Biology subjects

McQueen, P.

Publications and source records attributed to McQueen, P..

6 recordsLinked to original sources

bioRxiv2026

Non-homologous end-joining is implicated in rapid and efficient caspofungin adaptation in Nakaseomyces glabratus

Antifungal resistance in Nakaseomyces glabratus is a major clinical challenge, yet the cellular processes that shape its evolution remain poorly understood. Here, we used experimental evolution to investigate the role of the error-prone double-strand break repair pathway, non-homologous end joining (NHEJ), in adaptation to fluconazole and caspofungin. Wild-type and NHEJ-deficient (lig4{Delta}) populations were evolved under antifungal selection for 25 days. Fluconazole resistance emerged rapidly in both genetic backgrounds and was associated with recurrent PDR1 mutations and aneuploidies. In contrast, caspofungin adaptation was delayed and less efficient in lig4{Delta} populations, with several lineages failing to survive. All wild-type caspofungin-evolved isolates carried canonical FKS2 hotspot mutations, whereas lig4{Delta} isolates predominantly acquired resistance through alternative genetic pathways. Caspofungin adaptation also frequently conferred cross-resistance to fluconazole and was accompanied by changes in the abundance of ergosterol-associated proteins. Together, these findings implicate NHEJ in promoting efficient evolution of FKS-mediated echinocandin resistance and demonstrate that DNA repair capacity can shape antifungal resistance trajectories in N. glabratus.

microbiology↗

bioRxiv2026

Characterization of Atypical Ebola Virus Disease in Ferrets

Ebola virus (EBOV) typically results in a severe--and often lethal--acute disease. However, increasing evidence suggests that EBOV can persist in certain immune-privileged tissues, which may then serve as reservoirs for the later reemergence of EBOV and disease recrudescence. Here, we report atypical EVD recrudescence in a ferret model inoculated with an otherwise lethal dose of EBOV and treated with low doses of a highly potent monoclonal antibody cocktail. Among 32 antibody-treated ferrets, 14 animals survived, while 8 succumbed to acute EVD within about 5-8 days. The remaining 10 animals succumbed to atypical EVD between 12 and 18 days post-infection (DPI) despite having shown no, or very minor, signs of illness during the acute phase of disease. While viremia disappeared by 14 DPI in most animals that succumbed to atypical EVD, it rebounded modestly just prior to death. Unlike animals that died of acute EVD, those that died of atypical EVD showed only a moderate systemic inflammatory response and few signs of organ dysfunction, in line with low levels of virus in the liver and spleen. Interestingly, however, ferrets that died of atypical EVD showed high levels of virus in the brain, consistent with increased markers of inflammation in the central nervous system and significant pathological changes, including a breakdown in the blood-brain barrier and severe meningoencephalitis. Not only does this study shed important light on the atypical and underappreciated manifestations of EVD, but it also establishes the ferret as a valuable model of EBOV persistence and recrudescence. AUTHOR SUMMARYOver the last several years, it has become increasingly apparent that Ebola virus is capable of persisting in survivors and, occasionally, reemerging to cause a recrudescent disease that is often distinct from the acute illness and characterized by neurological involvement. Since nearly all existing Ebola virus animal models are uniformly lethal, it has been difficult to understand the processes that lead to persistence and atypical manifestations of disease. In this study, we describe a late-onset, atypical Ebola virus disease in ferrets that was characterized by high levels of virus in the brain and significant markers of brain inflammation. Our comprehensive analysis of the pathogenic processes that contributed to this disease not only provides critical insight into Ebola virus persistence and recrudescence, but it also establishes the ferret as the first tractable model for investigating these atypical outcomes.

microbiology↗

bioRxiv2024

A role for the putative error-prone polymerase REV1 in DNA damage and antifungal drug resistance in Candida albicans

Antimicrobial-induced DNA damage, and subsequent repair via upregulation of DNA repair factors, including error-prone translesion polymerases, can lead to the increased accumulation of mutations in the microbial genome, and ultimately increased risk of acquired mutations associated with antimicrobial resistance. While this phenotype is well described in bacterial species, it is less thoroughly investigated amongst microbial fungi. Here, we monitor DNA damage induced by antifungal agents in the fungal pathogen Candida albicans, and find that commonly used antifungal drugs are able to induce DNA damage, leading to the upregulation of transcripts encoding predicted error-prone polymerases and related factors. We focus on REV1, encoding a putative error-prone polymerase, and find that while deleting this gene in C. albicans leads to increased sensitivity to DNA damage, it also unexpectedly renders cells more likely to incur mutations and evolve resistance to antifungal agents. We further find that deletion of REV1 leads to a significant depletion in the uncharacterized protein Shm1, which itself plays a role in fungal mutagenesis. Together, this work lends new insight into previously uncharacterized factors with important roles in the DNA damage response, mutagenesis, and the evolution of antifungal drug resistance.

microbiology↗

bioRxiv2023

Generating human neural diversity with a multiplexed morphogen screen in organoids

Morphogens choreograph the generation of remarkable cellular diversity in the developing nervous system. Differentiation of stem cells toward particular neural cell fates in vitro often relies upon combinatorial modulation of these signaling pathways. However, the lack of a systematic approach to understand morphogen-directed differentiation has precluded the generation of many neural cell populations, and knowledge of the general principles of regional specification remain in-complete. Here, we developed an arrayed screen of 14 morphogen modulators in human neural organoids cultured for over 70 days. Leveraging advances in multiplexed RNA sequencing technology and annotated single cell references of the human fetal brain we discovered that this screening approach generated considerable regional and cell type diversity across the neural axis. By deconvoluting morphogen-cell type relationships, we extracted design principles of brain region specification, including critical morphogen timing windows and combinatorics yielding an array of neurons with distinct neuro-transmitter identities. Tuning GABAergic neural subtype diversity unexpectedly led to the derivation of primate-specific interneurons. Taken together, this serves as a platform towards an in vitro morphogen atlas of human neural cell differentiation that will bring insights into human development, evolution, and disease.

neuroscience↗

bioRxiv2023

β-carotene accelerates resolution of atherosclerosis by promoting regulatory T cell expansion in the atherosclerotic lesion

{beta}-carotene oxygenase 1 (BCO1) catalyzes the cleavage of {beta}-carotene to form vitamin A. Besides its role in vision, vitamin A regulates the expression of genes involved in lipid metabolism and immune cell differentiation. BCO1 activity is associated with the reduction of plasma cholesterol in humans and mice, while dietary {beta}-carotene reduces hepatic lipid secretion and delays atherosclerosis progression in various experimental models. Here we show that {beta}-carotene also accelerates atherosclerosis resolution in two independent murine models, independently of changes in body weight gain or plasma lipid profile. Experiments in Bco1-/- mice implicate vitamin A production in the effects of {beta}-carotene on atherosclerosis resolution. To explore the direct implication of dietary {beta}-carotene on regulatory T cells (Tregs) differentiation, we utilized anti-CD25 monoclonal antibody infusions. Our data show that {beta}-carotene favors Treg expansion in the plaque, and that the partial inhibition of Tregs mitigates the effect of {beta}-carotene on atherosclerosis resolution. Our data highlight the potential of {beta}-carotene and BCO1 activity in the resolution of atherosclerotic cardiovascular disease.

immunology↗

bioRxiv2019

Abl signaling shapes the intrinsic fluctuations of actin to direct growth of a pioneer axon in Drosophila

The fundamental problem in axon growth and guidance is to understand how cytoplasmic signaling modulates the cytoskeleton to produce directed growth cone motility. We show here that the TSM1 pioneer axon of Drosophila extends by using Abl tyrosine kinase to shape the intrinsic fluctuations of a mass of accumulated actin in the distal axon. The actin mass fluctuates stochastically in length, but with a small, forward bias that drives the axon along its trajectory by promoting emergence of protrusions in leading intervals where actin accumulates, and collapse of protrusions in lagging intervals that actin has vacated. The actin mass is sculpted by Abl signaling, which probabilistically modulates its key parameters - its width and internal disorder - to drive its advance, while maintaining internal coherence. Comparison of TSM1 to other systems suggests that the mechanism we demonstrate here is apt to be common among pioneer axons in many organisms.

cell biology↗