Biology subjects

Higham, J.

Publications and source records attributed to Higham, J..

8 recordsLinked to original sources

bioRxiv2026

Inhibition of TYK2 attenuates hyper IL-6- and Oncostatin M-mediated Calcium Signalling in Sensory Neurons

Inflammatory bowel disease (IBD) is characterised by chronic pain, a debilitating symptom for which effective treatments are few and far between. IBD pathogenesis includes the prevalence of a variety of pro-inflammatory cytokines, including the Interleukin-6 (IL-6) family members Il-6 and Oncostatin M (OSM). Previous research has shown disruption of OSM signaling can modulate nociceptor sensitization and activation, however the downstream signalling pathway is unknown. When an in silico analysis of murine colonic sensory neuronal populations was undertaken for receptor expression for OSM and other factors necessary for intracellular signaling, we can find diverse expression indicative of functional signaling. We were able to observe that hyper Il-6 (Il-6 bound to the soluble Il-6 receptor) and OSM can elicit activation of a subset of murine sensory neurons by finding an increase in calcium mobilization following superfusion. This could then be attenuated by the pharmacologic inhibition of all janus kinases or interestingly, TYK2 alone. Furthermore, inhibition of transient receptor potential vanilloid 1 or transient receptor potential ankyrin 1 ion channels, which are known to be sensitized by OSM in other sensory neurons also reduced the proportion of OSM-responsive neurons. This further understanding of OSM signaling in sensory neurons creates avenues for more extensive research into the molecular mechanisms occurring as well as the potential to exploit these therapeutically to induce analgesia in a subset of neurons.

neuroscience↗

bioRxiv2025

GPR68, a proton-sensing GPCR, mediates acid-induced visceral nociception

Background & AimsLocalised acidification from immune cell infiltration and heightened glycolysis contributes to colitis pathology by activating acid-sensing receptors such as GPR68, a proton-sensing GPCR expressed on immune and stromal cells. Single-cell RNAseq analysis revealed GPR68 is also expressed in colonic sensory neurons, prompting us to investigate its role in acid-induced colonic nociception. MethodsExpression of GPR68 in colonic nociceptors and tissue from people with colitis was confirmed by in silico analysis of our RNAseq databases. Its contribution to disease activity was assessed using the acute dextran sulphate sodium (DSS) model of colitis. Acid-evoked sensory signalling was evaluated via colonic afferent recordings and Ca{superscript 2} imaging in DRG neurons from wild-type and GPR68-/- mice, supported by pharmacological studies using Ogerin (a GPR68 positive allosteric modulator) and Ogremorphin (a GPR68 antagonist). ResultsRNAseq analysis showed GPR68 is robustly expressed in Trpv1 colonic nociceptors and upregulated in tissue from people with inflammatory bowel disease, consistent with reduced disease activity in DSS-treated GPR68-/- mice. Genetic deletion of GPR68 abolished colonic afferent responses to acid, which were also attenuated by Ogremorphin and enhanced by Ogerin. In Ca{superscript 2}-free buffer, DRG neurons from GPR68-/- mice or those pre-treated with Ogremorphin showed significantly reduced acid-evoked intracellular Ca{superscript 2} responses. By contrast the colonic afferent and DRG Ca2+ response (in Ca2+-containing buffer) to capsaicin was comparable between tissue from wild-type and GPR68-/- mice highlighting the involvement of divergent proton-dependent cellular signalling cascades. ConclusionsThese findings identify GPR68 as a key mediator of acid-induced colonic nociception and highlight its potential as a therapeutic target for the treatment of pain in colitis. SynopsisWe demonstrate that the proton-sensing receptor GPR68 mediates acid-induced signalling in colonic sensory neurons. Genetic and pharmacological modulation confirms GPR68s role in visceral nociception and supports its potential as a therapeutic target for pain management in colitis.

neuroscience↗

bioRxiv2023

Socioecological drivers of injuries in female and male rhesus macaques (Macaca mulatta)

Competition over access to resources, such as food and mates, is believed to be one of the major costs associated with group living. Two socioecological factors suggested to predict the intensity of competition are group size and the relative abundance of sexually active individuals. However, empirical evidence linking these factors to injuries and survival costs is scarce. Here, we leveraged 10 years of data from free-ranging rhesus macaques where injuries inflicted by conspecifics are associated with a high mortality risk. We tested if group size and adult sex ratio predicted the occurrence of injuries and used data on physical aggression to contextualise these results. We found that males were less likely to be injured when living in larger groups, potentially due to advantages in intergroup encounters. Females, instead, had higher injury risk when living in larger groups but this was not explained by within-group aggression among females. Further, male-biased sex ratios predicted a weak increase in injury risk in females and were positively related to male-female aggression, indicating that male coercion during mating competition may be a cause of injuries in females. Overall, our results provide insights into sex differences in the fitness-related costs of competition and empirical evidence for long-standing predictions on the evolution of group living.

evolutionary biology↗

bioRxiv2023

Natural disaster alters the adaptive benefits of sociality

Weather-related disasters can radically alter ecosystems. When disaster-driven ecological damage persists, the selective pressures exerted on individuals can change, eventually leading to phenotypic adjustments. For group-living animals, social relationships are believed to help individuals cope with environmental challenges and may be a critical mechanism enabling adaptation to ecosystems degraded by disasters. Yet, whether natural disasters alter selective pressures on patterns of social interactions and whether group-living animals can, as a result, adaptively change their social relationships remains untested. Here, we leveraged unique data collected on rhesus macaques from 5 years before to 5 years after a category 4 hurricane, leading to persistent deforestation which exacerbated monkeys exposure to intense heat. In response, macaques increased tolerance for and decreased aggression toward other monkeys, facilitating access to scarce shade critical for thermoregulation. Social tolerance predicted individual survival for 5 years after the hurricane, but not before it, revealing a clear shift in the adaptive function of social relationships in this population. We demonstrate that an extreme climatic event altered selection on sociality and triggered substantial and persistent changes in the social structure of a primate species. Our findings unveil the function and adaptive flexibility of social relationships in degraded ecosystems and identify natural disasters as potential evolutionary drivers of sociality. One-Sentence SummaryTestard et al. show that a natural disaster altered selection on sociality in group-living primates triggering persistent changes in their social structure.

animal behavior and cognition↗

bioRxiv2022

Age-related differences in ocular features of a naturalistic free-ranging population of rhesus macaques

PurposeRhesus macaques (Macaca mulatta) are the premier nonhuman primate model for studying human health and disease. We aimed to investigate if age was associated with ocular features of clinical relevance in a large cohort of free-ranging rhesus macaques from Cayo Santiago, Puerto Rico. MethodsWe evaluated 120 rhesus macaques (73 males, 47 females) aged from 0 to 29 years old (mean{+/-}SD: 12.6{+/-}6.4) from September to December, 2021. The ophthalmic evaluation included IOP assessment, corneal pachymetry, anterior segment biomicroscopy, A-Scan biometry, automated refraction, and fundus photography after pupil dilation. The effects of age on the outcome variables were investigated through multilevel mixed-effects models adjusted for sex and weight. ResultsOn average, IOP, pachymetry, axial length, and automated refraction spherical equivalent were 15.47{+/-}2.47 mmHg, 474.43{+/-}32.21 m, 19.49{+/-}1.24 mm, and 0.30{+/-}1.70 D, respectively. Age was significantly associated with pachymetry (Coef.= -1.20; 95%CI: -2.27 to -0.14; p=0.026), axial length (Coef.= 0.03; 95%CI: 0.01 to 0.05; p=0.002), and spherical equivalent (Coef.= -0.12; 95%CI: -0.22 to -0.02; p=0.015). No association was detected between age and IOP. The prevalence of cataracts in either eye was 10.83% (95% CI: 6.34 - 17.89%) and was significantly associated with age (OR= 1.20; 95%CI: 1.06 - 1.36; p=0.004). Retinal drusen in either eye was observed in 15.00% (95% CI: 9.60 - 22.68%) of the animals, which was also significantly associated with age (OR=1.14; 95%CI: 1.02 - 1.27; p=0.020). ConclusionsRhesus macaques exhibit age-related ocular associations similar to those observed in human aging, including decreased corneal thickness, increased axial length, myopic shift, and higher occurrence of cataract and retinal drusen.

systems biology↗

bioRxiv2021

Local CpG density affects the trajectory of age-associated epigenetic changes

DNA methylation is an epigenetic mark associated with gene repression and genome stability. Its pattern in the genome is disrupted with age and these changes can be used to statistically predict age with epigenetic clocks. Rates of aging inferred from these clocks correlate with human health. However, the molecular mechanisms underpinning age-associated DNA methylation changes are unknown. Local DNA sequence plays a strong role in programming DNA methylation levels at individual loci independently of age, but its influence on age-associated DNA methylation changes is unknown. We analysed longitudinal human DNA methylation trajectories at 345,895 CpGs from 600 individuals aged between 67 and 80 to understand the factors responsible for age-associated epigenetic changes at individual CpGs in the genome. We show that changes in methylation with age are especially apparent at 8,322 low CpG density loci. Using SNP data from the same individuals we demonstrate that DNA methylation trajectories are affected by local sequence polymorphisms at 1,487 loci with low CpG density. More generally, we find that local CpG density is a strong determinant of a CpGs methylation trajectory and that CpGs located in low CpG density regions are particularly prone to change. Overall, our results demonstrate that local DNA sequence influences age-associated DNA methylation changes in humans in vivo. We suggest that this occurs because interactions between CpGs reinforce maintenance of methylation patterns in CpG dense regions.

genetics↗

bioRxiv2019

An epigenetic predictor of death captures multi-modal measures of brain health

Individuals of the same chronological age exhibit disparate rates of biological ageing. Consequently, a number of methodologies have been proposed to determine biological age and primarily exploit variation at the level of DNA methylation (DNAm) - a commonly studied epigenetic mechanism. A novel epigenetic clock, termed DNAm GrimAge has outperformed its predecessors in predicting the risk of mortality as well as a number of age-related morbidities. However, the association between DNAm GrimAge and cognitive or neuroimaging phenotypes remains unknown. We explore these associations in the Lothian Birth Cohort 1936 (n=709, mean age 73 years). Higher DNAm GrimAge was strongly associated with all-cause mortality over twelve years of follow-up (Hazard Ratio per standard deviation increase in GrimAge: 1.81, P < 2.0 x 10-16). Higher DNAm GrimAge was associated with lower age 11 IQ ({beta}=-0.11), lower age 73 general cognitive ability ({beta}=-0.18), decreased brain volume ({beta}=-0.25) and increased brain white matter hyperintensities ({beta}=0.17). Sixty-eight of 137 health- and brain-related phenotypes tested were significantly associated with DNAm GrimAge. Adjusting all models for childhood cognitive ability attenuated to non-significance a small number of associations (12/68 associations; 6 of which were cognitive traits), but not the association with general cognitive ability (33.9% attenuation). Higher DNAm GrimAge cross-sectionally associates with lower cognitive ability and brain vascular lesions in older age, independently of early life cognitive ability. Thus, this epigenetic predictor of mortality is also associated with multiple different measures of brain health and may aid in the prediction of age-related cognitive decline.

neuroscience↗

bioRxiv2019

De novo DNA methyltransferase activity in colorectal cancer is directed towards H3K36me3 marked CpG islands

The aberrant gain of DNA methylation at CpG islands (CGIs) is frequently observed in colorectal tumours and may silence the expression of tumour suppressors such as MLH1. Current models propose that these CGIs are targeted by de novo DNA methyltransferases (DNMTs) in a sequence-specific manner but this has not been tested. Using ectopically integrated CGIs, we find that aberrantly methylated CGIs are subject to low levels of de novo DNMT activity in colorectal cancer cells. By delineating DNMT targets, we find that instead de novo DNMT activity is targeted primarily to CGIs marked by the histone modification H3K36me3, a mark associated with transcriptional elongation. These H3K36me3 marked CGIs are heavily methylated in colorectal tumours and the normal colon suggesting that de novo DNMT activity at CGIs in colorectal cancer is focused on similar targets to normal tissues and not greatly remodelled by tumourigenesis.

genetics↗