Biology subjects

Bull, J.

Publications and source records attributed to Bull, J..

5 recordsLinked to original sources

bioRxiv2026

Effects of Liraglutide on Gut Bacterial Community Dynamics

Liraglutide, a GLP-1 receptor agonist, is used to induce weight loss. However, limited information exists on liraglutides effects on the gut bacterial community and their restoration after washout. We investigated liraglutides effect on the gut bacterial community in diet-induced obese (DIO) mice and whether these changes persist after washout. Twenty-four male C57BL/6J mice on high-fat (HFC) or low-fat (LFC) diets were monitored for 21 days. A subgroup of high-fat mice received daily liraglutide for 14 days (HFL), followed by a 7-day washout. Liraglutide induced significant weight loss by Day 4, which persisted during treatment and partially reversed post-treatment. For bacterial community analysis, 7.1 million 16S rRNA gene sequences were retrieved using Illumina paired-end sequencing. We observed distinct shifts in gut bacterial community structure during liraglutide treatment, which mostly returned to baseline after the 7-day washout. Using SIMPER analysis, 21 amplicon sequence variants (ASVs) were identified as major contributors. Nine ASVs, related to Lactobacillus gasseri, L. paragasseri, L. johnsonii, and Leptogranulimonas caecicola, significantly increased during treatment and declined post-washout. The remaining 12 ASVs, associated with protein- and carbohydrate-fermenting bacteria (Romboutsia, Faecalicatena, Oscillibacter), decreased during treatment. Comparison across all groups identified 29 ASVs, clustering into seven phylogenetic groups, highlighting liraglutides enrichment of bile-acid- and mucin-associated taxa and suppression of carbohydrate-fermentative genera. These findings demonstrate that liraglutide induces rapid, diet-dependent, yet reversible shifts in the gut microbiome, favoring lactic acid-producing bacteria while reducing fermentative taxa. Such microbial changes may contribute to liraglutides metabolic effects and provide insight into host- microbiome interactions in obesity treatment. IMPORTANCEObesity and overweight states are intricately linked to the gut bacterial community, yet the effects of common obesity treatments such as GLP-1 receptor agonists on gut bacteria remain unclear. Here, we show that liraglutide, a GLP-1 analog, reshapes the gut bacterial community in diet-induced obese mice relative to untreated obese and lean controls. By including baseline samples when mice were at a normal weight, we distinguished bacterial changes due to the drug from those due to obesity progression, as well as how the community structure is affected during a washout period. Liraglutide treatment selectively increased beneficial gut bacteria (e.g., Lactobacillaceae) under high-fat conditions. These bacterial shifts during GLP-1 therapy may contribute to its metabolic benefits and broaden our understanding of host bacterial interactions in the context of diet and weight management.

microbiology↗

bioRxiv2025

Exploring the relationship between vascular remodelling and tumour growth using agent-based modelling

We develop a multiscale agent-based model (ABM) to investigate the effect that mechanical interactions between proliferating tumour cells and the surrounding vasculature have on the oxygen supply to the tumour microenvironment (TME), the tumours growth dynamics, and its response to radiotherapy. Our model extends existing models of tumour spheroid growth by incorporating vessel deformation due to mechanical forces between vessel walls and neighbouring tumour cells. These forces generate an effective pressure which compresses vessels, driving occlusion and pruning. This, in turn, leads to a hypoxic oxygen landscape which stimulates angiogenesis. A key feature of our model is the treatment of mechanical cell interactions with the tumour microenvironment, which we represent with two forces. The first is Stokes drag which is widely used in ABMs to represent resistance to cell movement. The second is a friction force which accounts for resistance due to the continual breaking and reforming of cell-extracellular matrix (ECM) adhesions. The importance of this friction force is demonstrated by numerical simulation. When Stokes drag dominates, pressure gradients dissipate across the tissue and vessel compression is negligible. By contrast, as the strength of the friction force increases, larger pressure gradients form, leading to significant vessel compression. We perform extensive numerical simulations to investigate how model parameters that control vascular remodelling and friction influence tumour vascularisation, which we spatially quantify using the cross-pair correlation function. This, in turn, alters the oxygen landscape and drives changes in tumour morphology. Finally, we highlight the importance of accounting for both mechanisms when simulating tumour responses to treatment with radiotherapy. We observe that vascular remodelling critically alters the tumours susceptibility to treatment and post-radiotherapy regrowth. Tumour regrowth is especially impacted by vessel remodelling, with certain vascular landscapes able to rebound quickly post-radiotherapy, resulting in fast tumour regrowth. Author SummaryWe have created an agent-based model (ABM) that accounts for mechanical interactions between tumour cells and associated vasculature. The model simulates vessel occlusion and pruning due to compression by neighbouring tumour cells; and growth of new vessels in response to hypoxia. Incorporating pressure-mediated vessel occlusion into our ABM required development of a friction force representing cell-extracellular matrix (ECM) adhesion. Through numerical simulations, we show that when friction is neglected, pressure gradients dissipate throughout the tissue and vessel compression is negligible. By contrast, as the strength of the friction force increases, larger pressure gradients form, leading to significant vessel compression. We perform extensive model simulations, to investigate how changes in the oxygen landscape caused by vascular remodelling affect the tumours growth dynamics and composition. We show further how vessel remodelling influences a tumours response to radiotherapy. We find tumour regrowth to be especially sensitive to vessel remodelling, with certain vascular landscapes growing rapidly post-radiotherapy, and accelerating tumour regrowth.

cancer biology↗

bioRxiv2024

Standardized methods for rearing a moth larva, Manduca sexta, in a laboratory setting

The larval tobacco hornworm, Manduca sexta, has been used in a laboratory setting for physiological studies and for pathogen virulence studies. This moth offers a much larger size than the commonly used wax moth (Galleria mellonella), and it can thus be used for a greater variety of assays, such as repeated sampling of the same individual, growth measurements, and tissue sampling. Yet their occasional use in research has led to a minimally documented set of rearing methods. To facilitate further adoption of this insect model, we expanded on previously reported protocols and developed our own rearing methods, which we report here. Our protocol requires little specialized equipment, with a cost less than $100/month for the feeding and maintenance of a laboratory colony of about five hundred larvae of differing instar phases. The low cost generalized equipment and supplies, and the simplification of the standardized protocols allows for an easy entry point for rearing tobacco hornworm populations. We also describe a few methods that are relevant to the uses of these organisms as infection models.

physiology↗

bioRxiv2018

Highly accelerated rates of heritable large-scale mutations under prolonged exposure to a metal mixture of copper and nickel

Mutation rate variation has been under intense investigation for decades. Despite these efforts, little is known about the extent to which environmental stressors accelerate mutation rates and influence the genetic load of populations. Moreover, most studies have focused on point mutations rather than large-scale deletions and duplications (copy number variations or \"CNVs\"). We estimated mutation rates in Daphnia pulex exposed to low levels of environmental stressors as well as the effect of selection on de novo mutations. We conducted a mutation accumulation (MA) experiment in which selection was minimized, coupled with an experiment in which a population was propagated under competitive conditions in a benign environment. After an average of 103 generations of MA propagation, we sequenced 60 genomes and found significantly accelerated rates of deletions and duplications in MA lines exposed to ecologically relevant concentrations of metals. Whereas control lines had gene deletion and duplication rates comparable to other multicellular eukaryotes (1.8 x 10-6 per gene per generation), a mixture of nickel and copper increased rates fourfold. The realized mutation rate under selection was reduced to 0.4x that of control MA lines, providing evidence that CNVs contribute to mutational load. Our CNV breakpoint analysis revealed that nonhomologous recombination associated with regions of DNA fragility is the primary source of CNVs, plausibly linking metal-induced DNA strand breaks with higher CNV rates. Our findings suggest that environmental stress, in particular multiple stressors, can have profound effects on large-scale mutation rates and mutational load of populations.

genomics↗

bioRxiv2018

Combinatorial Approaches to Viral Attenuation

Attenuated viruses have numerous applications, in particular in the context of live viral vaccines. However, purposefully designing attenuated viruses remains challenging, in particular if the attenuation is meant to be resistant to rapid evolutionary recovery. Here we develop and analyze a new attenuation method, promoter ablation, using an established viral model, bacteriophage T7. Ablating promoters of the two most highly expressed T7 proteins (scaffold and capsid) led to major reductions in transcript abundance of the affected genes, with the effect of the double knockout approximately additive of the effects of single knockouts. Fitness reduction was moderate and also approximately additive; fitness recovery on extended adaptation was partial and did not restore the promoters. The fitness effect of promoter knockouts combined with a previously tested codon deoptimization of the capsid gene was less than additive, as anticipated from their competing mechanisms of action. In one design, the engineering created an unintended consequence that led to further attenuation, the effect of which was studied and understood in hindsight. Overall, the mechanisms and effects of genome engineering on attenuation behaved in a predictable manner. Therefore, this work suggests that the rational design of viral attenuation methods is becoming feasible.\n\nImportanceLive viral vaccines rely on attenuated viruses that can successfully infect their host but have reduced fitness or virulence. Such attenuated viruses were originally developed through trial- and-error, typically by adaptation of the wild-type virus to novel conditions. That method was haphazard, with no way of controlling the degree of attenuation, the number of attenuating mutations, or preventing evolutionary reversion. Synthetic biology now enables rational design and engineering of viral attenuation, but rational design must be informed by biological principles to achieve stable, quantitative attenuation. This work shows that in a model system for viral attenuation, bacteriophage T7, attenuation can be obtained from rational design principles, and multiple different attenuation approaches can be combined for enhanced overall effect.

microbiology↗