Biology subjects

Gaudin, M.

Publications and source records attributed to Gaudin, M..

11 recordsLinked to original sources

bioRxiv2026

Functional diversity of Vγ9Vδ2 T cells overcomes glioblastoma state plasticity and antigen heterogeneity

Glioblastoma (GBM) is characterized by a high degree of cellular plasticity and intra-tumoral heterogeneity, which frequently leads to the failure of standard therapies, including immunotherapies. While chimeric antigen receptor (CAR) T cells offer a potent means of MHC-independent tumor recognition, their efficacy is hampered by the coexistence of distinct molecular states, gathered as proneural (PN) and mesenchymal (MES) phenotypes. Here, we demonstrate that gangliosides GD2 and O-acetylated GD2 (OAcGD2) are preferentially expressed by PN cells whereas MES cells display reduced expression due to upregulated ganglioside catabolism. Conversely, MES cells are known to exhibit high expression of stress-induced ligands recognized by V{gamma}9V{delta}2 T cells. We show that while engineering V{delta}2T cells with GD2- or OAcGD2-specific CAR enables the elimination of PN cells, it also facilitates the immune escape of MES cells in heterogeneous 3D-tumoroid models. Mechanistically, we reveal a hierarchy of receptor engagement, where CAR signaling predominates leading to the structural and functional exclusion of endogenous TCR from the immunological synapse. To address this receptor competition, we propose a strategy that leverages the functional effector diversity by combining untransduced and CAR-engineered V{delta}2T cells. This dual approach provides a dynamic safety net by ensuring the simultaneous elimination of PN and MES cells and preventing the selective outgrowth of resistant cells. Our findings establish a conceptual framework for designing off-the-shelf immunotherapies tailored to the metabolic and phenotypic plasticity of resistant solid tumors.

cancer biology↗

bioRxiv2026

L-serine diet restores impaired adult neurogenesis in the hippocampus of 3xTg-AD mice

Altered adult neurogenesis is reported in Alzheimers disease (AD) in humans and rodent models, though the mechanisms remain unclear. L-serine, a non-essential amino acid that plays a critical role in cell proliferation and survival, is produced by neuroepithelial cells and radial glia in the developing brain, as well as by astrocytes and neural precursors in the adult brain. Its production is altered in AD, particularly in the hippocampus. We sought to determine whether a deficiency of L-serine availability contributes to the reduced adult neurogenesis in AD. We confirm that phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme of the L-serine biosynthetic pathway, is expressed by neural stem cells (NSCs) of the mouse dentate gyrus (DG). We further report PHGDH expression in cells with somata located in the subgranular zone (SGZ) of the human DG and displaying the typical radial morphology associated with NSCs in rodents. We observed a significant decrease in the number of proliferating cells (proliferating cell nuclear antigen, PCNA+) as well as immature neurons (doublecortin, DCX+) in the DG of 12-month-old 3xTg-AD mice compared to their age-matched controls. Importantly, chronic dietary supplementation with a L-serine-enriched diet for 8 months significantly increased plasma L- and D-serine levels and partially rescued adult neurogenesis deficits in 3xTg-AD mice, while having no significant impact on the progression of amyloidosis. Our results suggest that chronic metabolic impairment in L-serine production, and the resulting shortage of D-serine, likely contributes to reduced survival of newborn neurons in the DG of 3xTg-AD mice.

neuroscience↗

bioRxiv2026

A stepwise route to polyploidy in yeast

Polyploidy, the presence of multiple chromosome sets within a genome, is widespread and has played a major role in genome evolution in plants, fungi, and animals. Although polyploidization is generally attributed to mitotic genome doubling or unreduced gamete fusion, the mechanisms underlying ploidy increases, particularly triploid formation, remain unclear. Here, we identify a novel route to autopolyploidization in Saccharomyces cerevisiae, termed Sporulate-Endoreplicate-Mate (SEM), in which one gamete, or spore, undergoes postmeiotic endoreplication and subsequently mates with a nearby non-endoreplicated sibling spore after ascus breakdown, increasing ploidy by one haploid genome. We experimentally demonstrate stepwise transitions from diploidy to triploidy and from triploidy to tetraploidy. Intact asci can spontaneously generate new triploid and tetraploid strains upon one or two successive SEM cycles. Natural polyploids exhibit genomic signatures consistent with SEM being a major natural route to polyploidization in yeast. SEM establishes triploids as central intermediates in yeast polyploidization, analogous to the triploid bridge described in plants, and raises the possibility that a similar mechanism may contribute to polyploid genome formation in other eukaryotes.

genomics↗

bioRxiv2026

Multi-omics uncovers nutrient stress-driven interactions in the Prymnesium parvum holobiont, with vitamin B12 limitation highlighting mutualism.

Microalgal-bacterial interactions are central to nutrient cycling and ecosystem functioning in marine habitats, yet the mechanisms structuring these associations under defined nutrient constraints remain poorly resolved. Using a synthetic 15-member bacterial community (SynCom) and controlled nitrogen (N), phosphorus (P), and vitamin B12 limitation, we investigated how nutrient scarcity shapes the physiology, metabolism, and transcriptional activity of the harmful alga Prymnesium parvum and its associated microbiota. Under N- and P-limitation, the SynCom had minimal impact on algal growth despite nutrient-dependent shifts in toxin production and metabolite profiles. In contrast, B12-limitation triggered a strong mutualistic interaction in which the SynCom enabled a three-fold increase in algal biomass and drove restructuring of intracellular and extracellular metabolomes, including the accumulation of ectoine and membrane-associated lipids and the depletion of thiamine-like and stress-associated metabolites. Metabarcoding revealed stable community composition but enrichment of B12-producing taxa under B12-limited conditions, while metatranscriptomics uncovered functional divergence among SynCom members. Bacteria segregated into specialized B12- or N-responsive strains and metabolically plastic generalists sustaining broad transcriptional activity across all nutrient regimes. B12 producers (Marinovum algicola, Roseobacter sp., Halomonas sp.) upregulated cobalamin biosynthesis exclusively under B12 limitation, whereas several dependent taxa induced B12 transport and B12-requiring enzymes, indicating active vitamin exchange within the holobiont. P. parvum displayed nutrient-specific transcriptional programs, with B12-limited co-cultures shifting toward growth-associated gene expression despite constitutive expression of the B12-dependent metH gene. These results demonstrate that vitamin auxotrophy acts as a key metabolic lever reorganizing holobiont function, driving reciprocal benefits and reprogramming algal-bacterial metabolism in our synthetic system.

microbiology↗

bioRxiv2025

Co-occurrence drives horizontal gene transfer among marine prokaryotes

Understanding the drivers and consequences of horizontal gene transfer (HGT) is a key goal of microbial evolution research. Although co-occurring taxa have long been appreciated to undergo HGT more often, this association is confounded with other factors, most notably their phylogenetic relatedness. To disentangle these factors, we analyzed 15,339 marine prokaryotic genomes (mainly bacteria) and their distribution in the global ocean. We identified HGT events across these genomes and enrichments for functions previously shown to be prone to HGT. By mapping metagenomic reads from 1,862 ocean samples to these genomes, we also identified co-occurrence patterns and environmental associations. Although we observed an expected negative association between HGT rates and phylogenetic distance, we only detected an association between co-occurrence and phylogenetic distance for closely related taxa. This observation refines the previously reported trend to closely related taxa, rather than a consistent pattern across all taxonomic levels, at least here within marine environments. In addition, we identified a significant association between co-occurrence and HGT, which remains even after controlling for phylogenetic distance and measured environmental variables. In a subset of samples with extended environmental data, we identified higher HGT levels associated with particle-attached bacteria and associations of varying directions with specific environmental variables, such as chlorophyll a and photosynthetically available radiation. Overall, our findings demonstrate the significant influence of ecological associations in shaping marine bacterial evolution through HGT.

evolutionary biology↗

bioRxiv2023

Absence of chromosome axis proteins recruitment prevents meiotic recombination chromosome-wide in the budding yeast Lachancea kluyveri

Meiotic recombination shows broad variations across species and along chromosomes, and is often suppressed at and around genomic regions determining sexual compatibility such as mating type loci in fungi. Here we show that the absence of Spo11-DSBs and meiotic recombination on Lakl0C-left, the chromosome arm containing the sex locus of the Lachancea kluyveri budding yeast, results from the absence of recruitment of the two chromosome axis proteins Red1 and Hop1, essential for proper Spo11-DSBs formation. Furthermore, cytological observation of spread pachytene meiotic chromosomes reveals that Lakl0C-left does not undergo synapsis. However, we show that the behavior of Lakl0C-left is independent of its particularly early replication timing and is not accompanied by any peculiar chromosome structure as detectable by Hi-C in this yet poorly studied yeast. Finally, we observed an accumulation of heterozygous mutations on Lakl0C-left and a sexual dimorphism of the haploid meiotic offspring, supporting a direct effect of this absence of meiotic recombination on L. kluyveri genome evolution and fitness. Because suppression of meiotic recombination on sex chromosomes is widely observed across eukaryotes, the novel mechanism for recombination suppression described here may apply to other species, with the potential to impact sex chromosome evolution.

genetics↗

bioRxiv2023

Genome-scale community modelling reveals conserved metabolic cross-feedings in epipelagic bacterioplankton communities

Marine microorganisms form complex communities of interacting organisms that influence central ecosystem functions in the ocean such as primary production and nutrient cycling. Identifying the mechanisms controlling their assembly and activities is a major challenge in microbial ecology. Here, we integrated Tara Oceans meta-omics data to predict genome-scale community interactions within prokaryotic assemblages in the euphotic ocean. A global genome-resolved co-activity network revealed a significant number of inter-lineage associations across large phylogenetic distances. Identified co-active communities included species displaying smaller genomes but encoding a higher potential for quorum sensing, biofilm formation, and secondary metabolism. Community metabolic modelling revealed a higher potential for interaction within co-active communities and pointed towards conserved metabolic cross-feedings, in particular of specific amino acids and group B vitamins. Our integrated ecological and metabolic modelling approach indicates genome streamlining and metabolic auxotrophies as central joint mechanisms shaping bacterioplankton community assembly in the surface global ocean.

ecology↗

bioRxiv2022

Remarkably high rate of meiotic recombination in the fission yeast Schizosaccharomyces pombe

In most eukaryotes, the number of meiotic crossovers (COs) is limited to 1-3 per chromosome, which are prevented from occurring close to one another by CO interference. The fission yeast Schizosaccharomyces pombe, an exception to this general rule, lacks CO interference and seems to have the highest CO number per chromosome. However, global CO frequency was indirectly estimated in this species, raising doubts about this exceptional recombination level. Here, we used an innovative strategy to directly determine COs genome-wide in S. pombe. We confirm the absence of crossover interference and reveal the presence of co-variation in CO number across chromosomes within tetrads, suggesting that a limiting pro-CO factor varies stochastically between meiocytes. CO number per chromosome varies linearly with chromosome size, with the three chromosomes having, on average, 15.9, 12.5, and 7.0 COs, respectively. This is significantly lower than previous estimates but reinforces S. pombes exceptional status as the eukaryote with the highest CO number per chromosome described to date and among the species with the highest rate of COs per unit of DNA.

genetics↗

bioRxiv2022

Combined in vivo and in situ genome-resolved metagenomics reveals novel symbiotic nitrogen fixing interactions between non-cyanobacterial diazotrophs and microalgae

BackgroundNon-cyanobacteria diazotrophs (NCDs) were shown to dominate in surface waters shifting the long-held paradigm of cyanobacteria dominance and raising fundamental questions on how these putative heterotrophic bacteria thrive in sunlit oceans. The absence of laboratory cultures of these bacteria significantly limits our ability to understand their behavior in natural environments and, consequently, their contribution to the marine nitrogen cycle. ResultsHere, we used a multidisciplinary approach and report an unprecedented finding in the diatom Phaeodactylum tricornutum (Pt) of NCDs in the phycosphere or the pelagic community sustaining its survival in the absence of bioavailable nitrogen. We sequenced the bacterial metacommunity associated with Pt and assembled several bacterial genomes, identifying multiple NCDs from the Rhizobiales order, including Bradyrhizobium, Mesorhizobium, Georhizobium and Methylobacterium. We demonstrated the nitrogen-fixing ability of PtNCDs through in silico identification of nitrogen fixation genes, or by using PCR, acetylene reduction, or 15N incorporation. We showed the wide occurrence of this type of interactions with the isolation of NCDs from other microalgae, their identification in the environment, and their predicted associations with photosynthetic microalgae. ConclusionsOur study underscores the importance of microalgae interactions with NCDs to permit and support nitrogen fixation. This work provides a unique model Pt-NCDs to study the ecology of this interaction advancing our understanding of the key drivers of global marine nitrogen fixation.

microbiology↗

bioRxiv2021

The JAK2-STAT3 pathway controls a beneficial proteostasis response of reactive astrocytes in Huntington disease

Huntingtons disease is a fatal neurodegenerative disease characterized by striatal neurodegeneration, aggregation of mutant Huntingtin and the presence of reactive astrocytes. Astrocytes are important partners for neurons and engage in a specific reactive response in Huntingtons disease that involves morphological, molecular and functional changes. How reactive astrocytes contribute to Huntingtons disease is still an open question, especially because their reactive state is poorly reproduced in experimental mouse models. Here, we show that the JAK2-STAT3 pathway, a central cascade controlling astrocyte reactive response, is activated in the putamen of Huntingtons disease patients. Selective activation of this cascade in astrocytes through viral gene transfer reduces the number and size of mutant Huntingtin aggregates in neurons and improves neuronal defects in two complementary mouse models of Huntingtons disease. It also reduces striatal atrophy and increases glutamate levels, two central clinical outcomes measured by non-invasive magnetic resonance imaging. Moreover, astrocyte-specific transcriptomic analysis shows that activation of the JAK2-STAT3 pathway in astrocytes coordinates a transcriptional program that increases their intrinsic proteolytic capacity, through the lysosomal and ubiquitin-proteasome degradation systems. This pathway also enhances their production and exosomal release of the co-chaperone DNAJB1, which contributes to mutant Huntingtin clearance in neurons. Together, our results show that the JAK2-STAT3 pathway controls a beneficial proteostasis response in reactive astrocytes in Huntingtons disease, which involves bi-directional signalling with neurons to reduce mutant Huntingtin aggregation, eventually improving disease outcomes.

neuroscience↗

bioRxiv2019

Dramatic HIV DNA degradation associated with spontaneous HIV suppression and disease-free outcome in a young seropositive woman following her infection

Strategies to cure HIV-infected patients by virus-targeting drugs have failed to date. We identified a HIV-1-seropositive woman who spontaneously suppressed HIV replication and had normal CD4-cell counts, no HIV disease, no replication-competent virus and no cell HIV DNA detected with a routine assay. We suspected that dramatic HIV DNA degradation occurred postinfection. We performed multiple nested-PCRs followed by Sanger sequencing and applied a multiplex-PCR approach. Furthermore, we implemented a new technique based on two hybridization steps on beads prior to next-generation sequencing that removed human DNA then retrieved integrated HIV sequences with HIV-specific probes. We assembled {approx}45% of the HIV genome and further analyzed the G-to-A mutations putatively generated by cellular APOBEC3 enzymes that can change tryptophan codons into stop codons. We found more G-to-A mutations in the HIV DNA from the woman than in that of her contaminator. Moreover, 74% of the tryptophan codons were changed to stop codons (25%) or were deleted as a possible consequence of gene inactivation. Finally, we found that this womans cells remained HIV-susceptible in vitro. Our findings show that she does not exhibit innate HIV resistance but has been cured of it by extrinsic factors, a plausible candidate for which is the gut microbiota.

microbiology↗