Biology subjects

Wolfe, E.

Publications and source records attributed to Wolfe, E..

3 recordsLinked to original sources

bioRxiv2024

A percolation-type criticality threshold controls immune protein coating of surfaces

When a material enters the body, it is immediately attacked by hundreds of proteins, organized into complex networks of binding interactions and reactions. How do such complex systems interact with a material, "deciding" whether to attack? We focus on the "complement" system of [~]40 blood proteins that bind microbes, nanoparticles, and medical devices, initiating inflammation. We show a sharp threshold for complement activation upon varying a fundamental material parameter, the surface density of potential complement attachment points. This sharp threshold manifests at scales spanning single nanoparticles to macroscale pathologies, shown here for diverse engineered and living materials. Computational models show these behaviors arise from a minimal subnetwork of complement, manifesting percolation-type critical transitions in the complement response. This criticality switch explains the "decision" of a complex signaling network to interact with a material, and elucidates the evolution and engineering of materials interacting with the body.

biophysics↗

bioRxiv2022

Leveraging a Billion-Edge Knowledge Graph for Drug Re-purposing and Target Prioritization using Genomically-Informed Subgraphs

Drug development is a resource and time-intensive process resulting in attrition rates of up to 90%. As a result, repurposing existing drugs with established safety and pharmacokinetic profiles is gaining traction as a way of accelerating therapeutics development. Here we have developed unique machine learning-driven Natural Language Processing and biomedical semantic technologies that mine over 53 million biomedical documents to automate the generation of a 911M edge knowledge graph. We then applied subgraph queries that relate drugs to diseases using genetic evidence to identify potential drug repurposing candidates for a broad range of diseases. We use Carney Complex, a disease with no known treatment, to illustrate our approach. This analysis revealed Ruxolitinib (Incyte, trade name Jakafi), a JAK1/2 inhibitor with an established safety and efficacy profile approved to treat myelofibrosis, as a potential candidate for the treatment of Carney Complex through off-target drug activity.

bioinformatics↗

bioRxiv2022

The transcriptional and epigenetic reprogramming mediated by chronic IL1β exposure drives self-renewal ability and myeloid priming in TET2 deficient stem and progenitor cells.

Clonal hematopoiesis (CH) increases the risk for the development of hematological malignancy and cardiovascular disease. IL1{beta} is elevated in patients with CH and its inhibition mitigates cardiovascular risk in murine models with Tet2 loss-of-function. How IL1{beta} alters population dynamics of hematopoietic cells upon Tet2 deletion (Tet2-KO) is not well understood. We demonstrated IL1{beta} expands Tet2-KO monocytes/macrophages, and long-term hematopoietic stem cells. IL1{beta} promoted myeloid bias over other lineages of Tet2-KO HSPCs coinciding with the failure to demethylate lineage-associated enhancer and transcription factor binding sites. IL1{beta} enhanced the self-renewal ability of Tet2-KO HSPCs by upregulating genes associated with self-renewal and by resisting the demethylation of binding sites of transcription factors promoting terminal differentiation. The IL1{beta}-mediated premalignant phenotype is suppressed by the IL1{beta} antagonist or deletion of the IL1 receptor-1, in vivo in aged mice. Our results demonstrate that targeting IL1 signaling could be an efficient early intervention strategy in preleukemic disorders. STATEMENT OF SIGNIFICANCEIL1{beta} promoted myeloid expansion and self-renewal capacity of TET2-null pre-leukemic cells. Lineage bias occurred early within progenitors towards pro-inflammatory macrophages. Genes specific to aging and with roles in promoting self-renewal capacity, and myeloid bias were upregulated. Hypermethylation occurred within lymphoid and erythroid lineage-specific regulatory elements. Targeting IL1R1 reduced aberrant myeloid bias and premalignant phenotype.

cancer biology↗