Biology subjects

Mathieu, J.

Publications and source records attributed to Mathieu, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Integrin-independent Tie2 activation using de novo designed proteins

The Angiopoietin-Tie2 pathway is a key regulator of vascular stability, but therapeutic exploitation has been limited by the poor developability of Angiopoietin-1 (Ang1), and there are key unresolved mechanistic questions. Ang1 binds both Tie2 and 5{beta}1 integrin, and the role of the 5{beta}1 interaction in signaling has been unclear. We used RFdiffusion to design a stable, high-affinity Tie2 minibinder that has no affinity for 5{beta}1. The binder is a selective antagonist in monomeric form, and a potent agonist when assembled into an octavalent architecture (H8mb) which drives Tie2 clustering. H8mb signals as potently as Ang1, indicating that integrin engagement is not required for Tie2 activation. However, the duration of signaling is reduced, and internalization of H8mb-Tie2 complexes is more rapid, suggesting that integrin may function as a co-receptor for Ang1 that prolongs signaling by extending the lifetime of the receptor ligand complex on the cell surface. In a mouse model of acute respiratory distress syndrome (ARDS), H8mb markedly improved survival. These results demonstrate that de novo designed receptor binders can enable dissection of co-receptor control of signaling dynamics, and the more stable and manufacturable H8mb provides routes to more developable therapeutic candidates.

biochemistry↗

bioRxiv2026

Designed Minibinders Rewire Receptor Signaling to Enable Functional Human Myogenic Reprogramming

Sarcopenia, loss of muscle mass is a considerable health burden that demands immediate societal attention. Direct myogenic somatic cell reprogramming, a potential muscle regeneration method is constrained by an inability to control the signaling logic that governs cell fate. Here, we show that this barrier can be overcome using AI-designed receptor modulators. Screening de novo minibinders, we identify a synthetic protein cocktail, C6-DPC, that drives efficient human fibroblast-to-muscle transdifferentiation with robust structural and metabolic maturation. C6-DPC reprograms extracellular signaling by activating pro-myogenic FGFR1/2c pathways while suppressing anti-myogenic inputs through ALK1 and TGFBR2; targeted depletion of ALK1 is sufficient to lower the reprogramming barrier. Inflammatory signaling via gp130 emerges as a dominant checkpoint, and its inhibition further enhances conversion. Engineered tissues generate high twitch and tetanic forces in both wild-type and dystrophin-deficient human cells. These findings demonstrate that programmable synthetic ligands can rewrite receptor-level signaling to direct cell fate and enable functional tissue regeneration.

biochemistry↗

bioRxiv2026

Phosphoproteomics of Hypertrophic Cardiomyopathy Patient Myocardium and Novel hiPSC-CM Model Reveal Protein Kinase A as a Modulator of Microtubule Repolymerization

Background and aimsIncreased levels of -tubulin and its post-translational modifications (PTMs) are found in human heart failure and could initiate diastolic dysfunction by modulating cardiomyocyte stiffness. How these modifications occur and how they may underlie cardiac dysfunction remains unknown. Upstream kinases may play a critical role, but this has not been explored. Methods and resultsHere we address this question by, for the first time ever, determining levels of the enzymes involved in microtubule (MT) detyrosination and acetylation (TAT1, HDAC6) in a well-characterized cohort of patients with hypertrophic cardiomyopathy (HCM). In HCM patients (N=10-11), protein levels of detyrosination enzymes remain unaltered, whilst levels of TAT1 and HDAC6 were decreased and increased, respectively. Phosphoproteomics in HCM (N=24) and control (N=8) myocardium identified significant differences in over 1900 serine/threonine and 160 tyrosine phosphosites, in addition to increased EGFR/IGF1R-MAPK signaling in HCM. We subsequently showed that MT repolymerization was increased in HCM MYBPC3Arg943X hiPSC-CMs. Isoprenaline-mediated PKA activation decreased MT repolymerization in hiPSC-CMs and revealed CLASP1, MAST4 and MAP1A as potential MT modifiers in HCM. ConclusionsWe show that the altered HCM MT code cannot be attributed to levels of key MT-modifying enzymes. By combining kinome analyses in human HCM hearts with hiPSC-CM studies on MT dynamics, PTMs and contractility we unveiled a regulatory role for MTs in the cardiomyocyte response to beta-adrenergic receptor stimulation. Disease-mediated changes in the MT code thereby exert both a direct, and indirect effect on cardiac function via mediating the response to adrenergic activation. Graphical Abstract created with BioRender.com O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/706710v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1c58dc4org.highwire.dtl.DTLVardef@de502eorg.highwire.dtl.DTLVardef@1621512org.highwire.dtl.DTLVardef@557b82_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2025

Aligning gene trees with family trees

Relatedness between individuals can be measured at the genealogical level (by describing shared ancestors in a pedigree) or at a genetic level (by describing shared haplotypes across the genome). The shared haplotype structure can be conveniently summarized as a sequence of trees along the genome, where each tree describes the last shared genetic ancestors between individuals at a locus. While many tools exist to infer tree sequences from genetic data, and many large pedigree datasets are available, few tools exist to identify the relationship between the two - finding which genetic ancestor corresponds to which pedigree ancestor, and conversely. In this paper, we propose an algorithm to solve this problem by providing, for each genetic tree, the list of all consistent ancestry paths within a genealogical tree. We also provide variants of the algorithm with moderate robustness to both tree sequence and pedigree errors. We demonstrate the scalability of our approach on the BALSAC genealogical dataset, which includes millions of individuals in Quebec, Canada. We find that 20 carriers usually provide enough information to reliably identify a common ancestor 15 generations ago or find the parent of origin of alleles among probands, but the number of possible ancestry paths within the pedigree can remain large. We apply the method to reconstruct the inheritance of a causal allele for type 1 myotonic dystrophy.

bioinformatics↗

bioRxiv2025

Direct cell reprogramming by a designed agonist inducing HER2-FGFR proximity

Growth factor induced receptor dimerization and activation of downstream pathways can modulate cell fate decisions. Here, we investigate the potential of de novo designed synthetic ligands, termed Novokines, to reprogram cell identity by inducing proximity of novel pairs of receptor subunits. We find that a design, H2F, that brings together HER2 (which has no known natural ligand) and the FGF receptor has potent signaling activity. H2F induces robust signaling and reprograms fibroblasts into myogenic cells. Unlike native FGF ligands, H2F selectively activates the MAPK pathway without engaging PLC{gamma}-mediated Ca{superscript 2} signaling. FRET assays confirm H2F-mediated HER2-FGFR proximity, and phosphoproteomic analysis reveals activation of MAPK effectors. H2F-induced ERK phosphorylation is abolished in cells expressing a kinase-dead FGFR1 (K514M) mutant, confirming the requirement for FGFR catalytic activity. H2F treatment significantly increases myofiber formation from adult patient-derived primary myoblasts, demonstrating its capacity to promote myogenic regeneration. Our findings demonstrate that synthetic receptor pairings can rewire signaling outputs to drive regeneration, providing a programmable platform for cell fate engineering.

biochemistry↗

bioRxiv2025

Human iPSC-derived salivary gland organoids model diabetic salivary gland dysfunction

Salivary glands are highly susceptible to injury and degeneration. To facilitate studies in human salivary gland disease, we developed a rapid protocol for 3D hiPSC-derived salivary gland organoids that recapitulate human fetal salivary gland gene expression and function, have both ductal and acinar cell types, secretory capacity, and the ability to respond to cholinergic agonism. Oral health issues resulting from diabetes mellitus have been attributed to salivary gland dysfunction, leading to chronic xerostomia and increased dental caries. To study diabetic salivary gland hypofunction, we further developed a diabetic model, demonstrating diabetic hallmarks including FOXO1 nuclear localization, AGE-RAGE signaling, and defective oxidative phosphorylation, which were by treatment with the diabetic drug Metformin. Our model has implications for the development of effective therapeutics against salivary gland dysfunction in diabetes and other metabolic diseases in exocrine tissues.

developmental biology↗

bioRxiv2025

Molecular mechanisms of altered contraction with the β-myosin R403Q mutation in porcine ventricular muscle and a human stem cell-derived cardiomyocyte model.

I.The R403Q mutation in the sarcomere protein beta-myosin heavy chain ({beta}-MHC) is a known genetic cause of hypertrophic cardiomyopathy (HCM), associated with ventricular hypercontractility, impaired relaxation, and cardiac arrhythmias. Despite extensive research, the mutations impact on myosin contractile properties remains unclear, likely due, at least in part, to discrepancies cross different model systems. In this study, we used a multidisciplinary approach to explore mutational effects using two distinct heterozygous R403Q systems: a Yucatan minipig model and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). X-ray diffraction of R403Q minipig ventricular muscle demonstrated reduced order of the thick filament, suggesting destabilization of the inhibited OFF (vs. ON) state of myosin in relaxed muscle, which correlated with elevated force at submaximal calcium. Super-resolution, single-molecule fluorescence microscopy indicated elevated ATPase activity in thick filament zones lacking cMyBP-C. Furthermore, R403Q myofibrils exhibited slower activation and relaxation kinetics, with reduced sensitivity to ADP. Molecular dynamics simulations suggested that altered interactions at the actomyosin interface contribute to these effects, rather than changes at the nucleotide binding pocket, typically associated with ADP release. Human engineered heterozygous R403Q hiPSC-CMs exhibited reduced maximal myofibril force, slowed contractile kinetics, and hypercontraction in engineered heart tissue constructs-consistent with HCM phenotypes observed in the heterozygous porcine model. Our results demonstrate that the R403Q mutation induces early and persistent contractile dysfunction, and that hypercontractility and slower contractile kinetics may result from a combination of an increased population of activated (ON) myosin heads and delayed detachment during cross-bridge cycling, respectively.

biophysics↗

bioRxiv2025

Designed NGF mimetics with reduced nociceptive signatures in neurons

The clinical use of Nerve Growth Factor (NGF) for neuronal regeneration has been hampered by pain sensitization side effects. NGF signals through the receptor tyrosine kinase TrkA and the co-receptor p75NTR; pain sensitization is thought to involve p75NTR. We sought to overcome this limitation by de novo design of a TrkA agonist that does not bind p75NTR. We designed homodimeric TrkA engaging constructs that dimerize TrkA subunits in a variety of geometries, and identified those eliciting the strongest signaling. The resulting designed agonists are able to stimulate transdifferentiated neurons and neuroblastoma cell lines, leading to neurite outgrowth and neuronal differentiation, with considerably reduced transcription of inflammation and pain related genes. These agonists are promising candidates for promoting neuronal regeneration without adverse side effects. HighlightsO_LIDe novo designed TrkA agonists activate MAPK and PI3K-AKT signaling C_LIO_LIRigid fusions allow for highly tunable signaling signatures C_LIO_LITrkA agonists lead to neurite outgrowth in neuroblastoma cells comparable to retinoic acid C_LIO_LIModulation of the TrkA pathway without co-stimulating p75NTR leads to a downregulation of inflammatory and nociceptive signature in neurons. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/648806v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@c48066org.highwire.dtl.DTLVardef@c9c5a7org.highwire.dtl.DTLVardef@cf8ebdorg.highwire.dtl.DTLVardef@a4345a_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2025

Designed Soluble Notch Agonist Drives Human Ameloblast Maturation for Tooth Regeneration

Enamel, the hardest material in the human body, is required to protect our living organ, tooth. However, over 90% of adults have lost or damaged enamel and cannot regenerate the protective structure due to lack of enamel producing cells, ameloblasts. iPSC derived mature Ameloblasts (iAM) have promise in future regenerative dentistry. Today it is not known why iAM maturation requires intimate contact with the dentin producing cell type, odontoblast. Here we reveal that one of the critical signaling ligands emanating from odontoblasts for ameloblast maturation is Delta, the ligand for Notch receptor. We showed that our designed, soluble Notch agonist can induce iAM organoid maturation in an unprecedented manner, without interactions with odontoblast layer. This novel maturation procedure enables us to analyze the specific requirements of DLX3 function in ameloblasts, independent of its known function in odontoblasts. We now show that DLX3, the gene associated with Amelogenesis Imperfecta, is required on a cell-autonomous manner in ameloblasts for the expression of Enamelin and MMP20.

developmental biology↗

bioRxiv2024

A can of worms: estimating the global number of earthworm species

Estimating the overall species number for a given taxon is a central issue in ecology and conservation biology. This is especially topical for soil organisms, which comprise most known species but whose taxonomy remains largely understudied. Here, we estimated the global number of earthworm species based on the Joppa approach, which models taxonomic effort over time to estimate the total number of known and as yet unknown species in a given taxa. Our Bayesian estimation of the Joppa model suggests a global diversity of the order of 30,000 species, suggesting that the 5,679 earthworm taxa already described only represent around 20% of the actual global species diversity. However, the uncertainty around this estimate is considerable due to severe undersampling and as the model cannot unambiguously decide whether we are describing few species because of a small pool of as yet unknown species, or because of a lack of taxonomic efficiency. Considering the current rate of new species description, we calculate that it would take at least 120 years to describe all the earthworm species existing on Earth, and we discuss thedifferent strategies that should be developed to facilitate and accelerate the discovery and naming of species new to science.

ecology↗

bioRxiv2024

The applicability of Regional Red List assessments for soil invertebrates: First assessment of five native earthworm species in Canada

Earthworms (Annelida: Clitellata: Crassiclitellata) are prominent members of the soil community, important to many ecosystem functions. Despite this, and like many other soil invertebrates, they are rarely considered in conservation assessments, including the IUCN Red List assessments used to assess species extinction risk. To investigate the applicability of the IUCN Regional Red Listing protocol to soil invertebrates, we assessed the conservation status of five earthworm species known to be native to Canada using this protocol and all available occurrence records. In Canada, no earthworm species have yet been assessed by the Committee on the Status of Endangered Wildlife in Canada (COSEWIC). Due to the lack of data on population sizes and their trends, all five species were assessed using their Extent of Occurrence (EOO) (Criterion B). One species was assessed as Vulnerable, two were assessed in non-threatened categories, and two were assessed as Data Deficient. For the majority, the main threats identified were the continuing loss of potential habitat due to land conversion and resource exploitation, as well as the effects of climate change. Increasing the amount of data, including but not limited to distribution and habitat preferences, would make the assessment process easier and status decisions better supported. By undertaking regional assessments for five native earthworm species in Canada, we show that Regional Red List assessments are feasible for soil invertebrates.

ecology↗

bioRxiv2024

Two non-coding variants associated with isolated orofacial cleft promote binding of transcriptional repressors FOXE1 or ETS2 and reduce expression of IRF6

Oral facial cleft (OFC) is a multifactorial disorder that can present as a cleft lip with or without cleft palate (CL/P) or a cleft palate only. Genome wide association studies (GWAS) of isolated OFC have identified common single nucleotide polymorphisms (SNPs) at the 1q32/IRF6 locus and many other loci where, like IRF6, the presumed OFC-relevant gene is expressed in embryonic oral epithelium. To identify the functional subset of SNPs at eight such loci we conducted a massively parallel reporter assay in a cell line derived from fetal oral epithelium, revealing SNPs with allele-specific effects on enhancer activity. We filtered these against chromatin-mark evidence of enhancers in relevant cell types or tissues, and then tested a subset in traditional reporter assays, yielding six candidates for functional SNPs in five loci (1q32/IRF6, 3q28/TP63, 6p24.3/TFAP2A, 20q12/MAFB, and 9q22.33/FOXE1). We further tested two SNPs near IRF6 and one near FOXE1 by engineering the genome of induced pluripotent stem cells, differentiating the cells into embryonic oral epithelium, and measuring expression of IRF6 or FOXE1 and binding of transcription factors; the results strongly supported their candidacy. Conditional analyses of a meta-analysis of GWAS suggest that the two functional SNPs near IRF6 account for the majority of risk for CL/P associated with variation at this locus. This study connects genetic variation associated with orofacial cleft to mechanisms of pathogenesis.

genetics↗

bioRxiv2023

Space use of invertebrates in terestrial habitats: phylogenetic, functional and environmental drivers of interspecific variations

AimWe present the first global database of movement patterns of terrestrial invertebrates, focusing on active dispersal and foraging movements. We depict interspecific variations in movement distances among invertebrates, and assess potential drivers of these variations. LocationWorldwide. MethodsWe conducted a meta-analysis using 174 studies from the scientific literature. They provided 401 movement estimates (163 of foraging and 238 of dispersal) from 216 species, 82 families and 22 orders, complemented by the following co-variables: body mass, diet, locomotion mode, tracking method and environmental variables (gross primary productivity and mean temperature of the warmest quarter of the year). We computed allometric relationships between movement distances and body mass both globally and separately for each taxonomic order with sufficient data. We tested the relative influence of the co-variables on movement distances through model selection. ResultsWe reveal a general positive allometric relationship between movement distance and body mass that holds across most taxonomic orders. We evidence a strong phylogenetic signal in movement distances that translates in variable allometries of movement distances with body mass across taxonomic orders. We further find that interspecific variations of movement distances are primarily driven by functional differences rather than by environmental conditions. Locomotion mode appears to be the most important driver of both dispersal and foraging distances, with larger distances among flying individuals followed by walking and crawling ones for a given body mass. Trophic guild also significantly impacted movement distances with carnivores foraging further than herbivores and decomposers for most body sizes. We finally found little effect of the environmental variables tested. Main conclusionsOur study provides general allometric equations for terrestrial movement distances of invertebrates. It further reveals important functional drivers of their interspecific variation in space use with a dominant role of their evolutionary history.

ecology↗

bioRxiv2023

Cell based dATP delivery as a therapy for chronic heart failure.

Withdrawal StatementThe authors have withdrawn this manuscript because the senior authors have identified inconsistencies in the data presented in this manuscript, which affect the reliability of the main conclusions. In keeping with our commitment to scientific rigor and transparency, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding authors.

pathology↗

bioRxiv2022

Unexpected finding of Fusobacterium varium abundance in cattle rumen: implications for liver abscess interventions

Fusobacterium varium has been generally overlooked in cattle rumen microbiome studies relative to the presumably more abundant, liver abscess-causing Fusobacterium necrophorum. Here, we revisit that conventional wisdom and report greater relative abundance of F. varium than F. necrophorum in both raw rumen samples and in lactate-supplemented enrichments tailored for F. necrophorum growth, despite its consistent inadvertence in past ruminal surveys and putative inability to metabolize lactate. Our observation that F. varium grows under restrictive conditions used to enumerate F. necrophorum suggests that previous estimations were inaccurate and F. varium is an underestimated player within the ruminal community. Exposure to tylosin, the current gold standard among prophylactic liver abscess prevention strategies in cattle, consistently reduced growth of all F. necrophorum strains screened by greater than 67% relative to unexposed controls. In contrast, F. varium strains were completely or highly resistant (0 - 11% reduction in maximum yield). Monensin, an ionophore fed to cattle to improve feed efficiency also had stronger inhibitory activity against F. necrophorum than against F. varium. Finally, preliminary genomic analysis of two F. varium bovine isolates revealed the presence of virulence genes related to those of pathogenic F. varium human isolates associated with active invasion of mammalian cells. ImportanceJudicious antibiotic use is essential to mitigate the spread of antimicrobial resistance. Dogmatic prophylactic use of in-feed tylosin to control cattle liver abscesses hinges on the assumption that F. necrophorum in the rumen is the main etiologic agent. However, our unexpected finding of abundance of F. varium in the rumen and its resistance to antibiotics, in hand with the potential pathogenicity of this species, calls for increased attention to F. varium. Further investigation into F. varium is necessary to better understand bovine liver abscess development and devise higher-precision alternatives to antibiotic treatment.

microbiology↗

bioRxiv2022

Feeding and growth variations affect delta13C and delta15N budgets during ontogeny in a lepidopteran larva

AO_SCPLOWBSTRACTC_SCPLOWIsotopes are widely used in ecology to study food webs and physiology. The fractionation observed between trophic levels in nitrogen and carbon isotopes, explained by isotopic biochemical selectivity, is subject to important within-trophic level variations, leading to imprecision in trophic level estimation. Understanding the drivers of these variations is thus important to improve the study of food webs. In this study, we characterized this variation by submitting Spodoptera littoralis larvae to a gradient of starvation levels, a factor that we hypothesized would change the trophic fractionation between individuals. The various growth rates that were induced from these starvation levels resulted in a ~ 1-1.5{per thousand} within-trophic level variation of the trophic fractionation in both carbon and nitrogen, which is substantial compared to the 3-4{per thousand}classically associated with between-trophic levels variations. Hence starved animals sampled in natura may be ranked at a higher trophic level than they really are. We were able to gain an understanding of the effect of growth rate on isotopes fluxes between three easy-to-measure biological materials, food, organism and its wastes (frass), giving insight into physiological processes at play but also conveying helpful information to the sampling framework of field studies.

ecology↗

bioRxiv2022

Cell-intrinsic and -extrinsic functions of the ESCRT-III component Shrub in cytokinetic abscission of Drosophila Sensory Organ precursor

While the molecular mechanisms underlying the abscission of isolated cells are largely decrypted, those of fast-cycling, epithelial progenitors surrounded by epidermal cells (ECs) connected by junctions remain largely unexplored. Here, we investigated the remodeling of the permeability barrier ensured by septate junctions (SJs) during cytokinesis of Drosophila sensory organ precursor (SOP). We report that SOP cytokinesis involves the coordinated polarized assembly and remodeling of SJs in the dividing cell and its neighbors, which remained connected via membrane protrusions pointing toward the SOP midbody. SJs assembly and midbody basal displacement occur more rapidly in SOP than in ECs, leading to a faster disentanglement of the protrusions that precedes midbody release. As reported in isolated cells, the endosomal sorting complex required for transport-III component Shrub/CHMP4B is recruited at the midbody and cell-autonomously regulates abscission. In addition, we found that Shrub is recruited to membrane protrusions, is required for SJ integrity, and that alteration of SJ integrity leads to premature abscission. Our study uncovers cell-intrinsic and -extrinsic functions of Shrub in epithelial abscission to support the coordination of permeability barrier maintenance and abscission in SOPs.

developmental biology↗

bioRxiv2022

Human iPSC Derived Enamel Organoid Guided by Single-Cell Atlas of Human Tooth Development

Tooth enamel secreted by ameloblasts is the hardest material in the human body, acting as a shield protecting the teeth. However, the enamel is gradually damaged or partially lost in over 90% of adults and cannot be regenerated due to a lack of ameloblasts in erupted teeth. Here we use sci-RNA-seq to establish a spatiotemporal single-cell atlas for the developing human tooth and identify regulatory mechanisms controlling the differentiation process of human ameloblasts. We reveal key signaling pathways involved between the support cells and ameloblasts during fetal development and recapitulate those findings in a novel human ameloblast in vitro differentiation from iPSCs. We furthermore develop a mineralizing enamel organ-like 3D organoid system. These studies pave the way for future regenerative dentistry and therapies toward genetic diseases affecting enamel formation.

developmental biology↗