Biology subjects

Matthews, L.

Publications and source records attributed to Matthews, L..

13 recordsLinked to original sources

bioRxiv2026

Decoding Spatial Programs in Human Glioblastoma Through Surprisal Information-Theoretical Analysis

Glioblastoma (GBM) is a highly heterogeneous and invasive brain tumor in which complex interactions among tumor cells, immune cells, and neurons shape disease progression and therapeutic resistance. Resolving spatial patterns programs in glioblastoma (GBM) requires analytical approaches that go beyond variance-driven embeddings. Here, we applied thermodynamic surprisal analysis, an information-theoretic decomposition framework, to spatial transcriptomic sequencing from human GBM specimens to identify orthogonal constraint modes that capture dominant and previously hidden spatial programs. Surprisal analysis revealed structured patterns in the data that are not highlighted by standard approaches such as PCA or cell type deconvolution, including immune-activation-associated signatures as well as spatial programs consistent with synapse remodeling. Coupling surprisal decomposition with spatial ligand-receptor interaction analysis, NICHES, along with multiplexed protein imaging connected these spatial hidden modes to reveal potential communication networks. Together, these results position surprisal analysis as a powerful, complementary strategy for interrogating spatial tumor architecture, enabling discovery of non-obvious spatial programs and interactions that are obscured by variance-based methods.

systems biology↗

bioRxiv2026

User-driven development and evaluation of an agentic framework for analysis of large pathway diagrams

As biomedical knowledge keeps growing, resources storing available information multiply and grow in size and complexity. Such resources can be in the format of molecular interaction maps, which represent cellular and molecular processes under normal or pathological conditions. However, these maps can be complex and hard to navigate, especially to novice users. Large Language Models (LLMs), particularly in the form of agentic frameworks, have emerged as a promising technology to support this exploration. In this article, we describe a user-driven process of prototyping, development, and user testing of Llemy, an LLM-based system for exploring these molecular interaction maps. By involving domain experts from the very first prototyping in the form of a hackathon and collecting both fine-grained and general feedback on more refined versions, we were able to evaluate the perceived utility and quality of the developed system, in particular for summarising maps and pathways, as well as prioritise the development of future features. We recommend continued user-driven development and benchmarking to keep the community engaged. This will also facilitate the transition towards open-weight LLMs to support the needs of the open research environment in an ever-changing technology landscape.

bioinformatics↗

bioRxiv2025

Application of Large Language Models for Annotating Genes into Reactome Pathways

Reactome is the most comprehensive, open source, open access biological pathway knowledgebase, widely used in the research community. To ensure the highest quality of its content, human pathway data in Reactome is manually curated. However, manual curation is labor-intensive, time-consuming, and increasingly difficult to keep up with the ever-growing biomedical literature. Large language model (LLM)-driven artificial intelligence (AI) technologies are transforming many fields, including bioinformatics resource development. Applying LLM/AI technologies in Reactome may offer a powerful way to scale curation and consolidate pathway-related data into a single resource. This manuscript describes the first stage of our attempt to adopt LLM/AI technologies for Reactome manual curation. We developed an LLM workflow that can assist curators in adding new genes to existing pathways and refining the functional annotations of existing ones. The workflow predicts pathways in which genes are likely to function, identifies PubMed-indexed literature that may support these predictions, generates text summaries describing potential molecular mechanisms, and extracts functional relationships among biological entities from full-text PDF papers. To validate the workflow output, we used a computational approach based on semantic similarity between LLM workflow-generated summaries and Reactome manual annotations. The results show significant enrichment of high-similarity matches. Manual evaluation of 19 genes indicated that more than half of the outputs are useful for supporting curation. Based on these results, we developed an enhanced workflow that incorporates protein-protein interaction data, facilitating Reactomes reaction-based annotation. In summary, our initial adoption of LLM/AI technologies produced encouraging results and provides a practical framework for integrating AI-assisted methods into Reactomes curation pipeline. The strategies described here may be broadly applicable to community knowledgebases in general.

bioinformatics↗

bioRxiv2023

ChatGPT usage in the Reactome curation process

Appreciating the rapid advancement and ubiquity of generative AI, particularly ChatGPT, a chatbot using large language models like GPT, we endeavour to explore the potential application of ChatGPT in the data collection and annotation stages within the Reactome curation process. This exploration aimed to create an automated or semi-automated framework to mitigate the extensive manual effort traditionally required for gathering and annotating information pertaining to biological pathways, adopting a Reactome "reaction-centric" approach. In this pilot study, we used ChatGPT/GPT4 to address gaps in the pathway annotation and enrichment in parallel with the conventional manual curation process. This approach facilitated a comparative analysis, where we assessed the outputs generated by ChatGPT against manually extracted information. The primary objective of this comparison was to ascertain the efficiency of integrating ChatGPT or other large language models into the Reactome curation workflow and helping plan our annotation pipeline, ultimately improving our protein-to-pathway association in a reliable and automated or semi-automated way. In the process, we identified some promising capabilities and inherent challenges associated with the utilisation of ChatGPT/GPT4 in general and also specifically in the context of Reactome curation processes. We describe approaches and tools for refining the output given by ChatGPT/GPT4 that aid in generating more accurate and detailed output.

molecular biology↗

bioRxiv2023

Localized Rift Valley Fever Virus Persistence Depends on a High Transovarial Transmission Fraction

Rift Valley fever virus (RVFV) has spread beyond continental Africa and threatens to follow West Nile, chikungunya and Zika viruses into the Americas. Its impact in new localities and the capacity to control future outbreaks, depends on whether and how RVFV persists at small spatial scales. Transovarial transmission (TOT) is hypothesized as an important mechanism for local persistence, yet its role in RVFV ecology remains poorly understood. We examine whether RVFV can persist locally via TOT while maintaining a realistic seroprevalence pattern of interepidemic and epidemic transmission. We developed a mechanistic, compartmental model of RVFV dynamics within a single host (sheep) and two vector (mosquito) populations, driven by temperate climatic factors. Decades-long persistence was possible in our simulations, which generally captured the observed outbreak patterns in central South Africa with a mean annual seroprevalence ([~]23%) within the range reported during interepidemic periods (5-40%). Persistence was only possible with a substantial TOT fraction and over a narrow range of parameters. The basic reproduction number (R0) was close to one at mean vector population sizes, suggesting a relatively limited expansion of the infected vector population during outbreaks. This limited expansion provides the system with the flexibility to support both low-level transmission and large outbreaks and, counterintuitively, large outbreaks resulted in smaller infected Aedes egg populations. This has important consequences for control: low-level vaccination may prevent large outbreaks without eliminating RVFV and local control efforts may be most effective immediately following an outbreak, suggesting elimination may be possible after emergence in temperate regions.

ecology↗

bioRxiv2023

Pathway-based, reaction-specific annotation of disease variants for elucidation of molecular phenotypes

Disease variant annotation in the context of biological reactions and pathways can provide a standardized overview of molecular phenotypes of pathogenic mutations that is amenable to computational mining and mathematical modeling. Reactome, an open source, manually curated, peer-reviewed database of human biological pathways, provides annotations for over 4000 disease variants of close to 400 genes in the context of [~]800 disease reactions constituting [~]400 disease pathways. Functional annotation of disease variants proceeds from normal gene functions, through disease variants whose divergence from normal molecular behaviors has been experimentally verified, to extrapolation from molecular phenotypes of characterized variants to variants of unknown significance using criteria of the American College of Medical Genetics and Genomics (ACMG). Reactomes pathway-based, reaction-specific disease variant dataset and data model provide a platform to infer pathway output impacts of numerous human disease variants and model organism orthologs, complementing computational predictions of variant pathogenicity.

systems biology↗

bioRxiv2023

HDAC6 inhibition as a mechanism to prevent axon degeneration in the mSOD1G93A mouse model of ALS.

The loss of upper and lower motor neurons, and their axons is central to the loss of motor function and death in amyotrophic lateral sclerosis (ALS). Due to the diverse range of genetic and environmental factors that contribute to the pathogenesis of ALS, there have been difficulties in developing effective therapies for ALS. One dichotomy emerging in the field is that protection of the neuronal cell soma itself does not prevent axonal vulnerability and degeneration, suggesting the need for targeted therapeutics to prevent axon degeneration. Post-translational modifications of protein acetylation can alter the function, stability and half-life of individual proteins, and can be enzymatically modified by histone acetyltransferases (HATs) and histone deacetyltransferases (HDACs), which add, or remove acetyl groups, respectively. Maintenance of post-translational microtubule acetylation has been suggested as a potential mechanism to stabilise axons and prevent axonal loss and neurodegeneration in ALS. This study has utilized an orally dosed HDAC6 specific inhibitor, ACY-738, prevent deacetylation and stabilize microtubules in the mSOD1G93A mouse model of ALS. Furthermore, co-treatment with riluzole was performed to determine any effects or drug interactions and potentially enhance preclinical research translation. This study shows ACY-738 treatment increased acetylation of microtubules in the spinal cord of mSOD1G93A mice, reduced lower motor neuron degeneration in the lumbar spinal cord of female mice, ameliorated reduction in peripheral nerve axon puncta size, but did not prevent overt motor function decline. The current study also shows peripheral nerve axon puncta size to be partially restored after treatment with riluzole and highlights the importance of co-treatment to measure the potential effects of therapeutics in ALS. HighlightsO_LIACY-738 inhibits HDAC6 and leads to increased microtubule acetylation in spinal cord of mSOD1G93A mice. C_LIO_LIACY-738 treatment reduces lower motor neuron degeneration in the lumbar spinal cord of mSOD1G93A mice. C_LIO_LIACY-738 treatment restores peripheral nerve axon puncta size of mSOD1G93A mice. C_LIO_LIACY-738 treatment does not prevent overt motor function decline mSOD1G93A mice. C_LIO_LIRiluzole treatment partially restores peripheral nerve axon puncta size in mSOD1G93A mice. C_LI

neuroscience↗

bioRxiv2023

Illuminating Dark Proteins using Reactome Pathways

Limited knowledge about a substantial portion of protein coding genes, known as "dark" proteins, hinders our understanding of their functions and potential therapeutic applications. To address this, we leveraged Reactome, the most comprehensive, open source, open-access pathway knowledgebase, to contextualize dark proteins within biological pathways. By integrating multiple resources and employing a random forest classifier trained on 106 protein/gene pairwise features, we predicted functional interactions between dark proteins and Reactome-annotated proteins. We then developed three scores to measure the interactions between dark proteins and Reactome pathways, utilizing enrichment analysis and fuzzy logic simulations. Correlation analysis of these scores with an independent single-cell RNA sequencing dataset provided supporting evidence for this approach. Furthermore, systematic natural language processing (NLP) analysis of over 22 million PubMed abstracts and manual checking of the literature associated with 20 randomly selected dark proteins reinforced the predicted interactions between proteins and pathways. To enhance the visualization and exploration of dark proteins within Reactome pathways, we developed the Reactome IDG portal, deployed at https://idg.reactome.org, a web application featuring tissue-specific protein and gene expression overlay, as well as drug interactions. Our integrated computational approach, together with the user-friendly web platform, offers a valuable resource for uncovering potential biological functions and therapeutic implications of dark proteins.

bioinformatics↗

bioRxiv2023

Sterically enhanced control of enzyme-assisted DNA assembly

Traditional methods for the assembly of functionalised DNA structures, involving enzyme restriction and modification, present difficulties when working with small DNA fragments (<100bp), in part due to a lack of control over enzymatic action during the DNA modification process. This limits the design flexibility and range of accessible DNA structures. Here, we show that these limitations can be overcome by introducing chemical modifications into the DNA, which spatially restrict enzymatic activity. This approach, Sterically Controlled Nuclease Enhanced (SCoNE) DNA assembly, thereby circumvents the size limitations of conventional Gibson assembly (GA) and allows for the preparation of well-defined, functionalised DNA structures with multiple probes for specific analytes, such as IL-6, procalcitonin (PCT), and a biotin reporter group. Notably, using the same starting materials conventional GA under typical conditions fails. We demonstrate successful analyte capture based on standard and modified sandwich ELISA and also show how the inclusion of biotin probes provides additional functionality for product isolation.

biochemistry↗

bioRxiv2022

RET Signaling Persists in the Adult Intestine and Stimulates Motility by Limiting PYY Release from Enteroendocrine Cells

Background & AimsRET receptor tyrosine kinase is necessary for enteric nervous system (ENS) development. Loss-of-function RET mutations cause Hirschsprung disease (HSCR), in which infants are born with aganglionic bowel. Despite surgical correction, HSCR patients often experience chronic defecatory dysfunction and enterocolitis, suggesting that RET is important after development. To test this hypothesis, we determined the location of postnatal RET and its significance in gastrointestinal (GI) motility. MethodsRetCFP/+ mice and human transcriptional profiling data were studied to identify the enteric neuronal and epithelial cells that express RET. To determine whether RET signaling in these cells regulates adult gut motility in vivo, genetic and pharmacologic approaches were used to disrupt RET in either all RET-expressing cells, a major subset of enteric neurons, or intestinal epithelial cells. ResultsDistinct subsets of enteric neurons and enteroendocrine cells expressed RET in the adult intestine. RET disruption in the intestinal epithelium, rather than in enteric neurons, slowed GI motility selectively in adult male mice. This effect was phenocopied by RET kinase inhibition. Most RET+ epithelial cells were either enterochromaffin cells that release serotonin (5-HT) or L-cells that release peptide YY (PYY), both of which can alter motility. RET kinase inhibition exaggerated PYY release in a nutrient-dependent manner without altering 5-HT secretion. PYY receptor blockade fully rescued dysmotility in mice lacking epithelial RET. ConclusionRET signaling normally limits nutrient-dependent PYY release from L-cells and this activity is necessary for normal intestinal motility in male mice. These effects could contribute to post-operative dysmotility in HSCR, which predominantly affects males, and uncovers a mechanism that could be targeted to treat post-prandial GI dysfunction. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=82 SRC="FIGDIR/small/488514v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@4c8e83org.highwire.dtl.DTLVardef@204d13org.highwire.dtl.DTLVardef@a429d8org.highwire.dtl.DTLVardef@1b75265_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2021

An inactivated multivalent influenza A virus vaccine is broadly protective in mice and ferrets

Influenza A viruses (IAVs) present major public health threats from annual seasonal epidemics, from pandemics caused by novel virus subtypes, and from viruses adapted to a variety of animals including poultry, pigs and horses. Vaccines that broadly protect against all such IAVs, so-called "universal" influenza vaccines, do not currently exist, but are urgently needed. This study demonstrates that an inactivated, multivalent whole virus vaccine, delivered intramuscularly or intranasally, is broadly protective against challenges with multiple IAV HA/NA subtypes in both mice and ferrets, including challenges with IAV subtypes not contained in the vaccine. This vaccine approach indicates the feasibility of eliciting broad "universal" IAV protection, and identifies a promising candidate for influenza vaccine clinical development. One-Sentence SummaryAn inactivated, whole avian influenza virus vaccine delivered intramuscularly or intranasally provides extremely broad protection against antigenically divergent viral challenge and is a promising candidate for a "universal" influenza virus vaccine.

microbiology↗

bioRxiv2021

One Health or Three? Transmission modelling of Klebsiella isolates reveals ecological barriers to transmission between humans, animals and the environment

The Klebsiella group is highly diverse both genetically and ecologically, being commonly recovered from humans, livestock, plants, soil, water, and wild animals. Many species are opportunistic pathogens, and can harbour diverse classes of antimicrobial resistance (AMR) genes. K. pneumoniae is responsible for a high public-health burden, due in part to the rapid spread of health-care associated clones that are non-susceptible to carbapenems. Klebsiella thus represents a highly pertinent taxon for assessing the risk to public health posed by animal and environmental reservoirs. Here we report an analysis of 6548 samples and 3,482 genome sequences representing 15 Klebsiella species sampled over a 15-month period from a wide range of clinical, community, animal and environmental settings in and around the city of Pavia, in the northern Italian region of Lombardy. Despite carbapenem-resistant clones circulating at a high frequency in the hospitals, we find no genotypic or phenotypic evidence for non-susceptibility to carbapenems outside of the clinical environment. The non-random distribution of species and strains across sources point to ecological barriers that are likely to limit AMR transmission. Although we find evidence for occasional transmission between settings, hierarchical modelling and intervention analysis suggests that direct transmission from the multiple non-human (animal and environmental) sources included in our sample accounts for less than 1% of hospital disease, with the vast majority of clinical cases originating from other humans.

microbiology↗

bioRxiv2021

The genomic basis of domestic colonisation and dispersal in Chagas disease vectors

The biology of vector adaptation to the human habitat remains poorly understood for many arthropod-borne diseases but underpins effective and sustainable disease control. We adopted a landscape genomics approach to investigate gene flow, signatures of local adaptation, and drivers of population structure among multiple linked wild and domestic population pairs in Rhodnius ecuadoriensis, an important vector of Chagas Disease. Evidence of high triatomine gene flow (FST) between wild and domestic ecotopes at sites throughout the study area indicate insecticide-based control will be hindered by constant re-infestation of houses. Genome scans revealed genetic loci with strong signal of local adaptation to the domestic setting, which we mapped to annotated regions in the Rhodnius prolixus genome. Our landscape genomic mixed effects models showed Rhodnius ecuadoriensis population structure and connectivity is driven by landscape elevation at a regional scale. Our ecologically- and spatially-explicit vector dispersal model enables targeted vector control and recommends spatially discrete, periodic interventions to local authorities as more efficacious than current, haphazard approaches. In tandem, evidence for parallel genomic adaptation to colonisation of the domestic environment at multiple sites sheds new light on the evolutionary basis of adaptation to the human host in arthropod vectors.

genomics↗