Biology subjects

Roussel, M.

Publications and source records attributed to Roussel, M..

9 recordsLinked to original sources

bioRxiv2026

Sensory experience and mTORC1 interplay orchestrates the maturation of cortical interneuron connectivity and tactile sensitivity

Sensory abnormalities are core features of neurodevelopmental disorders, including autism. Although interneuron dysfunction is hypothesized to contribute to these deficits, the underlying mechanisms remain unclear. Here, we demonstrate that mTORC1 dysregulation in parvalbumin-expressing (PV) interneurons drives heightened tactile exploration and defensiveness. These behavioral changes coincide with whisker-evoked cortical responses characterized by increased power but degraded temporal precision. Excitatory inputs to PV cells, their intrinsic excitability and in vivo firing rate during tactile exploration are reduced, suggesting that mutant PV cells are hypoactive. Whisker trimming restricted to the third postnatal week prevented mTORC1 hyperactivation, PV cell input and output connectivity deficits as well as abnormal tactile cortical responses and behavior in adult mutant mice. Further, this manipulation rescued sociability deficits. Altogether, these data suggest that the interplay between mTORC1 signaling and sensory experience in PV cells regulates their connectivity, and contributes to the proper development of tactile and social behavior.

neuroscience↗

bioRxiv2024

A mouse model of cardiac AL amyloidosis unveils mechanisms of tissue accumulation and toxicity of amyloid fibrils

AL amyloidosis is one of the most common types of systemic amyloidosis, caused by the deposition in tissues of fibrillar aggregates of abnormal immunoglobulin (Ig) light chain (LC), leading to organ dysfunction. The most frequent and severe forms affect the kidneys and heart, the latter being associated with a poor prognosis. Despite extensive efforts to decipher the mechanisms of fibril formation and their toxicity, the lack of reliable in vivo models hinders the study of the disease in its physiological context. We developped a transgenic mouse model producing high amounts of a human AL light chain (LC). While mice exceptionnaly develop spontaneous AL amyloidosis and do not exhibit organ toxicity due to the circulating amyloidogenic free LC, a single injection of amyloid fibrils, made up of the variable domain (VL) of the human LC, or soluble VL led to amyloid deposits in the heart, vessels, spleen and, to a lesser extent, in the kidney and other visceral tissues. AL fibrils in mice contain both full length and fragmented LC with a fragmentation pattern highly superposable to that of human AL fibrils from the same LC subgroup (IGLV6-57). They also develop an early cardiac dysfunction closely resembling the human disease with increased NT-proBNP,and activation of pathways involved in the extracellular matrix remodeling and fibrosis. Overall, this transgenic AL model closely reproduces human cardiac AL amyloidosis and shares with humans the biochemical composition of the deposits, arguing for a conserved mechanism of amyloid fibrils formation. It also shows that a partial degradation of the LC is likely required to initiate amyloid fibril formations. This model offers a new avenue for research on AL amyloidosis and fills an important gap for the preclinical evaluation of new therapies.

pathology↗

bioRxiv2023

Disruption of immunoglobulin heavy and light chain assembly by antisense oligonucleotides impairs protein homeostasis and myeloma cell survival

Multiple myeloma (MM) is related to the accumulation of malignant plasma cells (PCs) in the bone marrow. MM accounts for approximatively 10% of hematological malignancies and despite major improvement in therapies and outcomes, relapses will virtually occur in all patients. Usually, the disease goes along with an excess production of a monoclonal immunoglobulin (Ig) component by the tumor PC clone. However, many questions remain regarding the consequences of a deregulated Ig production on PC survival. Recent advances in RNA-based therapy using antisense oligonucleotides (ASO) prompted us to examine the impact of altered Ig heavy to light chain (HC/LC) ratios in MM cells. We designed a pan IgG subclasses specific ASO targeting a consensus sequence found in the polyadenylation signal (PAS) of all secreted IGHG mRNAs (IgG-ASO). Remarkably, treatment with this compound strongly decreased IgG secretion in MM cell lines and patient cells. Consistent with a deregulated HC/LC ratio, a dose-dependent excess of free-LCs (as monomers and dimers) was observed in myeloma cells treated with IgG-ASO, compared to an irrevelant control ASO (CTRL). RNA-seq profiles further indicated that the expression of genes involved in cellular metabolism, unfolded protein response (UPR) and cell death pathways were altered after treatment with IgG-ASO. Interestingly, impaired survival of primary IgG-expressing cells isolated from MM patients was achieved upon treatment with IgG-ASO, whereas no major effect was observed for healthy cells. Altogether, our data provide evidence for efficient inhibition of IgG secretion upon ASO treatment and suggest that an excess of free-LC due to disruption of HC/LC stoichiometry is toxic for MM cells expressing complete Ig. Such RNA-based strategies targeting PC in an Ig isotype-dependent manner could open new avenues for selective therapeutic approaches in PC dyscrasias.

immunology↗

bioRxiv2023

Prospects and pitfalls of an intrusive model for the Chatelperronian stone tool industry during the Middle to Upper Palaeolithic transition in France and northern Spain

The Middle to Upper Palaeolithic transition in France and northern Spain reflects the transition from Neandertals to Homo sapiens and the emergence of novel cultural entities and standardised laminar technologies between ~50 and 40 thousand years ago. The Chatelperronian stone tool industry sits at the centre of this period, and is commonly considered as representing a geographically isolated archaeological entity produced by late Neandertals. However, debate as to the makers and origin of this industry has long persisted. Fuel has recently been thrown onto this discussion through the formulation of a hypothesis in which the Chatelperronian directly originates from the Northern Early Ahmarian industry of the Levant. This model proposes that the Chatelperronian is in fact indicative of a direct migration of a population of Homo sapiens from the Levant to France around 44-40 thousand years ago - potentially via the crossing (or series of crossings) of the Mediterranean Sea. Such a scenario would have significant implications for how we interpret this key portion of recent human evolutionary history. In this paper, we highlight some of the prospects and pitfalls of an intrusive origin model for the emergence of the Chatelperronian industry in western Europe - taking into account technological, chronological, geographic, and stratigraphic perspectives. To frame this discussion, we review the state of understanding on the Chatelperronian and provide a detailed, synthetic review of Chatelperronian lithic technology. Our review reinforces the distinctive and fully Upper Palaeolithic character of this industry, and we subsequently suggest a few avenues of research which, in our opinion, may help shed progressively clearer light on the demographic and cultural processes operating during the Middle to Upper Palaeolithic transition in western Europe.

ecology↗

bioRxiv2022

Single-cell profiling identifies clinically relevant interactions between tumor associated macrophages and blood endothelial cells in diffuse large B cell lymphoma

Diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) are the two most common B-cell lymphomas and are characterized by a dynamic crosstalk between tumor B cells and a heterogeneous tumor-supportive microenvironment, including immune, endothelial, and stromal components. Although their impact on the pathogenesis and prognosis of B-cell lymphoma has been acknowledged for years, tumor-associated macrophages (TAM) have not been extensively explored in DLBCL and FL. Herein, we investigate mononuclear phagocytes (MNP) heterogeneity at the single cell level and their potential co-regulation with the stromal and endothelial compartments in B-cell lymphoma lymph nodes compared to reactive secondary lymphoid organs, using a combination of mass cytometry, single cell RNA sequencing, and in silico approaches. We reveal a co-regulation between TAM and blood endothelial cells (BEC) in lymphoma. Moreover, we identify a specific interaction between Annexin A1 (ANXA1)-expressing BEC and formyl-peptide receptors (FPR1/2)-expressing monocytes/macrophages in DLBCL, which we confirm in situ by multiplex immunofluorescence and imaging mass cytometry. This crosstalk is associated to an immunosuppressive tumor microenvironment and an adverse prognosis in DLBCL.

immunology↗

bioRxiv2022

Functional Contribution of Mesencephalic Locomotor Region Nuclei to Locomotor Recovery After Spinal Cord Injury

Spinal cord injury (SCI) results in a disruption of information between the brain and the spinal locomotor circuit. Although the spinal cord contains all the neural circuits to generate locomotion, people with SCI are unable to walk due to the absence of descending commands from the brain. Electrical stimulation of supraspinal locomotor centers, such as the Mesencephalic Locomotor Region (MLR), can promote locomotor recovery in acute and chronic SCI rodent models. Although clinical trials are currently underway in SCI patients, there is still debate about the organization of this supraspinal locomotor center and which anatomical correlate of the MLR should be targeted to promote functional recovery. Combining kinematics, electromyographic recordings, anatomical analysis, and mouse genetics, our study reveals that glutamatergic neurons of the cuneiform nucleus contribute to locomotor recovery by enhancing motor efficacy in flexor and extensor hindlimb muscles, and by increasing locomotor rhythm and speed on a treadmill, over ground, and during swimming in mice with chronic SCI. In contrast, glutamatergic neurons of the pedunculopontine nucleus slow down locomotion. Therefore, our study identifies the cuneiform nucleus and its glutamatergic neurons as a therapeutical target to improve locomotor recovery in patients living with SCI. One Sentence SummaryGlutamatergic neurons of the mesencephalic locomotor region contribute to spontaneous locomotor recovery following spinal cord injury and selective activation of a discrete glutamatergic subpopulation in this region can further improve functional outcome in chronic spinal cord injury.

neuroscience↗

bioRxiv2022

COVFlow: virus phylodynamics analyses from selected SARS-CoV-2 sequences

Phylodynamic analyses can generate important and timely data to optimise public health response to SARS-CoV-2 outbreaks and epidemics. However, their implementation is hampered by the massive amount of sequence data and the difficulty to parameterise dedicated software packages. We introduce the COVFlow pipeline, accessible at https://gitlab.in2p3.fr/ete/CoV-flow, which allows a user to select sequences from the Global Initiative on Sharing Avian Influenza Data (GISAID) database according to user-specified criteria, to perform basic phylogenetic analyses, and to produce an XML file to be run in the Beast2 software package. We illustrate the potential of this tool by studying two sets of sequences from the Delta variant in two French regions. This pipeline can facilitate the use of virus sequence data at the local level, for instance, to track the dynamics of a particular lineage or variant in a region of interest.

bioinformatics↗

bioRxiv2021

Nonclassical monocytes are prone to migrate into tumor in diffuse large B-cell lymphoma

Absolute count of circulating monocytes has been proposed as an independent prognostic factor in diffuse large B-cell lymphoma (DLBCL). However, monocyte nomenclature includes various subsets with pro-, anti-inflammatory, or suppressive functions, and their clinical relevance in DLBCL has been poorly explored. Herein, we broadly assessed circulating monocyte heterogeneity in 91 DLBCL patients. Classical- (cMO, CD14pos CD16neg) and intermediate- (iMO, CD14pos CD16pos) monocytes accumulated in DLBCL peripheral blood and exhibited an inflammatory phenotype. On the opposite, nonclassical monocytes (ncMO, CD14low CD16pos) were decreased in peripheral blood. Tumor-conditioned monocytes presented similarities with ncMO phenotype from DLBCL and were prone to migrate in response to CCL3, CCL5, and CXCL12, and presented similarities with DLBCL-infiltrated myeloid cells, as defined by mass cytometry. Finally, we demonstrated the adverse value of an accumulation of nonclassical monocytes in 2 independent cohorts of DLBCL. Key pointsO_LINonclassical monocytes are prone to migrate to DLBCL tumor C_LIO_LIHigh count of circulating nonclassical monocytes is an independent adverse event in DLBCL C_LI

immunology↗

bioRxiv2020

Mass cytometry and artificial intelligence define CD169 as a specific marker of SARS-CoV2-induced acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is the main complication of COVID-19, requiring admission to Intensive Care Unit (ICU). Despite recent immune profiling of COVID-19 patients, to what extent COVID-19-associated ARDS specifically differs from other causes of ARDS remains unknown, To address this question, we built 3 cohorts of patients categorized in COVID-19negARDSpos, COVID-19posARDSpos, and COVID-19posARDSneg, and compared their immune landscape analyzed by high-dimensional mass cytometry on peripheral blood followed by artificial intelligence analysis. A cell signature associating S100A9/calprotectin-producing CD169pos monocytes, plasmablasts, and Th1 cells was specifically found in COVID-19posARDSpos, unlike COVID-19negARDSpos patients. Moreover, this signature was shared by COVID-19posARDSneg patients, suggesting severe COVID-19 patients, whatever they experienced or not ARDS, displayed similar immune dysfunctions. We also showed an increase in CD14posHLA-DRlow and CD14lowCD16pos monocytes correlated to the occurrence of adverse events during ICU stay. Our study demonstrates that COVID-19-associated ARDS display a specific immune profile, and might benefit from personalized therapy in addition to standard ARDS management. One Sentence SummaryCOVID-19-associated ARDS is biologically distinct from other causes of ARDS.

immunology↗