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Dubois, M.

Publications and source records attributed to Dubois, M..

At least 19 recordsLinked to original sources

A Cajal body assembly factor regulates cell fate transitions in Arabidopsis

Ribonucleoprotein (RNP) condensates are emerging as key regulators of cell fate transitions, yet their functions have been largely linked to mRNA storage and translational control. Here, we uncover a role for Cajal body (CB)-mediated pre-mRNA splicing in coordinating the transition from stem cell divisions to differentiation in plants. We identify THREE-DIVISION MUTANT 3 (TDM3) as a cell cycle-regulated factor required for post-mitotic CB assembly. Loss of TDM3 or the CB scaffold protein COILIN delays differentiation and prolongs formative cell divisions. Transcriptome analysis revealed that TDM3 and COILIN jointly regulate pre-mRNA splicing, including transcripts controlling cell cycle and fate transitions. These findings establish CB-mediated splicing as a mechanism linking cell cycle progression to cellular differentiation.

cell biology↗

Modelling the polygenicity and clinical heterogeneity of human depression in mice to identify biomarkers of antidepressant response

Major depressive disorders (MDD) are predicted to become the first cause of burden of disease worldwide in 2030, but 30% of patients still do not respond to antidepressants. Current rodent models of MDD mainly result either from one genetic or one environmental risk factor exposure, not recapitulating the multifactorial and polygenic nature of MDD. We recently generated a polygenic mouse model of MDD from selective breeding after mild stress in the Tail Suspension Test (TST), named H-TST. Here, we selected animals exhibiting high immobility during the Forced Swim Test (FST) to generate a new stable polygenic model of MDD, called H-FST. Unlike our previous H-TST model, H-FST mice did not exhibit any anxiety-or anhedonia-like behaviors, nor did they display any sleep disturbances. Moreover, H-TST and H-FST mice showed opposite response after administration of various antidepressant treatments. The gene expression level in the prefrontal cortex of H-TST and H-FST mice revealed little overlap in genes and biological pathways associated with depressive-like behaviors and opposite dysregulation of excitatory/inhibitory synaptic imbalance. Finally, these two models allowed in humans the identification biomarkers of treatment response specific of clinical subgroup of patients.

molecular biology↗

Extracellular DNASE1L3 dysfunction fuels obesity-driven inflammation and metabolic syndrome

Obesity, a global health crisis affecting 16% of the world population, is characterized by chronic inflammation that contributes to health complications such as type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). Emerging evidence suggests that self-DNA released from dying cells aberrantly activates inflammatory responses during obesity. However, the role of extracellular deoxyribonucleases (DNASEs), which at steady state regulate abundance of extracellular self-DNA, remains poorly understood in this context. Here, we show that individuals with obesity exhibit elevated levels of circulating cell-free DNA (cfDNA) with a distinctive end-motif signature, anti-DNASE1L3 autoantibodies and a reduction in circulating DNASE activity. These cfDNA alterations correlate with the severity of obesity and can be corrected by therapeutic intervention such as bariatric surgery. Similarly, mice fed a high-fat diet (HFD) displayed increased cfDNA levels and decreased DNASE activity. Genetic deficiency of the extracellular nuclease DNASE1L3 in mice worsened HFD-induced metabolic complications, including glucose intolerance, insulin resistance, MASLD, and metabolic tissue inflammation. Conversely, targeted supplementation of DNASE1L3 in the liver using adeno-associated viral vectors protected obese mice from developing MASLD and liver inflammation. These findings uncover a novel role of DNASE1L3 in controlling obesity-associated inflammation and its potential therapeutic use for preventing metabolic disease.

pathology↗

Cortical Microstructural Variations Explain Individual Differences in Gamified Exploration-Exploitation Behaviours

The exploration-exploitation trade-off is ubiquitous in our everyday lives, and individuals display considerable variability in their preferred decision-making strategies. Most previous work pertaining to neural signatures of exploration is restricted to functional pathways. However, the specific contributions of cortical microarchitectures to high-level cognitive processes such as decision-making are as yet unknown. Here, we investigated the neuroanatomical foundations of inter-individual variability in decision-making strategies. To this end, 122 healthy participants completed a gamified multi-armed bandit paradigm aimed at teasing apart distinct exploration-exploitation decision strategies. We also collected whole-brain quantitative MRI maps indexing microstructural features of cortical myelination and iron content. Through computational modelling, we disentangled individual-specific exploration strategies, including value-free random exploration. Whole-brain regression analyses identified significant associations between value-free exploration and increased cortical myelination in right frontal brain areas with reported links to impulsivity. By elucidating the brain microstructural correlates of distinct exploration-exploitation strategies, we aimed to further our understanding of why individuals differ in their decision-making capabilities, and how decision-making may become aberrant in mental health conditions.

neuroscience↗

A comprehensive analysis of humanized mouse models for the study of cancer immunotherapies

Humanized immune system (HIS) mouse models, generated by engrafting tumors and hematopoietic cells of human (Hu) origin into immunodeficient host mice, effectively recapitulate key aspects of the crosstalk between human immune cells and tumors. These models represent a valuable tool for the preclinical evaluation of immunotherapies. In this study, we provide a comprehensive comparison of two widely used HIS models: the Hu-CD34+ model, which engrafts Hu-hematopoietic cells derived from Hu-CD34+ hematopoietic stem cells (HSCs), and the Hu-PBMC model, which utilizes Hu-peripheral blood mononuclear cells (PBMCs). We assess the kinetics, quality and extent of immune cell engraftment, as well as the development of graft-versus-host disease (GVHD). Additionally, we investigate the impact of different immunodeficient host mouse strains on immune cell reconstitution in the Hu-CD34+ model. Both HIS models were engrafted with human tumors derived from either cell lines or patient-derived xenografts (PDX), revealing distinct immune-tumor interactions that influenced antitumor responses. Notably, tumor responses to T-cell-directed therapies, including anti-PD1 antibodies, IL-2-anti-IL-2 antibody complexes, and T-cell engagers, varied across these models. Our findings provide novel insights into the properties and limitations of HIS models, offering a critical resource for optimizing next-generation immuno-oncology strategies and guiding the design of future therapeutic interventions.

immunology↗

Anti-PD-1/PD-L1 Therapy Triggers Cognitive Deficits and Anxiety-Like Behaviors Through Tumor-Initiated Neuroinflammatory Niches in Male Mice

Checkpoint inhibitors are promising immunotherapy to treat cancer patients, but their cognitive impact has not been evaluated despite several neurological adverse events. We studied the impact of immune desert or inflamed cancers when combined with immune checkpoint inhibitors (ICI) anti-PD-1/anti-PD-L1 on mouse behaviors and brain immune cells infiltration/homeostasis, and neuroinflammation in male mice. We showed that systemic inflammation, brain-barriers permeability accompanying meningeal infiltration of peripheral macrophages and neuroinflammation as well as deficits in cognition or emotional reactivity, depending on immuno-inflammatory or immune-desert cancer type. Combined with cancers, anti-PD-1 and PD-L1 treatments exacerbated the decline in executive functions and hippocampal vascular inflammation. PD-L1 specifically relayed the infiltration of the T{gamma}{delta} lymphocytes subpopulation in choroid plexus and leptomeninges implicated, whose systemic neutralization counteracted anti-PDL1-induced cognitive deficits and anxiety in mice bearing immune-inflamed cancer. Our findings highlight new systemic biomarkers of cold or hot cancer, treated with anti-PD-1/anti-PDL-1, and associated with cognitive and emotional alterations in mice; guiding ways of intervention to secure the cancer curation and improve patients quality of life under ICI treatment. Competing Interest StatementThe authors have declared no competing interest. One Sentence SummaryImpact of cancer and checkpoint inhibitors on cognitive functions

cancer biology↗

A temporary challenge by tumor cells can lead to a permanent partial-impairment of memory CD8 T cell function

Memory CD8 T cells typically exhibit improved effector functions compared to their naive counterparts. However, under certain activation conditions, such as chronic viral infections or cancer, these cells may develop functional defects. In this study, we compared the functional quality of memory CD8 T cells generated following tumor rejection with those arising from an acute viral infection. We found that tumor-induced (Tum-CD8) memory cells exhibited a distinct phenotype and transcriptomic profile compared with viral-induced (Vir-CD8) memory cells. These memory cells are characterized by the expression of inhibitory receptors and displayed altered functions including reduced IFN{gamma} and TNF production as well as changes in integrin expression. Additionally, the protective capacity of Tum-CD8 memory cells was flawed relative to that of Vir-CD8 memory cells. Importantly, the functional defects of Tum-CD8 persisted upon viral recall. Together, these findings indicate that transient tumoral stimulation can imprint a stable partial exhaustion-like program on memory CD8 T cells.

immunology↗

Light quantity impacts early response to cold and cold acclimation in young leaves of Arabidopsis

Plant reactions to stress vary with development stage and fitness. This study assessed the relationship between light and chilling stress in Arabidopsis acclimation. By analyzing the transcriptome and proteome responses of expanding leaves subjected to varying light intensity and cold, 2251 and 2064 early response genes and proteins were identified, respectively. Many of these represent as yet unknown part of early response to cold, illustrating development-dependent response to stress and a duality in plant adaptations. While standard light promoted photosynthetic upregulation, plastid maintenance, and increased resilience, low light triggered a unique metabolic shift, prioritizing ribosome biogenesis and lipid metabolism and attenuating expression of genes associated with plant immunity. The comparison of early response in young leaves with that in expanded ones showed striking differences, suggesting a sacrifice of expanded leaves to support young ones. Validations of selected DEGs in mutant background confirmed a role of HSP90-1, transcription factor FLZ13, and Phospholipase A1 (PLIP) in response to cold, and the PLIP family emerged as crucial in promoting acclimation and freezing stress tolerance. The findings highlight the dynamic mechanisms that enable plants to adapt to challenging environments and pave the way for the development of genetically modified crops with enhanced freezing tolerance.

plant biology↗

Dual and spatially resolved drought responses in the Arabidopsis leaf mesophyll revealed by single-cell transcriptomics

Drought stress imposes severe challenges on agriculture by impacting crop performance. Understanding drought responses in plants at a cellular level is a crucial first step towards engineering improved drought resilience. However, the molecular responses to drought are complex as they depend on multiple factors including the severity of drought, the profiled organ, its developmental stage or even the cell types therein. Thus, deciphering the transcriptional responses to drought is specially challenging. Here, we investigated tissue-specific responses to mild drought in young Arabidopsis thaliana (Arabidopsis) leaves using single-cell RNA sequencing (scRNA-seq). To preserve transcriptional integrity during cell isolation, we inhibited RNA synthesis using the transcription inhibitor actinomycin D, demonstrating the benefits of transcriptome fixation for studying mild stress responses at single-cell level. We present a curated and validated single-cell atlas comprising 50,797 high-quality cells from almost all known cell types present in the leaf. We show that the mesophyll contains two spatially separated cell populations with distinct responses to drought: one enriched in canonical abscisic acid-related drought-responsive genes, and another one depicting iron starvation responses. Our study thus reveals a dual adaptive mechanism of the leaf mesophyll in response to mild drought and provides a valuable resource for future research on stress responses.

plant biology↗

Early life adversities affect expected value signaling in the adult brain

BackgroundEarly adverse experiences are assumed to affect fundamental processes of reward learning and decision-making. However, computational neuroimaging studies investigating these circuits are sparse and limited to studies that investigated adversities retrospectively in adolescent samples. MethodsWe used prospective data from a longitudinal birth cohort study (n=156, 87 females, mean age=32.2) to investigate neurocomputational components underlying reinforcement learning in an fMRI-based passive avoidance task. We applied a principal component analysis to capture common variation across seven prenatal and postnatal adversity measures. The resulting adversity factors (factor 1: postnatal psychosocial adversities and prenatal maternal smoking, factor 2: prenatal maternal stress and obstetric adversity, and factor 3: lower maternal stimulation) and single adversity measures were then linked to computational markers of reward learning (i.e. expected value, prediction errors) in the core reward network. ResultsUsing the adversity factors, we found that adversities were linked to lower expected value representation in striatum, ventromedial prefrontal cortex (vmPFC) and anterior cingulate cortex (ACC). Expected value encoding in vmPFC further mediated the relationship between adversities and psychopathology. In terms of specific adversity effects, we found that obstetric adversity was associated with lower prediction error signaling in the vmPFC and ACC, whereas lower maternal stimulation was related to lower expected value encoding in the striatum, vmPFC, and ACC. ConclusionsOur results suggested that adverse experiences have a long-term disruptive effect on reward learning in several important reward-related brain regions, which can be associated with non-optimal decision-making and thereby increase the vulnerability of developing psychopathology.

neuroscience↗

EARLY AND MID-GESTATION ZIKA VIRUS (ZIKV) INFECTION IN THE OLIVE BABOON (PAPIO ANUBIS) LEADS TO FETAL CNS PATHOLOGY BY TERM GESTATION

Zika virus (ZIKV) infection in pregnancy can produce catastrophic teratogenic damage to the developing fetus including microcephaly and congenital Zika syndrome (CZS). We previously described fetal CNS pathology occurring by three weeks post-ZIKV infection in Olive baboons at mid-gestation, including neuroinflammation, loss of radial glia (RG), RG fibers, neuroprogenitor cells (NPCs) resulting in disrupted NPC migration. In the present study, we explored fetal brain pathologies at term gestation resulting from ZIKV infection during either first or second trimester in the Olive baboon. In all dams, viremia resolved after 7 days post infection (dpi). One first trimester infected dam aborted at 5 dpi. All dams developed IgM and IgG response to ZIKV with ZIKV IgG detected in fetal serum. Substantial placental pathology and inflammation was observed including disruption of syncytiotrophoblast layers, delayed villous maturation, partially or fully thrombosed vessels, calcium mineralization and fibrin deposits. In the uterus, ZIKV was detected in [3/4] first trimester but not in second trimester infected dams. While ZIKV was not detected in any fetal tissue at term, all fetuses exhibited varying degrees of neuropathology. Fetal brains from ZIKV infected dams exhibited a range of gross brain pathologies including irregularities of the major gyri and sulci of the cerebral cortex and cerebellar pathology. Frontal cortices of ZIKV fetuses showed a general disorganization of the six-layered cortex with degree of disorganization varying among the fetuses from the two groups. Frontal cortices from first but not second trimester infections exhibited increased microglia and astrocyte numbers (white matter) in both trimester infections. In the cerebellum, increased microglia were observed in both first and second trimester infected fetuses and decreased oligodendrocyte precursor cell populations in the cerebellar white matter in first trimester infections. In general, our observations are in accordance with those described in human ZIKV infected fetuses.

pathology↗

The prostate cancer therapy enzalutamide compared with abirateroneacetate/prednisone impacts motivation for exploration, spatial learning andalters dopaminergic transmission in aged castrated mice

Cognitive side effects after cancer treatment, threatening quality of life (QoL) and adherence to treatments, now constitute a major challenge in oncology. Abiraterone acetate plus prednisone (AAP) and enzalutamide (ENZ) are next generation therapy (NGT) administered with androgen deprivation therapy to metastatic castration-resistant prostate cancer (mCRPC) patients. NGT significantly improved mCRPC overall survival but neurological side effects such as fatigue and cognitive impairment have been recently reported. We developed a behavioral 17 months-aged and castrated mouse model receiving per os AAP or ENZ during 5 days per week for six consecutive weeks. After behavioral tests, brain and plasma were collected for immunohistochemical studies. The objective was to elucidate the impact of NGT on spontaneous activity, cognitive functions and emotional reactivity, as well as neurobiological functions. ENZ exposure reduced spontaneous activity and exploratory behavior associated with a decreased tyrosine hydroxylase (TH)-dopaminergic activity in the substantia nigra pars compacta and the ventral tegmental area. A decrease in TH+-DA afferent fibers and Phospho-DARPP32-related dopaminergic neuronal activities in the striatum and the ventral hippocampus, highlighted ENZ-induced dopaminergic regulation whithin the nigrostriatal and mesolimbocortical pathways. ENZ and AAP treatments did not substantially modify spatial learning and memory or behavioral flexibility performances, but ENZ led to a thygmotaxis behavior impacting the cognitive score, and reduced c-fos-related activity of NeuN+-neurons in the dorsal hippocampus. These results establish the consequences of the mCRPC treatment ENZ in aged castrated mouse motivation to exploration and cognition, of particular importance for future management of patients elderly postrate cancer patients and their QoL.

animal behavior and cognition↗

The Arabidopsis F-box protein FBW2 degrades AGO1 to avoid spurious loading of illegitimate small RNA

RNA silencing is a conserved mechanism in eukaryotes and is involved in development, heterochromatin maintenance and defense against viruses. In plants, ARGONAUTE1 (AGO1) protein plays a central role in both microRNA (miRNA) and small interfering RNA (siRNA)-directed silencing and its expression is regulated at multiple levels. Here, we report that the F-box protein FBW2 targets proteolysis of AGO1 by a CDC48-mediated mechanism. We found that FBW2 assembles an SCF complex that recognizes the MID-PIWI domain of AGO1 and requires its C-terminal domain containing a GW motif for AGO1 turnover. We showed that FBW2 prefers the unloaded and some mutated forms of AGO1 protein. While FBW2 loss of function does not lead to strong growth or developmental defects, it significantly increases RNA silencing activity. Interestingly, under conditions in which small RNA production or accumulation is affected, the failure to degrade AGO1 in fbw2 mutants becomes more deleterious for the plant. Hence, the non-degradable AGO1 protein assembles high molecular weight complexes and binds illegitimate small RNA leading to the cleavage of new target genes that belong to stress responses and cellular metabolic processes. Therefore, the control of AGO1 homeostasis by ubiquitin ligases plays an important role in quality control to avoid off-target cleavage.

cell biology↗

Altered basal lipid metabolism underlies the functional impairment of naive CD8+ T cells in elderly humans

BackgroundAging is associated with functional deficits in the naive T cell compartment, which compromise the generation of de novo immune responses against previously unencountered antigens. The mechanisms that underlie this phenomenon have nonetheless remained unclear. MethodsBiochemical and functional properties of naive CD8+ T cells were characterized and compared between middle aged and older individuals. FindingsWe identified an age-related link between altered basal lipid metabolism in naive CD8+ T cells and their impaired responsiveness to stimulation, characterized by low proliferative potential and susceptibility to apoptosis. Reversal of the bioenergetic anomalies with lipid-altering drugs, such as rosiglitazone, improved the functional capabilities of naive CD8+ T cells in elderly subjects. InterpretationInterventions that favor lipid catabolism may find utility as adjunctive therapies in the elderly to promote vaccine-induced immunity against emerging pathogens or tumors. FundingA full list of the funding sources is detailed in the Acknowledgment section of the manuscript. RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSOld subjects are highly susceptible to infections and tumors and usually present with low responses to vaccine. This is mainly due to the age-related loss of primary immune resources, i.e. a quantitative decline of naive CD8+ T cells. Nonetheless, few studies have also underlined, within this cell subset, qualitative defects in elderly subjects. Added value of this studyConsidering the well-demonstrated link between nutrient usage and lymphocyte functions, we characterized the bioenergetics features of old naive CD8+ T cells. Our data show an age-dependent altered basal metabolism in this cell subset, mostly at the levels of fatty acids and mitochondrial functions. These alterations were associated with functional defects which were partially reverted through the use of lipid-lowering strategies. Implications of all the available evidenceThis study highlights the potential role of an altered cellular lipid metabolism in immunosenescence, providing clues to understand the epidemiological profile of emerging infections or tumors and to develop preventive and therapeutic strategies based on metabolic manipulation.

immunology↗

Distinct Cellular Strategies Determine Sensitivity to Mild Drought of Arabidopsis Natural Accessions

The world-wide distribution of Arabidopsis thaliana (Arabidopsis) accessions imposes different types of evolutionary pressures, which contributes to various responses of these accessions to environmental stresses. Drought stress responses have been well studied, particularly in Columbia, a common Arabidopsis accession. However, the reactions to drought stress are complex and our understanding of which of these responses contribute to the plants tolerance to mild drought is very limited. Here, we studied the mechanisms by which natural accessions react to mild drought at a physiological and molecular level during early leaf development. We documented variations in mild drought tolerance among natural accessions and used transcriptome sequencing of a drought-sensitive accession, ICE163, and a drought-tolerant accession, Yeg-1, to get insights into the mechanisms underlying this tolerance. This revealed that ICE163 preferentially induces jasmonates and anthocyanin-related pathways, which are beneficial in biotic stress defense, while Yeg-1 has a more pronounced activation of abscisic acid signaling, the classical abiotic stress response. Related physiological traits, including content of proline, anthocyanins and ROS, stomatal closure and cellular leaf parameters, were investigated and linked to the transcriptional responses. We conclude that most of these processes constitute general drought response mechanisms that are regulated similarly in drought-tolerant and -sensitive accessions. However, the capacity to close stomata and maintain cell expansion under mild drought appeared to be major factors that contribute to a better leaf growth under mild drought. One-sentence summaryThis paper demonstrates that an efficient closure of stomata and maintenance of cell expansion during drought conditions are crucial to maximally preserve plant growth during water deficit.

plant biology↗

Adrenomedullin-CALCRL Axis Controls Relapse-Initiating Drug Tolerant Acute Myeloid Leukemia Cells

Drug tolerant leukemic cell subpopulations may explain frequent relapses in acute myeloid leukemia (AML), suggesting that these Relapse-Initiating Cells (RICs) persistent after chemotherapy represent bona fide targets to prevent drug resistance and relapse. We uncovered that the G-protein coupled receptor CALCRL is expressed in leukemic stem cells (LSCs) and RICs, and that the overexpression of CALCRL and/or of its ligand adrenomedullin (ADM) and not CGRP correlates to adverse outcome in AML. CALCRL knockdown impairs leukemic growth, decreases LSC frequency and sensitizes to cytarabine in patient-derived xenograft (PDX) models. Mechanistically, the ADM-CALCRL axis drives cell cycle, DNA repair and mitochondrial OxPHOS function of AML blasts dependent on E2F1 and BCL2. Finally, CALCRL depletion reduces LSC frequency of RICs post-chemotherapy in vivo. In summary, our data highlight a critical role of ADM-CALCRL in post-chemotherapy persistence of these cells, and disclose a promising therapeutic target to prevent relapse in AML.

cancer biology↗

Tabula-rasa exploration decreases during youth and is linked to ADHD symptoms

During childhood and adolescence, exploring the unknown is important to build a better model of the world. This means that youths have to regularly solve the exploration-exploitation trade-off, a dilemma in which adults are known to deploy a mixture of computationally light and heavy exploration strategies. In this developmental study, we investigated how youths (aged 8 to 17) performed an exploration task that allows us to dissociate these different exploration strategies. Using computational modelling, we demonstrate that tabula-rasa exploration, a computationally light exploration heuristic, is used to a higher degree in children and younger adolescents compared to older adolescents. Additionally, we show that this tabula-rasa exploration is more extensively used by youths with high attention-deficit/hyperactivity disorder (ADHD) traits. In the light of ongoing brain development, our findings show that children and younger adolescents use computationally less burdensome strategies, but that an excessive use thereof might be a risk for mental health conditions.

neuroscience↗

Noradrenaline modulates tabula-rasa exploration

An exploration-exploitation trade-off, the arbitration between sampling a lesser-known against a known rich option, is thought to be solved using computationally demanding exploration algorithms. Given known limitations in human cognitive resources, we hypothesised the presence of additional cheaper strategies. We examined for such heuristics in choice behaviour where we show this involves a value-free random exploration, that ignores all prior knowledge, and a novelty exploration that targets novel options alone. In a double-blind, placebo-controlled drug study, assessing contributions of dopamine (400mg amisulpride) and noradrenaline (40mg propranolol), we show that value-free random exploration is attenuated under the influence of propranolol, but not under amisulpride. Our findings demonstrate that humans deploy distinct computationally cheap exploration strategies and where value-free random exploration is under noradrenergic control. Data and materials availabilityData and code will be provided upon acceptance.

neuroscience↗