Biology subjects

Girard, C.

Publications and source records attributed to Girard, C..

14 recordsLinked to original sources

bioRxiv2026

Bottlenose whales are more socially connected when in poor body condition

Social relationships are strongly linked to health and biological fitness in humans and other animals. For example, social support may buffer individuals against harsh ecological conditions. Reciprocally, better health may allow for greater investment in social relationships. We examined links between health and social behaviour in an endangered population of northern bottlenose whales (Hyperoodon ampullatus). Using photo-identifications spanning 37 years, we visually classified whether individuals had poor body condition on each day they were observed (N = 3,086 whale-days). We then used generalized linear mixed models to explore how body condition varied with sex, age, and within-individual deviations in group size or other social metrics derived from Bayesian social networks. Approximately 11% of individuals were classified as being in poor condition at any time, though the prevalence of poor condition varied across raters and years. Visually assessed condition was successfully validated with morphometric measures, though there was only weak evidence that poor condition predicted apparent survival. Contrary to expectations, whales in poor condition were found in larger groups and had more social partners than their average across the study period. These findings run counter to the expectation that health and social connectedness are positively correlated in social mammals.

animal behavior and cognition↗

bioRxiv2026

A JAK-STAT-activated myeloid hub at ulceration sites underlies resistance to anti-TNF therapy in Crohn's disease

Despite major advances in immunotherapies, durable disease control in immune-mediated inflammatory diseases (IMIDs) is frequently limited by resistance driven by maladaptive immune programs, resulting in progressive tissue damage. Myeloid cells are central effectors across IMIDs, including inflammatory bowel disease (IBD), yet how discrete myeloid states govern disease progression and therapeutic response remains incompletely defined. Here, using integrative single-cell transcriptomic and molecular analyses of inflamed human ileum in Crohns disease (CD), we identify combinatorial transcriptional programs that revealed previously unrecognized axes of monocyte-macrophage (mo-mac) heterogeneity. These myeloid states and programs were conserved and validated across multiple independent cohorts. We delineate a pathogenic mo-mac subset, interferon-associated inflammatory monocytes (IFIM), shaped by convergent NF-{kappa}B and IFN{gamma} signaling and enriched in advanced disease. Baseline abundance of IFIM programs predicted resistance to anti-TNF therapy and severe postoperative recurrence, with IFIM-derived ligands sustaining epithelial injury. IFIM exhibited robust JAK-STAT activation, indicating susceptibility to JAK inhibition with clinically approved agents, including upadacitinib. Exemplified by IFIM-driven inflammation, these findings identify pathogenic myeloid state remodeling as a molecular basis of anti-TNF resistance and provide a framework for mechanism-guided therapeutic strategies across chronic inflammatory diseases.

immunology↗

bioRxiv2025

Industrialization drives convergent microbial and physiological shifts in the human metaorganism

Understanding how host lifestyle and industrialization shape the human gut microbiome and intestinal physiology requires multimodal analyses across diverse global host contexts. Here, we generate multivariate data from the Global Microbiome Conservancy cohort, including gut microbiome, IgA-sequencing, host genotyping, diet, lifestyle and fecal biomarker profiles, to investigate host-microbiome interactions across gradients of industrialization and geography. We show that industrialization is associated with homogenized microbial compositions, reduced microbial diversity, and lower community stability, independent of host confounders. We further show that industrialization is linked to elevated markers of gut stress, increased IgA secretion, and altered patterns of IgA-bacteria interactions. Finally, we show that microbiome-based disease predictors trained on industrialized populations lose accuracy in less industrialized cohorts, highlighting limited cross-population transferability. Together, our results suggest profound restructuring of host-microbiome interactions due to industrialized lifestyles, and emphasize the need for inclusive, globally representative data to improve translational microbiome applications across diverse human populations.

microbiology↗

bioRxiv2025

Season and city shape urban bioaerosol composition beyond vegetation and socioeconomic gradients

Urban vegetation varies with socio-economic gradients, as lower-income neighborhoods often host sparser and less diverse green spaces. This disparity may affect respiratory health by influencing exposure to bioaerosols. Understanding the characteristics of this aerobiome could help anticipate risks related to allergies and other respiratory conditions. Here, we hypothesized that urban vegetation cover and socio-economic status shape urban bioaerosols. We sampled bioaerosols at 65 sites across three Canadian cities of varying population size and density using an active air sampler over four months, and characterized their bacterial, fungal, and pollen composition using amplicon sequencing. Seasonal alpha diversity varied significantly for fungi and pollen. Based on beta diversity, sampling period alone explained up to 40% of pollen, 29% of fungal, and 11% of bacterial community composition variation. In contrast, vegetation cover explained only a minor portion of the variance in bioaerosol composition, and median household income, almost none. These findings provide a critical baseline for understanding the urban aerobiome and highlight the need to study how vegetation identity and diversity, rather than cover alone, may shape bioaerosol dynamics in cities. As cities grow and urban greening initiatives expand, demystifying the aerobiome dynamics becomes an urgent public health priority.

microbiology↗

bioRxiv2025

Polymorphism can extensively reshape the genome-wide crossover landscape in Arabidopsis thaliana.

Meiotic recombination, via the formation of crossovers (COs), re-assorts parental alleles and dictate which traits are inherited together, or not. The recombination rate is not homogeneous across the genome, and uncovering the causes of these fluctuations can inform our understanding of DNA recombination and genome evolution. In this study we show that presence of sequence divergence (polymorphism) between homologous chromosomes increases the local recombination rate in Arabidopsis thaliana. This effect is observed genome-wide, turning cold regions of the genome hot. This relocation of COs towards polymorphic regions occurs at the expense of non-polymorphic ones, which become colder. This global overhaul of the CO landscape is dependent on the mismatch repair (MMR) machinery. This suggests that MMR has a pro-CO role, driving COs to regions of the genome where it could detect sequence differences between homologous chromosomes. Our study demonstrates that polymorphism can be a major recombination driver in A. thaliana.

genetics↗

bioRxiv2024

FIGL1 attenuates meiotic interhomolog repair and is counteracted by RAD51 paralog XRCC2 and chromosome axis protein ASY1 during meiosis

Two recombinases, RAD51 and DMC1, catalyze meiotic break repair to ensure crossovers (COs) between homologous chromosomes (interhomolog) rather than between sisters (intersister). FIDGETIN-LIKE-1 (FIGL1) downregulates both recombinases. However, the understanding of FIGL1 functions in meiotic repair remains limited. Here, we discover new genetic interactions of Arabidopsis thaliana FIGL1 that are important in vivo determinants of meiotic repair outcome. In figl1, compromising the RAD51-dependent repair by either losing RAD51 paralogs (RAD51B or XRCC2) or RAD54 or inhibiting RAD51s catalytic activity results in either unrepaired breaks or meiotic CO defects. Further, XRCC2 physically interacts with FIGL1 and partially counteracts FIGL1 for RAD51 focus formation. Our data support that RAD51-mediated repair mechanisms compensate for the FIGL1 dysfunction. FIGL1 is dispensable for intersister repair in dmc1 but is essential for meiotic repair completion in mutants with impaired DMC1 functions and interhomolog bias such as asy1. We show that FIGL1 attenuates interhomolog repair, and ASY1 counteracts FIGL1 to promote interhomolog recombination.

plant biology↗

bioRxiv2021

Disentangling heterogeneity of Malignant Pleural Mesothelioma through deep integrative omics analyses

Malignant Pleural Mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Using the largest series of whole-genome sequencing data integrated with transcriptomic and epigenomic data using multi-omic factor analysis, we demonstrate that MPM heterogeneity arises from four sources of variation: tumor cell morphology, ploidy, adaptive immune response, and CpG island methylator phenotype. Previous genomic studies focused on describing only the tumor cell morphology factor, although we robustly find the three other sources in all publicly available cohorts. We prove how these sources of variation explain the biological functions performed by the cancer cells, and how genomic events shape MPM molecular profiles. We show how these new sources of variation help understand the heterogeneity of the clinical behavior of MPM and drug responses measured in cell lines. These findings unearth the interplay between MPM functional biology and its genomic history, and ultimately, inform classification, prognostication and treatment. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/461908v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@b6c43corg.highwire.dtl.DTLVardef@10d45a9org.highwire.dtl.DTLVardef@58746eorg.highwire.dtl.DTLVardef@143f880_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

Blockade of pro-fibrotic response mediated by the miR-143/-145 cluster prevents targeted therapy-induced phenotypic plasticity and resistance in melanoma

Lineage dedifferentiation towards a mesenchymal-like state is a common mechanism of adaptive response and resistance to targeted therapy in melanoma. Yet, the transcriptional network driving this phenotypic plasticity remains elusive. Remarkably, this cellular state displays myofibroblast and fibrotic features and escapes MAPK inhibitors (MAPKi) through extracellular matrix (ECM) remodeling activities. Here we show that the anti-fibrotic drug Nintedanib/BIBF1120 is active to normalize the fibrous ECM network, enhance the efficacy of MAPK-targeted therapy and delay tumor relapse in a pre-clinical model of melanoma. We also uncovered the molecular networks that regulate the acquisition of this resistant phenotype and its reversion by Nintedanib, pointing the miR-143/-145 pro-fibrotic cluster as a driver of the therapy-resistant mesenchymal-like phenotype. Upregulation of the miR-143/-145 cluster under BRAFi/MAPKi therapy was observed in melanoma cells in vitro and in vivo and was associated with an invasive/undifferentiated profile of resistant cells. The 2 mature miRNAs generated from this cluster, miR-143-3p and miR-145-5p collaborated to mediate phenotypic transition towards a drug resistant undifferentiated mesenchymal-like state by targeting Fascin actin-bundling protein 1 (FSCN1), modulating the dynamic crosstalk between the actin cytoskeleton and the ECM through the regulation of focal adhesion dynamics as well as contributing to a fine-tuning of mechanotransduction pathways. Our study brings insights into a novel miRNA-mediated regulatory network that contributes to non-genetic adaptive drug resistance and provides proof-of-principle that preventing MAPKi-induced pro-fibrotic stromal response is a viable therapeutic opportunity for patients on targeted therapy.

cancer biology↗

bioRxiv2020

Industrialization is associated with elevated rates of horizontal gene transfer in the human microbiome

Horizontal Gene Transfer, the process by which bacteria acquire new genes and functions from non-parental sources, is common in the human microbiome 1,2. If the timescale of HGT is rapid compared to the timescale of human colonization, then it could have the effect of personalizing bacterial genomes by providing incoming strains with the genes necessary to adapt to the diet or lifestyle of a new host. The extent to which HGT occurs on the timescale of human colonization, however, remains unclear. Here, we analyzed 6,188 newly isolated and sequenced gut bacteria from 34 individuals in 9 human populations, and show that HGT is more common among bacteria isolated from the same human host, indicating that the timescale of transfer is short compared to the timescale of human colonization. Comparing across 9 human populations reveals that high rates of transfer may be a recent development in human history linked to industrialization and urbanization. In addition, we find that the genes involved in transfer reflect the lifestyle of the human hosts, with elevated transfer of carbohydrate metabolism genes in hunter gatherer populations, and transfer of antibiotic resistance genes among pastoralists who live in close contact with livestock. These results suggest that host-associated bacterial genomes are not static within individuals, but continuously acquire new functionality based on host diet and lifestyle.

microbiology↗

bioRxiv2019

Targeting DDR1 and DDR2 overcomes matrix-mediated melanoma cell adaptation to BRAF-targeted therapy

Resistance to BRAF and MEK inhibitors in BRAFV600E mutant melanomas remains a major obstacle that limits patient benefit. Microenvironment components including the extracellular matrix (ECM) can support tumor cell adaptation and tolerance to targeted therapies, however the underlying mechanisms remain poorly understood. Here, we investigated the process of matrix-mediated drug resistance (MM-DR) in response to BRAF inhibition in melanoma. We demonstrate that physical and structural cues from fibroblast-derived ECM abrogate anti-proliferative responses to BRAF/MEK inhibition. MM-DR is mediated by the drug-induced clustering of DDR1 and DDR2, two tyrosine kinase collagen receptors. Genetic depletion and pharmacological inhibition of DDR1 and DDR2 overcome ECM-mediated resistance to BRAF inhibition. In melanoma xenografts, targeting DDRs by Imatinib enhances BRAF inhibitor efficacy, counteracts drug-induced collagen remodeling and delays tumor relapse. Mechanistically, DDR-mediated MM-DR fosters a targetable pro-survival NIK/IKK/NF-{kappa}B2 pathway. Our study reveals a novel role of collagen-rich matrix and DDRs in tumor cell adaptation and therapy resistance, thus providing important insights into environment-mediated drug resistance and a pre-clinical rationale for targeting DDR1/2 signaling in combination with BRAF-targeted therapy in melanoma.

cancer biology↗

bioRxiv2019

Spatial Regulation of Polo-like Kinase Activity during C. elegans Meiosis by the Nucleoplasmic HAL-2/HAL-3 Complex

Proper partitioning of homologous chromosomes during meiosis relies on the coordinated execution of multiple interconnected events: Homologs must locate, recognize and align with their correct pairing partners. Further, homolog pairing must be coupled to assembly of the synaptonemal complex (SC), a meiosis-specific tripartite structure that maintains stable associations between the axes of aligned homologs and regulates formation of crossovers between their DNA molecules to create linkages that enable their segregation. Here we identify HAL-3 (Homolog Alignment 3) as an important player in coordinating these key events during C. elegans meiosis. HAL-3 and the previously-identified HAL-2 are interacting and interdependent components of a protein complex that localizes to the nucleoplasm of germ cells. hal-3 (or hal-2) mutants exhibit multiple meiotic prophase defects including failure to establish homolog pairing, inappropriate loading of SC subunits onto unpaired chromosome axes, and premature loss of synapsis checkpoint protein PCH-2. Further, loss of hal function results in misregulation of the subcellular localization and activity of polo-like kinases (PLK-1 and PLK-2), which dynamically localize to different defined subnuclear sites during wild-type prophase progression to regulate distinct cellular events. Moreover, loss of PLK-2 activity partially restores tripartite SC structure in a hal mutant background, suggesting that the defect in pairwise SC assembly in hal mutants reflects inappropriate PLK activity. Together our data support a model in which the nucleoplasmic HAL-2/HAL-3 protein complex constrains both localization and activity of meiotic Polo-like kinases, thereby preventing premature interaction with stage-inappropriate targets.

genetics↗

bioRxiv2018

Multi-scale mapping along the auditory hierarchy using high-resolution functional UltraSound in the awake ferret

A major challenge in neuroscience is to longitudinally monitor whole brain activity across multiple spatial scales in the same animal. Functional UltraSound (fUS) is an emerging technology that offers images of cerebral blood volume over large brain portions. Here we show for the first time its capability to resolve the functional organization of sensory systems at multiple scales in awake animals, both within structures by precisely mapping sensory responses, and between structures by elucidating the connectivity scheme of top-down projections. We demonstrate that fUS provides stable (over days), yet rapid, highly-resolved 3D tonotopic maps in the auditory pathway of awake ferrets, with unprecedented sharp functional resolution (100m). This was performed in four different brain regions, including small (1-2mm3 size), subcortical (8mm deep) and previously undescribed structures in the ferret. Furthermore, we used fUS to map longdistance projections from frontal cortex, a key source of sensory response modulation, to auditory cortex.

neuroscience↗

bioRxiv2017

Interdependent and separable functions of C. elegans MRN-C complex members couple formation and repair of meiotic DSBs

Faithful inheritance of genetic information through sexual reproduction relies on the formation of crossovers between homologous chromosomes during meiosis, which in turn relies on the formation and repair of numerous double-strand DNA breaks (DSBs). As DSBs pose a potential threat to the genome, mechanisms that ensure timely and error-free DSB repair are crucial for successful meiosis. Here we identify NBS-1, the Caenorhabditis elegans ortholog of the NBS1 subunit of the conserved MRE11-RAD50-NBS1/Xrs2 (MRN) complex, as a key mediator of DSB repair via homologous recombination (HR) during meiosis. Loss of nbs-1 leads to: severely reduced loading of recombinase RAD-51, ssDNA binding protein RPA and pro-crossover factor COSA-1 during meiotic prophase progression; aggregated and fragmented chromosomes at the end of meiotic prophase; and 100% progeny lethality. These phenotypes reflect a role for NBS-1 in processing of meiotic DSBs for HR that is shared with its interacting partners MRE-11-RAD-50 and COM-1 (ortholog of Com1/Sae2/CtIP). Unexpectedly, in contrast to MRE-11 and RAD-50, NBS-1 is not required for meiotic DSB formation. Meiotic defects of the nbs-1 mutant are partially suppressed by abrogation of the non-homologous end-joining (NHEJ) pathway, indicating a role for NBS-1 in antagonizing NHEJ during meiosis. Our data further reveal that NBS-1 and COM-1 play distinct roles in promoting HR and antagonizing NHEJ. We propose a model in which different components of the MRN-C complex work together to couple meiotic DSB formation with efficient and timely engagement of HR, thereby ensuring crossover formation and restoration of genome integrity prior to the meiotic divisions.\n\nSignificance StatementDouble-strand breaks (DSBs) are deleterious DNA lesions, and impairment of the DSB repair machinery can lead to devastating diseases such as the Nijmegen Breakage Syndrome (NBS). During meiosis, DSBs represent a \"necessary evil\": they are required to promote formation of crossovers between homologous chromosomes. Crossovers in turn ensure correct chromosome inheritance during gamete formation, which is essential for viability and normal development of embryos. During meiosis, numerous DSBs are actively created, so meiotic cells must ensure that all breaks are properly repaired to ensure crossover formation and restore genomic integrity. Here we identify C. elegans NBS-1 as essential to properly process meiotic DSBs, both to promote crossover formation and antagonize an error-prone DSB repair pathway, thereby ensuring faithful chromosome inheritance.

genetics↗

bioRxiv2017

FIGL1 and its novel partner FLIP form a conserved complex that regulates homologous recombination.

Homologous recombination is central to repair DNA double-strand breaks (DSB), either accidently arising in mitotic cells or in a programed manner at meiosis. Crossovers resulting from the repair of meiotic breaks are essential for proper chromosome segregation and increase genetic diversity of the progeny. However, mechanisms regulating CO formation remain elusive. Here, we identified through protein-protein interaction and genetic screens FIDGETIN-LIKE-1 INTERACTING PROTEIN (FLIP) as a new partner of the previously characterized anti-crossover factor FIDGETIN-LIKE-1 (FIGL1) in Arabidopsis thaliana. We showed that FLIP limits meiotic crossover together with FIGL1. Further, FLIP and FIGL1 form a protein complex conserved from Arabidopsis to Human. FIGL1 interacts with the recombinases RAD51 and DMC1, the enzymes that catalyze the DNA stand exchange step of homologous recombination. Arabidopsis flip mutants recapitulates the figl1 phenotype, with enhanced meiotic recombination associated with change in DMC1 dynamics. Our data thus suggest that FLIP and FIGL1 form a conserved complex that regulates the crucial step of strand invasion in homologous recombination.

genetics↗