubicin, leads to durable remissions in vivo.

cancer biology↗

bioRxiv2022

Perivascular macrophages collaborate to facilitate chemotherapy resistance in cancer

A subset of tumor associated macrophages (TAMs) identified by their expression of the lymphatic vessel endothelial hyaluronan receptor-1 (Lyve-1) reside proximal to blood vasculature and contribute to disease progression. Using a spontaneous murine model of mammary adenocarcinoma (MMTV-PyMT), we show that Lyve-1+ TAMs, which co-express heme oxygenase-1, form coordinated multi-cellular nest structures in the perivascular niche. We show that TAM nest formation is dependent on IL-6 and a communication axis involving CCR5 and its cognate ligands CCL3/4. We demonstrate that Lyve-1+ TAM nests are associated with CD8+ T-cell exclusion from the tumor and the resistance to immune-stimulating chemotherapeutics. This study highlights an unappreciated collaboration between TAMs and uncovers a spatially driven therapeutic resistance mechanism of these cells in cancer which can be therapeutically targeted.

cancer biology↗

bioRxiv2020

An NF-κB/IRF1 axis programs cDC1s to drive anti-tumor immunity

Conventional type 1 dendritic cells (cDC1s) are critical for anti-tumor immunity. They acquire antigens from dying tumor cells and cross-present them to CD8+ T cells, promoting the expansion of tumor-specific cytotoxic T cells. However, the signaling pathways that govern the anti-tumor functions of cDC1s are poorly understood. We mapped the molecular pathways regulating intra-tumoral cDC1 maturation using single cell RNA sequencing. We identified NF-{kappa}B and IFN pathways as being highly enriched in a subset of functionally mature cDC1s. The specific targeting of NF-{kappa}B or IFN pathways in cDC1s prevented the recruitment and activation of CD8+ T cells and the control of tumor growth. We identified an NF-{kappa}B-dependent IFN{gamma}-regulated gene network in cDC1s, including cytokines and chemokines specialized in the recruitment and activation of cytotoxic T cells. We used single cell transcriptomes to map the trajectory of intra-tumoral cDC1 maturation which revealed the dynamic reprogramming of tumor-infiltrating cDC1s by NF-{kappa}B and IFN signaling pathways. This maturation process was perturbed by specific inactivation of either NF-{kappa}B or IRF1 in cDC1s, resulting in impaired expression of IFN-{gamma}-responsive genes and consequently a failure to efficiently recruit and activate anti-tumoral CD8+ T cells. Finally, we demonstrate the relevance of these findings to cancer patients, showing that activation of the NF-{kappa}B/IRF1 axis in association with cDC1s is linked with improved clinical outcome. The NF-{kappa}B/IRF1 axis in cDC1s may therefore represent an important focal point for the development new diagnostic and therapeutic approaches to improve cancer immunotherapy. One Sentence SummaryNF-{kappa}B and IRF1 coordinate intra-tumoral cDC1 maturation and control of immunogenic tumor growth.

immunology↗

bioRxiv2020

Lyve-1 expressing perivascular macrophages orchestrate pericyte expansion to sustain angiogenesis in cancer

Tumor associated macrophages (TAMs) are a highly plastic stromal cell type which support cancer progression. Using single-cell RNA-sequencing of TAMs from a spontaneous murine model of mammary adenocarcinoma (MMTV-PyMT) we characterize a subset of these cells expressing lymphatic vessel endothelial hyaluronic acid receptor 1 (Lyve-1) which spatially reside proximal to blood vasculature. We demonstrate that Lyve-1+ TAMs support tumor growth and identify a pivotal role for these cells in maintaining a population of perivascular mesenchymal cells which express alpha-smooth muscle actin and phenotypically resemble pericytes. Using photolabeling techniques show that mesenchymal cells maintain their prevalence in the growing tumor through proliferation and uncover a role for Lyve-1+ TAMs in orchestrating a selective platelet-derived growth factor-CC-dependent expansion of the perivascular mesenchymal population, creating a pro-angiogenic niche. This study highlights the inter-reliance of the immune and non-immune stromal network which support cancer progression and provides therapeutic opportunities for tackling the disease.

cancer biology↗

bioRxiv2020

Sympathetic axonal sprouting induces changes in macrophage populations and protects against pancreatic cancer

Recent evidence has highlighted the presence of neuronal nerve processes in the tumor microenvironment. However, the origin of intra-tumoral nerves remains poorly known, in part because of technical difficulties in tracing nerve fibers via regular histological preparations. Here, we employed three-dimensional (3D) imaging of cleared tissues for a comprehensive analysis of sympathetic innervation in pancreatic ductal adenocarcinoma (PDAC). The results support two independent, but coexisting, mechanisms: passive engulfment of pre-existing nerves within tumors and active, localized sprouting of nerve terminals into non-neoplastic lesions and tumor periphery. Nerve ablation revealed an inverse correlation between sympathetic innervation and tumor growth and spread. Furthermore, sympathectomy increased CD163+ macrophage levels, which contributed to worse outcomes. Altogether, our findings revealed protective properties of the sympathetic nervous system in PDAC immunity and progression that could pave the way for new treatments.

cancer biology↗

bioRxiv2018

Robust Estimation of the Phylogenetic Origin of Plastids Using a tRNA-Based Phyloclassifier

The trait of oxygenic photosynthesis was acquired by the last common ancestor of Archaeplastida through endosymbiosis of the cyanobacterial progenitor of modern-day plastids. Although a single origin of plastids by endosymbiosis is broadly supported, recent phylogenomic studies report contradictory evidence that plastids branch either early or late within the cyanobacterial Tree of Life. Here we describe CYANO-MLP, a general-purpose phyloclassifier of cyanobacterial genomes implemented using a Multi-Layer Perceptron. CYANO-MLP exploits consistent phylogenetic signals in bioinformatically estimated structure-function maps of tRNAs. CYANO-MLP accurately classifies cyanobacterial genomes into one of eight well-supported cyanobacterial clades in a manner that is robust to missing data, unbalanced data and variation in model specification. CYANO-MLP supports a late-branching origin of plastids: we classify 99.32% of 440 plastid genomes into one of two late-branching cyanobacterial clades with strong statistical support, and confidently assign 98.41% of plastid genomes to one late-branching clade containing unicellular starch-producing marine/freshwater diazotrophic Cyanobacteria. CYANO-MLP correctly classifies the chromatophore of Paulinella chromatophora and rejects a sister relationship between plastids and the early-branching cyanobacterium Gloeomargarita lithophora. We show that recently applied phylogenetic models and character recoding strategies fit cyanobacterial/plastid phylogenomic datasets poorly, because of heterogeneity both in substitution processes over sites and compositions over lineages.

evolutionary biology↗