Biology subjects

Thompson, E. A.

Publications and source records attributed to Thompson, E. A..

11 recordsLinked to original sources

bioRxiv2026

Spatial Logic Reconciles Gene-signature Methods in Triple Negative Breast Cancer

Triple-Negative Breast Cancer (TNBC) presents a significant clinical challenge due to its heterogeneity and lack of targeted treatment options, with chemotherapy and immunotherapy combinations currently serving as the main therapeutic strategy. Efforts to address TNBC heterogeneity have largely focused on classifying intrinsic cancer subtypes based on differential tumor mRNA expression, a strategy that has proven effective in hormone receptor-positive breast cancers but has yet to yield a clinically useful predictor of survival or treatment response in TNBC. We hypothesize that both the intrinsic characteristics of TNBC and the surrounding immune microenvironment influence treatment outcomes and that immune cell infiltration affects TNBC subtype classification and response variability. To explore this hypothesis, we compared the predictive and prognostic capabilities of cancer subtype-based (TNBC-type) gene signatures and immune cell deconvolution methods (CIBERSORT) within the same TNBC datasets. We found that immune cell abundance outperformed TNBC subtype-signatures and multicellular immune cell aggregates showed the highest performance of all. More specifically, aggregate immune cells associated with tertiary lymphoid structures and tumor associated macrophages/monocytes demonstrated statistically significant predictive value. These findings were confirmed in an independent cohort of 67 TNBC patients treated with neoadjuvant chemotherapy. Further, single-cell RNA sequencing analysis revealed that the predictive power of cancer-subtype could be partially explained by immune- and stromal features. Examination of single-cell resolution spatial transcriptomic data confirmed presence of TLS-like, TAM- and cancer-stromal niches within TNBC biopsy samples that were associated with treatment response. Overall, our results highlight that immune cell aggregates, which capture the spatial organization of the TME, outperform cell-type specific gene signatures in predicting TNBC outcomes. Our novel approach provides a robust framework for interpreting spatial relationships in bulk RNA-seq data, offering a pathway for reconciling past data with current advancements in spatial profiling technologies. This work paves the way for future studies to leverage the multi-cellular complexity of TNBC, enhancing diagnostic precision and facilitating the development of therapies that strategically modulate the tumor microenvironment for improved anti-cancer responses.

cancer biology↗

bioRxiv2025

Mechanisms of sex differences in acute and long COVID sequelae in mice

Males are more likely to suffer severe outcomes during acute COVID-19 and a greater proportion of females develop post-acute sequalae of COVID-19 (PASC). To identify mechanisms of PASC, mice were infected with SARS-CoV-2 and viral, inflammatory, and neurocognitive outcomes were evaluated through 84 days post-infection. Sex differences were not observed in virus replication or persistence of viral RNA in pulmonary or extrapulmonary tissues. After infectious virus clearance, females exhibited persistent neurocognitive impairments, and greater frequencies of inflammatory myeloid cells, neuroinflammation, and dysregulated T cells, including effector memory and Tregs. Sex differences in persistent inflammation and cognitive impairments during PASC were mediated by the presence of two X chromosomes and infection-induced upregulation of the X-linked genes Xist and Tlr7, which was reversed by pharmacological inhibition of TLR7 activity during the PASC phase. Sustained X-linked TLR7-mediated inflammation underlies how the burden of PASC is greater for females and provides a therapeutic target.

immunology↗

bioRxiv2025

Single-cell multiomics identifies both shared and unique features of immune dysfunction in the colon, plasma and stool from individuals diagnosed with Parkinson's disease or inflammatory bowel disease

Parkinsons disease (PD) is the fastest growing neurodegenerative disease in the world1. Gastrointestinal (GI) dysfunction can occur decades before motor impairments and in up to 80% of individuals living with PD2,3,4. We investigated peripheral relationships that may underlie mechanisms along the gut-blood axis that contribute to PD pathogenesis. Single-cell multiomic spatial molecular imaging (SMI) of colonic tissue localized inflammatory injury within epithelial cells that appear to be associated with iron mishandling in both inflammatory bowel disease (IBD) and PD biosamples. We found that both the single-cell SMI of RNA and protein revealed parallel cross-modal dysregulation in the gut epithelium, in both IBD and PD biosamples. These data are accompanied by plasma (PD) and stool (IBD) protein depletion of CCL22. Our findings suggest iron mishandling along the gut barrier likely contributes to systemic inflammation, which may be the catalyst that primes circulating immune cells to body-first PD pathogenesis.

neuroscience↗

bioRxiv2024

Fast simulation of identity-by-descent segments

The worst-case runtime complexity to simulate haplotype segments identical by descent (IBD) is quadratic in sample size. We propose two main techniques to reduce the compute time, both of which are motivated by coalescent and recombination processes. We provide mathematical results that explain why our algorithm should outperform a naive implementation with high probability. In our experiments, we observe average compute times to simulate detectable IBD segments around a locus that scale approximately linearly in sample size and take a couple of seconds for sample sizes that are less than ten thousand diploid individuals. In contrast, we find that existing methods to simulate IBD segments take minutes to hours for sample sizes exceeding a few thousand diploid individuals. When using IBD segments to study recent positive selection around a locus, our efficient simulation algorithm makes feasible statistical inferences, e.g., parametric bootstrapping in analyses of large biobanks, that would be otherwise intractable.

genetics↗

bioRxiv2024

Identity-by-descent in large samples

If two haplotypes share the same alleles for an extended gene tract, these haplotypes are likely to be derived identical-by-descent from a recent common ancestor. Identity-by-descent segment lengths are correlated via unobserved ancestral tree and recombination processes, which commonly presents challenges to the derivation of theoretical results in population genetics. We show that the proportion of detectable identity-by-descent segments around a locus is normally distributed when the sample size and the scaled population size are large. We generalize this central limit theorem to cover flexible demographic scenarios, multi-way identity-by-descent segments, and multivariate identity-by-descent rates. We use efficient simulations to study the distributional behavior of the detectable identity-by-descent rate. One consequence of non-normality in finite samples is that a genome-wide scan looking for excess identity-by-descent rates may be subject to anti-conservative control of family-wise error rates. HighlightsO_LIWe show the asymptotic normality of the detectable identity-by-descent rate, a mean of correlated binary random variables that arises in population genetics studies. C_LIO_LIWe generalize our main central limit theorem to cover scenarios of nonconstant population sizes, multi-way identity-by-descent segments, and identity-by-descent rates of multiple samples from the same population. C_LIO_LIIn enormous simulation studies, we use an efficient algorithm to characterize distributional properties of the detectable identity-by-descent rate. C_LI

genetics↗

bioRxiv2021

Persistent CAD activity in memory CD8+ T cells supports rRNA synthesis and ribosomal biogenesis required at rechallenge

Memory CD8+ T cells are characterized by their ability to persist long after the initial antigen encounter and their ability to generate a rapid recall response. Recent studies have identified a role for metabolic reprogramming and mitochondrial function in promoting the longevity of memory T cells. However, detailed mechanisms involved in promoting the rapid recall response are incompletely understood. Here we identify a novel role for the initial and continued activation of the trifunctional rate-limiting enzyme of the de novo pyrimidine synthesis pathway CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase) as critical in promoting the rapid recall response of previously-activated CD8+ T cells. CAD is rapidly phosphorylated upon T cell activation in an mTORC1-dependent manner yet remains phosphorylated long after initial activation. Previously-activated CD8+ T cells display continued de novo pyrimidine synthesis in the absence of mitogenic signals and interfering with this pathway diminishes the speed and magnitude of cytokine production upon rechallenge. Inhibition of CAD does not affect cytokine transcript levels, but diminishes available pre-rRNA, the polycistronic rRNA precursor whose synthesis is the rate-limiting step in ribosomal biogenesis. CAD inhibition additionally decreases levels of detectable ribosomal proteins in previously-activated CD8+ T cells. Overexpression of CAD improves both the cytokine response and proliferation of memory T cells. Overall, our studies reveal a novel and critical role for CAD-induced pyrimidine synthesis and ribosomal biogenesis in promoting the rapid recall response characteristic of memory T cells. One Sentence SummaryPyrimidine synthesis fuels ribosomal biogenesis to facilitate rapid recall responses in CD8+ T cells

immunology↗

bioRxiv2021

Comparing Heritability Estimators under Alternative Structures of Linkage Disequilibrium

SNP heritability of a trait is the proportion of its variance explained by the additive effects of the genome-wide single nucleotide polymorphisms (SNPs). The existing approaches to estimate SNP heritability can be broadly classified into two categories. One set of approaches model the SNP effects as fixed effects and the other treats the SNP effects as random effects. These methods make certain assumptions about the dependency among individuals (familial relationship) as well as the dependency among markers (linkage disequilibrium, LD) to provide consistent estimates of SNP heritability as the number of individuals increases. While various approaches have been proposed to account for such dependencies, it remains unclear which estimates reported in the literature are more robust against various model mis-specifications. Here we investigate the impact of different structures of LD and familial relatedness on heritability estimation. We show that the performance of different methods for heritability estimation depends heavily on the structure of the underlying pattern of LD and the degree of relatedness among sampled individuals. However, contrary to the claim in the current literature, we did not find significant differences in the performance of these fixed-SNP-effects and random-SNP-effects approaches. Moreover, we established the equivalence between the two method-of-moments estimators, one from each of these two lines of approaches.

genetics↗

bioRxiv2021

Sulforaphane exhibits in vitro and in vivo antiviral activity against pandemic SARS-CoV-2 and seasonal HCoV-OC43 coronaviruses

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), has incited a global health crisis. Currently, there are no orally available medications for prophylaxis for those exposed to SARS-CoV-2 and limited therapeutic options for those who develop COVID-19. We evaluated the antiviral activity of sulforaphane (SFN), a naturally occurring, orally available, well-tolerated, nutritional supplement present in high concentrations in cruciferous vegetables with limited side effects. SFN inhibited in vitro replication of four strains of SARS-CoV-2 as well as that of the seasonal coronavirus HCoV-OC43. Further, SFN and remdesivir interacted synergistically to inhibit coronavirus infection in vitro. Prophylactic administration of SFN to K18-hACE2 mice prior to intranasal SARS-CoV-2 infection significantly decreased the viral load in the lungs and upper respiratory tract and reduced lung injury and pulmonary pathology compared to untreated infected mice. SFN treatment diminished immune cell activation in the lungs, including significantly lower recruitment of myeloid cells and a reduction in T cell activation and cytokine production. Our results suggest that SFN is a promising treatment for prevention of coronavirus infection or treatment of early disease.

microbiology↗

bioRxiv2019

Impact of RNA Extraction and Target Capture Methods on RNA Sequencing Using Formalin-Fixed, Paraffin Embedded Tissues

Formalin fixed paraffin embedded (FFPE) tissues are commonly used biospecimen for clinical diagnosis. However, RNA degradation is extensive when isolated from FFPE blocks making it challenging for whole transcriptome profiling (RNA-seq). Here, we examined RNA isolation methods, quality metrics, and the performance of RNA-seq using different approaches with RNA isolated from FFPE and fresh frozen (FF) tissues. We evaluated FFPE RNA extraction methods using six different tissues and five different methods. The reproducibility and quality of the prepared libraries from these RNAs were assessed by RNA-seq. We next examined the performance and reproducibility of RNA-seq for gene expression profiling with FFPE and FF samples using targeted (Kinome capture) and whole transcriptome capture based sequencing. Finally, we assessed Agilent SureSelect All-Exon V6+UTR capture and the Illumina TruSeq RNA Access protocols for their ability to detect known gene fusions in FFPE RNA samples. Although the overall yield of RNA varied among extraction methods, gene expression profiles generated by RNA-seq were highly correlated (>90%) when the input RNA was of sufficient quality ([≥]DV200 30%) and quantity ([≥] 100 ng). Using gene capture, we observed a linear relationship between gene expression levels for shared genes that were captured using either All-Exon or Kinome kits. Gene expression correlations between the two capture-based approaches were similar using RNA from FFPE and FF samples. However, TruSeq RNA Access protocol provided significantly higher exon and junction reads when compared to the SureSelect All-Exon capture kit and was more sensitive for fusion gene detection. Our study established pre and post library construction QC parameters that are essential to reproducible RNA-seq profiling using FFPE samples. We show that gene capture based NGS sequencing is an efficient and highly reproducible strategy for gene expression measurements as well as fusion gene detection.

genomics↗

bioRxiv2018

The Epistasis Boundary: Linear vs. Nonlinear Genotype-Phenotype Relationships

Nonlinearity in the genotype-phenotype relationship can take the form of dominance, epistasis, or gene-environment interaction. The importance of nonlinearity, especially epistasis, in real complex traits is controversial. Network models in systems biology are typically highly nonlinear, yet the predictive power of linear quantitative genetic models is rarely improved by addition of nonlinear terms, and association studies detect few strong gene-gene interactions. We find that complex traits satisfying certain conditions can be well represented by a linear genetic model on an appropriate scale despite underlying biological complexity. Recent mathematical results in separability theory determine these conditions, which correspond to three biological criteria (Directional Consistency, Environmental Compensability, and Pathway Redundancy) together making up an Epistatic Boundary between systems suitable and unsuitable for linear modeling. For nonlinear traits, we introduce a classification of types of nonlinearity from a systems perspective, and use this to illustrate how upstream controlling genes, potentially more important to explaining biological function, can be intrinsically harder to detect by GWAS than their downstream controlled counterparts.

genomics↗

bioRxiv2018

The Viral protein Corona Directs Viral Pathogenesis and Amyloid Aggregation

Artificial nanoparticles accumulate a protein corona layer in biological fluids, which significantly influences their bioactivity. As nanosized obligate intracellular parasites, viruses share many biophysical properties with artificial nanoparticles in extracellular environments and here we show that respiratory syncytial virus (RSV) and herpes simplex virus 1 (HSV-1) accumulate a rich and distinctive protein corona in different biological fluids. Moreover, we show that corona pre-coating differentially affects viral infectivity and immune cell activation. Additionally, we demonstrate that viruses bind amyloidogenic peptides in their corona and catalyze amyloid formation via surface-assisted heterogeneous nucleation. Importantly, we show that HSV-1 catalyzes the aggregation of the amyloid beta peptide (A{beta}42), a major constituent of amyloid plaques in Alzheimers disease, in-vitro and in animal models. Our results highlight the viral protein corona as an acquired structural layer that is critical for viral-host interactions and illustrate a mechanistic convergence between viral and amyloid pathologies.

microbiology↗