Biology subjects

Sullivan, K.

Publications and source records attributed to Sullivan, K..

12 recordsLinked to original sources

bioRxiv2026

Inhibition of NLRP3 Differentially Regulates Blood Pressure and Inflammation in Male versus Female DOCA-Salt Sprague Dawley Rats

BackgroundDeoxycorticosterone acetate (DOCA)-salt induces greater increases in blood pressure (BP) and a more pro-inflammatory T cell profile in males compared to females. T cells contribute to DOCA-salt hypertension, however, the mechanisms driving T cell activation remain unclear. The NLRP3 inflammasome has been implicated in DOCA hypertension in male mice. Little is known regarding NLRP3 in females. The goal of the current study was to test the hypothesis that NLRP3 contributes to greater increases in BP and renal inflammation with DOCA in males vs. females. MethodsRenal NLRP3 protein levels were measured in normotensive and hypertensive male and female subjects and in male and female Sprague Dawley uni-nephrectomized (UNX) control and DOCA-salt rats. Additional 11-wk-old Sprague Dawley rats were UNX and randomized to: 1) DOCA + vehicle or 2) DOCA + the NLRP3 inhibitor MCC950 (10 mg/kg/day in saline) from 11-14 wks of age. At 14-wks-of-age rats were euthanized, terminal plasma samples and remaining kidneys were collected for flow cytometric analysis of T cells. ResultsRenal NLRP3 levels were significantly greater in hypertensive males and females vs. normotensive controls. DOCA increased BP in both sexes, with greater elevations in males. MCC950 attenuated DOCA-induced increases in BP in male, but not female rats. MCC950 decreased circulating and renal CD4 and Th17 cells in both sexes, although the effect was greater in males. ConclusionDespite both males and females exhibiting an increase in NLRP3 in hypertension, NLRP3 contributes to BP elevations only in DOCA-salt males.

physiology↗

bioRxiv2025

Transcriptomic study of WSSV infection in Litopenaeus vannamei lymphoid organ via single nuclei RNA sequencing

BackgroundAquaculture is the fastest growing farmed food sector and is a key part of global food security. Crustacean aquaculture, while being one of the most profitable sectors, is threatened by pathogenic diseases such as white spot disease (WSD), which results in severe stock losses and threatens animal health and welfare. In this study, we used novel techniques to study the impact of white spot syndrome virus (WSSV), the causative agent of WSD, on Pacific whiteleg shrimp (Litopenaeus vannamei), and uncover additional information that may be used in creating WSSV-resistant shrimp stocks. ResultsWe successfully developed a novel nuclei isolation protocol optimized for shrimp tissues to prepare our samples for single nuclei RNA-sequencing following a pathogen challenge comprising of 32 adult whiteleg shrimp infected with WSSV either through their feed or by injection. We constructed the first penaeid shrimp lymphoid organ cell atlas to improve our understanding of the characteristics of this immune organ, constructed the UMAPs and identified marker genes that define distinct cell clusters to reveal the biological functions of different cell types within this organ. ConclusionBy comparing gene expression between the control and WSSV-infected samples we uncovered multiple genes of interest that that have the potential to be used as targets for CRISPR gene editing for WSSV-resistance in Pacific whiteleg shrimp. These genes have the potential to be valuable assets for future gene editing studies in commercially important penaeid shrimp species. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=90 SRC="FIGDIR/small/693182v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1be071org.highwire.dtl.DTLVardef@2c3da6org.highwire.dtl.DTLVardef@835e67org.highwire.dtl.DTLVardef@aacff1_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2024

Metabolic vulnerabilities in Down syndrome B-cell acute lymphoblastic leukemia can be targeted using Venetoclax

Children with Down syndrome (DS) and B-cell acute lymphoblastic leukemia (B-ALL) are at increased risk for treatment-related mortality and relapse, highlighting the need for new therapies. Leukemia cell lines (CLs) have been fundamental to understanding therapeutic responses to pharmacological agents. We generated three DS B-ALL CLs characterized with diverse genomic alterations, including IGH::CRLF2 rearrangement (BCR::ABL1 like), mutations in FLT3 and TP53, and a novel ERG::CEBPD rearrangement. DS CLs had diminished proliferation, metabolism, and mitochondrial function when compared to non-DS (NDS) CLs and interestingly, these findings were similar to NDS Philadelphia chromosome-like (Ph-like) B-ALL CLs. Based on similar mitochondrial defects and prior preclinical data using Venetoclax for Ph-like B-ALL, we hypothesized that Venetoclax would be effective in DS. Intriguingly, Venetoclax was more effective in DS when compared to both NDS and Ph-like CLs. Efficacy was observed in DS patient derived xenografts (PDXs) and diagnostic/relapsed patient samples treated with Venetoclax, which synergized with Trametinib and Vincristine. Mass spectrometry-based multiomics analyses in DS and NDS B-ALL patient samples revealed an enriched metabolite profile in DS, particularly in the hubs of glucose metabolism and polyunsaturated phosphatidylcholines and phosphatidylinositols. Transcriptome analyses in DS B-ALL patients (n=249) supported enhanced glucose and fatty acid metabolism. Glucose regulated B-ALL viability through de novo serine biosynthesis. Targeting serine synergized with Venetoclax in DS B-ALL CLs. In summary, we have generated novel tools for studying DS B-ALL and identify altered metabolism in DS that responds to Venetoclax.

cancer biology↗

bioRxiv2024

Lower perceived stress enhances neural synchrony in perceptual and attentional cortices during naturalistic processing

Perceived stress is the subjective appraisal of the level of stress experienced by an individual in response to external or internal demands. Recent research on perceived stress has highlighted its role in influencing cognition, leading to a disruption in cognitive processes, such as emotional processing, attention, and perception. However, most neuroimaging studies examining stress have used static stimuli (e.g., still images) that do not encapsulate real-life multimodal processing in the brain. The current research uses data from the Naturalistic Neuroimaging Database (v2.0; Aliko et al., 2020) to examine differences in neural synchrony (as measured by intersubject correlations; ISCs) associated with perceived stress using functional magnetic resonance imaging (fMRI). We evaluated how self-reported perceived stress levels influence neural synchrony patterns in response to different naturalistic stimuli by examining the differences in neural synchrony between individuals with low and high perceived stress levels. We determined that lower perceived stress was observed with greater neural synchrony areas associated with perceptual and attention processing, including the lateral occipital cortex, superior temporal gyrus, superior parietal lobule, orbital frontal cortex, and the occipital pole. These results indicate that high levels of perceived stress heavily alter neural processing of complex audiovisual stimuli. Together, these results provide evidence that perceived stress influences cognitive processing in everyday life.

neuroscience↗

bioRxiv2024

Synergistic Cytotoxicity of Permethrin and N,N-Diethyl-Meta-Toluamide on Sinonasal Epithelial Cells

BackgroundN,N-Diethyl-Meta-Toluamide (DEET) and permethrin are pesticides commonly used in combination due to their synergistic insecticidal and repellent properties. This study investigates whether simultaneous exposure to these compounds elicits synergistic cytotoxicity in sinonasal epithelial cells (SNECs). Material and MethodsEthmoid sinus mucosal specimens were procured from eight patients during endoscopic sinus surgery. SNECs were expanded on culture plates and exposed to various concentrations of DEET and permethrin (0-5m), individually and concurrently, for up to 156 hours. Experiments were replicated in triplicates and cell viability was recorded every 2 hours using IncuCyte real-time cell imaging system. Synergy score was calculated on the basis of Loewe additivity synergy finder model. ResultsDEET and permethrin exhibited synergistic cytotoxicity across all eight tissues, albeit with variations in onset and magnitude. Peak synergy was observed at 144h for tissue 1 (SLoewe 4.2, 95% CI 1.8-7.3; [permethrin concentration, DEET concentration] [2.5M, 1.25M]), 48h for tissue 2 (19.9, 16.5-23.6; [1.25, 0.625]), 144h for tissue 3 (15.2, 3.9-30.4; [0.625, 1.25]), 144h for tissue 4 (6.4, -3.6 to 18.0; [0.625, 0.625]), 48h for tissue 5 (10.1, 8.9-12.5; [0.625, 1.25]), 96h for tissue 6 (24.7, 12.2-36.3; [0.625, 0.625]), 48h for tissue 7 (47.7, 29.6-62.2; [0.625, 1.25]), and 96h for 8 (47.4, 26.8-67.0; [0.625, 0.625]). ConclusionThe concurrent exposure of DEET and permethrin can lead to synergistic cytotoxicity in sinonasal epithelia. Further research is warranted in preclinical animal models to explore whether this synergy accelerates the pathogenesis of chronic rhinosinusitis.

pharmacology and toxicology↗

bioRxiv2024

Arc mediates intercellular synaptic plasticity via IRSp53-dependent extracellular vesicle biogenesis.

Current models of learning and memory have focused on cell-autonomous regulation of synaptic strength; however, intercellular signaling between cells in the brain is important for normal cognition. The immediate early gene Arc is a repurposed retrotransposon critical for long-term forms of synaptic plasticity and memory. Arc protein forms virus-like capsids released in extracellular vesicles (EVs) that mediate intercellular signaling of unknown function. Here, we find that long-term potentiation stimuli induce the biogenesis of Arc EVs by recruiting the I-BAR protein IRSp53, which facilitates Arc capsid assembly, trafficking, and release from actin-rich filopodial structures in dendrites. Arc EVs transfer Arc protein and mRNA to neighboring dendrites, where translation of transferred Arc mRNA induces a loss of surface AMPA-type glutamate receptors. These results show that Arc EVs mediate an intercellular form of synaptic plasticity that may be critical for memory consolidation and reveals a new neuronal EV biogenesis pathway.

neuroscience↗

bioRxiv2023

C5aR Expression in Kidney Tubules, Macrophages and Fibrosis

The anaphylatoxin C5a and its receptor C5aR (CD88) are complement pathway effectors implicated in renal diseases, including ANCA-associated vasculitis. We investigated the kidney expression of C5aR and a second C5a receptor C5L2 by using immunohistochemistry and in situ hybridization on formalin-fixed, paraffin-embedded human and mouse kidney. C5aR was detected on interstitial macrophages and in multiple tubular regions, both distal and proximal; C5L2 had a similar expression pattern. The 5/6 nephrectomy model of chronic kidney injury exhibited increased C5aR expression by infiltrating cells within the fibrotic regions. Functional assessment of myeloid C5aR in vitro revealed that C5a induced the expression of chemokines and remodeling factors by macrophages, including CCL-3/-4/-7,-20, MMP-1/-3/-8/-12, and F3, and promoted survival by blocking neutrophil apoptosis. C5a activity was C5aR dependent, as demonstrated by reversal with the C5aR inhibitor avacopan. Collectively, these results suggest that myeloid C5aR may induce excessive inflammation in the kidney via immune cell recruitment, extracellular matrix destruction, and remodeling, resulting in fibrotic tissue deposition.

immunology↗

bioRxiv2023

Psychological well-being modulates neural synchrony during naturalistic fMRI

Psychological well-being (PWB) is a combination of self-acceptance, life purpose, personal growth, positive relationships, and autonomy, and has a significant relationship with physical and mental health. Previous studies using resting-state functional magnetic resonance imaging (fMRI) and static picture stimuli have implicated the anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), orbitofrontal cortex (OFC), insula and thalamus in PWB, however, the replication of associations across studies is scarce, both in strength and direction, resulting in the absence of a model of how PWB impacts neurological processing. Naturalistic stimuli better encapsulate everyday experiences and can elicit more "true-to-life" neurological responses, and therefore may be a more appropriate tool to study PWB. The current study seeks to identify how differing levels of PWB modulate neural synchrony in response to an audiovisual film. With consideration of the inherent variability of the literature, we aim to ascertain the validity of the regions previously mentioned and their association with PWB. We identified that higher levels of PWB were associated with heightened neural synchrony in the bilateral OFC and left PCC, and that lower levels of PWB were associated with heightened neural synchrony in the right temporal parietal junction (TPJ) and left superior parietal lobule (SPL), regions related to narrative processing. Taken together, this research confirms the validity of several regions in association with PWB and suggests that varying levels of PWB produce differences in the processing of a narrative during complex audiovisual processing.

neuroscience↗

bioRxiv2023

Trait level somatic arousal modulates fMRI neural synchrony to naturalistic stimuli

Somatic arousal refers to the physiological and bodily responses that occur in reaction to different emotional and psychological stimuli and is a crucial component of the fight or flight response. Symptoms associated with higher levels of somatic arousal such as higher heart and respiration rates have been shown to impact the blood oxygenation level dependent (BOLD) signal during functional magnetic resonance imaging (fMRI) studies. Differences in baseline levels of somatic arousal may therefore modulate the brains response to incoming stimuli during fMRI. Previous studies typically investigate somatic arousal as a state, rather than as a trait, in which some individuals are more likely to have heightened physiological responses to psychological stimuli, causing the neurological mechanisms behind baseline somatic arousal levels to remain poorly understood. The current study seeks to identify how differing levels of baseline somatic arousal modulate neural synchrony in response to an audiovisual film. We hypothesize that individuals with higher levels of somatic arousal will show overall heightened neural synchrony in response to a complex audiovisual stimulus. We identified that higher levels of somatic arousal are associated with widespread neural synchrony across the brain, including frontal gyri, parietal and temporo-occipital cortices. Taken together, this research suggests that baseline somatic arousal levels should be measured during naturalistic fMRI paradigms, as baseline somatic arousal levels may have a profound influence on synchronous neural activity.

neuroscience↗

bioRxiv2023

Mapping the Changing Neural Architecture of Narrative Processing Using Naturalistic Stimuli: an fMRI Study

A narrative is a coherent representation of actual or fictional events designed to connect experiences. Narratives provide a unique opportunity to investigate brain functions in scenarios more closely resembling real-world experiences. However, most neuroimaging studies examining narrative formation have utilized static stimuli that fail to capture the intricacies of narrative construction in everyday life, particularly how cognitive demands change over the course of narrative processing. The current research uses functional magnetic resonance imaging (fMRI) to examine dynamic narrative processing over the course of a full-length audiovisual narrative. We examined changes in neural synchrony (as quantified by intersubject correlations) in areas related to semantic memory, episodic memory, and visuospatial attention between the beginning, middle, and end of the narrative. Results from two experiments identified two core narrative processing networks responsible for constructing coherent representations across extended timescales. The first network is associated with the early narrative construction, and includes the right intraparietal sulcus/superior parietal lobule, bilateral angular gyrus, bilateral precuneus, and left fusiform gyrus. The second network consists of the right ventral frontal cortex and bilateral parahippocampal cortices, and is associated with longer term narrative integration. Together, these regions provide the framework for successful narrative processing during naturalistic stimuli.

neuroscience↗

bioRxiv2022

Migration and division in cell monolayers on substrates with topological defect

Collective movement and organization of cell monolayers are important for wound healing and tissue development. Recent experiments highlighted the importance of liquid crystal order within these layers, suggesting that +1 topological defects have a role in organizing tissue morphogenesis. We study fibroblast organization, motion and proliferation on a substrate with micron-sized ridges that induce +1 and -1 topological defects using simulation and experiment. We model cells as selfpropelled deformable ellipses that interact via a Gay-Berne potential. Unlike earlier work on other cell types, we see that density variation near defects is not explained by collective migration. We propose instead that fibroblasts have different division rates depending on their area and aspect ratio. This model captures key features of our previous experiments: the alignment quality worsens at high cell density and, at the center of the +1 defects, cells can adopt either highly anisotropic or primarily isotropic morphologies. Experiments performed with different ridge heights confirm a new prediction of this model: suppressing migration across ridges promotes higher cell density at the +1 defect. Our work enables new mechanisms for tissue patterning using topological defects.

cell biology↗

bioRxiv2022

Animal-reliance bias in publishing is a potential barrier to scientific progress

Publication of scientific findings is fundamental for research, pushing innovation and generating interventions that benefit society, but it is not without biases. Publication bias is generally recognized as journals preference for publishing studies based on the direction and magnitude of results. However, early evidence of a newly recognized type of publication bias has emerged in which journal policy, peer reviewers, or editors request that animal data be provided to validate studies produced using nonanimal-based approaches. We describe herein "animal methods bias" in publishing: a preference for animal-based methods where they may not be necessary or where nonanimal-based methods may be suitable, which affects the likelihood of a manuscript being accepted for publication. To gather evidence of animal methods bias, we set out to collect the experiences and perceptions of scientists and reviewers related to animal- and nonanimal-based experiments during peer review. We created a survey with 33 questions that was completed by 90 respondents working in various biological fields. Twenty-one survey respondents indicated that they have carried out animal-based experiments for the sole purpose of anticipating reviewer requests. Thirty-one survey respondents indicated that they have been asked by peer reviewers to add animal experimental data to their nonanimal study; 14 of these felt the request was sometimes justified, and 11 did not think it was justified. The data presented provide preliminary evidence of animal methods bias and indicate that status quo and conservatism biases may explain such attitudes by peer reviewers and editors.

scientific communication and education↗