Biology subjects

Dickinson, S.

Publications and source records attributed to Dickinson, S..

4 recordsLinked to original sources

bioRxiv2025

THC Reverses SIV-Induced Senescence in Astrocytes: Possible Compensatory Mechanism Against HIV Associated Brain Injury?

Despite effective combination antiretroviral therapy (cART), chronic neuroinflammation and glial dysfunction continues to be an important yet understudied issue with people living with HIV (PLWH). The endocannabinoid system is increasingly recognized as a potential therapeutic target for modulating neuroimmune environments, given its role in regulating synaptic plasticity, immune responses, and neuroinflammatory cascades. However, the extent to which cannabinoids influence HIV-associated neuroinflammation remains unclear. This study investigates the impact of {Delta}9-tetrahydrocannabinol (THC) on astrocyte growth characteristics, viability, and senescence-associated cytokine release following exposure to HIV Tat protein using primary mixed glial cultures derived from rhesus macaques. Real-time impedance-based cellular integrity assessments were conducted using the xCELLigence system, while morphological analyses and cytokine quantification were performed using phase-contrast microscopy and multiplex immunoassays. Treatment of macaques with THC protected the astrocytes from virus-induced senescence. Further, THC facilitated a rapid recovery from Tat-induced decline in astrocyte adhesion, suggesting a compensatory effect. THC promoted glial process elongation and morphological complexity, indicative of a shift toward a neuroprotective phenotype. Furthermore, THC significantly reduced inflammatory cytokine secretion, including TNF-, IL-6, and IL-1{beta}, in an apparently dose-dependent manner. These findings suggest that THC may modulate neuroinflammation in PLWH by promoting astrocytic survival, suppressing inflammatory cytokine secretion, and enhancing neurotrophic signaling. However, prolonged exposure to high-dose THC may negatively impact glial survival. The results underscore the complexity of cannabinoid signaling in the CNS and highlight the potential of cannabinoid-based interventions to mitigate HIV-associated neuroinflammation.

neuroscience↗

bioRxiv2025

Improving Statistical Rigor in Animal Aging Research by Addressing Clustering and Nesting Effects: Illustration with the National Institute on Aging's Intervention Testing Program Data

Clustering effects, such as those introduced by housing animals in shared cages, are often overlooked in preclinical lifespan studies, despite their potential to distort variance estimates and inflate Type I error rates, leading to misleading conclusions. This methodological oversight reduces statistical rigor and may undermine the reliability of findings. To address this gap, the current study examines the impact of accounting for clustering and nesting effects on lifespan analyses by comparing the results of statistical models which both account for and ignore these effects. Using 2019 data from the Interventions Testing Program (ITP), a large-scale initiative evaluating the effects of compounds on lifespan in UM-HET3 mice as a case study, we illustrate how different modeling approaches influence statistical estimates and conclusions. Clustering and nesting effects were addressed using linear mixed effects, and Cox frailty models, both of which explicitly account for cage-level dependencies and different levels of data nesting. Comparisons were made between unadjusted lifespan analyses and those incorporating clustering and nesting adjustments. The results of this case study indicate that properly adjusting for clustering and nesting effects can change the conclusions drawn from statistical significance tests as compared to unadjusted model approaches, and so it remains best practice to properly account for clustering and nesting to reduce the potential for inflated Type I error rates. These findings highlight the importance of accounting for clustering and nesting in preclinical research to ensure valid and robust statistical inference. By demonstrating the practical application of clustering adjustments, this work underscores the broader implications for improving reproducibility and rigor in lifespan studies and other experimental designs.

systems biology↗

bioRxiv2021

A Reevaluation of the Effect of Dietary Restriction on Different Recombinant Inbred (RI) Lines of Male and Female Mice

Dietary restriction (DR) was reported to either have no effect or reduced the lifespan of the majority of the 41-recombinant inbred (RI)-lines studied (Liao et al., 2010). In an appropriately power longevity study (n > 30 mice/group), we measured the lifespan of the four RI-lines (115-RI, 97-RI, 98-RI, and 107-RI) that were reported to have the greatest decrease in lifespan when fed 40% DR. DR increased the median lifespan of female and male 115-RI mice and female 97-RI and 107-RI mice. DR had little effect (less than 4%) on the median lifespan of female and male 98-RI mice and male 97-RI mice and reduced the lifespan of male 107-RI mice over 20%. While our study was unable to replicate the effect of DR on the lifespan of the RI-mice (except male 107-RI mice) reported by Liao et al. (2010), we found that the genotype of a mouse had a major impact on the effect of DR on lifespan, with the effect of DR ranging from a 50% increase to a 22% decrease. No correlation was observed between the changes in either body composition or glucose tolerance induced by DR and the changes observed in lifespan of the four RI-lines of male and female mice. These four RI-lines of mice give the research community a unique resource where investigators for the first time can study the anti-aging mechanism of DR by comparing mice in which DR increases lifespan to mice where DR has either no effect or reduces lifespan. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/449984v1_ufig1.gif" ALT="Figure 1"> View larger version (11K): org.highwire.dtl.DTLVardef@1a11d22org.highwire.dtl.DTLVardef@7fd855org.highwire.dtl.DTLVardef@153b5bborg.highwire.dtl.DTLVardef@c013f3_HPS_FORMAT_FIGEXP M_FIG C_FIG Brief AbstractIn this study we reevaluate the effect of the genotype and sex of the recombinant inbred strains of mice on their response to dietary restriction. Out of the eight lines studied, half of the groups showed an increase in lifespan when the diet was restricted by 40% and the other half either did not respond or showed a decrease in lifespan. The recombinant inbred lines used in this study are potentially important resource for aging research to identify pathways and understand the mechanism involved in the anti-aging action of DR.

molecular biology↗

bioRxiv2018

Fine-tuned adaptation of embryo-endometrium pairs at implantation revealed by gene regulatory networks

Interactions between embryo and endometrium at implantation are critical for the progression and the issue of pregnancy. These reciprocal actions involve exchange of paracrine signals that govern implantation and placentation. However, it remains unknown how these interactions between the conceptus and the endometrium are coordinated at the level of an individual pregnancy. Under the hypothesis that gene expression of endometrium is dependent on gene expression of extraembryonic tissues, we performed an integrative analysis of transcriptome profiles of paired conceptuses and endometria obtained from pregnancies initiated by artificial insemination. We quantified strong dependence (|r|>0.95, eFDR<0.01) in transcript abundance of genes expressed in the extraembryonic tissues and genes expressed in the endometrium. The profiles of connectivity revealed distinct co-expression patterns of extraembryonic tissues with caruncular and intercaruncular areas of the endometrium. Notably, a subset of highly co-expressed genes between conceptus (n=229) and caruncular areas of the endometrium (n=218, r>0.9999, eFDR<0.001) revealed a blueprint of gene expression specific to each pregnancy. Functional analyses of genes co-expressed between conceptus and endometrium revealed significantly enriched functional modules with critical contribution for implantation and placentation, including \"in utero embryonic development\", \"placenta development\" and \"regulation of transcription\". Functional modules were remarkably specific to caruncular or intercaruncular areas of the endometrium. The quantitative and functional association between genes expressed in conceptus and endometrium emphasize a coordinated communication between these two entities in mammals. To our knowledge, we provide first evidence that implantation in mammalian pregnancy relies on the ability of the conceptus and the endometrium to develop a fine-tuned adaptive response characteristic of each pregnancy.

developmental biology↗