Biology subjects

Jay, A.

Publications and source records attributed to Jay, A..

10 recordsLinked to original sources

bioRxiv2026

Population genomics of Candida albicans reveals genetic footprints that allow the prediction of antifungal resistance

Rapid detection of drug resistance in fungi is becoming increasingly urgent. While multiple loci and mutations were linked to antifungal resistance in Candida albicans, the utility of whole genome sequencing in predicting resistance has not been tested thoroughly. We address this by integrating more than 1000 C. albicans genomes, with associated resistance phenotypes to six antifungals, a curated repository of resistance-causing mutations and variant effect predictors. We used Genome Wide Association Studies and Machine Learning approaches to associate genetic variants to resistance phenotypes. We found that well curated databases like FungAMR are able to accurately identify markers predictive antifungal resistance. Curated mutations were detected in 56 to 74% of isolates with reduced azole susceptibility and 57 to 90% of those with reduced echinocandin susceptibility, revealing incomplete coverage of resistance across both drug classes. Complementary variant- and gene-level association analyses recovered established resistance determinants and uncovered additional candidate loci, whereas copy-number changes provided limited independent explanatory power. Genomic prediction declined when genetic backgrounds were absent from training, and when leading predictive features differed among backgrounds. We also found that models trained on a curated list of mutations and variant effect predictors performed well when classifying drug-susceptible strains, but the drug-resistance trait was predicted with lower accuracy. These findings support the potential of genome-based resistance prediction while highlighting the need for broader population sampling, functional validation of candidate variants and expanded resistance catalogues to improve prediction across genetic backgrounds.

microbiology↗

bioRxiv2025

Lineage-determining transcription factors constrain cohesin to drive multi-enhancer oncogene regulation

Multiple enhancers, often located across vast genomic distances, regulate key genes. However, how chromatin topology organization at individual alleles enables cell-type-restricted multi-enhancer gene regulation remains unclear. Using acute protein degradation and time-course population-average chromatin conformation capture in lymphoma, we found that the B-cell- lineage-determining transcription factor EBF1 preferentially positions multiple enhancers at loci containing sparsely distributed genes essential for B-cell identity and oncogenesis. Our time-resolved sub-diffraction optical chromatin architecture tracing of >100,000 alleles in individual lymphoma cells further revealed diverse topological conformations facilitating multi-enhancer interactions. Mechanistically, we found that positioning of enhancers at allelic topological centers is required for their interactions with target promoters, with EBF1 serving as a barrier to the loop-extruding cohesin on enhancers. These findings, which we demonstrate their generalizability to the T-cell-lineage-determining transcription factor TCF1 in T-cell leukemia, suggest that lineage-determining transcription factors radially position enhancers and promoters to enable multi-enhancer regulation of key oncogenes.

cancer biology↗

bioRxiv2025

OLIVE Provides Rapid Visualization and Analysis of Chromatin Tracing Experiments

Optical chromatin tracing experiments directly capture the three-dimensional folding of thousands of individual alleles, highlighting the need for a tool that enables fast, interactive, and analytical browsing of such data. Here, we introduce Optical Looping Interactive Viewing Engine (OLIVE), a web-based tool designed for high-throughput chromatin tracing data that functions similarly to genome browsers. OLIVE allows users, regardless of computational expertise, to input their own data for automated reconstruction of chromatin fibers at individual alleles or to browse annotated publicly available datasets. Using OLIVEs functionalities, users can interact with three-dimensional presentation of traced alleles and query them based on spatial features, including pairwise distances and perimeters between their segments. Finally, OLIVE calculates and presents several polymer physics metrics of each allele, providing quantitative summaries for hypothesis-driven studies. OLIVE is an open-source project accessible at https://faryabilab.github.io/chromatin-traces-vis/.

bioinformatics↗

bioRxiv2025

Single-Allele Chromatin Tracing Reveals Genomic Clustering of Paralogous Transcription Factors as a Mechanism for Developmental Robustness in T Cells

In metazoans, gene duplication has given rise to paralogous transcription factors, which have functionally diversified to control cellular differentiation. While the majority of paralogous TFs are dispersed across different chromosomes, some remain clustered raising the question of whether genomic proximity confers any evolutionary advantage for TF clusters. To address this, we investigated a [~]1 Mbp locus containing two ETS family paralogs, Ets1 and Fli1. Using a sub-diffraction sequential imaging technique called Optical Reconstruction of Chromatin Architecture (ORCA), we traced the 3D organization of this region in single alleles of T cells from genetically engineered mice with targeted deletions of key regulatory elements. In wild-type T cells, the predominant chromatin conformation spatially links Ets1 to its proximal super-enhancer, segregating Ets1 from Fli1. This topology correlates with high Ets1 and low Fli1 expression. Deletion of the Ets1 super-enhancer abolishes this configuration, triggering locus-wide architectural rewiring that increases Ets1-Fli1 promoter-promoter interactions and subsequently the co-expression of two genes within individual cells. Remarkably, this compensatory interaction bypasses insulated chromatin domains, sustaining Ets1 levels necessary for T cell development despite enhancer loss. Our results reveal that genomic clustering of TF paralogs enables dynamic architectural plasticity: while a super-enhancer fine-tunes paralog expression balance in wild-type contexts, its deletion unmasks latent promoter-driven coordination, suggesting that proximity safeguards functional redundancy and transcriptional resilience critical for cellular fitness.

genomics↗

bioRxiv2022

Humoral immunogenicity of a Coronavirus Disease 2019 (COVID-19) DNA Vaccine in Rhesus Macaques (Macaca mulatta) Delivered using Needle-free Jet Injection

A SARS-CoV-2 DNA vaccine targeting the spike protein and delivered by jet injection, nCOV-S(JET), previously shown to protect wild-type and immunosuppressed Syrian hamsters (Mesocricetus auratus), was evaluated via two needle-free delivery methods in rhesus macaques (Macaca mulatta). The methods included intramuscular delivery of 2 mg per vaccination with the PharmaJet Stratis device and intradermal delivery of 0.4 mg per vaccination with the PharmaJet Tropis device. We hypothesized that the nCOV-S(JET) vaccine would mount detectable neutralizing antibody responses when delivered by needle-free jet injection by either the intradermal or intramuscular route. When delivered intramuscularly, the vaccines elicited neutralizing and variant (Beta, Gamma, and Delta) cross-neutralizing antibodies against SARS-CoV-2 in all six animals after three vaccinations. When delivered at a lower dose by the intradermal route, strong neutralizing antibody responses were only detected in two of six animals. This study confirms that a vaccine previously shown to protect in a hamster model can elicit neutralizing and cross-neutralizing antibodies against SARS-CoV-2 in nonhuman primates. We posit that nCOV-S(JET) has the potential for use as booster vaccine in heterologous vaccination strategies against COVID-19.

immunology↗

bioRxiv2022

A SARS-CoV-2 Spike Ferritin Nanoparticle Vaccine is Protective and Promotes a Strong Immunological Response in the Cynomolgus Macaque Coronavirus Disease 2019 (COVID-19) Model

The COVID-19 pandemic has had a staggering impact on social, economic, and public health systems worldwide. Vaccine development and mobilization against SARS-CoV-2 (the etiologic agent of COVID-19) has been rapid. However, novel strategies are still necessary to slow the pandemic, and this includes new approaches to vaccine development and/or delivery, which improve vaccination compliance and demonstrate efficacy against emerging variants. Here we report on the immunogenicity and efficacy of a SARS-CoV-2 vaccine comprised of stabilized, pre-fusion Spike protein trimers displayed on a ferritin nanoparticle (SpFN) adjuvanted with either conventional aluminum hydroxide or the Army Liposomal Formulation QS-21 (ALFQ) in a cynomolgus macaque COVID-19 model. Vaccination resulted in robust cell-mediated and humoral responses and a significant reduction of lung lesions following SARS-CoV-2 infection. The strength of the immune response suggests that dose sparing through reduced or single dosing in primates may be possible with this vaccine. Overall, the data support further evaluation of SpFN as a SARS-CoV-2 protein-based vaccine candidate with attention to fractional dosing and schedule optimization.

microbiology↗

bioRxiv2022

Distribution and frequency of salivary gland tumours: an international multicenter study

BackgroundSalivary gland tumours (SGT) are a relatively rare group of neoplasms with a wide range of histopathological appearance and clinical features. To date, most of the epidemiological studies on salivary gland tumours are limited for a variety of reason including being out of date, extrapolated from either a single centre or country studies, or investigating either major or minor glands only. MethodsThis study aimed to mitigate these shortcomings by analysing epidemiological data including demographic, anatomical location and histological diagnoses of SGT from multiple centres across the world. The analysed data included age, gender, location and histological diagnosis from fifteen centres covering the majority of the world health organisation (WHO) geographical regions between 2006 and 2019. ResultsA total of 5798 cases were analysed including 65% benign and 35% malignant tumours. A slight female predilection (54%) and peak incidence between the fourth and seventh decade for both benign and malignant tumours was observed. The majority (69%) of the SGT presented in major and 31% in the minor glands. The parotid gland was the most common location (70%) for benign and minor glands (46%) for malignant tumours. Pleomorphic adenoma (70%), and Warthins tumour (17%), were the most common benign tumours whereas mucoepidermoid carcinoma (25%) and adenoid cystic carcinoma (16%) were the most frequent malignant tumours. ConclusionsThis multicentre investigation presents the largest cohort study to date analysing salivary gland tumour data from tertiary centres scattered across the globe. These findings should serve as a baseline for future studies evaluating the epidemiological landscape of these tumours.

pathology↗

bioRxiv2021

Aerosol Exposure of Cynomolgus Macaques to SARS-CoV-2 Results in More Severe Pathology than Existing Models

The emergence of SARS-CoV-2 pandemic has highlighted the need for animal models that faithfully recapitulate the salient features of COVID-19 disease in humans; these models are necessary for the rapid down-selection, testing, and evaluation of medical countermeasures. Here we performed a direct comparison of two distinct routes of SARS-CoV-2 exposure, combined intratracheal/intranasal and small particle aerosol, in two nonhuman primate species: rhesus and cynomolgus macaques. While all four experimental groups displayed very few outward clinical signs, evidence of mild to moderate respiratory disease was present on radiographs and at the time of necropsy. Cynomolgus macaques exposed via the aerosol route also developed the most consistent fever responses and had the most severe respiratory disease and pathology. This study demonstrates that while all four models were suitable representations of mild COVID-like illness, aerosol exposure of cynomolgus macaques to SARS-CoV-2 produced the most severe disease, which may provide additional clinical endpoints for evaluating therapeutics and vaccines.

microbiology↗

bioRxiv2020

Development of a Coronavirus Disease 2019 Nonhuman Primate Model Using Airborne Exposure

Airborne transmission is predicted to be a prevalent route of human exposure with SARS-CoV-2. Aside from African green monkeys, nonhuman primate models that replicate airborne transmission of SARS-CoV-2 have not been investigated. A comprehensive and comparative evaluation of COVID-19 in African green monkeys, rhesus macaques, and cynomolgus macaques following airborne exposure to SARS-CoV-2 was performed to define parameters critical to disease progression and the extent to which they correlate with human COVID-19. Respiratory abnormalities and viral shedding were noted for all animals, indicating successful infection. Cynomolgus macaques developed fever, and thrombocytopenia was measured for African green monkeys and rhesus macaques. Type II pneumocyte hyperplasia and alveolar fibrosis were more frequently observed in lung tissue from cynomolgus macaques and African green monkeys. The data indicate that, in addition to African green monkeys, macaques can be successfully infected by airborne SARS-CoV-2, providing viable macaque natural transmission models for medical countermeasure evaluation. One Sentence SummaryNonhuman primates develop COVID-19 following airborne virus exposure.

microbiology↗

bioRxiv2018

Interplay between the epigenetic enzyme lysine (K)-specific demethylase 2B and Epstein-Barr virus infection.

Histone modifier lysine (K)-specific demethylase 2B (KDM2B) plays a role in hematopoietic cells differentiation and its expression appears to be deregulated in certain cancers of hematological and lymphoid origins. We have previously found that KDM2B gene is differentially methylated in cell lines derived from the Epstein-Barr virus (EBV) associated endemic Burkitts lymphomas (eBL) compared to EBV negative sporadic BL cells. However, whether KDM2B plays a role in eBL development has never been previously demonstrated. Oncogenic viruses have been shown to hijack the host cell epigenome to complete their life cycle and to promote the transformation process by perturbing cell chromatin organization. Here we investigated whether EBV would alter KDM2B levels to enable its life cycle and promote B-cells transformation. We show that infection of B-cells with EBV leads to down-regulation of KDM2B levels. We also show that LMP1, one of the main EBV transforming proteins, induces increased DNMT1 recruitment to KDM2B gene and augments its methylation. By altering KDM2B levels and performing chromatin immunoprecipitation in EBV infected B-cells, we were able to show that KDM2B is recruited to the EBV gene promoters and inhibits their expression. Furthermore, forced KDM2B expression in immortalized B-cells led to altered mRNA levels of some differentiation-related genes. Our data show that EBV deregulates KDM2B levels through an epigenetic mechanism and provide evidence for a role of KDM2B in regulating virus and host cell gene expression, warranting further investigations to assess the role of KDM2B in the process of EBV-mediated lymphomagenesis.\n\nIMPORTANCE. In Africa, Epstein-Barr virus infection is associated with endemic Burkitt lymphoma, a pediatric cancer. The molecular events leading to its development are poorly understood compared to the sporadic Burkitt lymphoma. In a previous study, by analyzing the DNA methylation changes in endemic compared to sporadic Burkitt lymphomas cell lines, we identified several differential methylated genomic positions in proximity of genes with a potential role in cancer, among them the KDM2B gene. KDM2B encodes a histone H3 demethylase already shown to be involved in some hematological disorders. However, whether KDM2B plays a role in the development of Epstein-Barr virus-mediated lymphoma has never been investigated before. In this study we show that Epstein-Barr virus deregulates KDM2B expression and describe the underlying mechanisms. We also reveal a role of the demethylase in controlling viral and B-cells genes expression, thus highlighting a novel interaction between the virus and the cellular epigenome.

microbiology↗