Biology subjects

McNamara, L.

Publications and source records attributed to McNamara, L..

6 recordsLinked to original sources

bioRxiv2025

Stress-dependent growth of breast cancer models emerges from a cellular volume checkpoint

Mechanoresponsive cell proliferation is a feature of growing tumours, despite the suppression of many other regulatory checkpoints in cancer, but the underlying cell-scale mechanisms driving this behaviour have not yet been established. In this study we propose a biophysical model for cell growth as governed by actively controlled osmolarity, which we integrate with a discrete particle framework to simulate growth and remodelling of breast cancer spheroids. Confinement and biomechanical feedback from the extracellular environment are analysed through a neuralnetwork-accelerated finite element solver. Combining the framework with experiments, our model reveals that stress-dependent spheroid growth can arise from a sizing checkpoint for mitosis. Under sufficient extracellular loading, cell growth is restricted by high hydrostatic forces in competition with osmotic pressure from biomolecule synthesis, which prevents cells from surpassing a critical volume. Our model provides new insight into mechanosensitive growth arrest in breast cancer, potentially serving as a computational tool for analysing growth in a wider range of normal and malignant biological tissues.

cancer biology↗

bioRxiv2025

Cross-species proteomics quantification pipeline distinguishes donor versus host extracellular matrix in explanted biomaterials

Xenogenic biomaterial durability, including bioprosthetic heart valves (BPVs), is compromised by pathological extracellular matrix (ECM) remodeling, resulting in progressive structural degeneration. Mass spectrometry-based proteomics can help reveal BPV degeneration mechanisms; however, peptide sequence similarity between donor and host species complicates protein-level analysis. We present a cross-species proteomic analytical strategy for xenogenic biomaterials and cross-species proteomic datasets. In silico tryptic digestion of human and bovine protein databases identified over 400 overlapping proteins with a high protein percent identity. Explanted human BPV tissue was divided into macroscopically distinct regions of degeneration and analyzed by mass spectrometry. A peptide-level strategy quantified protein abundances in a species-delineated analysis. We highlighted degeneration region-specific depositions of key human ECM proteins and bovine ECM proteins whose abundance is time dependent. We demonstrated that single-species analysis of a cross-species proteome results in inaccurate quantification. This study highlights the importance of distinguishing between donor and host species proteomes for accurate protein quantification. While focused on clinically explanted biomaterials, our approach is broadly applicable to all forms of xenotransplantation and the use of xenogenic matrices.

bioengineering↗

bioRxiv2024

A modelling framework to estimate vector dispersal and disease spread in an important agricultural pathosystem

Cereals are some of the most agriculturally important crops grown worldwide. Cereal aphids are small sap-feeding insects that infest cereals and vector devastating cereal pathogens, principally the yellow dwarf viruses, with severe infection reducing yields by 20 - 80%. Currently, farmers are advised to apply insecticide if a single cereal aphid is found within the crop. However, this is an oversimplification of the biology and ecology of the vector-virus system: Each aphid species can transmit a range of yellow dwarf virus species with variable efficiency, and intra-species diversity within a vector species (genotype) can influence this further. Accounting for this variation in decision-making processes has the potential to help with developing bespoke management options based on the composition of the local vector-virus population, and represents a novel avenue that could be explored to develop more sustainable management strategies. Here we describe a stage-structured model that can estimate vector dispersal and disease spread. We use data for the two main cereal aphid species and the two yellow dwarf virus species of greatest concern in Europe to examine how diversity at each level of the vector-virus system impacts disease spread. More broadly, our modelling framework represents a tool that can be used to explore vector-virus-host interactions in greater detail, and we use cereal systems as a case study. Our modelling scenarios highlight diversity at each scale as an important factor. We show that the two main vector species have contrasting dispersal patterns, and that this interacts with virus transmission efficacy to influence disease spread; genetic variation within a vector population is a key driver behind disease spread and disease risk; and for vector species that transmit multiple virus species, the specific vector-virus species combination is a key risk factor to consider.

ecology↗

bioRxiv2024

Estrogen Deficiency alters Vascularization and Mineralization dynamics: insight from a novel 3D Humanized and Vascularized Bone Organoid Model

Osteoporosis is not merely a disease of bone loss but also involves changes in the mineral composition of the bone that remains. In vitro studies have investigated these changes and revealed that estrogen deficiency alters osteoblast mineral deposition, osteocyte mechanosensitivity and osteocyte regulation of osteoclastogenesis. During healthy bone development, vascular cells stimulate bone mineralization via endochondral ossification, but estrogen deficiency impairs vascularization. Yet, existing in vitro bone models overlook the role of vascular cells in osteoporosis pathology. Thus, here we (1) develop an advanced 3D vascularized, mineralized and humanized bone model following the endochondral ossification process, and (2) apply this model to mimic postmenopausal estrogen withdrawal and provide a mechanistic understanding of changes in vascularization and bone mineralization in estrogen deficiency. We confirmed the successful development of a vascularized and mineralized human bone model via endochondral ossification, which induced self-organization of vasculature, associated with hypertrophy (collagen X), and promoted mineralization. When the model was applied to study estrogen deficiency, we reported the development of distinct vessel-like structures (CD31+) in the postmenopausal 3D constructs. Moreover, during estrogen withdrawal vascularized bone demonstrated a significant increase in mineral deposition and apoptosis, which did not occur in non-vascularized bone. These findings reveal a potential mechanism for bone mineral heterogeneity in osteoporotic bone, whereby vascularized bone becomes highly mineralized whereas in non-vascularised regions this effect is not observed. New and NoteworthyHere we develop an in vitro 3D vascularized and humanized bone model following an endochondral ossification approach. We applied the model to recapitulate estrogen deficiency as representative of osteoporotic phenotype. The results of this study reveal that estrogen deficiency exacerbates formation of 3D vessel like structures in vascularized models and thereby drives mineral deposition.

bioengineering↗

bioRxiv2022

A novel mechanobiological model of bone metastasis reveals that mechanical stimulation inhibits the pro-osteoclastogenic effects of breast cancer cells

Bone is highly susceptible to cancer metastasis, and both tumour and bone cells enable tumour invasion through a "vicious cycle" of biochemical signalling. Tumor metastasis into bone also alters biophysical cues to both tumour and bone cells, which are highly sensitive to their mechanical environment. However, the mechanobiological feedback between these cells that perpetuates this cycle has not been studied. Here, we develop highly novel in vitro and computational models to provide an advanced understanding of how tumor growth is regulated by the synergistic influence of tumour-bone cell signaling and mechanobiological cues. In particular, we develop the first multicellular healthy and metastatic bone models, which can account for physiological mechanical signals within a custom bioreactor. These models successfully recapitulated mineralization, mechanobiological responses, osteolysis and metastatic activity. Ultimately we demonstrate that mechanical stimulus provided protective effects against tumor-induced osteolysis, confirming the importance of mechanobiological factors in bone metastasis development.

bioengineering↗

bioRxiv2020

Grain aphids (Sitobion avenae) with knockdown resistance (kdr) to insecticide exhibit fitness trade-offs, including increased vulnerability to the natural enemy Aphidius ervi.

The development of insecticide-resistance mechanisms in aphids has been associated with inhibitory, pleiotropic fitness costs. Such fitness costs have not yet been examined in the UKs most damaging cereal aphid, Sitobion avenae (grain aphid) (Hemiptera: Aphididae). This study aimed to evaluate the fitness trade-offs of the insecticide-resistant S. avenae clone versus an insecticide-susceptible S. avenae clone. Additionally, the parasitoid, Aphidius ervi (Hymenoptera: Braconidae), was introduced to examine its potential as a biological control agent. This study found that insecticide-resistant clones had significantly lower population growth and individual relative growth rate. Furthermore, insecticide-resistant clones suffered from a significantly greater rate of parasitisation (mummification) compared to their insecticide-susceptible counterparts. The successfulness of the parasitoid as a biological control agent could prevent the spread of the insecticide-resistant genotype. However, for this to be possible, insecticide spraying regimes need to be moderated, and habitat modification and parasitoid manipulation must be considered.

ecology↗