Biology subjects

Grant, E.

Publications and source records attributed to Grant, E..

17 recordsLinked to original sources

bioRxiv2026

Development and Validation of Thalia: A High-ResolutionPediatric Computational Model of a 10-Month-Old Infant

Numerical human models are essential to advance medical device design, safety assessment, and study how anatomical development influences physiological processes. Despite increasing availability of pediatric models, a critical gap remains in high-resolution, non-morphed whole-body models representing children around one year of age. Existing pediatric models are often derived from morphing older anatomies or lack sufficient tissue segmentation to accurately capture early developmental anatomy. This study introduces Thalia, a non-morphed, high-resolution numerical model of a healthy 10-month-old female. The model was constructed by segmenting 442 tissues from Magnetic Resonance Imaging data. Brain tissues were automatically segmented using an infant-specific FreeSurfer framework, followed by semi-automated and manual refinement in 3DSlicer. The model was validated by expert review and quantitative comparison with age-matched anatomical values reported in the literature. The resulting whole-body model provides detailed anatomical representation across the brain, musculoskeletal system, vasculature, and internal organs, enabling realistic assignment of tissue-specific properties for computational studies. It provides a versatile platform for pediatric medical device development, dosimetry, safety assessment, and bioelectromagnetic simulations. This pediatric numerical anatomical model is openly available as an open-source resource. HighlightsO_LIHigh-resolution model of a 10-month-old child developed from MRI data C_LIO_LI442 tissues segmented to capture early anatomical development accurately C_LIO_LIModel validated against expert review and age-matched anatomical data C_LIO_LIIllustrative Example of a pediatric transcranial magnetic stimulation use case C_LI

bioengineering↗

bioRxiv2026

Real-time mass-resolved label-free single-molecule immunoassay

Protein-protein interactions govern the biomolecular logic of immunity, signalling, and disease. Elementary rates of association, dissociation, and inhibition underpin our understanding of life processes and remain a limiting factor at the frontier of therapeutic discovery. Yet existing assays infer these processes indirectly through ensemble-averaged signals or molecular labels that obscure native dynamics. Here, we introduce a label-free, real-time, mass-resolved single-molecule immunoassay based on interferometric scattering microscopy (iSCAT) that directly observes individual protein-protein binding events in complex biological samples. By detecting light scattered from single proteins as they bind to an antibody-functionalized surface, we resolve discrete antibody-antigen interactions with single-molecule sensitivity and molecular-weight discrimination. Using IgM as a model system, we demonstrate real-time detection of individual binding events, with measured association rates that scale linearly with concentration over three orders of magnitude. Direct counts of IgM binding events in human serum yield quantitative concentrations that agree with bulk measurements obtained by enzyme-linked immunosorbent assay (ELISA). This bioaffinity iSCAT platform unifies molecular specificity, label-free detection, real-time kinetics, and mass-resolved single-molecule sensitivity, enabling direct access to protein-protein recognition processes and establishing a general framework for quantitative, single-molecule immunoassays.

biophysics↗

bioRxiv2024

Deletion of endocannabinoid synthesizing enzyme DAGLα from cerebellar Purkinje cells decreases social preference and elevates anxiety

The endocannabinoid (eCB) signaling system is robustly expressed in the cerebellum starting from the embryonic developmental stages to adulthood. There it plays a key role in regulating cerebellar synaptic plasticity and excitability, suggesting that impaired eCB signaling will lead to deficits in cerebellar adjustments of ongoing behaviors and cerebellar learning. Indeed, human mutations in DAGL are associated with neurodevelopmental disorders. In this study, we show that selective deletion of the eCB synthesizing enzyme diacylglycerol lipase alpha (Dagl) from mouse cerebellar Purkinje cells (PCs) alters motor and social behaviors, disrupts short-term synaptic plasticity in both excitatory and inhibitory synapses, and reduces Purkinje cell activity during social exploration. Our results provide the first evidence for cerebellar-specific eCB regulation of social behaviors and implicate eCB regulation of synaptic plasticity and PC activity as the neural substrates contributing to these deficits. O_FIG O_LINKSMALLFIG WIDTH=173 HEIGHT=200 SRC="FIGDIR/small/607068v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@1a0a1d8org.highwire.dtl.DTLVardef@e17f34org.highwire.dtl.DTLVardef@665a75org.highwire.dtl.DTLVardef@1bcc7f1_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstract.C_FLOATNO Cerebellar anatomy, morphology of Purkinje cells, localization, density, and spontaneous activity of excitatory and inhibitory synapses are normal in cerebellar-Purkinje-cell-specific Dagl KOs. However, endocannabinoid-dependent short-term synaptic plasticity (DSE and DSI) and activity of Purkinje cells in lobe VI during social exploration are dramatically reduced, and the KO mice exhibit alterations in sensorimotor coordination, deceased social preference, and increased anxiety. C_FIG

neuroscience↗

bioRxiv2024

Meta-analyses of Culex blood-meals indicates strong regional effect on feeding patterns

Understanding host utilization by mosquito vectors is essential to assess the risk of vector-borne diseases. Many studies have investigated the feeding patterns of Culex mosquitoes by molecular analysis of blood-meals from field collected mosquitoes. However, these individual small-scale studies only provide a limited understanding of the complex host-vector interactions when considered in isolation. Here, we analyse the Culex blood-feeding data from 90 publications over the last 15 years to give a global insight into the feeding patterns of Culex mosquitoes, with particular reference to vectors of currently emerging Culex-borne viruses such as West Nile and Usutu. Data on 26,857 blood-meals from 71 different Culex species were extracted from published literature. The percentage of blood-meals on amphibian, avian, human, non-human mammalian, and reptilian hosts was determined for each Culex species. Our analysis showed that feeding patterns were not significantly explained by mosquito species-level phylogeny, indicating that external factors play an important role in determining mosquito feeding patterns. For Cx. quinquefasciatus, Cx. pipiens complex, and Cx. tritaeniorhynchus, feeding patterns were compared across the worlds seven biogeographical realms. Culex tritaeniorhynchus, Cx. pipiens complex and Cx. quinquefasciatus all had significantly varied feeding patterns between realms. These results demonstrate that feeding patterns of Culex mosquitoes vary between species but can also vary between geographically distinct populations of the same species, indicating that regional or population-level adaptations are major drivers of host utilization. Ultimately, these findings support the surveillance of vector-borne diseases by specifying which host groups are most likely to be at risk. Author summaryBeing aware of mosquito biting behaviour is essential to determine the threat of mosquito-borne diseases. Studying the feeding patterns of Culex mosquitoes is crucial as these mosquitoes are vectors of currently emerging or re-emerging arboviruses such as West Nile and Usutu. Feeding behaviour of Culex mosquitoes has been examined in many individual small-scale studies. These studies only focus on the feeding patterns in a specific area. To gain a more global understanding of these feeding patterns we analysed all available Culex blood-feeding data from the last 15 years. In summary, data on 26,857 blood-meals from 71 different Culex species was collected. For each species the percentage of blood-meals on different host groups was determined. We analysed the relationship between feeding patterns and mosquito phylogeny, which showed that phylogeny alone could not explain feeding patterns. These results indicate that external factors such as land use and climate could play an important role in determining feeding patterns. For further analysis we determined the feeding patterns for three important vector species, Cx. quinquefasciatus, Cx. pipiens complex, and Cx. tritaeniorhynchus in different biogeographical realms. All three species showed different feeding patterns in the included realms. Thus, the same species can have different feeding patterns in different regions, indicating the importance of local surveillance.

ecology↗

bioRxiv2024

The 2023 wildfire season in Quebec: an overview of extreme conditions, impacts, lessons learned and considerations for the future.

The 2023 wildfire season in Quebec set records due to extreme warm and dry conditions, burning 4.5 million hectares and indicating persistent and escalating impacts associated with climate change. The study reviews the unusual weather conditions that led to the fires, discussing their extensive impacts on the forest sector, fire management, boreal caribou habitats, and particularly the profound effects on First Nation communities. The wildfires led to significant declines in forest productivity and timber supply, overwhelming fire management resources, and necessitating widespread evacuations. First Nation territories were dramatically altered, facing severe air quality issues and disruptions. While caribou impacts were modest across the province, the broader ecological, economical, and social repercussions were considerable. To mitigate future extreme wildfire seasons, the study suggests changes in forest management practices to increase forest resilience and resistance, adapting industrial structures to new timber supplies, and enhancing fire suppression and risk management strategies. It calls for a comprehensive, unified approach to risk management that incorporates the lessons from the 2023 fire season and accounts for ongoing climate change. The study underscores the urgent need for detailed planning and proactive measures to reduce the growing risks and impacts of wildfires in a changing climate.

ecology↗

bioRxiv2023

Diet-driven differential response of Akkermansia muciniphila modulates pathogen susceptibility

The erosion of the colonic mucus layer by a dietary fiber-deprived gut microbiota results in heightened susceptibility to an attaching and effacing pathogen, Citrobacter rodentium. Nevertheless, the questions of whether and how specific mucolytic bacteria aid in the increased pathogen susceptibility remain unexplored. Here, we leverage a functionally characterized, 14-member synthetic human microbiota in gnotobiotic mice to deduce which bacteria and functions are responsible for the pathogen susceptibility. Using strain dropouts of mucolytic bacteria from the community, we show that Akkermansia muciniphila renders the host more vulnerable to the mucosal pathogen during fiber deprivation. However, the presence of A. muciniphila reduces pathogen load on a fiber-sufficient diet, highlighting the context-dependent beneficial effects of this mucin specialist. The enhanced pathogen susceptibility is not owing to altered host immune or pathogen responses, but is driven by a combination of increased mucus penetrability and altered activities of A. muciniphila and other community members. Our study provides novel insights into the mechanisms of how discrete functional responses of the same mucolytic bacterium either resist or enhance enteric pathogen susceptibility.

microbiology↗

bioRxiv2023

Dynamic changes in subplate and cortical plate microstructure precede the onset of cortical folding in vivo

Cortical gyrification takes place predominantly during the second to third trimester, alongside other fundamental developmental processes, such as the development of white matter connections, lamination of the cortex and formation of neural circuits. The mechanistic biology that drives the formation cortical folding patterns remains an open question in neuroscience. In our previous work, we modelled the in utero diffusion signal to quantify the maturation of microstructure in transient fetal compartments, identifying patterns of change in diffusion metrics that reflect critical neurobiological transitions occurring in the second to third trimester. In this work, we apply the same modelling approach to explore whether microstructural maturation of these compartments is correlated with the process of gyrification. We quantify the relationship between sulcal depth and tissue anisotropy within the cortical plate (CP) and underlying subplate (SP), key transient fetal compartments often implicated in mechanistic hypotheses about the onset of gyrification. Using in utero high angular resolution multi-shell diffusion-weighted imaging (HARDI) from the Developing Human Connectome Project (dHCP), our analysis reveals that the anisotropic, tissue component of the diffusion signal in the SP and CP decreases immediately prior to the formation of sulcal pits in the fetal brain. By back-projecting a map of folded brain regions onto the unfolded brain, we find evidence for cytoarchitectural differences between gyral and sulcal areas in the late second trimester, suggesting that regional variation in the microstructure of transient fetal compartments precedes, and thus may have a mechanistic function, in the onset of cortical folding in the developing human brain.

neuroscience↗

bioRxiv2023

Enhancing Neurocognitive Outcome Prediction in Congenital Heart Disease Patients: The Role of Brain Age Biomarkers and Beyond

This paper aimed to investigate the predictive power of combining demographic, socioeconomic, and genetic factors with a brain MRI-based quantified measure of accelerated brain aging (referred to as deltaAGE) for neurocognitive outcomes in adolescents and young adults with Congenital Heart Disease (CHD). Our hypothesis posited that including the brain age biomarker (deltaAGE) would enhance neurocognitive outcome predictions compared to models excluding it. We conducted comprehensive analyses, including leave-one-subject-out and leave-one-group-out cross-validation techniques. Our results demonstrated that the inclusion of deltaAGE consistently improved prediction performance when considering the Pearson correlation coefficient, a preferable metric for this study. Notably, the deltaAGE -augmented models consistently outperformed those without deltaAGE across all cross-validation setups, and these correlations were statistically significant (p-value < 0.05). Therefore, our hypothesis that incorporating the brain-age biomarker alongside demographic, socioeconomic, and genetic factors enhances neurocognitive outcome predictions in adolescents and young adults with CHD is supported by the findings.

bioinformatics↗

bioRxiv2023

Gut microbiome-based prediction of autoimmune neuroinflammation

Gut commensals are linked to neurodegenerative diseases, yet little is known about causal and functional roles of microbial risk factors in the gut-brain axis. Here, we employed a pre-clinical model of multiple sclerosis in mice harboring distinct complex microbiotas and six defined strain combinations of a functionally-characterized synthetic human microbiota. Discrete microbiota compositions resulted in different probabilities for development of severe autoimmune neuroinflammation. Nevertheless, assessing presence or the relative abundances of a suspected microbial risk factor failed to predict disease courses across different microbiota compositions. Importantly, we found considerable inter-individual disease course variations between mice harboring the same microbiota. Evaluation of multiple microbiome-associated functional characteristics and host immune responses demonstrated that the immunoglobulin A-coating index of Bacteroides ovatus before disease onset is a robust individual predictor for disease development. Our study highlights that the "microbial risk factor" concept needs to be seen in the context of a given microbial community network, and host-specific responses to that community must be considered when aiming for predicting disease risk based on microbiota characteristics.

microbiology↗

bioRxiv2023

Can deep learning predict human intelligence from structural brain MRI?

Can brain structure predict human intelligence? T1-weighted structural brain magnetic resonance images (sMRI) have been correlated with intelligence. Nevertheless, population-level association does not fully account for individual variability in intelligence. To address this, individual prediction studies emerge recently. However, they are mostly on predicting fluid intelligence (the ability to solve new problems). Studies are lacking to predict crystallized intelligence (the ability to accumulate knowledge) or general intelligence (fluid and crystallized intelligence combined). This study tests whether deep learning of sMRI can predict an individual subjects verbal, comprehensive, and full-scale intelligence quotients (VIQ, PIQ, FSIQ), which reflect both fluid and crystallized intelligence. We performed a comprehensive set of 432 experiments, using different input images, six deep learning models, and two outcome settings, on 850 autistic and healthy subjects 6-64 years of age. Results show promise with statistical significance, and also open up questions inviting further future studies.

bioengineering↗

bioRxiv2023

Influence of Demographic, Socio-economic, and Brain Structural Factors on Adolescent Neurocognition: A Correlation Analysis in the ABCD Initiative

The Adolescent Brain Cognitive Development (ABCD) initiative is a longitudinal study aimed at characterizing brain development from childhood through adolescence and identifying key biological and environmental factors that influence this development. The study measures neurocognitive abilities across a multidimensional array of functions, with a focus on the critical period of adolescence during which physical and socio-emotional changes occur and the structure of the cortical and white matter changes. In this study, we perform a correlation analysis to examine the linear relation of adolescent neurocognition functions with the demographic, socio-economic, and magnetic resonance imaging-based brain structural factors. The overall goal is to obtain a comprehensive understanding of how natural and nurtural factors influence adolescent neurocognition. Our results on > 10,000 adolescents show many positive and negative statistical significance interrelations of different neurocognitive functions with the demographic, socioeconomic, and brain structural factors, and also open up questions inviting further future studies.

bioinformatics↗

bioRxiv2022

Structure and function of a Notch-like proteolytic switch domain in the extracellular matrix receptor dystroglycan

The dystrophin glycoprotein complex (DGC), anchored by the transmembrane protein dystroglycan, functions to mechanically link the extracellular matrix to the actin cytoskeleton to drive critical aspects of development and adult homeostasis. Breaking this connection via mutation of the actin adaptor protein dystrophin or impaired glycosylation of dystroglycan are strongly associated with diseases such as Muscular Dystrophy, yet cleavage of the dystroglycan protein by matrix metalloproteinases (MMPs) remains an understudied mechanism to disrupt the DGC. We solved X-ray structures of the membrane-adjacent domain of dystroglycan to understand the molecular underpinnings of dystroglycan MMP cleavage regulation. Dystroglycan proteolysis occurs within the versatile SEAL domain, which supports proteolysis in diverse receptors to facilitate mechanotransduction, protection of cell membranes, and even viral entry. The structure reveals a c-terminal extension of the SEAL domain that buries the MMP cleavage site by packing into a hydrophobic pocket, a unique mechanism of MMP cleavage regulation. We further demonstrate that structure-guided and disease-associated mutations disrupt proteolytic regulation using a new cell-surface proteolysis assay. Finally, we find that disruption of proteolysis leads to altered cellular mechanics and migration using high-throughput DNA tension probe and wound healing assays. These findings highlight that disrupted proteolysis is a relevant mechanism for "breaking" the DGC link to contribute to disease pathogenesis and may offer new therapeutic avenues for dystroglycanopathies.

biochemistry↗

bioRxiv2022

Unravelling specific diet and gut microbial contributions to inflammatory bowel disease

Inflammatory bowel diseases (IBDs) are chronic conditions characterized by periods of spontaneous intestinal inflammation and are increasing in industrialized populations. Combined with host genetics, diet and gut bacteria are thought to contribute prominently to IBDs, but mechanisms are still emerging. In mice lacking the IBD-associated cytokine, Interleukin-10, we show that low dietary fiber promotes bacterial erosion of colonic mucus, leading to lethal colitis. A fiber-free exclusive enteral nutrition diet also induces mucus erosion but inhibits inflammation by simultaneously increasing an anti-inflammatory bacterial metabolite, isobutyrate. Diet-induced inflammation is driven by Th1 immune responses, which increase in the presence of mucin-degrading bacteria and are preceded by expansion of natural killer cells and altered immunoglobulin-A coating of some bacteria. Inflammation occurs first in intestinal regions with thinner mucus. Our work underscores the importance of focusing on microbial functions--not taxa--contributing to IBDs and some diet-mediated functions block those that promote disease.

microbiology↗

bioRxiv2022

Urbanization alters phenology of plant reproduction, foliar infection, and herbivory

O_LIUrbanization involves numerous environmental changes that may affect the timing of plant reproduction and foliar damage by pathogens, herbivores, and human activities. Yet such relationships have not been examined simultaneously in plant populations across levels of urbanization. C_LIO_LIWe conducted monthly surveys of 22 populations of Plantago lanceolata and P. rugelii in parks spanning an urbanization gradient. We quantified plant reproductive development and prevalence of powdery mildew infection, insect herbivory, and mowing damage. Additionally, we placed potted "sentinel" plants into field populations to directly measure infection and herbivory rates. C_LIO_LIUrbanization was associated with earlier flowering and more seed production for P. rugelii, but less seed maturation for P. lanceolata. Mildew epidemics on P. rugelii started earlier and achieved greater prevalence in more urban sites. Correspondingly, sentinels only became infected in suburban and urban sites. There was less infection on P. lanceolata, including sentinels, suggesting low availability of pathogen genotypes able to infect this species. Early-summer herbivory on both plant species was accelerated in urban sites. C_LIO_LIUrbanization has species-specific associations with reproductive phenology and is associated with increased early-summer herbivory, larger epidemics of a foliar pathogen, and more mowing damage on two weedy herbs C_LI

ecology↗

bioRxiv2021

Low antigen abundance limits efficient T-cell recognition of highly conserved regions of SARS-CoV-2

Understanding the immune response to severe acute respiratory syndrome coronavirus (SARS-CoV-2) is critical to overcome the current coronavirus disease (COVID-19) pandemic. Efforts are being made to understand the potential cross-protective immunity of memory T cells, induced by prior encounters with seasonal coronaviruses, in providing protection against severe COVID-19. In this study we assessed T-cell responses directed against highly conserved regions of SARS-CoV-2. Epitope mapping revealed 16 CD8+ T-cell epitopes across the nucleocapsid (N), spike (S) and ORF3a proteins of SARS-CoV-2 and five CD8+ T-cell epitopes encoded within the highly conserved regions of the ORF1ab polyprotein of SARS-CoV-2. Comparative sequence analysis showed high conservation of SARS-CoV-2 ORF1ab T-cell epitopes in seasonal coronaviruses. Paradoxically, the immune responses directed against the conserved ORF1ab epitopes were infrequent and subdominant in both convalescent and unexposed participants. This subdominant immune response was consistent with a low abundance of ORF1ab encoded proteins in SARS-CoV-2 infected cells. Overall, these observations suggest that while cross-reactive CD8+ T cells likely exist in unexposed individuals, they are not common and therefore are unlikely to play a significant role in providing broad pre-existing immunity in the community.

immunology↗

bioRxiv2019

Fecal microbiota dysbiosis in macaques and humans within a shared environment

Traditional zoonotic disease research focuses on detection of recognized pathogens and may miss opportunities to understand broader microbial transmission dynamics between humans, animals, and the environment. We studied human-macaque microbiome overlap in Kosum Phisai District, Maha Sarakham Province, Thailand, where a growing population of long-tailed macaques (Macaca fascicularis) in Kosumpee Forest Park interact with humans from an adjacent village. We surveyed workers in or near the park with elevated exposure to macaques to characterize tasks resulting in exposure to macaque feces in addition to dietary and lifestyle factors that influence gut microbiome composition. Fecal samples were collected from 12 exposed workers and 6 controls without macaque exposure, as well as 8 macaques from Kosumpee Forest Park and 4 from an isolated forest patch with minimal human contact. The V4 region of the 16S rRNA gene from fecal sample extracted DNA was amplified and sequenced using Illumina HiSeq to characterize the microbial community. A permuted betadisper test on the weighted UniFrac distances revealed significant differences in the dispersion patterns of gut microbiota from exposed and control macaques (p=0.03). The high variance in gut microbiota composition of macaques in contact with humans has potential implications for gut microbiome stability and susceptibility to disease, described by the Anna Karenina principle (AKP). Human samples had homogenous variance in beta diversity but different spatial medians between groups (p=0.02), indicating a shift in microbial composition that may be explained by fundamental lifestyle differences between the groups unrelated to exposure status. SourceTracker was used to estimate the percent of gut taxa in exposed humans that was contributed by macaques. While one worker showed evidence of elevated contribution, the overall trend was not significant. Task observations among workers revealed opportunities to employ protective measures or training to reduce exposure to occupational hazards. These results suggest the potential for hygiene measures to mitigate negative aspects of contact between humans and macaques in order to optimize the health of both populations.

microbiology↗

bioRxiv2018

ESCRT-III accumulates in micronuclei with ruptured nuclear envelopes

1.Micronuclei represent the cellular attempt to compartmentalize DNA to maintain genomic integrity threatened by mitotic errors and genotoxic events. Micronuclei show aberrant nuclear envelopes that collapse, generating damaged DNA and promoting complex genome alterations. However, ruptured micronuclei also provide a pool of cytosolic DNA that stimulates anti-tumour immunity, revealing the complexity of micronuclei impact on tumour progression.\n\nThe ESCRT-III complex ensures nuclear envelope (NE) resealing during late mitosis and NE repair in interphase. Therefore, ESCRT-III activity maybe crucial for maintaining the integrity of other genomic structures enclosed by a nuclear envelope. ESCRT-III activity at the nuclear envelope is coordinated by the subunit CHMP7.\n\nWe show that CHMP7 and ESCRT-III protects against the genomic instability associated with micronuclei formation. Loss of ESCRT-III activity increases the population of micronuclei with ruptured nuclear envelopes, in interphase cells. Surprisingly, ESCRT-III is retained at acentric micronuclei suggesting that ESCRT-III cannot repair these structures. Depletion of CHMP7 expression removes ESCRT-III accumulations at ruptured micronuclei, and removes the population of micronuclei with damaged DNA also containing a sensor for cytosolic DNA.\n\nThus, ESCRT-III activity appears to protect from the consequence of genomic instability in a dichotomous fashion. Membrane repair activity prevents the occurrence of MN with weak envelopes; conversely, aberrant membrane remodelling at micronuclei generates a steady state pool of cytosolic DNA that may contribute to sustaining pro-inflammatory pathways in cancer cells.

cancer biology↗