Biology subjects

Hopkins, C.

Publications and source records attributed to Hopkins, C..

11 recordsLinked to original sources

bioRxiv2026

Vertical climbing in mice: a translationally relevant measure of pain-related impact on natural behaviour

Despite urgent need for better analgesics, drug development has been complicated by incomplete bench-to-bedside translation. A likely contributing factor is the poor connection between the experimenter-evoked pain-related measures often used in preclinical models, and the clinical symptoms, like broader functional impairment, reported by patients. Here, we asked whether vertical climbing, a species-specific elective behaviour in mice, could serve as a measure of pain-related impairment. We tested male and female mice in a wide range of pain-related models including models of post-operative pain, inflammatory injury, osteoarthritis, rheumatoid arthritis, cancer-induced bone pain, fibrous dysplasia, neuropathic pain, migraine-related pain and facial neuropathy. Vertical climbing was reduced in all models, across five different laboratories, demonstrating the robustness and consistency of this type of behaviour as a novel pain-related outcome measure. Reduced climbing correlated significantly with established pain-related measures, but its time course diverged from that of evoked mechanical allodynia, while aligned more closely with other non-evoked behaviours, like burrowing, home cage activity, wheel running or weight bearing. Pharmacological validation was bidirectional: gabapentin restored climbing in mice with neuropathic injury, and naltrexone reinstated the climbing deficit in mice that had recovered from intraplantar CFA, consistent with persistent pain held in remission by endogenous opioid signalling. Overall, our results indicate that voluntary vertical climbing is a stable, elective behaviour that provides a robust and translationally relevant measure of pain-related functional impairment in mice.

neuroscience↗

bioRxiv2026

Netrin-1 inhibition does not attenuate cancer-induced bone pain in three translational models

1.Cancer-induced bone pain (CIBP) occurs in a majority of patients when primary or metastatic cancer develops within the bone. This pain has a significant impact on quality of life, yet there are limited effective treatment options available. Nerve sprouting is a complex mechanism that has been implicated in CIBP. Netrin-1 is a neuronal guidance molecule that is produced by numerous cell types, including cancer cells. In this study we aimed to determine whether netrin-1 inhibition (with NP137 - a humanized IGg1 monoclonal antibody) could ameliorate nerve sprouting, and nociception by extension, in three models of CIBP - osteosarcoma, metastatic breast cancer, and metastatic prostate cancer. Sustained administration of NP137 failed to produce an anti-nociceptive effect in these models, but a delayed onset was observed in the osteosarcoma model. NP137 did not produce a disease-modifying effect, as micro-computed tomography did not reveal reduced bone destruction in the NP137-treated groups. Additionally, there was no nerve fibre density reduction in any of the groups at the late-stage of the disease, suggesting that nerve sprouting occurs in early- to mid-stage CIBP development. Investigation of NP137 exposure indicated that serum levels of NP137 were comparable between the sham and cancer groups. Our study indicates that netrin-1 may play a role in early-stage CIBP development, but inhibition of this mechanism does not produce robust anti-nociception.

pharmacology and toxicology↗

bioRxiv2026

Pax9 governs anterior identity and deployment of sclerotome to the median fins

The caudal fin is an anomaly among vertebrate locomotory appendages: its internal skeleton is as asymmetric as the human hand, but it lacks the Shh-secreting Zone of Polarizing Activity (ZPA) and the Gli3/HoxD/Hand2 programs that govern anterior-posterior patterning in other appendages. As the caudal fin was also the first appendage to evolve, deciphering its alternative patterning program may provide clues to the ancestral state. Pax9 is one of few conserved appendage patterning factors reported to also be active in the caudal fin, specifically in the anterior domain. We report that loss of pax9 function in zebrafish not only disrupts anterior-specific caudal fin anatomy, but also results in a spectacular fusion of the caudal and anal fins along the ventral midline. The dorsal fin is also expanded to a lesser degree, the paired fins not at all. The mutant caudal fin initially forms as an irregularly patterned structure lacking anterior molecular identity, with supernumerary elements spilling out beyond the normal anterior boundary. Unexpectedly, this phenotype is subsequently compounded by neighboring trunk somites erroneously deploying skeletal mesenchyme in the normally finless caudal peduncle region, completing the ectopic skeleton. scRNAseq analysis at caudal fin bud stage indicates that pax9 mutants gain skeletal mesenchyme at the expense of a specialized type of fibroblast involved in the formation of fin fold actinotrichia. Median fin skeletal mesenchyme and fin fold fibroblasts both arise from the sclerotome, a somite compartment that also robustly expresses pax9. We propose that, within the sclerotome, Pax9 pushes progenitors towards fin fold fibroblast fate, limiting how many cells will later be available to make median fin skeleton. Within the fin bud, it drives anterior identity, with the strongest impact on the ZPA-free caudal fin bud. These dual sites of action make Pax9 a uniquely powerful governor of median fin development.

Developmental Biology↗

bioRxiv2025

Beliefs about a widely popularised human-wildlife conflict are largely unreflective of local experiences and ecological data in wild red foxes, Vulpes vulpes

Human-driven environmental changes, such as urbanisation, are increasing human-wildlife interactions, creating potential for conflict. Public beliefs and experiences with local wildlife are central to the success of place-based conservation initiatives, such as urban rewilding, because they impact public attitudes and tolerance of those species within neighbourhoods. Few studies, however, have examined whether peoples beliefs align with their real-life observations of wildlife within their local area and, more importantly, whether (or how) their beliefs might impact public attitudes independently of local experiences with those animals. The current study addressed this gap by assessing whether public beliefs about a conspicuous human-wildlife conflict - bin-raiding behaviour - aligned with residents own local experiences with a familiar and widespread urban carnivore, the red fox (Vulpes vulpes). The study also examined whether beliefs about bin-raiding predicted attitudes towards foxes even when people lacked firsthand observations of such behaviour within their area. Beliefs and attitudes towards foxes were evaluated using a nationwide questionnaire administered to 1,275 participants in the United Kingdom. Ecological surveys were also conducted in the city of Hull, UK, to compare public attitudes and beliefs (N= 248 households) with objective data on outdoor bin disturbances (N=4,239 bins) from the same area. Nationally, most respondents (59.3%) believed that foxes raid bins despite significantly fewer of these people (21.7%) having witnessed it firsthand within their neighbourhood. In Hull, <1% of bins showed evidence of disturbance even though significantly more residents (16.9%) believed foxes raided bins than the number of residents who had actually seen it happen. Among national and local Hull residents with no local experience observing bin-raiding foxes, these beliefs were nevertheless associated with more negative attitudes towards them. Together, these findings highlight the importance of taking into account other factors beyond local experiences (e.g., socio-cultural norms) when interpreting local reports of human-wildlife conflict, especially for place-based conservation.

animal behavior and cognition↗

bioRxiv2025

Spatial distribution of human-wildlife interactions predicts coexistence with a global urban carnivore, the red fox

Despite growing recognition that spatial factors such as urbanisation and geographic region shape human-wildlife interactions, few studies have examined - on a large geographic scale - how spatial factors reflect the subjective human dimensions to those interactions, including public attitudes and self-reported encounters with wildlife. Understanding how spatial factors shape these dimensions may have implications for urban rewilding because they can reflect local tolerance of animals and may potentially predict human-wildlife interactions. We examined how urbanisation type and geographic region are related to peoples attitudes, reported encounters (public feeding and bin-raiding), and reported use of control measures towards the worlds most urbanised terrestrial carnivore, the red fox, Vulpes vulpes. Online survey data were obtained from 1,275 participants in the United Kingdom. Reports of fox bin-raiding were associated with increased reports of wildlife feeding, more negative attitudes towards foxes, and greater reported use of professional and do-it-yourself control measures. However, the role of spatial factors varied among these relationships. Specifically, urbanisation and geographic region significantly predicted reports of fox binraiding, with urban residents - particularly from London - more likely to report such behaviour. Urbanisation predicted reports of wildlife feeding and use of professional pest control of foxes within their area. Geographic region predicted reports of do-it-yourself control measures. Neither urbanisation nor geographic region significantly predicted public attitudes towards foxes. Together, these findings highlight the complex interactions between spatial context and the subjective human dimensions of wildlife interactions, underscoring the importance of nuanced, context-specific strategies to support human-wildlife coexistence and urban rewilding initiatives. HighlightsO_LIUrban rewilding success depends on public tolerance of local wildlife. C_LIO_LIWe studied spatial factors and subjective human dimensions of fox interactions. C_LIO_LIReports of bin-raiding, wildlife feeding, fox-related attitudes, and pest control covaried. C_LIO_LIThe role of urbanisation and geography varied in predicting these reports. C_LIO_LISuch spatial complexity should be considered in designing urban rewilding strategies. C_LI

ecology↗

bioRxiv2024

Wheel running, but not home cage activity in Digital Ventilated Cages(R) is impaired in a mouse model of breast cancer-induced bone pain

IntroductionCancer-induced bone pain (CIBP) due to metastatic breast cancer is common and debilitating. Effective, long-term treatment options have side effects that reduce patients quality of life. Preclinical models are a valuable tool to test novel analgesics, but new methods that are translationally and clinically relevant are necessary. This study aimed to assess spontaneous pain-like behaviour of home cage activity and wheel running in Digital Ventilated Cages(R). MethodTwenty BALB/cAnNHsd mice were housed in Digital Ventilated Cages(R) from Tecniplast(R) with GYM500 home cage running wheels. Mice were assessed by limb use analysis and static weight bearing to determine the development of CIBP and this was compared to the dark-phase home cage activity and wheel running in the Digital Ventilated Cages(R). Ten mice underwent 4T1-Luc2 mammary gland adenocarcinoma cell inoculation into the right femur to establish CIBP and another ten mice underwent a sham surgical procedure. ResultsThe 4T1-inoculated mice displayed pain-like behaviour in limb use and weight bearing tests, demonstrating a preference for the contralateral limb. The limb use scores were compared with home cage activity and wheel running. A reduced wheel running distance corresponded to reduced limb use scores, with the shortest wheel running distances corresponding to the lowest limb use scores. However, this behavioural pattern was not observed in home cage activity, which remained consistent over the study period. DiscussionReduced wheel running corresponded with reduced limb use scores. This suggests that wheel running behaviour is affected by the development of metastatic breast cancer. However, the home cage activity was not influenced by disease development. Digital Ventilated Cage(R) wheel running may be a useful behavioural assessment of spontaneous pain-like behaviour of CIBP and may be useful to assess analgesic efficacy.

animal behavior and cognition↗

bioRxiv2023

Animal psychology research changes public attitudes, but not tolerance, towards a wild carnivore beyond non-psychological information

Studies on wild animal psychology are growing in popularity due to the important role they play in understanding how wildlife is responding to human-driven environmental changes. However, communicating psychological information to the general public could undermine specific conservation objectives by encouraging greater persecution of a species (e.g., "bold" predators). Through a national-level survey (n = 1,364 participants), we tested whether communicating information about the boldness and problem-solving abilities of a wild carnivore, the red fox (Vulpes vulpes), influences peoples tolerance of them. Half of participants were given information on fox psychology (either a video or a press release about fox boldness and problem-solving), the other half were given content related to animal ecology (either a video or a press release about fox habitat use). Afterwards, all participants completed the same 24-item questionnaire evaluating their tolerance of foxes. Although the participants given information about fox psychology were more likely to report a perceived attitude change due to the content they were given, their attitudes relating to fox tolerance remained unaffected regardless of content or format. We encourage further research to understand how communicating different types of information might influence, either positively or negatively, peoples tolerance of a species as more studies on wild animal psychology are published, and the publics awareness of how animal psychology relates to human-wildlife interactions becomes more widespread. HighlightsO_LIStudies on wild animal psychology are growing in popularity C_LIO_LIThe impact of animal psychology research on public attitudes is unclear C_LIO_LIWe tested if fox psychology research influences public tolerance C_LIO_LIPeople given fox psychology information reported greater attitude change C_LIO_LIThis perceived change did not impact peoples overall tolerance of foxes C_LI

animal behavior and cognition↗

bioRxiv2023

Caenorhabditis elegans models for striated muscle disorders caused by missense variants of human LMNA

Striated muscle laminopathies caused by missense mutations in the nuclear lamin gene LMNA are characterized by cardiac dysfunction and often skeletal muscle defects. Attempts to predict which LMNA variants are pathogenic and to understand their physiological effects lags behind variant discovery. We created Caenorhabditis elegans models for striated muscle laminopathies by introducing pathogenic human LMNA variants and variants of unknown significance at conserved residues within the lmn-1 gene. Severe missense variants reduced fertility and/or motility in C. elegans. Nuclear morphology defects were evident in the hypodermal nuclei of many lamin variant strains, indicating a loss of nuclear envelope integrity. Phenotypic severity varied within the two classes of missense mutations involved in striated muscle disease, but overall, variants associated with both skeletal and cardiac muscle defects in humans lead to more severe phenotypes in our model than variants predicted to disrupt cardiac function alone. We also identified a separation of function allele, lmn-1(R204W), that exhibited normal viability and swimming behavior but had a severe nuclear migration defect. Thus, we established C. elegans avatars for striated muscle laminopathies and identified LMNA variants that offer insight into lamin mechanisms during normal development. Author summaryMuscular dystrophy is a progressive muscle-wasting disorder that eventually leads to cardiac disease. Mutations in the LMNA gene, which encodes an intermediate filament protein involved in the structure and organization of the nucleus, is a common but poorly understood cause of this disease. How variants across the breadth of LMNA contribute to mechanistic cellular defects that lead to disease is poorly understood, leading to hurdles in diagnosing disease and developing treatments. We found that by introducing amino acid substitutions found in patients with striated muscle disorders caused by LMNA into the conserved lmn-1 gene of the nematode C. elegans, we could rapidly test the function of these variants to better understand their roles. We found that variants modeling diseases that involve both skeletal and cardiac muscle in humans were the most pathogenic in C. elegans, typically affecting both viability and movement, while those that modeled cardiac disease alone had less deleterious effects in C. elegans. Furthermore, we uncovered molecular mechanisms for how lamins interact with other nuclear envelope proteins to carry out their cellular functions. Thus, our new C. elegans models can be used to diagnose and predict the severity of new variants of human LMNA as well as better understanding the molecular mechanisms of lamins in normal development.

cell biology↗

bioRxiv2023

mPD5, an efficacious PICK1 inhibitor for treating chronic pain

Chronic pain is a complex, debilitating, and escalating health problem worldwide, impacting one in five adults. Current treatment is compromised by dose-limiting side effects including high abuse liability, loss of ability to function socially and professionally, fatigue, drowsiness, and apathy. PICK1 has emerged as a promising target for the treatment of chronic pain conditions. Here, we develop and characterize a cell-permeable fatty acid conjugated bivalent peptide inhibitor of PICK1 and assess its effects on acute and chronic pain. The myristoylated myr-NPEG4-(HWLKV)2, (mPD5), self-assembles into core-shell micelles that provide favourable pharmacodynamic properties and relieves ongoing and evoked mechanical hypersensitivity, thermal hypersensitivity as well as anxio-depressive symptoms in mouse models of neuropathic and inflammatory pain following subcutaneous administration. No overt no side effects were associated with mPD5 administration, and it has no effect on acute nociception. Finally, neuropathic pain is relieved far into the chronic phase (18 weeks post SNI surgery) and while the effect of a single injection ceases after a few hours, repeated administration provides pain relief lasting up to 20 hours after the last injection.

pharmacology and toxicology↗

bioRxiv2018

Utilizing comprehensive and mini-kinome panels to optimize the selectivity of quinoline inhibitors for cyclin G associated kinase (GAK)

We demonstrate an innovative approach utilising both fit-for-purpose kinase mini-panels and kinome-wide panels to progress discovery programs in the optimization of inhibitor potency and selectivity. We present a focused case study on development of a selective inhibitor of cyclin G associated kinase (GAK) using the quin(az)oline inhibitor chemotype. These results exemplify a versatile, efficient approach to drive kinome selectivity during inhibitor development programs.

pharmacology and toxicology↗

bioRxiv2017

Microevolutionary processes underlying macroevolutionary patterns of electric signal diversity in mormyrid fish

The mormyrid fish species Paramormyrops kingsleyae emits an electric organ discharge (EOD) with a dual role in communication and electrolocation. Populations of P. kingsleyae have either biphasic or triphasic EODs, a feature which characterizes interspecific signal diversity among the Paramormyrops genus. We quantified variation in EODs of 327 P. kingsleyae from 9 populations throughout Gabon and compared it to genetic variation estimated from 5 neutral microsatellite loci. We found no correlation between electric signal and genetic distances, suggesting that EOD divergence between populations of P. kingsleyae cannot be explained by drift alone. An alternative hypothesis is that EOD differences are a cue for assortative mating, which would require P. kingsleyae be capable of differentiating between divergent EOD waveforms. Using a habituation-dishabituation assay, we found that P. kingsleyae can discriminate between triphasic and biphasic EOD types. Nonetheless, patterns of genetic and electric organ morphology divergence provide evidence for hybridization between signal types. Although reproductive isolation with respect to signal type is not absolute, our results suggest that EOD variation in P. kingsleaye has the potential to serve as a cue for assortative mating and point to selective forces rather than drift as important drivers of signal evolution.

evolutionary biology↗