Biology subjects

Saad, E.

Publications and source records attributed to Saad, E..

4 recordsLinked to original sources

bioRxiv2024

Single-cell epigenetic profiling reveals an interferon response-high program associated with BAP1 deficiency in kidney cancer

Renal cell carcinoma (RCC) is characterized by recurrent somatic mutations in epigenetic regulators, which stratify patients into clinically significant subgroups with distinct prognoses and treatment responses. However, the cell type-specific epigenetic landscape of RCC--broadly and in the context of these mutations--is incompletely understood. To investigate these open questions, we integrated single nucleus ATAC sequencing data from RCC tumors across four independent cohorts. In clear cell RCC tumors, we identified four shared malignant epigenetic programs related to angiogenesis, proximal tubule-like features, interferon (IFN) signaling, and one that lacked distinct genomic regions with increased accessibility. Among the mutated epigenetic regulators, BAP1 mutation exhibited the most significant impact on chromatin accessibility in tumor cells, and the associated epigenetic changes were linked to IFN response. We identify multiple potential sources of elevated IFN signaling in these lesions, such as increased immune infiltration and increased accessibility and expression of an IFN-associated ERV, ERV3-16A3_LTR. We find that the expression of ERV3-16A3_LTR may itself be a negative prognostic biomarker in ccRCC. Our findings highlight the convergence of malignant epigenetic programs across ccRCC tumors and suggest that BAP1 loss, potentially through ERV3-16A3_LTR dysregulation, is associated with an IFN response-high epigenetic program.

cancer biology↗

bioRxiv2024

Concurrent maintenance of visual imagery and short-term memory provides evidence for their distinct representations

Recent research indicates there is overlap in the neural resources used during imagery and visual short-term memory. But do visual short-term memory and visual imagery operate on similar representations during recall? Here we investigated this question by asking participants to perform a delayed match to sample task for the contrast of visual gratings as cues. In the "Imagery" condition, participants were asked to form an accurate mental image of the visual cue, and at the end of the trial, perform a matching task on the mental image contrast. In the "Memory" condition, participants were not required to perform visual imagery but merely instructed to perform the delayed contrast-matching task. In Experiment 1, participants were told at the beginning of each block whether to engage in memory or imagery. The results showed that for the relevant contrast feature, matching judgments were more accurately in the "Memory" than in the "Imagery" condition. Thus imagery did not maintain an accurate representation of the encoded image, even when the visual features could still be maintained in visual short-term memory. In Experiment 2, participants were required to engage in memory and imagery simultaneously, and were told which to base their judgment on after each trial. The key finding was that the superior accuracy for memory over imagery remained, indicating that the contents of VSTM and imagery are based on distinct representations.

neuroscience↗

bioRxiv2023

Epigenomic signatures as circulating and predictive biomarkers in sarcomatoid renal cell carcinoma

Renal cell carcinoma with sarcomatoid differentiation (sRCC) is associated with poor survival and heightened response to immune checkpoint inhibitors (ICIs). Two major barriers to improving outcomes for sRCC are (1) a limited understanding of its gene regulatory programs and (2) difficulty identifying sarcomatoid differentiation on tumor biopsies due to spatial heterogeneity. To address these challenges, we characterized the epigenomic landscape of sRCC by profiling 107 epigenomic libraries in tissue and plasma samples from 50 patients with RCC and healthy volunteers. We identified highly recurrent epigenomic reprogramming, as assessed by histone modifications and DNA methylation, that distinguishes sRCC from non-sarcomatoid RCC. Computational analysis of RCC epigenomic profiles and CRISPRa experiments implicated the transcription factor FOSL1 in activating sRCC-associated gene regulatory programs. Analysis of two randomized clinical trials identified FOSL1 expression as a predictive biomarker of response to ICIs in RCC. Finally, we demonstrate that epigenomic signatures of sRCC are detectable in patient plasma, establishing an approach for blood-based diagnosis of this clinically important phenotype. These findings provide a framework for the discovery and non-invasive detection of epigenomic correlates of tumor histology via liquid biopsy.

genomics↗

bioRxiv2021

Reemergence of yellow fever virus in southeastern Brazil, 2017-2018: what sparked the spread?

BackgroundThe 2017-2018 yellow fever virus (YFV) outbreak in southeastern Brazil marked a reemergence of YFV in urban states that had been YFV free for nearly a century. Unlike earlier urban YFV transmission, this epidemic was also driven by forest mosquitos. The objective of this study was to evaluate environmental drivers of this outbreak. Methodology/Principal FindingsUsing surveillance data from the Brazilian Ministry of Health of human and non-human primate (NHP) cases of yellow fever, we traced the spatiotemporal progression of the outbreak. We then assessed the epidemic timing in relation to drought using a monthly Standardized Precipitation Evapotranspiration Index (SPEI). Lastly, we evaluated demographic risk factors for rural or outdoor exposure amongst YFV cases. Both human and NHP cases were first identified in a hot, dry, rural area in northern Minas Gerais before spreading southeast into the more cool, wet urban states of Espirito Santo, Sao Paulo, and Rio de Janeiro. Outbreaks also coincided with drought in all four southeastern states of Brazil. Confirmed YFV cases had an increased odds of being male (OR 2.58; 95% CI 2.28-2.92), working age (OR: 2.03; 95% CI: 1.76-2.35), and reporting recent travel from an urban to a rural area (OR: 5.02; 95% CI: 3.76-6.69). Conclusions/SignificanceThe 2017-2018 YFV epidemic in Brazil originated in hot, dry rural areas of Minas Gerais before expanding south into urban centers. An unusually severe drought in this region may have created environmental pressures that sparked the reemergence of YFV in Brazils southeastern cities. Author SummaryIn 2017-2018, cities in southeastern Brazil experienced an unusual outbreak of yellow fever virus. In the early 20th century, these cities had large outbreaks of yellow fever, spread by Aedes mosquitos. But until this recent outbreak, they had been free of yellow fever for nearly a century. While this outbreak was spread by Haemagogous forest mosquitos, the reemergence of yellow fever in densely populated urban areas raises serious concerns about it reestablishing ongoing transmission in cities, spread by urban Aedes mosquitos. Our study sought to understand how and why yellow fever virus remerged in this area. We traced the outbreak, finding that it started in hot, dry, rural areas and spread south into cool, wet urban areas. Additionally, the outbreak coincided with a severe drought; this extreme weather may have promoted the spread of yellow fever. Infection was also associated with rural and outdoor exposure, further suggesting this epidemic originated in rural areas.

ecology↗