Biology subjects

Durbin, J.

Publications and source records attributed to Durbin, J..

3 recordsLinked to original sources

bioRxiv2026

Pulmonary Hypertension Engine for Linked Experiments (PHELEX): a platform for the re-analysis of public transcriptomic data related to pulmonary hypertension in both animal models, and humans.

Pulmonary hypertension (PH) is a vasculopathy that results in elevated mean pulmonary arterial pressures over 20mmHg. Despite significant advances in research, PH still has a high mortality rate, and there is currently no cure for the disease. As with all biomedical fields, PH researchers have embraced the power of next generation technologies such as microarrays and RNA sequencing. Most of these data can be found on public repositories, which is usually a requirement for publication. While these repositories are rich sources of data, they require intermediate to advanced bioinformatics skills to access, download, and make these data useful. Here we present Pulmonary Hypertension Engine for Linked Experiments (PHELEX), which represents a comprehensive catalogue of all RNA sequencing data related to PH that is currently available on the Gene Expression Omnibus (GEO), hosted by the US National Centre for Biotechnology Information (NCBI). We identified 2,278 bulk RNA sequencing samples from human, mouse and rat, and built a searchable tool based on the metadata that is associated with each sample. PHELEX is a functional tool that allows selected studies to be highlighted, and parsed through Confidence, an analysis tool we have created, which will model the data based on user-defined classifiers, perform differential gene expression and pathway analysis, and present these data using standard graphics, and text-file results. PHELEX also allows PH researchers to cross-cut between discrete studies, facilitating de novo understanding of these data. As a robust searchable repository of genomic data, we hope that PHELEX will accelerate PH innovation and discovery, by allowing researchers to mine existing genomic data and thus better understand the molecular signatures that underpin PH.

genomics↗

bioRxiv2023

Tracing cancer evolution and heterogeneity using Hi-C

Chromosomal rearrangements can initiate and drive cancer progression, yet it has been challenging to evaluate their impact, especially in genetically heterogeneous solid cancers. To address this problem we developed HiDENSEC, a new computational framework for analyzing chromatin conformation capture in heterogeneous samples, which can infer somatic copy number alterations, characterize large-scale chromosomal rearrangements, and estimate cancer cell fractions. We validated HiDENSEC with in silico and in vitro controls, and then characterized chromosome-scale evolution during melanoma progression in formalin-fixed tumor samples from three patients. The resulting comprehensive annotation of the genomic events includes copy number neutral translocations that disrupt tumor suppressor genes such as NF1, whole chromosome arm exchanges that result in loss of CDKN2A, and whole-arm copy-number neutral loss of homozygosity involving PTEN. These findings show that large-scale chromosomal rearrangements occur throughout cancer evolution and characterizing these events yields insights into drivers of melanoma progression.

genomics↗

bioRxiv2021

The In Vivo Source of Type I and Type III IFNs is Pathogen Dependent

Type I (-, {beta}) and type III (-{lambda}) interferons (IFNs) are produced in response to virus infection and upregulate a largely overlapping set of IFN stimulated genes which mediate the protective effects of these antiviral cytokines. In vitro studies have demonstrated the redundancy of these two cytokine families which activate the same transcription factor, IFN stimulated gene factor 3 (ISGF3), via distinct ligands and receptors. However, in vivo, these IFN types do have distinct functions based on receptor distribution, but also ligand availability. Using a newly generated IFN-{lambda} reporter mouse strain we have observed that both type I and type III IFNs are produced in response to respiratory tract infection by Newcastle disease virus (NDV) and influenza A virus (IAV). In the case of NDV these IFNs are synthesized by different cell types. Type I IFNs are produced primarily by alveolar macrophages, type III IFNs are made only by epithelial cells, and production of either is dependent on MAVS. While epithelial cells of the respiratory tract represent the primary target of IAV infection, we found that they did not significantly contribute to IFN-{lambda} production, and IFN-{lambda} protein levels were largely unaffected in the absence of MAVS. Instead we found that pDCs, a cell type known for robust IFN- production via TLR/MyD88 signaling, were the major producers of IFN-{lambda} during IAV infection, with pDC depletion during influenza infection resulting in significantly reduced levels of both IFN- and IFN-{lambda}. In addition, we were able to demonstrate that pDCs rely on type I IFN for optimal IFN-{lambda} production. These studies therefore demonstrate that the in vivo producers of Type III IFNs in response to respiratory virus infection are pathogen dependent, a finding which may explain the varying levels of cytokine production induced by different viral pathogens.

immunology↗