Biology subjects

Sexton, C.

Publications and source records attributed to Sexton, C..

11 recordsLinked to original sources

bioRxiv2026

The Endocannabinoid System's Contribution to Placebo Analgesia

Placebo analgesia--pain reduction from inert treatments--varies widely across individuals, yet its neurochemical basis remains poorly understood. While endogenous opioids, specifically {beta}-endorphin, contribute to placebo effects, mu-opioid receptor blockade does not fully abolish analgesia, implicating additional systems. Here, we investigate the endogenous cannabinoid (eCB) systems contribution to placebo analgesia in 48 healthy adults using a validated placebo paradigm with blood sampling. We quantified circulating levels of eCB ligands and {beta}-endorphin at baseline, as well as before and after placebo and control conditions to determine condition-related changes. Individual differences in placebo analgesia were associated with increases in fatty acid amide hydrolase (FAAH) substrates--a composite of anandamide, palmitoylethanolamide, and oleoylethanolamide--but not 2-arachidonoylglycerol or {beta}-endorphin alone. Critically, {beta}-endorphin moderated this relationship: FAAH substrates were strongly associated with pain reduction only when {beta}-endorphin levels were low. These findings provide evidence that eCB and opioid systems interact in a state-dependent manner during placebo analgesia in humans, with implications for understanding individual variability in treatment responses.

neuroscience↗

bioRxiv2025

The Contribution of Circulating Endocannabinoid Tone to Individual Differences in Human Pain Sensitivity: A Quantitative Sensory Testing Study

The endocannabinoid (eCB) system--comprising cannabinoid receptors, eCBs (anandamide-- AEA, 2-arachidonoylglycerol--2-AG) and related N-acylethanolamines (NAEs; N-palmitoylethanolamide--PEA, and N-oleoylethanolamide--OEA), and metabolizing enzymes (e.g., fatty acid amide hydrolase; FAAH)--modulates nociceptive circuits in rodents. In humans, the FAAH C385A polymorphism is associated with reduced pain sensitivity, suggesting eCB tone influences individual pain differences, but this has yet to be tested. Here, we determined whether the eCB system is associated with somatosensory and pain sensitivity measured with quantitative sensory testing (QST) in 91 healthy participants (39 males, 52 females). We tested three hypotheses: (1) FAAH C385A polymorphism, cannabis use, and sex affect serum eCB/NAE concentrations; (2) FAAH C385A carriers show altered pain sensitivity versus non-carriers; and (3) baseline serum eCB/NAE concentrations are associated with QST measures. eCB/NAE concentrations were not statistically different based on sex (p > .05), based on FAAH genotype (p > .05), and based on cannabis use (p > .05). To address collinearity of AEA, OEA and PEA, we performed a principal components analysis, which identified a single component of FAAH substrates. Linear regressions found that FAAH genotype did not affect QST measures and that baseline 2-AG and FAAH substrate concentrations were not associated with QST measures, except pressure pain thresholds (PPT; p = 0.003), which were associated with AEA and OEA. Baseline eCB/NAE levels and FAAH genotype are not associated with the outcome measures of standard QST tests that rely on point estimates in healthy adult humans; nonetheless, circulating FAAH substrate levels were associated with PPT.

neuroscience↗

bioRxiv2024

Testing for heavy metals in drinking water collected from Dog Aging Project participants

Heavy metals are commonly found in groundwater and can affect the quality of drinking water. In this pilot study, we analyzed the quality of drinking water for dogs participating in the Dog Aging Project (DAP) who lived in homes not served by a municipal water supply. In order to capture both diverse and localized environmental factors that may affect drinking water, 200 owners of DAP dogs located in one of 10 selected states were invited to participate. We tested for the presence of 28 metals in dogs drinking water, including eight (8) heavy metals that have maximum contaminant levels (MCLs) designated by the Environmental Protection Agency (EPA) and five (5) heavy metals that have EPA health guidance levels. The eight metals with MCLs are known to cause chronic health issues in humans after long-term ingestion. Our aim in this pilot was to determine whether such elements could be detected by at-home sampling of dogs drinking water. We found detectable levels of all metals tested. There were 126 instances when an analyte (arsenic, lead, copper, sodium, strontium, nickel, or vanadium) was above the EPA MCL or health guidance level. We further identified potential association between the presence of titanium and chromium, and occurrence of a known health condition in dogs. This prompts further investigation with a larger, stratified sample analyzing dogs drinking water composition and long-term health and wellness outcomes in dogs living in diverse geographies. These results may impact veterinary care decisions and husbandry, and underscore the validity and importance of utilizing dogs as sentinels of human health outcomes in the context of drinking water contamination.

ecology↗

bioRxiv2024

Progressive multi-stage extrapolation of predictable motion in human visual cortex

Neural processing of sensory information takes time. Consequently, to estimate the current state of the world, the brain must rely on predictive processes - for example, extrapolating the motion of a ball to determine its probable present position. Some evidence implicates early (pre-cortical) processing in extrapolation, but it remains unclear whether extrapolation continues during later-stage (cortical) processing, where further delays accumulate. Moreover, the majority of such evidence relies on invasive neurophysiological techniques in animals, with accurate characterisation of extrapolation effects in the human brain currently lacking. Here, we address these issues by demonstrating how precise probabilistic maps can be constructed from human EEG recordings. Participants (N = 18, 2 sessions) viewed a stimulus moving along a circular trajectory while EEG was recorded. Using LDA classification, we extracted maps of stimulus location over time and found evidence of a forwards temporal shift occurring across temporally distinct processing stages. This accelerated emergence of position representations indicates extrapolation occurring at multiple stages of processing, with representations progressively shifted closer to real-time. We further show evidence of representational overshoot during early-stage processing following unexpected changes to an objects trajectory, and demonstrate that the observed dynamics can emerge without supervision in a simulated neural network via spike-timing-dependent plasticity.

neuroscience↗

bioRxiv2022

Sleep duration and brain structure - phenotypic associations and genotypic covariance

The question of how much sleep is best for the brain attracts scientific and public interest, and there is concern that insuficient sleep leads to poorer brain health. However, it is unknown how much sleep is sufficient and how much is too much. We analyzed 51,295 brain magnetic resonnance images from 47,039 participants, and calculated the self-reported sleep duration associated with the largest regional volumes and smallest ventricles relative to intracranial volume (ICV) and thickest cortex. 6.8 hours of sleep was associated with the most favorable brain outcome overall. Critical values, defined by 95% confidence intervals, were 5.7 and 7.9 hours. There was regional variation, with for instance the hippocampus showing largest volume at 6.3 hours. Moderately long sleep (> 8 hours) was more strongly associated with smaller relative volumes, thinner cortex and larger ventricles than even very short sleep (< 5 hours), but effect sizes were modest. People with larger ICV reported longer sleep (7.5 hours), so not correcting for ICV yielded longer durations associated with maximal volume. Controlling for socioeconomic status, body mass index and depression symptoms did not alter the associations. Genetic analyses showed that genes related to longer sleep in short sleepers were related to shorter sleep in long sleepers. This may indicate a genetically controlled homeostatic regulation of sleep duration. Mendelian randomization analyses did not suggest sleep duration to have a causal impact on brain structure in the analyzed datasets. The findings challenge the notion that habitual short sleep is negatively related to brain structure. Significance statementAccording to consensus recommendations, adults should sleep between 7 and 9 hours to optimize their health. We found that sleeping less than the recommended amount was associated with greater regional brain volumes relative to intracranial volume, and very short sleep was only weakly related to smaller volumes. Genetic analyses did not show causal effects of sleep duration on brain structure. Taken together, the results suggest that habitual short sleep is not an important contributor to lower brain volumes in adults on a group level, and that large individual dfferences in sleep need likely exist.

neuroscience↗

bioRxiv2022

PDX models of relapsed pediatric AML preserve global gene expression patterns and reveal therapeutic targets

As patient-derived xenograft (PDX) models of acute myeloid leukemia (AML) become increasingly common tools for preclinical evaluation of targeted therapies it becomes important to consider the fidelity with which this system recapitulates the disease state found in patients. Gene expression profiling of patient blasts has been successfully used to identify distinct subtypes of AML to uncover sub-type specific vulnerabilities and to predict response to therapy and outcomes. Currently, there is little information regarding how well PDX models of AML mimic global gene expression patterns found in patients. In order to address this point, we performed detailed RNA-Seq analysis of data obtained from a diverse series of pediatric AML PDXs, separately and compared to primary patient data. When unsupervised clustering was applied to the PDX sample dataset, we found grouping associated with KMT2A (MLL) gene status. Additionally, in combined analysis, PDX samples were found to align with primary patient samples harboring similar genetics. We found a strong correlation of expression levels of nearly all expressed transcripts in PDX and patient datasets thus demonstrating faithful recapitulation of gene expression signatures. Furthermore, paired patient/PDX samples showed strong concordance, suggesting retention of sample-specific gene expression in immune deficient mice. Comparisons of PDX models propagated in NOD/SCID/IL2rg -/- (NSG) mice compared to NSG mice with transgenic expression of human SCF, GM-CSF, and IL-3 (NSGS) revealed minimal differences related to increased JAK/STAT and macrophage activation pathways in NSGS. Additionally, a unique RAM immunophenotype associated expression signature pointed to discovery of cryptic CBFA2T3-GLIS2 rearrangement as the mechanistic driver mutation in two PDX models. Based on the relatively high BCL2 mRNA in these models, we tested the efficacy of venetoclax in combination with CPX-351 which resulted in reduced leukemia burden and prolonged survival. These results validate the PDX system as surrogate of the molecular signatures in high-risk pediatric AML and highlight this systems utility for pre-clinical therapeutic discovery, especially in very rare subtypes of disease.

cancer biology↗

bioRxiv2021

Effects of High-Volume versus High-Load Resistance Training on Skeletal Muscle Growth and Molecular Adaptations

AimWe evaluated the effects of higher-load (HL) versus (lower-load) higher-volume (HV) resistance training on skeletal muscle hypertrophy, strength, and muscle-level molecular markers. MethodsTrained men (n=15, age: 23{+/-}3 y; training experience: 7{+/-}3 y) performed unilateral lower body training for 6 weeks (3x weekly), where single legs were assigned to HV and HL paradigms. Vastus lateralis (VL) biopsies were obtained prior to study initiation (PRE) as well as 3 days (POST) and 10 days following the last bout (POSTPR). Body composition and strength tests were performed at each testing session, and biochemical assays were performed on muscle tissue after study completion. Two-way within subjects repeated measures ANOVAs were performed on all dependent variables except tracer data, which was compared using dependent samples t-tests. ResultsA significant (p<0.05) interaction existed for unilateral leg extension 1RM (HV<HL at POST and POSTPR). Six-week integrated sarcoplasmic protein synthesis (iSarcoPS) rates were higher in the HV versus HL leg, while no difference between legs existed for integrated myofibrillar protein synthesis rates. Main time effects existed for unilateral leg press strength (PRE<POST and POSTPR), knee extensor peak torque (PRE and POST<POSTPR), dual-energy x-ray absorptiometry (DXA)-derived upper leg lean mass (PRE<POST and POSTPR), ultrasound-derived VL thickness (PRE and POSTPR<POST), sarcoplasmic protein concentrations (POST and POSTPR<PRE), and tropomyosin and troponin protein abundances (POST and POSTPR<PRE). ConclusionsWith the exception of differences in leg extensor strength and iSarcoPS between legs, our data suggest that short-term (6 weeks) HV and HL training elicit similar hypertrophic, strength, and molecular-level adaptations.

physiology↗

bioRxiv2021

No reproductive benefits of dear enemy recognition in a territorial songbird

Territorial animals often respond less aggressively to neighbours than strangers. This dear enemy effect is hypothesized to be adaptive by reducing unnecessary aggressive interactions with non-threatening individuals. A key prediction of this hypothesis, that individual fitness will be affected by variation in the speed and the extent to which individuals reduce their aggression towards neighbours relative to strangers, has never been tested. We used a series of song playbacks to measure the change in response of male great tits to a simulated establishment of a neighbour on an adjacent territory during early stages of breeding, as an assay of individuals tendencies to form dear enemy relationships. Males reduced their approach to the speaker and sang fewer songs on later playback repetitions. However, only some males exhibited dear enemy behaviour by responding more strongly to a subsequent stranger playback, and when the playback procedure was repeated on a subset of males, there was some indication for consistent differences among individuals in the expression of dear enemy behaviour. We monitored nests and analysed offspring paternity to determine male reproductive success. Individuals that exhibited dear enemy behaviour towards the simulated neighbour did not suffer any costs associated with loss of paternity, but there was also no evidence of reproductive benefits, and no net effect on reproductive fitness. The general ability to discriminate between neighbours and strangers is likely adaptive, but benefits are probably difficult to detect because of the indirect link between individual variation in dear enemy behaviour and reproductive fitness, and because of the complex range of mechanisms affecting relations with territorial neighbours.

animal behavior and cognition↗

bioRxiv2020

Self-reported sleep problems are related to cortical thinning in aging but not memory decline and amyloid-β accumulation - results from the Lifebrain consortium

BackgroundOlder persons with poor sleep are more likely to develop neurodegenerative disease, but the causality underlying this association is unclear. To move towards explanation, we examine whether sleep quality and quantity are similarly associated with brain changes across the adult lifespan. MethodsAssociations between self-reported sleep parameters (Pittsburgh Sleep Quality Index;PSQI) and longitudinal cortical change were tested using five samples from the Lifebrain consortium (n=2205, 4363 MRIs, 18-92 years). Analyses were augmented by considering episodic memory change, gene expression from the Allen Human Brain Atlas, and amyloid-beta (A{beta}) accumulation (n=1980). ResultsPSQI components sleep problems and low sleep quality were related to thinning of the right lateral temporal cortex. The association with sleep problems emerged after 60 years, especially in regions with high expression of genes related to oligodendrocytes and S1 pyramidal neurons. BMI and symptoms of depression had negligible effects. Sleep problems were neither related to longitudinal change in episodic memory function nor to A{beta} accumulation, suggesting that sleep-related cortical changes were independent of AD neuropathology and cognitive decline. ConclusionWorse self-reported sleep in later adulthood was associated with more cortical thinning in regions of high expression of genes related to oligodendrocytes and S1 pyramidal neurons, but not to A{beta} accumulation or memory decline. The relationship to cortical brain change suggests that self-reported sleep parameters are relevant in lifespan studies, but small effect sizes, except for a few restricted regions, indicate that self-reported sleep is not a good biomarker of general cortical degeneration in healthy older adults.

neuroscience↗

bioRxiv2019

Self-reported sleep relates to hippocampal atrophy across the adult lifespan - results from the Lifebrain consortium

BackgroundPoor sleep is associated with multiple age-related neurodegenerative and neuropsychiatric conditions. The hippocampus plays a special role in sleep and sleep-dependent cognition, and accelerated hippocampal atrophy is typically seen with higher age. Hence, it is critical to establish how the relationship between sleep and hippocampal volume loss unfolds across the adult lifespan.\n\nMethodsSelf-reported sleep measures and MRI-derived hippocampal volumes were obtained from 3105 cognitively normal participants (18-90 years) from major European brain studies in the Lifebrain consortium. Hippocampal volume change was estimated from 5116 MRIs from 1299 participants, covering up to 11 years. Cross-sectional analyses were repeated in a sample of 21390 participants from the UK Biobank.\n\nResultsThe relationship between self-reported sleep and age differed across sleep items. Sleep duration, efficiency, problems, and use of medication worsened monotonously with age, whereas subjective sleep quality, sleep latency, and daytime tiredness improved. Women reported worse sleep in general than men, but the relationship to age was similar. No cross-sectional sleep - hippocampal volume relationships was found. However, worse sleep quality, efficiency, problems, and daytime tiredness were related to greater hippocampal volume loss over time, with high scorers showing on average 0.22% greater annual loss than low scorers. Simulations showed that longitudinal effects were too small to be detected as age-interactions in cross-sectional analyses.\n\nConclusionsWorse self-reported sleep is associated with higher rates of hippocampal decline across the adult lifespan. This suggests that sleep is relevant to understand individual differences in hippocampal atrophy, but limited effect sizes call for cautious interpretation.

neuroscience↗

bioRxiv2017

Automated detection of sleep-boundary times using wrist-worn accelerometry

ObjectiveCurrent polysomnography-validated measures of sleep status from wrist-worn accelerometers cannot be used in fully automated analysis as they rely on self-reported sleep-onset and -end (sleep-boundary) information. We set out to develop an automated, data-driven approach to sleep-boundary detection from wrist-worn accelerometer data.\n\nMethodsOn three separate occasions, participants were asked to wear a GENEActiv(R) wrist-worn accelerometer for nine days and concurrently complete sleep diaries with lights-off, asleep and wake-up information. We developed and evaluated three data-driven methods for sleep-boundary detection: a change-point detection based method, a thresholding method and a random forest classifier based method. Mean absolute errors between automatically-derived and self-reported sleep-onset and wake-up times were recorded in addition to kappa statistics for the minute-by-minute performance of each of the methods.\n\nResults46 participants provided 972 days of accelerometer recordings with corresponding self-reported sleep information. The three sleep-boundary detection methods resulted in mean absolute errors in sleep-onset and wake-up times per individual of 36 min, 34 min and 33 min and kappa statistics of 0.87, 0.89 and 0.89, respectively.\n\nConclusionOur methods provide a data-driven approach to detect sleep-onset and -end times without the need for self-reported sleep-boundary information. The methods are likely to be of particular use for large-scale studies where the collection of self-reported sleep diaries is impractical.\n\nSignificanceObjective measures of sleep are needed to reliably detect associations with health outcomes. This work lays the foundation for studies of objectively measured sleep duration and its health consequences in large studies.

epidemiology↗