Biology subjects

Leung, C.

Publications and source records attributed to Leung, C..

14 recordsLinked to original sources

bioRxiv2026

Statistical inference of virus evolution using ancestral recombination graphs

Ancestral recombination graphs (ARGs) represent the coalescent history at every locus in the genome, subject to mutation and recombination. Modelling viruses using the coalescent with recombination remains less explored, due to the potential for complex, multi-scale dynamics. Using perturbative methods, we establish mathematical bounds that describe the balance between inter-host and within-host coalescence, and demonstrate that the highly-recombinant Epstein-Barr Virus (EBV) coalesces predominantly at the inter-host level. We then modify SINGER, a tool from diploid genetics, for haploid ARG inference with fine-grained variable recombination rates. We provide insight into the paradox of high recombination rates and slow linkage disequilibrium decay, as ARG-based methods potentially allow us to disentangle epistatic effects from shared ancestry, and illustrate this using the coalescent topologies of EBV's host cell-entry glycoproteins. Our findings demonstrate that ARG-based methods recover gene-level selective structure, and provide a general method for analysing virus phylodynamics in the limit of small quantities.

evolutionary biology↗

bioRxiv2025

Posterior Cortex Isolation Enhances Detection of Alpha Desynchronization During Sustained Attention

Electroencephalography (EEG) is an essential tool for assessing the neural activity behind mental fatigue, a factor that can influence both cognitive and physical performance. Mental fatigue influences alpha-band oscillations (8-12 Hz), reflecting cortical engagement and attention stability. In this study, EEG recordings from 109 participants in the Physionet open-source EEG Motor Movement/Imagery Dataset (EEGMMIDB) were analyzed to characterize alpha power changes during sustained attention. Spectral analysis was performed across early and late task blocks to quantify alpha desynchronization over time. Participants demonstrated a consistent decrease in alpha power ({Delta} = -0.076 {+/-} 0.019 log10 units; p = 0.0001), indicating desynchronization associated with sustained attentional demand. These findings show the applicability of open-source EEG datasets for research. Furthermore, these findings support the isolation of posterior activation as a marker of mental fatigue through alpha desynchronization. One sentence overviewAlpha desynchronization is a marker for mental fatigue in EEGs. This paper illustrates that isolating the posterior cortical lobes enhances the resolution and sensitivity of alpha band changes associated with sustained attention.

neuroscience↗

bioRxiv2025

Past environments modulate response to fluctuating temperatures in a marine fish species

The rise in ocean temperatures predicted due to the global warming will impact the survival and structure of various marine organisms, in particular ectothermic organisms. Phenotypic plasticity enables species to cope with environmental changes, providing a vital buffer for evolutionary changes. Yet, the dynamics and the molecular mechanisms underpinning these plastic responses remain largely unexplored. Here, we assessed the impact of acclimation environment on organisms capacity for thermal plasticity. We conducted a genome-wide transcriptomic analysis on the Acadian redfish, S. fasciatus, exposed to four temperatures (2.5, 5.0, 7.5 and 10.0 ) over a long-term period (up to 10 months) followed by an acute temperature change (24 hours), simulating natural fluctuation condition the species could encounter. Our results showed a dynamic transcriptional response to temperature involving various genes functions. The rapid response to temperature shifts, coupled with the sustained expression of specific genes over an extended period highlighted the species capacity for plastic response to temperature changes. We also detected a significant effect of the interaction between the long and short terms temperature exposure on gene expression, highlighting the influence of the past environment on response to acute temperature changes. Specifically, fish acclimated to higher temperatures demonstrated an increased stress-related response to environmental fluctuations, as evidenced by both the shape of their reaction norms and the implication of stress-related gene functions. This result suggests that temperature conditions predicted for the near future in the Northwest Atlantic will trigger less adaptive plasticity to environmental fluctuations, highlighting the species vulnerability to ocean warming.

ecology↗

bioRxiv2025

Persistent antigen is essential for sustaining Leishmania-specific memory CD4+ T cells and long-term immunity

Memory T cells are critical for secondary immunity against pathogens, yet their persistence in the absence of antigen remains unclear. While memory CD8+ T cells are known to persist independently of their cognate antigen, the durability of memory CD4+ T cells in the absence of antigen remains controversial. Recovery from cutaneous leishmaniasis confers lifelong immunity, largely mediated by CD4+ T cells, but the necessity of persistent parasites for sustaining this immunity has not been empirically confirmed. We investigated immunity in mice infected with a dihydrofolate reductase-thymidylate synthase (dhfr-ts)-deficient Leishmania major, which cannot persist due to their thymidine salvage deficiency. These mice lost protection against wild-type challenge, correlating with a decline in Leishmania (PEPCK)-specific CD4+ T cells. To further dissect this relationship, we generated PEPCK-specific CD4+ TCR transgenic (PEG) mice, enabling precise tracking of Leishmania-specific memory CD4+ T cells. Both in vitro and in vivo-generated memory PEG cells gradually disappeared over time in the absence of antigen, irrespective of the hosts MHC II status, and this loss paralleled the erosion of infection-induced immunity. PEG and endogenous PEPCK-specific memory cells were not maintained in mice infected with dhfr-ts- or PEPCK-deficient L. major, resulting in loss of recall responses and secondary immunity. These findings demonstrate that continuous antigen presence is crucial for maintaining Leishmania-specific memory CD4+ T cells and highlight the role of persistent antigen in sustaining long-term immunity against chronic infections.

immunology↗

bioRxiv2024

WRAD core perturbation impairs DNA replication fidelity promoting immunoediting in pancreatic cancer

It is unclear how cells counteract the potentially harmful effects of uncoordinated DNA replication in the context of oncogenic stress. Here, we identify the WRAD (WDR5/RBBP5/ASH2L/DPY30) core as a modulator of DNA replication in pancreatic ductal adenocarcinoma (PDAC) models. Molecular analyses demonstrated that the WRAD core interacts with the replisome complex, with disruption of DPY30 resulting in DNA re-replication, DNA damage, and chromosomal instability (CIN) without affecting cancer cell proliferation. Consequently, in immunocompetent models, DPY30 loss induced T cell infiltration and immune-mediated clearance of highly proliferating cancer cells with complex karyotypes, thus improving anti-tumor efficacy upon anti-PD-1 treatment. In PDAC patients, DPY30 expression was associated with high tumor grade, worse prognosis, and limited response to immune checkpoint blockade. Together, our findings indicate that the WRAD core sustains genome stability and suggest that low intratumor DPY30 levels may identify PDAC patients who will benefit from immune checkpoint inhibitors.

cancer biology↗

bioRxiv2024

Linking selection to demography in experimental evolution of active death in a unicellular organism

Deciphering how natural selection emerges from demographic differences among genotypes, and reciprocally how evolution affects population dynamics, is key to understanding population responses to environmental stress. This is especially true in non-trivial ecological scenarios, such as programmed cell death (PCD) in unicellular organisms, which can lead to massive population decline in response to stress. To understand how selection may operate on this trait, we exposed monocultures and mixtures of two closely related strains of the microalga Dunalliela salina, one of which induces PCD, to multiple cycles of hyper-osmotic shocks, and tracked demography and selection throughout. Population dynamics were consistent between mixtures and monocultures, suggesting that selection on PCD does not involve strong ecological interactions. The PCD-inducing strain was maintained throughout the experiment despite an initial decline, by a combination of fast population rebound following each decline, and density-dependent competition dynamics near the stationary phase that were independent of these initial population fluctuations. As result of PCD maintenance, population decline in response to environmental stress was not counter-selected in our experiment, but persisted over 13 cycles of salinity. Our results highlight how analysing the demographic underpinnings of fitness and competition can shed light on the mechanisms underlying selection and eco-evolutionary dynamics.

evolutionary biology↗

bioRxiv2024

Diving into broad-scale and high-resolution population genomics to decipher drivers of structure and climatic vulnerability in a marine invertebrate

Species with widespread distributions play a crucial role in our understanding of climate change impacts on population structure. In marine species, population structure is often governed by both high connectivity potential and selection across strong environmental gradients. Despite the complexity of factors influencing marine populations, studying species with broad distribution can provide valuable insights into the relative importance of these factors and the consequences of climate-induced alterations across environmental gradients. We used the northern shrimp Pandalus borealis and its wide latitudinal distribution to identify current drivers of population structure and predict the species vulnerability to climate change. Individuals sampled across 24{degrees} latitude were genotyped at high geographic-(54 stations) and genetic-(14,331 SNPs) resolutions to assess genetic variation and environmental correlations. Four populations were identified in addition to finer substructure associated to local adaptation. Geographic patterns of neutral population structure reflected predominant oceanographic currents, while a significant proportion of the genetic variation was associated with gradients in salinity and temperature. Adaptive landscapes generated using climate projections suggest a larger genomic offset in the southern extent of the P. borealis range, where shrimp had the largest adaptive standing genetic variation. Our genomic results combined with recent observations point to the non-recovery in southern regions and an impending vulnerable status in the regions at higher latitude for P. borealis. They also provide rare insights into the drivers of population structure and climatic vulnerability of a widespread meroplanktonic species, which is crucial to understand future challenges associated with invertebrates essential to ecosystem functioning.

genomics↗

bioRxiv2022

The molecular basis of phenotypic plasticity evolves in response to environmental predictability

Phenotypic plasticity, the response of a given genotype to its environment of development, is a ubiquitous feature of life, enabling organisms to cope with variation in their environment. Theoretical studies predict that, under stationary environmental variation, the level of plasticity should evolve to match the predictability of selection at the timing of development. However, we still lack critical empirical evidence on the extent to which selection on phenotypic plasticity cascades down from higher phenotypic levels to their underlying molecular basis. Here, we used experimental evolution under controlled environmental fluctuations, to test whether the evolution of phenotypic plasticity in responses to environmental predictability ({rho}2) occurred across biological levels, going from DNA methylation to gene expression to cell morphology. Transcriptomic results indicate clear effects of salinity and{rho} 2xsalinity interaction on gene expression, thus identifying sets of genes involved in plasticity and its evolution. These transcriptomic effects were independent of DNA methylation changes in cis. However we did find{rho} 2-specific responses of DNA methylation to salinity change, albeit weaker than for gene expression. Overall, we found consistent evolution of reduced plasticity in less predictable environments for DNA methylation, gene expression, and cell morphology. Our results provide the first clear empirical signature of plasticity evolution at multiple levels in response to environmental predictability, and highlight the importance of experimental evolution to address predictions from evolutionary theory, as well as investigate the molecular basis of plasticity evolution.

evolutionary biology↗

bioRxiv2021

Plasticity across levels: relating epigenomic, transcriptomic, and phenotypic responses to osmotic stress in a halotolerant microalga

Phenotypic plasticity, the ability of a given genotype to produce alternative phenotypes in response to its environment of development, is an important mechanism for coping with variable environments. While the mechanisms underlying phenotypic plasticity are diverse, their relative contributions need to be investigated quantitatively to better understand the evolvability of plasticity across biological levels. This requires relating plastic responses of the epigenome, transcriptome, and organismal phenotype, and how they vary with the genotype. Here we carried out this approach for responses to osmotic stress in Dunaliella salina, a green microalga that is a model organism for salinity tolerance. We compared two strains that show markedly different demographic responses to osmotic stress, and showed that these phenotypic responses involve strain- and environment-specific variation in gene expression levels, but a relative low - but significant - effect of strain x environment interaction. We also found an important genotype effect on the genome-wide methylation pattern, but little contribution from environmental conditions to the latter. However, we did detect a significant marginal effect of epigenetic variation on gene expression, beyond the influence of genetic differences on epigenetic state, and we showed that hypomethylated regions are correlated with higher gene expression. Our results indicate that epigenetic mechanisms are either not involved in the rapid plastic response to environmental change in this species, or involve only few changes in trans that are sufficient to trigger concerted changes in the expression of many genes, and phenotypic responses by multiple traits.

genomics↗

bioRxiv2020

Projection of gut microbiome pre and post-bariatric surgery to predict surgery outcome

BackgroundBariatric surgery is often the preferred method to resolve obesity and diabetes, with ~800,000 cases worldwide yearly and high outcome variability. The ability to predict the long-term Body Mass Index (BMI) change following surgery has important implications on individuals and the health care system in general. Given the tight connection between eating habits, sugar consumption, BMI, and the gut microbiome, we tested whether the microbiome before any treatment is associated with different treatment outcomes, as well as other intakes (high-density lipoproteins (HDL), Triglycerides, etc.). ResultsA projection of the gut microbiome composition of obese (sampled before and after bariatric surgery) and slim patients into principal components was performed and the relation between this projection and surgery outcome was studied. The projection reveals 3 different microbiome profiles belonging to slim, obese, and obese who underwent bariatric surgery, with post-surgery more different from the slim than the obese. The same projection allowed for a prediction of BMI loss following bariatric surgery, using only the pre-surgery microbiome. ConclusionsThe gut microbiome can be decomposed into main components depicting the patients development and predicting in advance the outcome. Those may be translated into better clinical management of obese individuals planning to undergo metabolic surgery. ImportanceBMI and diabetes can affect the gut microbiome composition. Bariatric surgery has large variabilities in outcome. The microbiome was previously shown to be a good predictor for multiple diseases. We analyzed here the gut microbiome before and after bariatric surgery and show that: O_LIThe microbiome before surgery can be used to predict surgery outcome. C_LIO_LIPost-surgery microbiome drifts further away from the slim microbiome than pre-surgery obese patients. C_LI These results can lead to a microbiome-based pre-surgery decision whether to perform surgery.

microbiology↗

bioRxiv2020

3D single cell scale anatomical map of sex-dependent variability of the rat intrinsic cardiac nervous system

We developed and analyzed a single cell scale anatomical map of the rat intrinsic cardiac nervous system (ICNS) across 4 male and 3 female hearts. We find the ICNS has a reliable structural organizational plan across individuals that may provide the foundation for further analyses of the ICNS in cardiac function and disease. The distribution of the ICNS was evaluated by 3D visualization and using data-driven clustering. The pattern, distribution and clustering of ICNS neurons across all male and female rat hearts is highly conserved, demonstrating a coherent organizational plan in which distinct clusters of neurons are consistently localized. Female hearts had fewer neurons, lower packing density and slightly reduced distribution, but with the same localization. We registered the anatomical data from each heart to a geometric scaffold, normalizing their 3D coordinates for the standardization of common anatomical planes and providing the path where multiple experimental results and data types can be integrated and compared.

neuroscience↗

bioRxiv2019

Entry by multiple picornaviruses is dependent on a pathway that includes TNK2, WASL and NCK1

Comprehensive knowledge of the host factors required for picornavirus infection would facilitate antiviral development. Here we demonstrate roles for three human genes, TNK2, WASL, and NCK1, in infection by multiple picornaviruses. CRISPR deletion of TNK2, WASL or NCK1 reduced encephalomyocarditis virus (EMCV), coxsackievirus B3 (CVB3), poliovirus and enterovirus D68 infection, and chemical inhibitors of TNK2 and WASL decreased EMCV infection. Reduced EMCV lethality was observed in mice lacking TNK2. TNK2, WASL and NCK1 were important in early stages of the viral lifecycle, and genetic epistasis analysis demonstrated that the three genes function in a common pathway. Mechanistically, reduced internalization of EMCV was observed in TNK2 deficient cells demonstrating that TNK2 functions in EMCV entry. Domain analysis of WASL demonstrated that its actin nucleation activity was necessary to facilitate viral infection. Together, these data support a model wherein TNK2, WASL, and NCK1 comprise a pathway critical for multiple picornaviruses.

microbiology↗

bioRxiv2019

Globally elevating the AGE clearance receptor, OST48, does not protect against the development of diabetic kidney disease, despite improving insulin secretion.

The accumulation of advanced glycation end products (AGEs) have been implicated in the development and progression of diabetic kidney disease (DKD). There has been interest in investigating the potential of AGE clearance receptors, such as oligosaccharyltransferase-48kDa subunit (OST48) to prevent the detrimental effects of excess AGE accumulation seen in the diabetic kidney. Here the objective of the study was to increase the expression of OST48 to examine if this slowed the development of DKD by facilitating the clearance of AGEs. Groups of 8-week-old heterozygous knock-in male mice (n=9-12/group) over-expressing the gene encoding for OST48, dolichyl-diphosphooligosaccharide-protein glycosyltransferase (DDOST+/-) and litter mate controls were randomised to either (i) no diabetes or (ii) diabetes induced via multiple low-dose streptozotocin and followed for 24 weeks. By the study end, global over expression of OST48 increased glomerular OST48. This facilitated greater renal excretion of AGEs but did not affect circulating or renal AGE concentrations. Diabetes resulted in kidney damage including lower glomerular filtration rate, albuminuria, glomerulosclerosis and tubulointerstitial fibrosis. In diabetic mice, tubulointerstitial fibrosis was further exacerbated by global increases in OST48. There was significantly insulin effectiveness, increased acute insulin secretion, fasting insulin concentrations and AUCinsulin observed during glucose tolerance testing in diabetic mice with global elevations in OST48 when compared to diabetic wild-type littermates. Overall, this study suggested that despite facilitating urinaryrenal AGE clearance, there were no benefits observed on kidney functional and structural parameters in diabetes afforded by globally increasing OST48 expression. However, the improvements in insulin secretion seen in diabetic mice with global over-expression of OST48 and their dissociation from effects on kidney function warrant future investigation.

molecular biology↗

bioRxiv2019

Comprehensive Integrated Anatomical And Molecular Atlas Of Rodent Intrinsic Cardiac Nervous System

In this study, we developed, coordinated, and integrated several technologies including novel whole organ imaging, software development to support the very first precise 3D neuroanatomical mapping and molecular phenotyping of the intracardiac nervous system (ICN). While qualitative and gross anatomical descriptions of the anatomy of the ICN have been presented, we here bring forth the first comprehensive atlas at large scale of the entire ICN in rat at a single cell resolution. Our work for the first time provides a novel 3D model to precisely integrate anatomical, functional and molecular data in the 3D digitally reconstructed whole heart with high resolution at the micron scale. This work represents the cutting edge in a long history of attempts to understand the anatomical substrate upon which the neuronal control of cardiac function is built. To our knowledge, there has not yet been a comprehensive histological mapping to generate a neurocardiac atlas at cellular and molecular level for the whole heart of any species. We now display the full extent and the position of neuronal clusters on the base and posterior left atrium, and the distribution of molecular phenotypes in that context. In addition we display in this context distinct molecular phenotypes that are defined along the base-to-apex axis, and the present novel discovery of their phenotypical spatial gradients, have not been previously described. The development of these approaches needed to acquire these data has produced method pipelines which can not only achieve the goals of anatomical and molecular mapping of the heart, but also provide the method pipelines for mapping other organs (e.g., stomach, lung, kidney, and liver).

neuroscience↗