NCube/papyrus huggingface dataset:
Développement d’une nouvelle thérapie ciblant l’anomie des verbes d’action : validation comportementale et exploration des corrélats neurofonctionnels de ses effets dans les cas d’aphasie

Aphasia is a language impairment due to a brain lesion, most often following a stroke. Language impairments lead to multiple negative outcomes and significantly impoverish the quality of life of persons living with aphasia. Anomia is the most frequent and persistent symptom across all kinds of aphasia. Anomia can be observed for nouns, but also for verbs. Moreover, the latter are at the core of the sentences. Despite the fact that verb anomia is more frequent than anomia with nouns, there is much less interventions available to treat verbs’ anomia. Accordingly, with embodied cognition theory, sensorimotor strategies, such as action execution and action observation seem to improve verb naming. However, published studied show only a very limited generalization effect when this effect is the gold standard of clinical practice. These studies are generally based on only one strategy and did not use mental imagery which was found to be related with action processing. Moreover, these studies rarely include recommendations from the work in neuroscience. The present PhD project aims to (1) develop a new sensorimotor therapy taking into account these theoretical and methodological points, (2) evaluate its « efficacy » at a behavioural level, and (3) seek its neurofunctional underpinning functioning. The results reveal a significant improvement of the verb naming performance for the 10 persons with aphasia. More importantly, this improvement is also observed for the untrained verbs signalling a generalization effect. In addition, the effects are still present after two and six months following the end of the therapy. The neurofunctional results, for the two participants included, confirm the involvement of language and sensorimotor areas during action naming. Finally, resting state connectivity analyses performed with four participants suggest higher integration in the visuomotor and motor networks involved in action naming. These preliminary data support the idea that neurofonctional changes are associated with the nature of the therapy combining different sensorimotor strategies to improve verb naming.  Taken together, these results are very promising regarding the efficacy of this new therapy, mainly through the generalization effect. Even if the sample size is limited, the robustness of the analyses and the convergence of the results with the existing data of the literature and through the different modalities of the studies (behavioural and neurofunctional) allow to be optimistic for the clinical applications of the therapy. Finally, the theoretical perspectives, with the embodied cognition theory, as well as the practical ones, with the limits of the projects and the ongoing work, are discussed in light of the existing literature.

Keyphrases: neuroimagerie, aphasia, therapy, verb, embodied cognition, neuroimaging
Élaboration et validation d’une base de données haute résolution destinée à la calibration d’un patient virtuel utilisable pour l’enseignement et la prise en charge personnalisée des patients en réanimation pédiatrique

The complexity of the patients in the intensive care unit requires the use of clinical decision support systems. These systems bring together automated management protocols that enable adherence to guidelines and virtual physiological or patient simulators that can be used to safely customize management. These devices operating from algorithms and mathematical equations can only be developed from a large number of patients’ data. The main objective of the work was the elaboration of a high resolution database automatically collected from critically ill children. This database will be used to develop and validate a physiological simulator called SimulResp© . This manuscript presents the whole process of setting up the database from concept to use.

Keyphrases: big data, Database, Intensive care unit, clinical decision support system, children, computational model
La congestion veineuse comme déterminant des interactions cardio-rénales et cardio-intestinales en insuffisance cardiaque aiguë

Venous congestion has been shown to play a major role in worsening renal function in acute decompensated heart failure, and recent data have challenged the assumption that end-organ dysfunction was driven by other hemodynamic alterations in patients with heart failure. Decongestion is thus considered as a major therapeutic goal in the management of patients with acute heart failure. As such, real-time assessment of patient’s fluid status may allow for a better management of patients with heart failure, enabling for a personalized management. The aim of this work is to explore the deleterious effect of venous congestion in patient with heart failure, particularly in terms of end-organ dysfunction. We also aimed to characterize the role of extra cardiac ultrasound for the assessment of the volume status in patients with heart failure.

Keyphrases: Congestion, Volume status, Central venous pressure, Heart failure, Extra cardiac ultrasound
Rôle de la voie L-PGDS / PGD2 / DP1 dans l’OstéoArthrose

Osteoarthritis (OA) is the most common degenerative disease (or) and the leading cause of physical disability with significant socioeconomic costs. Clinical manifestations of osteoarthritis can include pain, stiffness, and reduced joint movement. Pathologically, OA is characterized by progressive degeneration of articular cartilage, increased expression of inflammatory and catabolic mediators, and subchondral bone remodeling. It has been shown that prostaglandin D2 protein (PGD2) is synthesized by different cell types and has pro and anti-inflammatory properties, depending on the activated receptor. Several pro-inflammatory stimuli have been discerned and studied, but the anti- inflammatory pathways remain an unexplored universe. The DP1 receptor of PGD2, as well as the synthetic enzyme L-PGDS, play important roles in inflammation and cartilage metabolism. However, their roles in the pathogenesis of osteoarthritis (OA) remain unknown. We undertook the study (of what) on the one hand, to explore the roles of L-PGDS and DP1 in the development of OA, and on the other hand to evaluate the efficacy of a selective agonist DP1 and an AAV2 / 5 virus encoding L-PGDS in the treatment of OA. First, our histology work demonstrated that cartilage degradation is more pronounced in L- PGDS Knock-out and DP1 mice compared to Wild-Type (WT) wild-type mice. Then an increase in the expression of catabolic mediators (ADAMTS5 and MMP-13), in L-PGDS - / - mice and DP1 - / - compared to WT was demonstrated. Subsequently, stimulation of cartilage explants with IL-α from L-PGDS - / - and DP1 - / - mice showed high degradation in proteoglycans. In addition, these mice also develop subchondral bone changes. Finally, our results suggest that following intraperitoneal injection of the DP1-specific agonist, BW245C attenuated the severity of cartilage degradation induced by medial meniscus destabilization (DMM) and bone changes in mice. WT. Similarly, the intra-atrial injection of AAV2 / 5 encoding L-PGDS also attenuated DMM-induced cartilage degradation and the expression of ADAMTS-5 and MMP-13 in L-PGDS - / - mice. In conclusion, all our results suggest that the recepteur DP1 and the L-PGDS enzyme in osteorthritis cartilage plays a very important role. It may be a potential therapeutic avenue in the treatment of OA and also in the treatment of other musculoskeletal conditions.

Keyphrases: Cartilage, L-PGDS, PGD2, DP1, Chondrocytes, Osteoarthritis
Étude du rôle biologique de l’interaction du CD154 avec l’intégrine α5β1 dans la promotion de la survie des cellules T

CD154 is a type II glycoprotein belonging to the tumor necrosis factors (TNF). It’s expressed in a transitory way on different cell types. There are two forms of CD154, membrane (mCD154) and soluble (sCD154). Both form are biologically active trimeric structure. CD154 has been identified on its role in the thymus dependent humoral response following its binding with its CD40 receptor. It has subsequently been shown that CD154 plays a role in various inflammatory responses, some of which may lead to pathogenic processes of chronic inflammatory and autoimmune diseases. Recently, studies have shown that other αIIbβ3, αMβ2, αvβ3 and α5β1 receptors belonging to the integrin family could interact with CD154. They play an important role in the control of many cellular processes such as cell proliferation and apoptosis. However, the biological role of the interaction of CD154 with its newly identified receptors remains poorly studied. T lymphocytes are key cells in the immune response. Their survival and persistence is a characteristic signature of numerous inflammatory and autoimmune diseases. In these latter, T cells express high levels of β1 integrins. Given the role attributed to integrins and in particular to β1 integrins in the inhibition of apoptotic events in T cells, we were very interested in studying the role of the CD154 / α5β1 interaction in promoting T cell survival. In this study we have demonstrated that sCD154 is able to specifically bind to T-cell expressed α5β1 integrin. This interaction inhibits Fas-induced apoptosis in Jurkat E6.1 and HUT-78 T cell lines following the inhibition of cleavage of caspase-8. We have also shown that the anti-apoptotic effect induced by the CD154 / α5β1 axis was not restricted to Fas, but was generalized to other TNF-like death receptors such as TRAIL and TNF. More interestingly, our results showed that preincubation with sCD154 of previously activated human T CD3+ cells, protects them from Fas-induced death. Finally, we have shown that, like sCD154, mCD154 was able to inhibit death induced by the different death receptors Fas, TRAIL and TNF, but only by a cis-dependent mechanism when CD154 and α5β1 are expressed at the same time surface of the same cells. These results enhance the importance of the CD154 / α5β1 interaction in the survival of T cells and thus in their biological roles. This new observation further induces CD154 and its  integrin receptors in initiation, but also in the progression and persistence of inflammatory and autoimmune pathologies, in particular. The specific inhibition of this axis may represent a potential therapeutic target in the treatment of pathologies.

Keyphrases: CD154, Inflammation, Maladies auto-immunes, Integrin, Cell survival, Autoimmune diseases
Analyse fonctionnelle des fimbriae de type chaperon-placier chez Salmonella enterica sérovar Typhi

Salmonella enterica serovar Typhi is a human-specific pathogenic bacteria and the etiologic agent of typhoid fever. Among its virulence factors, there are 14 putative adhesion systems named fimbriae identified in the S. Typhi genome. Each fimbria is clustered in an operon that encodes for extracellular proteinaceous structures, for the secretion and assembly machinery and sometime for regulators. Fimbrial genes are poorly expressed under laboratory conditions, with few studied in S. Typhi. Among the 14 fimbriae, 12 belong to the chaperone-usher class, where each one encodes a dedicated chaperone and usher that form the fimbrial structure. I propose that fimbriae are important for S. Typhi pathogenesis. The aim of this project is the functional analysis of all the chaperone-usher fimbriae of S. Typhi. My goals were to establish a general characterization of the 12 chaperone-usher fimbriae, and to study specifically the regulation of 2 fimbriae, Fim and Std. The general characterization of chaperone-usher fimbriae includes the determination of the expression of fimbrial promoters in different growth conditions mimicking infection, the observation of the presence and morphology of fimbriae at the bacterial surface, and the evaluation of the role of fimbriae on S. Typhi pathogenesis (biofilm formation, host-cells interactions and motility). Fimbrial expression was generally higher when cells were grown in minimal medium. I was able to observe for the first time the presence of 6 out of 12 fimbriae by transmission electron microscopy. Regarding the role of fimbriae in pathogenesis, each fimbria was involved in at least one step. Regulation of std and fim was studied by evaluating the implication of several general regulators and by screening a transposon-based library. Overall, I discovered that the std promoter was activated by Crp, responsible of catabolic repression, and that fim was modulated by the activity of the electron transport chain and by envelope perturbations. Finally, my results demonstrated that the chaperone-usher fimbriae are important for S. Typhi pathogenesis and two of them are regulated by important environmental signals encountered during bacterial infection.

Keyphrases: S. Typhi, fimbriae, Fim, Std, Chaperone-usher, Pathogenesis
Étude de l'interactome et identification de nouvelles cibles de la protéine virale Vpr du VIH-1

Human immunodeficiency virus (HIV-1) is the AIDS causal agent. This complex retrovirus encodes several accessory proteins; namely Nef, Vif, Vpr and Vpu; whose functions are to manipulate the cellular host environment in order to favor HIV-1 viral replication. This thesis focused on Vpr whose main activities are to induce a cell cycle arrest in the G2/M phase in dividing cells and to provide a replicative advantage to HIV-1 during infection of myeloid cells such as macrophages. The cellular mechanisms underlying these two activities are up to now misunderstood. The main goal of the work presented in this thesis is to identify new cellular factors that could potentially explain the previously described Vpr activities. To do so, we used the proximity labelling approach called BioID. The main strength of BioID is to tag in cellulo partners of the protein of interest. The development as well as optimization of the BioID approach is presented in the thesis first section.  Using BioID, we defined a network containing 352 cellular partners in close proximity with the viral protein Vpr. Amongst these cellular partners, several were organized into protein complexes or networks such as the anaphase promoting complex/cyclosome (APC/C) or the centrosome. Given that APC/C is a cell cycle master-regulator, we analyzed the interplay governing Vpr and APC/C interactions. We first demonstrated that Vpr could form a complex containing the scaffolding subunit APC1. APC/C coactivators, namely CDH1 and CDC20, could also be found in association with Vpr. We next showed that Vpr was inducing APC1 degradation and that Vpr residues N28 and G41 were essential to this activity. Surprisingly, the APC1-Vpr interplay does not relate to previously described Vpr activities. This work is presented in the second section of this thesis. Lastly, in the third section, a work done in collaboration analyzed the interplay between Vpr and the centrosomes. In this thesis we identified 200 new potential partners of Vpr, opening the doors to discover novel Vpr targets and activities. This thesis also defined APC/C as new Vpr target.  Taken together our results allow a better understanding on how HIV-1 modulates the cellular environment by using the viral accessory protein Vpr.

Keyphrases: BioID, APC1, human immunodeficiency virus (HIV-1), viral protein R (Vpr), proximity labelling, proteomic, anaphase promoting complex/cyclosome (APC/C)
Caractérisation des activités épigénétiques et anticancéreuses de la proscillaridine A dans les cancers pédiatriques

Cardiac glycosides are sodium/potassium pomps’ inhibitors used for the treatment of heart failure, and whose anticancer and epigenetic activities have been recently characterized. However, in order to repurpose cardiac glycosides as anticancer drugs, mechanistic studies are required to identify the anticancer and epigenetic mechanism of actions. In our experiments, proscillaridin A exhibited the most powerful anticancer and epigenetic activities in colon cancer, leukemia, and sarcoma cell lines. Moreover, we demonstrated that in a panel of 14 cancer cell lines, proscillaridin A anticancer activities positively correlated with MYC protooncogene expression level. In high MYC expressing cell lines such as leukemia, proscillaridin A inhibited MYC expression through protein destabilization and through transcriptomic and translational regulation of MYC targets. Theses inhibitions are induced by the loss of lysine acetylatransferase (KAT) expressions, which are epigenetic enzymes controlling the addition of acetyl-coenzyme A on histones and other proteins such as MYC. KAT inhibitions are responsible for the global loss of histone 3 acetylation and acetylome reprogrammation in high MYC expressing cancer cells. These chromatin changes induced transcriptomic and phenotypic reprogrammation, defined by a loss of the transcription of oncogenic programs and the induction of cell differentiation. To finish, we evaluated the anticancer and epigenetic synergic potential of proscillaridin A in combination with the epigenetic drug the decitabine in cancer cell lines expressing different MYC levels. In a cancer cell line resistant to proscillaridin A treatments and expressing low MYC level (colon cancer cell line), the combination of decitabine and proscillaridin A demonstrated synergistic epigenetic activity although, in a cell line sensitive to proscillaridin A treatments and expressing high MYC level (sarcoma cell line), the combination of decitabine and proscillaridin A exhibited synergistic anti-proliferative activity. To conclude, we highlighted the potential of repurposing proscillaridin A as an anticancer treatment in high MYC expressing cells. Furthermore, we demonstrated the anticancer and epigenetic synergistic potential of proscillaridin A in combination with decitabine and we propose to study the drug combination in cancers that are resistant to proscillaridin A treatment.

Keyphrases: Glycoside cardiotonique, Cardiac glycosides, Proscillaridin A, Drug repurposing, Anticancer treatments, MYC proto-oncogene, Lysine acetyltransferases (KATs), Histone acetylation, Drug combinations
Rôle et mécanisme d’action du récepteur B1 des kinines dans la rétinopathie diabétique et la dégénérescence maculaire liée à l’âge

The kallikrein-kinins system is a peptidergic system involved in inflammatory processes, the control of the vascular tone and permeability. These effects are mediated by two G proteincoupled receptors, the Bradykinin type 1 (B1R) and type 2 (B2R) receptors. While the B2R is a constitutive receptor, B1R is almost undetectable in physiological condition; it is, however, induced by oxidative stress, pro-inflammatory cytokines (interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α)) or by bacterial endotoxins at both systemic and local levels, notably in the retina. Recent studies from our laboratory supported an implication of B1R in the pathogenesis and progression of diabetic retinopathy and age-related macular degeneration (AMD). This thesis aims at unraveling: 1) the mechanism by which B1R is involved in diabetic retinopathy in rats; 2) the involvement of iNOS in the inflammatory cascade downstream to the B1R; and, 3) the expression and cellular localization of B1R in human retinae with exudative and atrophic AMD. Our results have shown the implication of B1R in diabetic retinopathy via the activation of the inducible nitric oxide synthase (iNOS) in a type 1 model of diabetes induced by streptozotocin (STZ) in rats. In addition to its generalized localization throughout the retina, B1R is expressed in the retinal pigment epithelium which forms the outer blood-retinal barrier. The protein and transcript expression of inflammatory markers; iNOS, carboxypeptidase M, IL-1β, TNF-α, vascular endothelium growth factor A (VEGF-A) and its receptor, VEGF-R2, including B1R as well as nitrosylated proteins are increased in the retina of diabetic rats at 2 weeks post-STZ. These upregulations, as well as the retinal vascular hyperpermeability induced by diabetes and by the intravitreal injection of an B1R agonist (R-838) are blocked by a topical one-week treatment by eye-drop with the selective iNOS inhibitor (1400W) (first manuscript). The results of the second manuscript show significant increases in the immunoreactivity of B1R in exudative AMD retinae. Despite a slight increase, B1R immunostaining does not reach statistical significance in the retina of donors with atrophic AMD. The reactivity of glial cells is more impressive in the exudative than in the atrophic form of AMD. B1R is co-expressed with markers of Müller cells, astrocytes, microglia, iNOS and fibrosis, suggesting an involvement of B1R in the inflammatory events and the formation of fibrosis in exudative AMD. On the other hand, the expression of B2R remains stable in the retinae of exudative and atrophic AMD, supporting a secondary role of this receptor in AMD in humans.

Keyphrases: Kallikrein-kinins system, Bradykinin type 1 receptor, Inducible nitric oxide synthase, Diabetic retinopathy, Age-related macular degeneration
Impact de la rigidité artérielle sur le cerveau et effets bénéfiques potentiels de l’œstradiol et de la vitamine K

Epidemiological studies have associated arterial stiffness with cognitive decline and dementia. However, its effects on the brain biology remain unknown. In our first study, using a new murine model of arterial stiffness, we wanted to characterize the effects of arterial stiffness on the brain independently of age and pressure. Our results indicate that arterial stiffness impairs the regulation of cerebral blood flow and the integrity of the cerebrovascular system, damaging the blood-brain barrier and leading to cognitive deficits. Arterial stiffness results in significant alterations in resting cerebral blood flow and mechanisms regulating cerebral blood flow such as cerebral autoregulation, neurovascular coupling, and endothelial function.  In our second study we sought to understand sexual dimorphism in arterial stiffness and its consequences on the brain in the same model. Our results show that arterial stiffness leads to impaired neurovascular coupling and endothelial-dependent vascular reactivity in male mice but not in female reproductive mice. In ovariectomized mice this protection was suppressed but was restored by estradiol treatment. In the third study, we wanted to study the possibility of preventing arterial stiffness and its subsequent effects on the brain. In this study, we used vitamin K (phylloquinone or VK1 and menaquinone-4 or MK-4) for its anti-calcifying action and its beneficial effects on the cognitive functions observed in other animal models and in humans. This study demonstrated that VK prevent cognitive impairment in part by restoring the resting cerebral blood flow but also by preventing vascular calcification. Learning abilities increase with the contribution of food VK, which in turn correlates with the VK content of the brain. These studies provide a better understanding of arterial stiffness and demonstrate the potential of VK and hormone therapy with estradiol in preventing its effects on the brain. However, further studies are needed to determine all the mechanisms involved in the brain protection by VK and estradiol.

Keyphrases: Oestradiol, VK, Arterial stiffness, Cognitive function, Cerebral blood flow, Estradiol