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Boyle, J.

Publications and source records attributed to Boyle, J..

6 recordsLinked to original sources

Inferring Cell-Cell Interaction Dynamics from Cell Trajectory Data Using Deep Attention Networks

Interactions between nearby cells are a key driver of cell movement in many biological systems, including collective cell migration and the immune response to cancer. However, inferring the interaction rules in a given system in a manner that is both accurate and biologically interpretable remains a challenge. A valuable experimental method for analysing cell-cell interaction dynamics is the tracking of individual cell locations over a series of time-lapse images, and in this work we present a model, based on the theory of deep attention networks, that learns how cell-cell interactions affect cell movement directly from cell trajectory data. Our approach requires no a priori assumptions about the mechanisms governing cell behaviour, enabling its application to cell trajectory data originating from a diverse range of biological systems. In addition to the model, we develop a suite of tools that exploit the models attention-based structure to present the learned interaction dynamics in an interpretable manner. Our model extends previous applications of deep attention networks to cell movement by providing deeper insights into cell-cell interaction dynamics, moving beyond inferring whether cells interact to inferring how these interactions affect cell movement, and providing the ability to infer type dependent cell-cell interaction dynamics in multi-type cell movement systems. By combining data-driven learning and structural interpretability, our approach represents a highly general methodology for linking cell trajectory data to mechanistic hypotheses, showing that deep attention networks constitute a powerful exploratory tool for characterising the effect of cell-cell interactions on cell movement in complex cellular systems.

cell biology↗

Dissecting the oncogenic mechanisms of POT1 cancer mutations through deep scanning mutagenesis

Mutations in the shelterin protein POT1 are associated with diverse cancers, but their role in cancer progression remains unclear. To resolve this, we performed deep scanning mutagenesis in POT1 locally haploid human stem cells to assess the impact of POT1 variants on cellular viability and cancer-associated telomeric phenotypes. Though POT1 is essential, frame-shift mutants are rescued by chemical ATR inhibition, indicating that POT1 is not required for telomere replication or lagging strand synthesis. In contrast, a substantial fraction of clinically-validated pathogenic mutations support normal cellular proliferation, but still drive ATR-dependent telomeric DNA damage signaling and ATR-independent telomere elongation. Moreover, this class of cancer-associated POT1 variants elongates telomeres more rapidly than POT1 frame-shifts, indicating they actively drive oncogenesis and are not simple loss-of-function mutations.

cancer biology↗

Behavioral Imitation with Artificial Neural Networks Leads to Personalized Models of Brain Dynamics During Videogame Play

Videogames provide a promising framework to understand brain activity in a rich, engaging, and active environment, in contrast to mostly passive tasks currently dominating the field, such as image viewing. Analyzing videogames neuroimaging data is however challenging, and relies on time-intensive manual annotations of game events, based on somewhat arbitrary rules. Here, we introduce an innovative approach using Artificial Neural networks (ANN) and brain encoding techniques to generate activation maps associated with videogame behaviour using functional magnetic resonance imaging (fMRI). As individual behavior is highly variable across subjects in complex environments, we hypothesized that ANNs need to account for subject-specific behavior to properly capture brain dynamics. In this study, we used data collected while subjects played Shinobi III: Return of the Ninja Master (Sega, 1993), an action-platformer videogame. Using imitation learning, we trained an ANN to play the game while closely replicating the unique gameplay style of individual participants. We found that hidden layers of our imitation learning model successfully encoded task-relevant neural representations, and predicted individual brain dynamics with higher accuracy than models trained on other subjects gameplay. Individual-specific models also outperformed a number of baselines to predict brain activity, such as pixel inputs, or button presses. The highest correlations between layer activations and brain signals were observed in biologically plausible brain areas, i.e. somatosensory, attention, and visual networks. Our results demonstrate that training subject-specific ANNs can successfully uncover brain correlates of complex behaviour. This new method combining imitation learning, brain imaging, and videogames opens new research avenues to study decision-making and psychomotor task solving in naturalistic and complex environments.

neuroscience↗

Temporal matches and mismatches between monarch butterfly and milkweed population changes over the past 12,000 years

In intimate ecological interactions, the interdependency of species may result in correlated demographic histories. For species of conservation concern, understanding the long-term dynamics of such interactions may shed light on the drivers of population decline. Here we address the demographic history of the monarch butterfly, Danaus plexippus, and its dominant host plant, the common milkweed Asclepias syriaca, using broad-scale sampling and genomic inference. Because genetic resources for milkweed have lagged behind those for monarchs, we first release a chromosome-level genome assembly and annotation for common milkweed. Next, we show that despite its enormous geographic range across eastern North America, A. syriaca is best characterized as a single, roughly panmictic population. Using Approximate Bayesian Computation via Random Forests (ABC-RF), a machine learning method for reconstructing demographic histories, we show that both monarchs and milkweed experienced concurrent range expansion during the most recent recession of North American glaciers [~]12,000 years ago. Our data identify an expansion of milkweed during the large-scale clearing of eastern forests ([~]200 years ago) but was inconclusive as to expansion or contraction of the monarch butterfly population during this time. Finally, our results indicate that neither species experienced a population contraction over the past 75 years. Thus, the well-documented decline of monarch abundance over the past 40 years is not visible in our genomic dataset, reflecting a possible mismatch of the overwintering census population to effective population size in this species.

evolutionary biology↗

Myocardial damage induced by a single high dose of isoproterenol in C57Bl/6J mice triggers a persistent adaptive immune response against the heart.

Heart failure is the common final pathway of a range of conditions resulting in myocardial damage and a major cause of morbidity and mortality worldwide. Strategies to improve tissue repair and prevent heart failure thus remain an urgent clinical need. Recent studies have documented activation of the adaptive immune system in response to myocardial damage and have implicated anti-heart autoimmunity in the development of heart failure. In an attempt to target anti-heart autoimmune responses as new therapeutic avenue, the number of experimental studies using in vivo models of myocardial damage to study the ensuing immune response has surged. The beta-adrenergic agonist isoproterenol-hydrochloride has been used for its cardiac effects in a variety of different dosing and administration regimes. Most prominently, low doses (<10mg/kg sc) over an extended time period induce cardiac hypertrophy and fibrosis. In addition, single injections of high doses (>100mg/kg) induce cardiomyocyte necrosis and have been used to mimic acute myocardial necrotic lesions as seen in myocardial infarction (MI). However, despite significant resource and animal welfare advantages, concerns about off-target effects and clinical relevance have so far limited uptake in the cardiovascular research community. To assess suitability of the isoproterenol model for the analysis of chronic post-MI immunological readouts, we treated C57BL/6J mice with a single intra-peritoneal bolus injection of 160mg/kg isoproterenol. Our results confirm the presence of necrotic lesions in the myocardium with significant resemblance of the histopathology of Type 2 MI. Kidneys develop mild fibrosis secondary to early cardiac damage, while other organs remain unaffected. Most importantly, we showed that isoproterenol treatment causes myocardial inflammation and fibrosis, activation of T cells in the heart-draining mediastinal lymph nodes, deposition of mature antibodies in the myocardium and the presence of auto-antibodies against the heart in the serum 12 weeks after the initial injury. In summary, this simple and cost-effective experimental model with significant animal welfare benefits induces myocardial damage reminiscent of human Type 2 MI, which is followed by a persistent adaptive immune response against the heart. This makes it a suitable and high-throughput model to study pathological mechanisms of anti-heart autoimmunity as well as to test potential immunomodulatory therapeutic approaches.

immunology↗

Population genomics and demographic sampling of the ant-plant Vachellia drepanolobium and its symbiotic ants from sites across its range in East Africa.

The association between the African ant plant, Vachellia drepanolobium, and the ants that inhabit it has provided insight into the boundaries between mutualism and parasitism, the response of symbioses to environmental perturbations, and the ecology of species coexistence. We use a landscape genomics approach at sites sampled throughout the range of this system in Kenya to investigate the demographics and genetic structure of the different partners in the association. We find that different species of ant associates of V. drepanolobium show striking differences in their spatial distribution throughout Kenya, and these differences are only partly correlated with abiotic factors. A comparison of the population structure of the host plant and its three obligately arboreal ant symbionts, Crematogaster mimosae, Crematogaster nigriceps, and Tetraponera penzigi, shows that the ants exhibit somewhat similar patterns of structure throughout each of their respective ranges, but that this does not correlate in any clear way with the respective genetic structure of the populations of their host plants. A lack of evidence for local coadaptation in this system suggests that all partners have evolved to cope with a wide variety of biotic and abiotic conditions.

ecology↗