Biology subjects

Lewis, M. A.

Publications and source records attributed to Lewis, M. A..

18 recordsLinked to original sources

bioRxiv2026

Integrating animal experience into state-switching habitat selection models

Movement models often assume that animal decisions depend on perceived environmental conditions. However, optimal foraging and cognition theory predict that accumulated experiences should drive changes in animal motivation and decision-making. Here, we propose a mechanistic framework that models state-switching habitat selection as a history-dependent process, where internal states, such as fear or energy, emerge as latent variables accumulating through environmental exposure. Simulations showed that our model accurately recovers memory timescales and cumulative effects of environmental exposure on behavioural switching that would be undetected by existing state-switching habitat selection models. Applied to woodland caribou, it reveals that an individual integrates predation risk experienced over the previous 15 days, but food intake over only 2 days, when deciding to remain or leave an area. Our model advances perspectives on movement ecology by quantifying how accumulated experiences shape changes in motivation driving animal movement decisions.

ecology↗

bioRxiv2026

Zfp719 is a transcription factor important for maintenance of hearing in mice

Zfp719 is a zinc finger transcription factor which, when mutated, results in hearing impairment in mice. Its closest human orthologue, OTK18, has been linked to tinnitus in large human cohorts. Here we present our investigation of the electrophysiological, structural and transcriptional phenotypes in Zfp719tm1a mutant mice. Homozygotes have near-normal hearing at two weeks old, but lose sensitivity rapidly between two and three weeks, suggesting that while Zfp719 is not required for development, it is important for maintaining hearing. Heterozygous mice exhibit progressive hearing impairment for high frequencies at older ages. We observed damaged and degenerating outer hair cells from as early as three weeks old in homozygotes. We carried out bulk RNAseq at three ages and found one gene consistently misregulated, a long non-coding RNA specific to mice, Gm15083. A better understanding of the genes regulated by Zfp719 may shed light on genes and proteins important for maintaining hearing in humans.

neuroscience↗

bioRxiv2026

D-alanine aminotransferase (Dat) promotes Staphylococcus aureus colonization fitness on human nasal respiratory epithelium

Nasal colonization by Staphylococcus aureus is an established risk factor for invasive infection, yet bacterial determinants promoting fitness on human nasal mucosa remain incompletely defined. To identify genes required for early colonization of human nasal respiratory epithelium, we colonized human nasal epithelial organoids differentiated at air-liquid interface (HNO-ALI) with a high-density transposon (Tn) library of the methicillin-resistant USA300 strain LAC. TnSeq analysis identified 165 genes that met our threshold for candidate colonization fitness factors. Among these, genes involved in D-alanine biosynthesis and use were enriched, including two encoding the enzymes that separately synthesize D-alanine in S. aureus: alanine racemase 1 (alr1) and D-alanine aminotransferase (dat). Disruption of dat reduced colonization fitness in competition with the parental strain by [≥] 1,000 fold across 4 different strains from clonal complexes 8, 5, and 30. In competition with the parental strain during HNO-ALI colonization, a dat::Tn mutant was 34-fold less fit than an alr1::Tn mutant. Genetic complementation with single-copy dat expressed from its native operon promoter restored parental colonization levels. Supplementation with exogenous D-alanine or L-alanine also rescued the dat::Tn colonization defect, whereas D-glutamate did not, consistent with Dat primarily producing D-alanine on nasal mucosa. Complementation with dat under control of a putative 5 intra-operon promoter substantially restored colonization but failed to support growth in chemically defined medium lacking L-alanine, suggesting a new layer of environment-specific regulation of dat transcription. Together, these findings demonstrate that Dat is a major source of D-alanine during colonization of human nasal mucosa and is required for S. aureus fitness in this environment. AUTHOR SUMMARYStaphylococcus aureus is the second leading cause of death due to bacterial infection globally, and nasal colonization is a major risk factor for invasive disease. Using a physiologically relevant, host-derived model of human nasal respiratory epithelium (HNO-ALI) and TnSeq, we identified 165 candidate genes contributing to S. aureus fitness during nasal mucosal colonization. We found that D-alanine aminotransferase (Dat) is the predominant source of D-alanine during nasal colonization, whereas alanine racemase (Alr1) predominates in rich medium, revealing an environment-specific hierarchy of D-alanine biosynthesis. Disruption of dat caused a > 1,000-fold defect in colonization in competition with the parental strain across multiple S. aureus clonal complexes, supporting a conserved role for dat in nasal colonization fitness. Additionally, we provide evidence that dat transcription from a previously cryptic promoter might be regulated by nasal mucosal conditions. Alr1 is proposed as an antimicrobial target in other bacterial pathogens; however, our data suggest that targeting Dat may be more effective for S. aureus nasal decolonization.

microbiology↗

bioRxiv2024

Modeling Mountain Pine Beetle Abundance in Novel Hosts

The mountain pine beetle has recently expanded its range into northern and central Alberta, posing an immediate threat to the novel host, jack pine. To date, some experiments suggest that jack pine has limited defensive capabilities despite of the restrictions from the physical environment. In this work, we explore the susceptibility of jack pine compared to the primary host, lodgepole pine, evaluating the risk of potential range expansion into Canadas boreal forest. We employ a hierarchical model, incorporating environmental and ecological covariates, to examine mountain pine beetle dynamics in a pine forest with lodgepole, hybrid and jack pines. Our results show that pine species significantly influence the probability of being killed, with jack pine being less likely to be infested than lodgepole pine, all else being equal. The hierarchical model demonstrates that beetles perform poorer in jack pine, characterized by a reproduction rate 0.16 times that of non-jack pine. Although jack pine is a suitable host, our results indicate that the number of infestations in jack pine could be lower than in lodgepole pine, with a reduced probability of emerging beetles.

ecology↗

bioRxiv2024

Modeling Mountain Pine Beetle Abundance and Distribution in a Changing Climate

The range of mountain pine beetle (Dendroctonus ponderosae Hopkins) is primarily constrained by climate, with winter temperatures playing a crucial role. Climate change is likely to increase the number of warm days and decrease cold days compared to historical norms, making higher latitudes more suitable habitats. In this work, we explore the potential impacts of environmental covariates on outbreaks of mountain pine beetle under climate change in a selected lodgepole pine area in Alberta. We employ a hierarchical model to examine mountain pine beetle dynamics approaching the end of the century. Our analysis assesses the impact of various climatic covariates and estimates the probability and expected number of infestations across different climate change scenarios. Our results from the hierarchical model underscore the critical role of degree days and overwinter survival probability, displaying an overall trend towards a higher probability and a greater number of outbreaks with increasing temperature. Our results indicate that Alberta is likely to experience widespread infestations in the future.

ecology↗

bioRxiv2024

Characterizing the speed and severity of mountain pine beetle spread under climate change with a mechanistic model

In the last few decades, mountain pine beetle (MPB) have spread into Alberta, partially facilitated by climate change and warmer winters. Future effects of climate change on pine beetle spread are uncertain as warming is likely to affect both forest growth and beetle development. We here present a mechanistic model of pine beetle dynamics and characterize simulated outbreaks under climate change. This model includes key aspects of pine beetle biology, and we determine plausible ranges for each model parameter from available data. We then consider how forest growth, beetle brood size, and host resistance are likely to change in Alberta by the end of the century, and how this will relate to changes in model parameters. We simulate beetle outbreaks and quantify how the projected change in the distribution of the parameters will affect the period, speed, and severity of pine beetle spread. We find that simulated beetle outbreaks move more quickly than historically and are more severe.

ecology↗

bioRxiv2024

Eruptive insect outbreaks from endemic populations under climate change

Insects, especially forest pests, are frequently characterized by eruptive dynamics. These types of species can stay at low, endemic population densities for extended periods of time before erupting in large-scale outbreaks. We here present a mechanistic model of these dynamics for mountain pine beetle. This extends a recent model that describes key aspects of mountain pine beetle biology coupled with a forest growth model by additionally including a fraction of low-vigor trees. These low-vigor trees, which may represent hosts with weakened defenses from drought, disease, other bark beetles, or other stressors, give rise to an endemic equilibrium in biologically plausible parameter ranges. The mechanistic nature of the model allows us to study how each model parameter affects the existence and size of the endemic equilibrium. We then show that under certain parameter shifts that are more likely under climate change, the endemic equilibrium can disappear entirely, leading to an outbreak.

ecology↗

bioRxiv2024

Pathological mechanisms and candidate therapeutic approaches in the hearing loss of mice carrying human MIR96 mutations

Progressive hearing loss is a common problem in the human population with no effective therapeutics currently available. However, it has a strong genetic contribution, and investigating the genes and regulatory interactions underlying hearing loss offers the possibility of identifying therapeutic candidates. Mutations in regulatory genes are particularly useful for this, and an example is the microRNA miR-96, a transcriptional regulator which controls hair cell maturation. Mice and humans carrying mutations in Mir96 all develop hearing loss, but different mutations result in different physiological, structural and transcriptional phenotypes. Here we present our characterisation of two lines of mice carrying different human mutations knocked-in to Mir96. While mice homozygous for either mutation are profoundly deaf from two weeks old, the heterozygous phenotypes differ markedly, with only one mutation resulting in hearing impairment in heterozygosis. Investigations of the structural phenotype showed that one mutation appears to lead to synaptic defects, while the other has a much more severe effect on the hair cell stereociliary bundles. Transcriptome analyses revealed a wide range of misregulated genes in both mutants which were notably dissimilar. We used the transcriptome analyses to investigate candidate therapeutics, and tested one, finding that it delayed the progression of hearing loss in heterozygous mice. Our work adds further support for the importance of the gain of novel targets in microRNA mutants, and offers a proof of concept for the identification of pharmacological interventions to maintain hearing.

genetics↗

bioRxiv2024

Mountain pine beetle spread in forests with varying host resistance

In the last few decades, mountain pine beetle (MPB) have spread into novel regions in Canada. An important aspect seldom captured in models of MPB spread is host resistance. Lodgepole pine, the predominant host of MPB, varies in resistance across the landscape. There is evidence for a genetic component of resistance, as well as evidence that hosts in areas where MPB has not been present historically are at risk of increased susceptibility. In addition to the spatially varying resistance of the primary host species, the eastward spread of MPB has brought them into jack pine forests. Host resistance in jack pine remains uncertain, but experiments indicate jack pine could be a suitable host. We develop a model of pine beetle spread that links pine beetle population dynamics and forest structure and resistance. We find that beetle outbreaks in the model are characterized by large transient outbreaks that move through the forest. We show how the speed of these outbreaks changes with host resistance and find that biologically plausible values for host resistance are able to stop the wave from advancing. We also find that near the threshold of resistance where the wave is able to advance, small changes in host resistance dramatically decrease the severity of the outbreak. These results indicate that planting trees selected for higher MPB resistance on the landscape may be able to slow or even stop the local spread of MPB. In terms of further eastward spread, our results indicate future outbreaks may move more quickly and be more severe if novel lodgepole pine hosts are indeed more susceptible to beetle attacks, although more research is needed into the susceptibility of jack pine.

ecology↗

bioRxiv2023

Targeted genome editing restores auditory function in adult mice with progressive hearing loss caused by a human microRNA mutation

Mutations in microRNA-96 (MIR96) cause dominant delayed onset hearing loss DFNA50 without treatment. Genome editing has shown efficacy in hearing recovery by intervention in neonatal mice, yet editing in the adult inner ear is necessary for clinical applications. Here, we developed an editing therapy for a C>A point mutation in the seed region of the Mir96 gene, Mir9614C>A associated with hearing loss by screening gRNAs for genome editors and optimizing Cas9 and sgRNA scaffold for efficient and specific mutation editing in vitro. By AAV delivery in pre-symptomatic (3-week-old) and symptomatic (6-week-old) adult Mir9614C>A mutant mice, hair cell on-target editing significantly improved hearing long-term, with an efficacy inversely correlated with injection age. We achieved transient Cas9 expression without the evidence of AAV genomic integration to significantly reduce the safety concerns associated with editing. We developed an AAV-sgmiR96-master system capable of targeting all known human MIR96 mutations. As mouse and human MIR96 sequences share 100% homology, our approach and sgRNA selection for efficient and specific hair cell editing for long-term hearing recovery lays the foundation for future treatment of DFNA50 caused by MIR96 mutations.

bioengineering↗

bioRxiv2023

A Standardized Antiviral Pipeline for Human Norovirus in Human Intestinal Enteroids Demonstrates No Antiviral Activity of Nitazoxanide

Human noroviruses (HuNoVs) are the leading cause of acute gastroenteritis. In immunocompetent hosts, symptoms usually resolve within three days; however, in immunocompromised persons, HuNoV infection can become persistent, debilitating, and sometimes life-threatening. There are no licensed therapeutics for HuNoV due to a near half-century delay in its cultivation. Treatment for chronic HuNoV infection in immunosuppressed patients anecdotally includes nitazoxanide, a broad-spectrum antimicrobial licensed for treatment of parasite-induced gastroenteritis. Despite its off-label use for chronic HuNoV infection, nitazoxanide has not been clearly demonstrated to be an effective treatment. In this study, we established a standardized pipeline for antiviral testing using multiple human small intestinal enteroid (HIE) lines representing different intestinal segments and evaluated whether nitazoxanide inhibits replication of 5 HuNoV strains in vitro. Nitazoxanide did not exhibit high selective antiviral activity against any HuNoV strains tested, indicating it is not an effective antiviral for norovirus infection. HIEs are further demonstrated as a model to serve as a pre-clinical platform to test antivirals against human noroviruses to treat gastrointestinal disease.

microbiology↗

bioRxiv2023

A parametric model for estimating the timing and intensity of animal migration

Animals of many different species, trophic levels, and life history strategies migrate, and the improvement of animal tracking technology allows ecologists to collect increasing amounts of detailed data on these movements. Understanding when animals migrate is important for managing their populations, but is still difficult despite modelling advancements. We designed a model that parametrically estimates the timing of migration from animal tracking data. Our model identifies the beginning and end of migratory movements as signaled by changes in step length and turning angle distributions. To this end, we can also use the model to estimate how an animals movement changes when it begins migrating. We tested our model on three datasets: migratory ferruginous hawks (Buteo regalis) in the Great Plains and barren-ground caribou (Rangifer tarandus groenlandicus) in northern Canada, and non-migratory brown bears (Ursus arctos) from the Canadian Arctic. We estimated the beginning and end of migration in caribou and hawks to the nearest day, while confirming a lack of migratory behaviour in the brown bear population. The flexibility of our modelling framework allowed us to assess intricacies associated with each dataset: long-term stopover behaviour in ferruginous hawks and a priori knowledge of caribou calving areas and behaviour. In addition to estimating when caribou and ferruginous hawks migrated, our model also identified differences in how the two populations migrated; ferruginous hawks achieved efficient migrations by increasing their movement rates while caribou migration was achieved through significant increases in directional persistence. Our approach is broadly applicable to many animal movement studies. We anticipate that rigorous assessment of migration metrics will aid understanding of both how and why animals move.

ecology↗

bioRxiv2022

Next-generation matrices for marine metapopulations: the case of sea lice on salmon farms

Classifying habitat patches as sources or sinks and determining metapopulation persistence requires coupling connectivity between habitat patches with local demographic rates. In this paper we show how next-generation matrices, originally popularized in epidemiology to calculate new infections after one generation, can be used in an ecological context to couple connectivity with local demography to calculate sources and sinks as well as metapopulation persistence in marine metapopulations. To demonstrate the utility of the method, we construct a next-generation matrix for a network of sea lice populations on salmon farms in the Broughton Archipelago, BC, an intensive salmon farming region on the west coast of Canada where certain salmon farms are currently being removed under an agreement between local First Nations and the provincial government. We identify the salmon farms which are acting as the largest sources of sea lice and show that in this region the most productive sea lice populations are also the most connected. We find that the farms which are the largest sources of sea lice have not yet been removed from the Broughton Archipelago, and that warming temperatures could lead to increased sea louse growth.

ecology↗

bioRxiv2022

Beyond resource selection: emergent spatio-temporal distributions from animal movements and stigmergent interactions

A principal concern of ecological research is to unveil the causes behind observed spatio-temporal distributions of species. A key tactic is to correlate observed locations with environmental features, in the form of resource selection functions or other correlative species distribution models. In reality, however, the distribution of any population both affects and is affected by those surrounding it, creating a complex network of feedbacks causing emergent spatio-temporal features that may not correlate with any particular aspect of the underlying environment. Here, we study the way in which the movements of populations in response to one another can affect the spatio-temporal distributions of ecosystems. We construct a stochastic individual-based modelling (IBM) framework, based on stigmergent interactions (i.e. organisms leave marks which cause others to alter their movements) between and within populations. We show how to gain insight into this IBM via mathematical analysis of a partial differential equation (PDE) system given by a continuum limit. We show how the combination of stochastic simulations of the IBM and mathematical analysis of PDEs can be used to categorise emergent patterns into homogeneous vs. heterogeneous, stationary vs. perpetually-fluctuating, and aggregation vs. segregation. In doing so, we develop techniques for understanding spatial bifurcations in stochastic IBMs, grounded in mathematical analysis. Finally, we demonstrate through a simple example how the interplay between environmental features and between-population stigmergent interactions can give rise to predicted spatial distributions that are quite different to those predicted purely by accounting for environmental covariates.

ecology↗

bioRxiv2022

Pancreas resident macrophage-induced fibrosis has divergent roles in pancreas inflammatory injury and PDAC

Tissue-resident macrophages (TRMs) are long-lived cells that maintain locally and can be phenotypically distinct from monocyte-derived macrophages (MDMs). However, whether TRMs and MDMs have functional distinction under differing pathologies is not understood. Here, we show a significant portion of macrophages that accumulated during pancreatitis and pancreatic cancer were expanded from TRMs. We further established that pancreas TRMs have a distinct extracellular matrix remodeling phenotype that was critical for maintaining tissue homeostasis during inflammation. Loss of TRMs led to exacerbation of severe pancreatitis and animal death, due to impaired acinar cell survival and recovery. In pancreatitis, TRMs elicited protective effects by triggering the accumulation and activation of fibroblasts, which was necessary for initiating fibrosis as a wound healing response. The same TRM-driven fibrosis, however, drove pancreas cancer pathogenesis and progression. Together, these findings indicate that TRMs play divergent roles in the pathogenesis of pancreatitis and cancer through regulation of stromagenesis.

immunology↗

bioRxiv2021

Time-dependent memory and individual variation in Arctic brown bears (Ursus arctos)

1Animal movement modelling provides unique insight about how animals perceive their landscape and how this perception may influence space use. When coupled with data describing an animals environment, ecologists can fit statistical models to location data to describe how spatial memory informs movement. We performed such an analysis on a population of brown bears (Ursus arctos) in the Canadian Arctic using a model incorporating time-dependent spatial memory patterns. Brown bear populations in the Arctic lie on the periphery of the species range, and as a result endure harsh environmental conditions. In this kind of environment, effective use of memory to inform movement strategies could spell the difference between survival and mortality. The model we fit tests four alternate hypotheses (some incorporating memory; some not) against each other, and we found a high degree of individual variation in how brown bears used memory. We found that 52% (11 of 21) of the bears used complex, time-dependent spatial memory to inform their movement decisions. These results, coupled with existing knowledge on individual variation in the population, highlight the diversity of foraging strategies for Arctic brown bears while also displaying the inference that can be drawn from this innovative movement model.

ecology↗

bioRxiv2021

Collateral damage: Identification and characterisation of spontaneous mutations causing deafness from a targeted knockout programme

Mice carrying targeted mutations are important for investigating gene function and the role of genes in disease, but the process of culturing embryonic stem cells during the making of a targeted allele offers opportunities for spontaneous mutations to arise. Identifying spontaneous mutations relies on the detection of phenotypes segregating independently of targeted alleles, and many phenotypes are easy to miss if not specifically looked for. Here we present data from a large, targeted knockout programme in which mice were analysed through a phenotyping pipeline. Twenty-five lines out of 1311 displayed different deafness phenotypes that did not segregate with the targeted allele. We have identified 8 different mutations causing deafness in 16 of these 25 lines and characterised the resulting phenotypes. Our data show that spontaneous mutations with observable effects on phenotype are a common side effect of intensive breeding programmes, including those underlying targeted mutation programmes.

genetics↗

bioRxiv2019

Hearing impairment due to Mir183/96/182 mutations suggests both loss and gain of function effects

The microRNA miR-96 is important for hearing, as point mutations in humans and mice result in dominant progressive hearing loss. Mir96 is expressed in sensory cells along with Mir182 and Mir183, but the roles of these closely-linked microRNAs are as yet unknown. Here we analyse mice carrying null alleles of Mir182, and of Mir183 and Mir96 together to investigate their roles in hearing. We found that Mir183/96 heterozygous mice had normal hearing and homozygotes were completely deaf with abnormal hair cell stereocilia bundles and reduced numbers of inner hair cell synapses at four weeks old. Mir182 knockout mice developed normal hearing then exhibited progressive hearing loss. Our transcriptional analyses revealed significant changes in a range of other genes, but surprisingly there were fewer genes with altered expression in the organ of Corti of Mir183/96 null mice compared with our previous findings in Mir96Dmdo mutants, which have a point mutation in the miR-96 seed region. This suggests the more severe phenotype of Mir96Dmdo mutants compared with Mir183/96 mutants, including progressive hearing loss in Mir96Dmdo heterozygotes, is likely to be mediated by the gain of novel target genes in addition to the loss of its normal targets. We propose three mechanisms of action of mutant miRNAs; loss of targets that are normally completely repressed, loss of targets whose transcription is normally buffered by the miRNA, and gain of novel targets. Any of these mechanisms could lead to a partial loss of a robust cellular identity and consequent dysfunction.

systems biology↗