Biology subjects

Duval, M.

Publications and source records attributed to Duval, M..

7 recordsLinked to original sources

bioRxiv2026

Bivalent CK2 Inhibition as a Potent Strategy Against SARS-CoV-2 and Other Coronaviruses

Protein kinase CK2 (CK2), a ubiquitously expressed serine/threonine kinase, has emerged as a key host factor exploited by several viruses, including Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we investigate the role of CK2 subunits in SARS-CoV-2 replication and evaluate the antiviral potential and broad-spectrum anti-coronavirus activity of two CK2 inhibitors: the previously described ATP-competitive inhibitor CX-4945 and a newly developed, highly selective bivalent inhibitor, AB668. The siRNA-mediated knockdown of CK2 subunits significantly reduced SARS-CoV-2 replication, highlighting its essential role in the viral lifecycle. Co-immunoprecipitation assays revealed that the SARS-CoV-2 nucleoprotein interacts with CK2. Furthermore, bio-layer interferometry assays demonstrated that the nucleoprotein specifically binds to the tetrameric CK2 holoenzyme (CK22{beta}2) but not to individual CK2 or CK2{beta} subunits. Pharmacological inhibition of CK2 with AB668 exhibited potent antiviral activity, significantly reducing viral replication by targeting a pre-replicative or RNA-replicative step of the viral life cycle. Importantly, AB668 displayed broad-spectrum antiviral activity, effectively inhibiting both HCoV-OC43 ({beta}-CoV) and HCoV-229E (-CoV). In summary, our findings establish CK2 as a critical host factor for SARS-CoV-2 replication and identify AB668 as a promising candidate for broad-spectrum antiviral therapy. With its high selectivity, minimized off-target effects, and efficacy against multiple coronaviruses, AB668 represents a valuable chemobiological and therapeutic tool.

microbiology↗

bioRxiv2026

NANOCUTSIGHT: A NANOPORE-SEQUENCING APPROACH AND ANALYSIS PIPELINE TO ASSESS GENOME EDITING EFFICACY IN VARIOUS CELL POPULATIONS

Genome editing has revolutionized biomedical sciences and is now an essential tool to define molecular pathways through genetic interaction and loss-of-function studies. Through its diverse variations, it allows for the generation of specific knockout cell lines or organisms, as well as the creation of endogenously edited gene regions. While high-throughput methodologies exist to map CRISPR/Cas9 genetic modifications, the validation of guide efficiencies in cell populations is often performed through analysis of the targeted gene product by western blotting or by deconvolution of Sanger sequencing chromatograms using TIDE or ICE assays. Here, we highlight a rapid nanopore sequencing pipeline, which we have named NanoCutSight, to quantify the percentage of indels at a specific genomic locus and to identify the types of modifications generated. We also benchmarked the methodology on various guide RNAs and in both cultured cell and organoid models. We believe that NanoCutSight will simplify the analysis of complex sample editing and enable the rapid screening of edited samples.

bioinformatics↗

bioRxiv2026

Nanopore Direct RNA Sequencing Enables Reproducible, Site-Resolved Pseudouridine Quantification in Human Ribosomal RNA

Pseudouridine is the most abundant post-transcriptional modification in human ribosomal RNA, with over 110 annotated sites and variable stoichiometry across biological contexts. Existing quantification methods are low-throughput or constrained to predefined panels. We benchmarked nanopore direct RNA sequencing using the Dorado v5.1 model against mass spectrometry-validated sites in human liver tissue, induced pluripotent stem cells, and HeLa cells. Nanopore sequencing detected 95 of 117 validated sites and accurately quantified stoichiometry at 85% of sites with high reproducibility. Low GC-content environments were the primary source of failure. These results establish nanopore sequencing as a scalable tool for epitranscriptomic pseudouridine profiling.

biochemistry↗

bioRxiv2025

Therapeutic Inducers of NK cell Killing (ThINKK)-induced NK cell cytotoxicity against childhood acute lymphoblastic leukemia: unraveling the dual role of TRAIL leads to the establishment of an efficacy biomarker

BackgroundTherapeutic Inducers of Natural Killer cell Killing (ThINKK) represent a novel class of immunotherapy designed to enhance the graft-versus-leukemia effect of hematopoietic stem cell transplantation in pediatric patients with high-risk or relapse leukemia. Our previous work identified high expression of TRAIL as a key signature of Natural Killer (NK) cell stimulation by ThINKK. In this study, we aim to elucidate the mechanisms underlying acute lymphoblastic leukemia (ALL) killing by ThINNK-stimulated NK cells and to identify predictive sensitivity markers of this innovative approach. MethodsWe performed NK cell cytotoxic assays using a panel of genetically diverse ALL cell lines and patients samples. Gene deletion and gene enforced expression in sensitive or resistant cell lines were performed to demonstrate the role of TRAIL-receptors expression and death receptor signaling pathway in ALL cell death induced by ThINKK-stimulated NK cells. These findings were further validated through the analysis of primary patients samples and transcriptomic profiling of a cohort of 320 ALL patients from the CHU Sainte-Justine. ResultsWe found that ALL sensitivity to ThINKK-stimulated NK cell killing was independent of their genetic background or their HLA expression. In addition, our data revealed the dual role of TRAIL: first, a strong NK cell activating receptor that induced rapid killing of ALL expressing TRAIL-R2, and second, a death-receptor ligand inducing ALL apoptosis following sustained engagement with its receptors. The transcriptomic analysis of ALL patients samples indicated that TRAIL-R2 and TRAIL-R1 are widely expressed across ALL subtypes and are not downregulated at relapse. ConclusionThese findings support the use of TRAIL receptor expression as a biomarker of sensitivity to ThINKK immunotherapy and establish a mechanistic framework to guide patient stratification and therapeutic optimization.

immunology↗

bioRxiv2023

Oxygen isotopes in orangutan teeth reveal recent and ancient climate variation

Studies of climate variation commonly rely on chemical and isotopic changes recorded in sequentially-produced growth layers, such as in corals, shells and tree rings, as well as in accretionary deposits--ice and sediment cores, and speleothems. Oxygen isotopic compositions ({delta}18O) of tooth enamel are a direct method of reconstructing environmental variation experienced by an individual animal. Here we utilize long-forming orangutan dentitions (Pongo spp.) to probe recent and ancient rainfall trends on a weekly basis over [~] 3-11 years per individual. We first demonstrate the lack of any consistent isotopic enrichment effect during exclusive nursing, supporting the use of primate first molar teeth as environmental proxies. Comparisons of {delta}18O values (n = 2016) in twelve molars from six modern Bornean and Sumatran orangutans reveal a high degree of overlap, with more consistent annual and bimodal rainfall patterns in the Sumatran individuals. Comparisons with fossil orangutan {delta}18O values (n = 955 measurements from six molars) reveal similarities between modern and late Pleistocene fossil Sumatran individuals, but differences between modern and late Pleistocene/early Holocene Bornean orangutans. These suggest drier and more open environments with reduced monsoon intensity during this earlier period in northern Borneo, consistent with other Niah Caves studies and long-term speleothem {delta}18O records in the broader region. This approach can be extended to test hypotheses about the paleoenvironments that early humans encountered in southeast Asia.

paleontology↗

bioRxiv2021

Escherichia coli ribosomal protein S1 enhances the kinetics of ribosome biogenesis and RNA decay

Escherichia coli ribosomal protein S1 is essential for translation initiation of mRNAs and for cellular viability. Two oligonucleotide binding (OB)-fold domains located in the C-terminus of S1 are dispensable for growth, but their deletion causes a cold-shock phenotype, loss of motility and deregulation of RNA mediated stress responses. Surprisingly, the expression of the small regulatory RNA RyhB and one of its repressed target mRNA, sodB, are enhanced in the mutant strain lacking the two OB domains. Using in vivo and in vitro approaches, we show that RyhB retains its capacity to repress translation of target mRNAs in the mutant strain but becomes deficient in triggering rapid turnover of those transcripts. In addition, the mutant is defective in of the final step of the RNase E-dependent maturation of the 16S rRNA. This work unveils an unexpected function of S1 in facilitating ribosome biogenesis and RyhB-dependent mRNA decay mediated by the RNA degradosome. Through its RNA chaperone activity, S1 participates to the coupling between ribosome biogenesis, translation, and RNA decay.

microbiology↗

bioRxiv2021

The RNA chaperone protein CspA stimulates translation during cold acclimation by promoting the progression of the ribosomes

CspA is an RNA binding protein expressed during cold-shock in Escherichia coli, capable of stimulating translation of several mRNAs - including its own - at low temperature. We used reconstituted translation systems to monitor the effects of CspA on the different steps of the translation process and probing experiments to analyze the interactions with its target mRNAs. We specifically focused on cspA mRNA which adopts a cold-induced secondary structure at temperatures below 20{degrees}C and a more closed conformation at 37{degrees}C. We show that at low temperature CspA specifically promotes the translation of the mRNA folded in the conformation less accessible to the ribosome (37{degrees}C form). CspA interacts with its mRNA without inducing large structural rearrangement, does not bind the ribosomal subunits and is not able to stimulate the formation of the translation initiation complexes. On the other hand, CspA promotes the progression of the ribosomes during translation of its mRNA at low temperature and this stimulation is mRNA structure-dependent. A similar structure-dependent mechanism may be responsible for the CspA- dependent translation stimulation observed with other probed mRNAs, for which the transition to the elongation phase is progressively facilitated during cold acclimation with the accumulation of CspA.

molecular biology↗