Biology subjects

Foxall, E.

Publications and source records attributed to Foxall, E..

5 recordsLinked to original sources

bioRxiv2025

A mouse model of PTEN Hamartoma Tumour Syndrome reveals that loss of the nuclear function of PTEN drives macrocephaly, lymphoid overgrowth, and late-onset cancer

PTEN Hamartoma Tumour Syndrome (PHTS) is a rare disorder characterized by germline heterozygous mutations in the PTEN tumour suppressor gene, leading to multi-organ/tissue overgrowth, autism spectrum disorder and increased cancer risk. PHTS individuals display heterogeneity in phenotypes, which has been linked in part to the diverse genetic alterations in the PTEN gene and the multifaceted functions of this protein. Indeed, while PTEN primarily functions as a PIP3 lipid phosphatase in the cytosol, regulating PI3K/AKT signalling, a pathway commonly deregulated in cancer, it also plays crucial roles in maintaining chromosomal stability through nuclear activities such as double strand (ds) DNA damage repair. Recent studies have identified a subset of missense PHTS variants that cause nuclear exclusion of PTEN, impairing its nuclear functions. Here, we present our findings from one such pathogenic variant, PTEN-R173C, frequently found in PHTS and somatic cancers. Using cell biological and mouse modelling approaches, we show that PTEN-R173C has higher PIP3 phosphatase activity than wild-type PTEN, resulting in effective regulation of canonical PI3K/AKT signalling. However, PTEN-R173C is unstable and excluded from the nucleus. Aligning with their near normal PI3K/AKT signalling, Pten+/R173Cmice display a low incidence of solid tumours compared to Pten+/-mice. Pten+/R173C mice also exhibit lymphoid hyperplasia and macrocephaly which correlates with compromised nuclear functions of PTEN-R173C. That nuclear functions are compromised is demonstrated by reduced dsDNA damage repair in Pten+/R173Cmice. Integrating PHTS patient data with findings from our mouse model, our study indicates that nuclear dysfunction of pathogenic PTEN variants is a key factor in predicting the onset of the different PHTS-associated phenotypes. We speculate that late-onset cancer in individuals with nuclear-excluded PTEN results from genetic alterations unrelated to PTEN itself, facilitated by impaired PTEN-mediated dsDNA damage repair.

genetics↗

bioRxiv2024

Dynamic energy budget model for a bumble bee colony: Predicting the spatial distribution and dynamics of colonies across multiple seasons

Bumble bees are important pollinators of many crops around the world. In recent decades, agricultural intensification has resulted in significant declines in bumble bee populations and the pollination services they provide. Empirical studies have shown that this trend can be reversed, however, by enhancing the agricultural landscape with natural habitat, such as adding wildflower patches adjacent to crops. Despite the empirical evidence, the mechanisms behind these positive effects are not fully understood, and the specific characteristics of the enhanced natural habitat that would maximize benefits are unclear at this time. Theoretical studies, in the form of mathematical models, have proven useful in elucidating the underlying mechanisms and determining the optimal natural habitat configurations. Existing models, however, generally focus only on particular aspects of bumble bee behaviour; some models are accurate at describing population dynamics, while others are accurate at describing their spatial distribution. In this work, we build a unique model coupling population dynamics, using a whole-colony Dynamic Energy Budget (DEB) approach, to a spatial distribution model based on the maximum energy principle. This coupling gives valuable new insights into the effects of spatial arrangements on population dynamics, and vice-versa. With our model, we answer questions such as when, how much, or what type of wildflower patches should be planted to maximize crop pollination services and minimize bee decline. We find that planting wildflowers that bloom before and after crop bloom is crucial to achieve high pollination services and preserving wild pollinator populations. We also find that small quantities of natural habitat are needed when the crop is nutritionally rich, but higher quantities are most beneficial when the crop is nutritionally deficient.

ecology↗

bioRxiv2022

How nutrition and energy needs affect bumble beepollination services: A mathematical model

The balance between nutrition and energy needs has an important impact on the spatial distribution of foraging animals. In the present paper, we focus on the case of bumble bees moving around a landscape in search of pollen (to meet nutritional needs) and nectar (to meet energy needs). Depending on the colony demands, bumble bees can concentrate their foraging effort towards either pollen rich flower species or nectar rich flower species. This behaviour allows us to establish a strategy - a spatial landscape design - which can maximize the pollination services of crops that are nutritionally deficient for pollinators by adding nutritionally rich wildflower patches. To do this, we formulate a mathematical partial integro-differential equation model to predict the spatial distribution of foraging bumble bees. We use our model to predict the location, composition and quantity of the wildflower patches adjacent to crop fields that will be most beneficial for crop pollination services. Our results show that relatively small quantities of wildflowers in specific locations with respect to the nest sites and the crop can have a positive impact on pollination services when the composition (i.e., pollen to nectar ratio) of the added wildflowers is significantly different from the composition of the existing crop flowers.

ecology↗

bioRxiv2018

Patient-specific detection of cancer genes reveals recurrently perturbed processes in esophageal adenocarcinoma

The identification of somatic alterations with a cancer promoting role is challenging in highly unstable and heterogeneous cancers, such as esophageal adenocarcinoma (EAC). Here we developed a machine learning algorithm to identify cancer genes in individual patients considering all types of damaging alterations simultaneously (mutations, copy number alterations and structural rearrangements). Analysing 261 EACs from the OCCAMS Consortium, we discovered a large number of novel cancer genes that, together with well-known drivers, help promote cancer. Validation using 107 additional EACs confirmed the robustness of the approach. Unlike known drivers whose alterations recur across patients, the large majority of the newly discovered cancer genes are rare or patient-specific. Despite this, they converge towards perturbing cancer-related processes, including intracellular signalling, cell cycle regulation, proteasome activity and Toll-like receptor signalling. Recurrence of process perturbation, rather than individual genes, divides EACs into six clusters that differ in their molecular and clinical features and suggest patient stratifications for personalised treatments. By experimentally mimicking or reverting alterations of predicted cancer genes, we validated their contribution to cancer progression and revealed EAC acquired dependencies, thus demonstrating their potential as therapeutic targets.

cancer biology↗

bioRxiv2017

Tragedy Of The Commons In The Chemostat

We present a proof of principle for the phenomenon of the tragedy of the commons that is at the center of many theories on the evolution of cooperation. We establish the tragedy in the context of a general chemostat model with two species, the cooperator and the cheater. Both species have the same growth rate function and yield constant, but the cooperator allocates a portion of the nutrient uptake towards the production of a public good -the \"Commons\" in the Tragedy-which is needed to digest the externally supplied nutrient. The cheater on the other hand does not produce this enzyme, and allocates all nutrient uptake towards its own growth. We prove that when the cheater is present initially, both the cooperator and the cheater will eventually go extinct, hereby confirming the occurrence of the tragedy. We also show that without the cheater, the cooperator can survive indefinitely, provided that at least a low level of public good or processed nutrient is available initially. Our results provide a predictive framework for the analysis of cooperator-cheater dynamics in a powerful model system of experimental evolution.

evolutionary biology↗