Biology subjects

Gilmore, E.

Publications and source records attributed to Gilmore, E..

3 recordsLinked to original sources

bioRxiv2025

Transcriptional impacts of substance use disorder and HIV on human ventral midbrain neurons and microglia

For people with HIV (PWH), substance use disorders (SUDs) are a prominent neurological risk factor, and the impacts of both on dopaminergic pathways are a potential point of deleterious convergence. Here, we profile, at single nucleus resolution, the substantia nigra (SN) transcriptomes of 90 postmortem donors in the context of chronic HIV and opioid/cocaine SUD, including 67 prospectively characterized PWH. We report altered microglial expression for hundreds of pro- and anti-inflammatory regulators attributable to HIV, and separately, to SUD. Stepwise, progressive microglial dysregulation, coupled to altered SN dopaminergic and GABAergic signaling, was associated with SUD/HIV dual diagnosis and further with lack of viral suppression in blood. In virologically suppressed donors, SUD comorbidity was associated with microglial transcriptional changes permissive for HIV infection. We report HIV-related downregulation of monoamine reuptake transporters specifically in dopaminergic neurons regardless of SUD status or viral load, and additional transcriptional signatures consistent with selective vulnerability of SN dopamine neurons.

genomics↗

bioRxiv2024

Regulation of replication timing in Saccharomyces cerevisiae

In order to maintain genomic integrity, DNA replication must be highly coordinated. Disruptions in this process can cause replication stress which is aberrant in many pathologies including cancer. Despite this, little is known about the mechanisms governing the temporal regulation of DNA replication initiation, thought to be related to the limited copy number of firing factors. Here, we present a high (1-kilobase) resolution stochastic model of Saccharomyces cerevisiae whole-genome replication in which origins compete to associate with limited firing factors. After developing an algorithm to fit this model to replication timing data, we validated the model by reproducing experimental inter-origin distances, origin efficiencies, and replication fork directionality. This suggests the model accurately simulates the aspects of DNA replication most important for determining its dynamics. We also use the model to predict measures of DNA replication dynamics which are yet to be determined experimentally and investigate the potential impacts of variations in firing factor concentrations on DNA replication.

systems biology↗

bioRxiv2020

The clinical and molecular significance associated with STING signaling in estrogen receptor-positive early breast cancer

STING signaling in cancer is a crucial component of response to immunotherapy and other anti-cancer treatments. Conversely, STING signaling can promote tumor invasion and metastasis. Currently, there is no robust method of measuring STING activation in cancer. Here, we describe an immunohistochemistry-based assay with digital pathology assessment of STING in tumor cells. Using this novel approach, we identify perinuclear-localized expression of STING (pnSTING) in estrogen receptor-positive (ER+) breast cancer as an independent predictor of good prognosis, associated with immune cell infiltration and upregulation of immune checkpoints. Tumors with low pnSTING are immunosuppressed with increased infiltration of "M2" -polarised macrophages. In ER-disease, pnSTING does not have a significant prognostic role, and STING appears to be uncoupled from interferon responses. Importantly, a gene signature defining low pnSTING expression in ER+ disease is predictive of poor prognosis in independent datasets. Low pnSTING is associated with chromosomal instability, MYC amplification and mTOR signaling, suggesting novel therapeutic approaches for this subgroup.

cancer biology↗