Biology subjects

Brown, A. E.

Publications and source records attributed to Brown, A. E..

15 recordsLinked to original sources

bioRxiv2026

Distinct genetic requirements underlie LITE-1-dependent photosensation and avoidance of high concentration of diacetyl in C. elegans

The eyeless nematode C. elegans can detect and respond to aversive blue and ultraviolet light using the gustatory receptor homolog LITE-1. In addition to its role in phototransduction, LITE-1 also functions as a chemoreceptor for the odorants diacetyl and 2,3-pentanedione. However, whether these different sensory modalities rely on the same downstream signalling components is unknown. In this study, we provide behavioural evidence that unlike its LITE-1-dependent photosensory function which relies on cGMP signalling components, its chemosensory function remains intact in mutants with disrupted cGMP signalling.

neuroscience↗

bioRxiv2025

How peak knee loads are affected by changing the mass of lower-limb body segments during walking

For individuals with knee osteoarthritis, increased knee loading is linked to disease progression and pain. Some approaches to treating osteoarthritis, such as specialized footwear, braces, and powered exoskeletons, also increase the mass of the lower limbs, which could lead to increases in knee loads. Prior studies have investigated the effect of changes in torso mass and total body mass on peak knee contact forces, but the effects of increased leg mass remain unclear. In this study, we created musculoskeletal simulations informed by experimental data to estimate tibiofemoral knee contact force under different lower-limb segment mass conditions. The mass of the foot, shank, and thigh were varied by adding weights to each segment, separately and concurrently, as healthy young adults (N = 10) walked on a treadmill. Kinematics, kinetics, and muscle activity were recorded. Our simulations used an optimal control framework that enforced experimental kinematics while minimizing a combination of net joint moment errors and mismatch between measured and estimated muscle activity. The simulations revealed that adding mass to the lower-limb segments linearly increased early- and late-stance peaks in knee contact force, but that the slope of this relationship was different for each peak and each mass placement location. For each 1% of body weight (BW) added per limb (2% BW total) at the thigh, shank, and foot, early-stance peak knee contact force increased by 1.5%, 2.1%, and 5.9%, while late-stance peak contact force increased by 1.6%, 0.9% and 3.0%, respectively. Adding mass to the thigh and shank increases peak contact force at or below the rate of increase in body mass, while adding mass to the foot disproportionately increases peak knee contact force. These detrimental effects should be considered when designing interventions for osteoarthritis. Author summaryFor individuals with knee osteoarthritis, increased knee loading is linked to disease progression and pain. Some approaches to treating knee OA, such as specialized footwear, braces, and exoskeletons, increase the mass of the lower limbs, which could lead to increases in knee loads. However, the effects of changing lower limb segment mass on knee loading remain unclear. In this study, we created computer simulations informed by experimental data to estimate knee loads while walking with different amounts of added mass to the lower limb segments. We collected experimental data from 10 healthy participants while they walked on a treadmill with various amounts of mass added to their lower limb segments (thigh, shank, foot). We used these data and a biomechanically accurate model of each participant to construct realistic computer simulations, from which we obtained estimates of internal knee forces that contribute to total knee load. We found that peak knee load increased linearly with amount of added mass, but that this relationship differed by segment. Adding mass to the feet had the greatest effect on knee contact force. Our results can help to inform the design of interventions for knee osteoarthritis.

systems biology↗

bioRxiv2023

Systematic creation and phenotyping of Mendelian disease models in C. elegens: towards large-scale drug repurposing

There are thousands of Mendelian diseases with more being discovered weekly and the majority have no approved treatments. To address this need, we require scalable approaches that are relatively inexpensive compared to traditional drug development. In the absence of a validated drug target, phenotypic screening in model organisms provides a route for identifying candidate treatments. Success requires a screenable phenotype, however the right phenotype and assay may not be obvious for pleiotropic neuromuscular disorders. Here we show that high-throughput imaging and quantitative phenotyping can be conducted systematically on a panel of C. elegans disease model strains. We used CRISPR genome-editing to create 25 worm models of human Mendelian diseases and phenotyped them using a single standardised assay. All but two strains were significantly different from wild-type controls in at least one feature. The observed phenotypes were diverse, but mutations of genes predicted to have related functions in their human orthologs led to similar behavioural differences in worms. As a proof-of-concept, we performed a drug repurposing screen of an FDA approved compound library, and identified two compounds that rescued the behavioural phenotype of a model of UNC80 deficiency. Our results show that a single assay to measure multiple phenotypes can be applied systematically to diverse Mendelian disease models. The relatively short time and low cost associated with creating and phenotyping multiple strains suggests that high-throughput worm tracking could provide a scalable approach to drug repurposing commensurate with the number of Mendelian diseases.

animal behavior and cognition↗

bioRxiv2023

A drug repurposing screen for whipworms informed by comparative genomics

Hundreds of millions of people worldwide are infected with the whipworm Trichuris trichiura. Novel treatments are urgently needed as current drugs, such as albendazole, have relatively low efficacy. We have investigated whether drugs approved for other human diseases could be repurposed as novel anti-whipworm drugs. In a previous comparative genomics analysis, we identified 409 drugs approved for human use that we predicted to target parasitic worm proteins. Here we tested these ex vivo by assessing motility of adult worms of Trichuris muris, the murine whipworm, an established model for human whipworm research. We identified 14 compounds with EC50 values of[≤] 50 M against T. muris ex vivo, and selected nine for testing in vivo. However, the best worm burden reduction seen in mice was just 19%. The high number of ex vivo hits against T. muris shows that we were successful at predicting parasite proteins that could be targeted by approved drugs. In contrast, the low efficacy of these compounds in mice suggest challenges due to their chemical properties (e.g. lipophilicity, polarity, molecular weight) and pharmacokinetics (e.g. absorption, distribution, metabolism, and excretion) that may (i) promote absorption by the host gastrointestinal tract, thereby reducing availability to the worms embedded in the large intestine, and/or (ii) restrict drug uptake by the worms. This indicates that identifying structural analogues that have reduced absorption by the host, and increased uptake by worms, may be necessary for successful drug repurposing against whipworms. Therefore, we recommend that prior to in vivo studies, future researchers first assess drug absorption by the host, for example, using human intestinal organoids or cell lines, and drug uptake by whipworms using intestinal organoids infected with T. muris.

pharmacology and toxicology↗

bioRxiv2021

Megapixel camera arrays for high-resolution animal tracking in multiwell plates

Tracking small laboratory animals such as flies, fish, and worms is used for phenotyping in neuroscience, genetics, disease modelling, and drug discovery. Current imaging systems are limited either in spatial resolution or throughput. A system capable of imaging a large number of animals with sufficient resolution to estimate their pose would enable a new class of experiments where detailed behavioural differences are quantified but at a scale where hundreds of treatments can be tested simultaneously. Here we report a new imaging system consisting of an array of six 12-megapixel cameras that can simultaneously record from all the wells of a 96-well plate with a resolution of 80 pixels/mm at 25 frames per second. We show that this resolution is sufficient to estimate the pose of nematode worms including head identification and to extract high-dimensional phenotypic fingerprints. We use the system to study behavioural variability across wild isolates, the sensitisation of worms to repeated blue light stimulation, the phenotypes of worm disease models, and worms behavioural responses to drug treatment. Because the system is compatible with standard multiwell plates, it makes computational ethological approaches accessible in existing high-throughput pipelines and greatly increases the scale of possible phenotypic screening experiments in C. elegans.

animal behavior and cognition↗

bioRxiv2020

Quantitative Behavioural Phenotyping to Investigate Anaesthesia-Induced Neurobehavioural Impairment

BackgroundVertebrate animal experiments have suggested that anaesthesia exposure to the developing nervous system causes neuroapoptosis and behavioural impairment. Mechanistic understanding is limited, and target-based approaches are challenging. High-throughput methods may be an important parallel approach to drug-discovery and mechanistic research. The nematode worm Caenorhabditis elegans is an ideal candidate as a model for this. A rich subset of its behaviour can be studied, and hundreds of morphological and behavioural features can be quantified, then aggregated to yield a signature. Perturbation of this behavioural signature may provide a tool that can be used to quantify the effects of anaesthetic regimes, and act as an outcome marker for drug screening and molecular target research. MethodsLarval C. elegans were exposed to: isoflurane, ketamine, morphine, dexmedetomidine, and lithium (and combinations). Behaviour was recorded, and videos analysed with automated algorithms to extract behavioural and morphological features. ResultsAnaesthetic exposure during early development leads to persisting morphological and behavioural variation (in total, 125 features/exposure combinations). Higher concentrations, and combinations of isoflurane with ketamine, lead to more feature hits. Morphine and dexmedetomidine do not appear to lead to behavioural impairment. Lithium rescues the neurotoxic phenotype produced by isoflurane. ConclusionsFindings correlate well with vertebrate research: impairment is dependent on agent, is concentration-specific, is more likely with combination therapies, and can potentially be rescued by lithium. These results suggest that C. elegans may be an appropriate model with which to pursue phenotypic screens for drugs that mitigate the neurobehavioural impairment. Some possibilities are suggested for how high-throughput platforms might be organised in service of this field.

animal behavior and cognition↗

bioRxiv2019

Multidimensional phenotyping predicts lifespan and quantifies health in C. elegans

Ageing affects a wide range of phenotypes at all scales, but an objective measure of ageing remains challenging, even in simple model organisms. We assumed that a wide range of phenotypes at the organismal scale rather than a limited number of biomarkers of ageing would best describe the ageing process. Hundreds of morphological, postural and behavioural features are extracted at once from high resolutions videos. A quantitative model using this multi-parametric dataset can predict the biological age and lifespan of individual C. elegans. We show that the quality of predictions on a held-out data set increases with the number of features added to the model, supporting our initial hypothesis. Despite the large diversity of ageing mechanisms, including stochastic insults, our results highlight a robust ageing trajectory, but variable ageing rates along that trajectory. We show that healthspan, which we defined as the range of abilities of the animals, is correlated to lifespan in wild-type worms.

systems biology↗

bioRxiv2019

Deep behavioural phenotyping reveals divergent trajectories of ageing and quantifies health state in C. elegans

Neurodegenerative diseases may be the cause or the consequence of an acceleration of physiological ageing. Evidence for this concept is lacking due to practical limitations of human studies. Here, we compared the processes of physiological and pathological ageing of individual C. elegans over their lifespan. Using multi-parametric phenotyping, trajectories of ageing can be defined within a phenotypic landscape made of a large set of phenotypical features. Rather than an acceleration of ageing, a model for synucleinopathy showed a divergent trajectory of ageing. The pathological progression in individual animals can be predicted from early phenotypes with high accuracy. Despite of similar lifespans, disease-model worms display an early onset of decline in their phenotypic range of ability. This loss of flexibility provides an index of health valid for physiological and pathological contexts. Finally, we demonstrate the power of multi-parametric dataset to describe ageing, to quantify health and to predict specific health risks.

systems biology↗

bioRxiv2018

Common behavioral mechanisms underlie C. elegans aggregation and swarming

In complex biological systems, simple individual-level behavioral rules can give rise to emergent group-level behavior. While such collective behavior has been well studied in cells and larger organisms, the mesoscopic scale is less understood, as it is unclear which sensory inputs and physical processes matter a priori. Here, we investigate collective feeding in the roundworm C. elegans at this intermediate scale, using quantitative phenotyping and agent-based modeling to identify behavioral rules underlying both aggregation and swarming--a dynamic phenotype only observed at longer timescales. Using fluorescent multi-worm tracking, we quantify aggregation behavior in terms of individual dynamics and population-level statistics. Based on our quantification, we use agent-based simulations and approximate Bayesian inference to identify three key behavioral rules that give rise to aggregation: cluster-edge reversals, a density-dependent switch between crawling speeds, and taxis towards neighboring worms. Our simulations suggest that swarming is simply driven by local food depletion but otherwise employs the same behavioral mechanisms as the initial aggregation. Hence, mesoscopic C. elegans uses mechanisms familiar from microscopic systems for aggregation, but implemented via more complex behaviors characteristic of macroscopic organisms.

biophysics↗

bioRxiv2018

Powerful and interpretable behavioural features for quantitative phenotyping of C. elegans

Behaviour is a sensitive and integrative readout of nervous system function and therefore an attractive measure for assessing the effects of mutation or drug treatment on animals. Video data provides a rich but high-dimensional representation of behaviour and so the first step of analysis is often some form of tracking and feature extraction to reduce dimensionality while maintaining relevant information. Modern machine learning methods are powerful but notoriously difficult to interpret, while handcrafted features are interpretable but do not always perform as well. Here we report a new set of handcrafted features to compactly quantify C. elegans behaviour. The features are designed to be interpretable but to capture as much of the phenotypic differences between worms as possible. We show that the full feature set is more powerful than a previously defined feature set in classifying mutant strains. We then use a combination of automated and manual feature selection to define a core set of interpretable features that still provides sufficient power to detect behavioural differences between mutant strains and the wild type. Finally, we apply the new features to detect time-resolved behavioural differences in a series of optogenetic experiments targeting different neural subsets.

animal behavior and cognition↗

bioRxiv2018

An open source platform for analyzing and sharing worm behavior data

Animal behavior is increasingly being recorded in systematic imaging studies that generate large data sets. To maximize the usefulness of these data there is a need for improved resources for analyzing and sharing behavior data that will encourage re-analysis and method development by computational scientists1. However, unlike genomic or protein structural data, there are no widely used standards for behavior data. It is therefore desirable to make the data available in a relatively raw form so that different investigators can use their own representations and derive their own features. For computational ethology to approach the level of maturity of other areas of bioinformatics, we need to address at least three challenges: storing and accessing video files, defining flexible data formats to facilitate data sharing, and making software to read, write, browse, and analyze the data. We have developed an open resource to begin addressing these challenges using worm tracking as a model.

animal behavior and cognition↗

bioRxiv2018

Mixing patterns of HIV transmission among men who have sex with men in the United Kingdom

BackgroundNear 60% of new HIV infections in the United Kingdom are estimated to occur in men who have sex with men (MSM). Patterns of mixing between different risk groups of MSM have been suggested to spread the HIV epidemics through age-disassortative partnerships and to contribute to ethnic disparities in infection rates. Understanding these mixing patterns in transmission can help to determine which groups are at a greater risk and guide prevention.\n\nMethodsWe analyzed combined epidemiologic data and viral sequences from MSM diagnosed with HIV as of mid-2015 at the national level. We applied a phylodynamic source attribution model to infer patterns of transmission between groups of patients by age, ethnicity and region.\n\nResultsFrom pair probabilities of transmission between 19 847 MSM patients, we found that potential transmitters of HIV subtype B were on average 5 months older than recipients. We also found a moderate overall assortativity of transmission by ethnic group and a stronger assortativity by region.\n\nConclusionsOur findings suggest that there is only a modest net flow of transmissions from older to young MSM in subtype B epidemics and that young MSM, both for Black or White groups, are more likely to be infected by one another than expected in a sexual network with random mixing.

epidemiology↗

bioRxiv2018

2,4-Diaminothienopyrimidines, a new class of anthelmintic with activity against adult and egg stages of whipworm

The human whipworm Trichuris trichiura is a parasite that infects around 500 million people globally, with consequences including damage to physical growth and educational performance. Current drugs such as mebendazole have a notable lack of efficacy against whipworm, compared to other soil-transmitted helminths. Mass drug administration programs are therefore unlikely to achieve eradication and new treatments for trichuriasis are desperately needed. All current drug control strategies focus on post-infection eradication, targeting the parasite in vivo. Here we propose developing novel anthelmintics which target the egg stage of the parasite in the soil as an adjunct environmental strategy. As evidence in support of such an approach we describe the actions of a new class of anthelmintic compounds, the 2,4-diaminothieno[3,2-d]pyrimidines (DATPs). This compound class has found broad utility in medicinal chemistry, but has not previously been described as having anthelmintic activity. Importantly, these compounds show efficacy against not only the adult parasite, but also both the embryonated and unembryonated egg stages and thereby may enable a break in the parasite lifecycle.\n\nAuthor SummaryThe human whipworm, Trichuris trichiura, infects around 500 million people globally, impacting on their physical growth and educational performance. There are currently huge mass drug administration (MDA) programs aiming to control whipworm, along with the other major soil transmitted helminths, Ascaris and hookworm. However single doses of albendazole and mebendazole, which are used in MDA, have particularly poor effectiveness against whipworm, with cure rates less than 40%. This means that MDA may not be able to control and eliminate whipworm infection, and risks the spread of resistance to albendazole and mebendazole in the parasite population.\n\nWe are attempting to develop new treatments for parasitic worm infection, particularly focused on whipworm. We report the identification of a class of compounds, diaminothienopyrimidines (DATPs), which have not previously been described as anthelmintics. These compounds are effective against adult stages of whipworm, and also block the development of the model nematode C. elegans.\n\nOur DATP compounds reduce the ability of treated eggs to successfully establish infection in a mouse model of human whipworm. These results support a potential environmental spray to control whipworm by targeting the infectious egg stage in environmental hotspots.

pharmacology and toxicology↗

bioRxiv2017

The study of animal behaviour as a physical science

Behaviour is the ultimate output of an animals nervous system and choosing the right action at the right time can be critical for survival. The study of the organisation of behaviour in its natural context, ethology, has historically been a primarily qualitative science. A quantitative theory of behaviour would advance research in neuroscience as well as ecology and evolution. However, animal posture typically has many degrees of freedom and behavioural dynamics vary on timescales ranging from milliseconds to years, presenting both technical and conceptual challenges. Here we review 1) advances in imaging and computer vision that are making it possible to capture increasingly complete records of animal motion and 2) new approaches to understanding the resulting behavioural data sets. With the right analytical approaches, these data are allowing researchers to revisit longstanding questions about the structure and organisation of animal behaviour and to put unifying principles on a quantitative footing. Contributions from both experimentalists and theorists are leading to the emergence of a physics of behaviour and the prospect of discovering laws and developing theories with broad applicability. We believe that there now exists an opportunity to develop theories of behaviour which can be tested using these data sets leading to a deeper understanding of how and why animals behave.

animal behavior and cognition↗

bioRxiv2017

An automated high-throughput system for phenotypic screening of chemical libraries on C. elegans and parasitic nematodes

Parasitic nematodes infect hundreds of millions of people and farmed livestock. Further, plant parasitic nematodes result in major crop damage. The pipeline of therapeutic compounds is limited and parasite resistance to the existing anthelmintic compounds is a global threat. We have developed an INVertebrate Automated Phenotyping Platform (INVAPP) for high-throughput, plate-based chemical screening, and an algorithm (Paragon) which allows screening for compounds that have an effect on motility and development of parasitic worms. We have validated its utility by determining the efficacy of a panel of known anthelmintics against model and parasitic nematodes: Caenorhabditis elegans, Haemonchus contortus, Teladorsagia circumcincta, and Trichuris muris. We then applied the system to screen the Pathogen Box chemical library in a blinded fashion and identified known anthelmintics, including tolfenpyrad, auranofin, and mebendazole and 14 compounds previously undescribed as anthelmintics, including benzoxaborole and isoxazole chemotypes. This system offers an effective, high-throughput system for the discovery of novel anthelmintics.

pharmacology and toxicology↗