Biology subjects

Pearson, R. M.

Publications and source records attributed to Pearson, R. M..

7 recordsLinked to original sources

bioRxiv2026

Mesaconate-Based Polyester Nanoparticles Reveal How Metabolite Isomerism Shapes Polymer Behavior, Macrophage Reprogramming, and Systemic Immunomodulation

Metabolite-based polymer nanoparticles can transform endogenous immunometabolites into intrinsically bioactive materials, yet most platforms have focused on itaconate or soluble metabolite analogs. Mesaconate is a downstream itaconate-derived immunometabolite with distinct metabolic activity, but its potential as an engineerable material building block remains largely unexplored. Here, mesaconic acid was used as a monomer to construct a degradable, cargo-free polyester nanoparticle platform. Poly(itaconate-co-decanediol) (pITA) and poly(mesaconate-co-decanediol) (pMSA) were synthesized using 1,10-decanediol and formulated into nanoparticles. Varying pMSA synthesis conditions generated distinct molecular-weight development, thermal organization, and degradation-associated behavior. Despite comparable particle size, surface charge, and morphology, pITA- and pMSA-derived nanoparticles produced activation-state-dependent macrophage immunomodulation. Under inflammatory stimulation, both nanoparticles modulated activation-associated surface molecules, whereas their transcriptomic responses diverged markedly. pITA-NPs preferentially engaged redox-, metabolic-, and cellular stress-associated programs, while pMSA-NPs exhibited a distinct lysosome-associated, inflammatory, and remodeling transcriptional profile and remained distinguishable from soluble 4-octyl itaconate. In LPS-induced endotoxemia, pMSA-NP treatment broadly modulated systemic cytokine responses, including a pronounced reduction in circulating IL-6, and improved seven-day survival relative to vehicle control. Together, these findings establish mesaconate as a synthesis-tunable polymeric immunometabolite and highlight metabolite-isomer identity and nanoparticle material state as complementary design parameters for cargo-free immunometabolic biomaterials.

bioengineering↗

bioRxiv2024

Lipid Nanoparticles from L. meyenii Walp Mitigate Sepsis through Multimodal Protein Corona Formation

BackgroundPlant-derived nanoparticles (PDNP) are nano-sized particles isolated from various edible plants that contain bioactive components involved in regulating cellular immune responses against pathogenic intrusion and inflammation. PurposeThis study describes a novel PDNP derived from Lepidium meyenii Walp (maca) that efficiently captures pro-inflammatory cytokines and acute phase proteins in its protein corona to enhance survival in two representative lethal models of sepsis. MethodsLipid nanoparticles were isolated from maca (MDNP) and triacylglycerols and phytoceramides were identified as major constituents using lipidomics. The physicochemical properties of MDNPs were determined, anti-inflammatory effects of MDNP were evaluated using in vitro models and in vivo using endotoxemia and cecal ligation and puncture (CLP) polymicrobial sepsis models. Proteomic analysis of MDNP in healthy or LPS-induced inflammatory plasma was used to determine the composition and inflammatory pathways modulated due to the MDNP protein corona. ResultsIn vitro studies showed that MDNP were non-toxic, reduced macrophage activation, and effectively sequestered pro-inflammatory cytokines to mitigate NF-{kappa}B activity under lipopolysaccharide (LPS) stimulation. In a pre-established LPS-induced endotoxemia model, MDNP-treated mice showed significantly reduced systemic pro-inflammatory cytokines and enhanced survival. Untargeted proteomics and pathway analysis of the MDNP protein corona identified an enrichment in acute phase proteins in MDNP-LPS plasma coronas. MDNP treatment also significantly improved survival in the CLP sepsis model in the absence of antibiotics. ConclusionThis work identified MDNP as an efficient, plant-derived lipid NP that broadly sequesters and neutralizes a compilation of inflammatory mediators in their coronas, offering multimodal therapeutic potential for treating inflammatory diseases.

bioengineering↗

bioRxiv2022

Lipid-polymer hybrid nanoparticles utilize B cells and dendritic cells to elicit distinct antigen-specific CD4+ and CD8+ T cell responses

Antigen presenting cells (APCs) have been extensively studied for treating cancers and autoimmune diseases. Dendritic cells (DCs) are potent APCs that uptake and present antigens (Ags) to activate immunity or tolerance. Despite their active use in cellular immunotherapies, DCs face several challenges that hinder clinical translation, such as inability to control Ag dosing for tuning immune responses and low abundance in peripheral blood. B cells are a potential alternative to DCs, but their poor non-specific Ag uptake capabilities compromise controllable priming of T cells. We developed phospholipid-conjugated Ags (L-Ags) and lipid-polymer hybrid nanoparticles (L/P-Ag NPs) as Ag delivery platforms to expand the range of accessible APCs for use in priming CD4+ and CD8+ T cells. These delivery platforms were evaluated using DCs, CD40-activated B cells, and resting B cells as a diverse set of APCs to understand the impact of various Ag delivery mechanisms for generation of Ag-specific T cell responses. L-Ag delivery (termed depoting) of MHC class I and II-restricted Ags successfully loaded all APC types in a tunable manner and primed both Ag-specific CD8+ and CD4+ T cells, respectively. Incorporating L-Ags and polymer-conjugated Ags (P-Ag) into NPs can direct Ags to different uptake pathways to engineer the dynamics of presentation and shape T cell responses. DCs were capable of processing and presenting Ag delivered from both L- and P-Ag NPs yet B cells could only utilize Ag delivered from L-Ag NPs. Multivariate analysis of cytokines secreted from APC:T cell co-cultures indicated that L-Ag NPs primed different T cell responses than P-Ag NPs. Altogether, we show that L-Ags and P-Ags can be rationally paired within a single NP to leverage distinct delivery mechanisms to access multiple Ag processing pathways in two APC types, offering a modular delivery platform for engineering immunotherapies.

bioengineering↗

bioRxiv2021

Hedgehog pathway inhibitors significantly reduce the formation of heterotopic ossification in a direct trauma/burn mouse model

Heterotopic ossification (HO), either acquired or hereditary, is featured by ectopic bone formation outside of the normal skeleton. The acquired form of HO is a debilitating and common complication of musculoskeletal trauma, central nervous system injury, burns, combat trauma, hip and elbow fractures, and total joint replacement surgeries. It can be characterized as abnormal bone formation that occurs mostly by endochondral ossification. Recent studies have implicated inflammation and dysregulation of Hedgehog (Hh) signaling as major early contributors to HO formation. Here, we demonstrate that administration of the Hh pathway inhibitor, arsenic trioxide (ATO), prevented acquired HO in a clinically-relevant trauma/burn mouse model. We further evaluated the effects of two additional Hh pathway antagonists: cholecalciferol and pravastatin on mitigating osteoblast differentiation. Finally, we assessed the effect of a combination of Hh pathway inhibitors on reducing systemic proinflammatory responses. A targeted combination approach using Hh pathway inhibitors may offer potential therapeutic benefits though targeting differential components of the Hh pathway. Taken together, our study demonstrates that the administration of single or multiple Hh pathway inhibitors may have the potential to reduce the formation of acquired HO.

pharmacology and toxicology↗

bioRxiv2019

Executive control of positive and negative information and adolescent depressive symptoms: cross-sectional and longitudinal associations in a population-based cohort.

BackgroundLarge population-based studies of neuropsychological factors that characterize or precede depressive symptoms are rare. Most studies use small case-control or cross-sectional designs, which may cause selection bias and cannot test temporality. In a large UK population-based cohort we investigated cross-sectional and longitudinal associations between executive control of positive and negative information and adolescent depressive symptoms. MethodsCohort study of 2315 UK adolescents (ALSPAC) who completed an affective go/no-go task at age 18. Depressive symptoms were assessed with the Clinical Interview Schedule Revised (CIS-R) and short Mood and Feeling Questionnaire (sMFQ) at age 18, and with the sMFQ 15 months later. Analyses were linear multilevel regressions (for cross-sectional associations) and traditional linear regressions (for longitudinal associations), before and after adjustment for confounders. ResultsCross-sectionally, at age 18, there was some evidence that adolescents with more depressive symptoms made more errors in executive control (after adjustments, errors increased by 0.17 of a point per 1 SD increase in sMFQ score, 95% CI 0.08 to 0.25). However, this cross-sectional association was not observed for the CIS-R (.03, 95% CI -.06 to .12). There was no evidence of a difference in executive control errors according to valence. Longitudinally, there was no evidence that reduced executive control was associated with future depressive symptoms. ConclusionsExecutive control of positive and negative information does not appear to be a marker of current or future depressive symptoms in adolescents and would therefore not be a useful target in interventions to prevent adolescent depression. According to our evidence, the affective go/no-go task is also not a good candidate for future neuroimaging studies of adolescent depression.

epidemiology↗

bioRxiv2019

Specific domains of early parenting, their heritability and differential association with adolescent behavioural and emotional disorders and academic achievement

BackgroundVariations in parenting across large populations have rarely been described. It also remains unclear which specific domains of parenting are important for which specific offspring developmental outcomes. The study describes different domains of early parenting behaviours, their genetic heritability, and then determines the extent to which specific domains of parenting are associated with later offspring outcomes.\n\nMethodsParenting behaviours (birth to 3 years) were extracted from self-reported questionnaires administered to 12,358 mothers from the UK-based birth cohort study, the Avon Longitudinal Study of Parents and Children, and modelled as a latent factor using Confirmatory Factor Analysis. Genetic heritability and correlations between parenting factors were estimated using wide complex trait analysis. Offspring emotional, behavioural and academic outcomes were assessed at age 16 years using the self-reported Short Mood and Feelings Questionnaire, the Development and Well-Being Assessment, and grades achieved in national English Language examination.\n\nResultsThree parenting factors were derived: parental enjoyment, conflictual relationships and stimulation; all showed low genetic heritability. There was no evidence of associations between parenting factors and offspring depressed mood. Stimulation was associated with better English grades after controlling for maternal education (standardised {beta}=0.058, p=0.007), and enjoyment was negatively associated with English grades ({beta}=-0.082, p=0.002). Conflictual relationships were associated with higher risk of offspring behavioural disorders after controlling for behavioural problems at age 3 years ({beta}=0.227, p=0.007). Higher enjoyment reduced the association between conflict and behavioural problems (interaction term {beta}=0.113, p<0.001).\n\nConclusionsWe found evidence for predictive specificity of early parenting domains for offspring outcomes in adolescence. Early stimulation, unlike enjoyment, promoted later educational achievement. Conflictual relationships were associated with greater risk of behavioural problems, buffered by increased enjoyment. These findings hold implications for parenting interventions, guiding their focus according to specificity of parenting domains and their long-term outcomes in children.

epidemiology↗

bioRxiv2017

Autistic traits and suicidal thoughts, plans and self-harm in late adolescence: population based cohort study

ImportanceThere have been recent concerns about a higher incidence of mortality by suicide in people with autism spectrum disorder (ASD). To our knowledge, no large cohort studies have examined which features of autism may lead to suicidal ideation and behaviour, and whether there are any potential modifiable mechanisms.\n\nObjectiveTo examine the hypothesis that ASD diagnosis and traits in childhood are associated with suicidal thoughts, plans and self-harm at 16 years, and that any of the observed associations are explained by depression in adolescence at 12 years.\n\nDesign, setting and participantsProspective investigation of associations between ASD diagnosis and autistic traits with suicidal ideation and behaviour and a potential risk pathway via depression in early adolescence in 5,031 members of the Avon Longitudinal Study of Parents and Children.\n\nMain outcomes and measuresHistory of self-harm with and without suicidal intent, suicidal thoughts and plans at 16 years assessed using a detailed self-report questionnaire. Exposures were ASD diagnosis and four measures (the coherence subscale of the Childrens Communication Checklist, the Social and Communication Disorders Checklist, a repetitive behaviour measure, and the sociability temperament subscale of the Emotionality, Activity and Sociability scale) dichotomised to represent the autism trait groups. Depressive symptoms in early adolescence were measured by the Short Moods and Feelings Questionnaire at 12 years.\n\nResultsChildren with impaired social communication had a higher risk of self-harm with suicidal intent (RR 2.10, 95% CI 1.28, 3.34), suicidal thoughts (1.42 times (95% CI 1.06, 1.91) and suicidal plans (RR 1.95, 95% CI 1.09, 3.47) by the age of 16 years as compared to those without. There was no evidence for an association between ASD diagnosis and the outcomes although these analyses were imprecise due to small numbers. There was also no evidence of an association between other autism trait measures and the outcomes. Approximately 32% of the total estimated association between social communication impairment and self-harm was explained by depressive symptoms at age 12 years.\n\nConclusionsImpairments in social communication are important in relation to suicidality. Early identification and management of depression may be a preventative mechanism and future research identifying other modifiable mechanisms may lead to preventative action or interventions against suicidal behaviour in this high-risk group.

epidemiology↗