NCube/papyrus huggingface dataset:
Direct catalytic macrolactonization and application of the phase separation strategy in complex molecule synthesis

Macrolactones are important structural motifs in numerous chemical industries particularly in the pharmaceutical and cosmetic markets. However, the traditional strategy for the preparation of macrolactones remains cumbersome, often requiring stoichiometric or excess amounts of activating reagents. Consequently, stoichiometric quantities of by-products are generated. They are often toxic, environmentally damaging, and/or require tedious purification methods to remove them. The following thesis describes the development of an efficient hafnium-catalyzed direct macrolactonization between carboxylic acid and primary alcohol functionalities, generating only water as a by-product and without the need for slow addition or azeotropic techniques. The protocol was also adapted for the direct synthesis of macrodiolides from equimolar mixtures of diols and dicarboxylic acids and for the selective head-to-tail dimerization of seco-acids. Macrocyclic musks and macrolactones relevant to medicinal chemistry were synthesized using the developed approach. A hafnium-catalyzed esterification protocol between carboxylic acids and primary alcohols was also developed. Different methods for the direct catalytic macrolactonization from secondary alcohols and carboxylic acids were studied. Furthermore, the phase separation strategy for macrocyclization in continuous flow was applied in the formal total synthesis of the macrolactone ivorenolide A. The key steps of the synthesis include the Glaser-Hay alkyne coupling macrocyclization and a Z-selective olefin metathesis reaction.

Keyphrases: macrolactonization, macrolactones, esters, macrodiolides, catalysis, hafnium, ivorenolide A, catalyse, formal total synthesis, macrocyclization, phase separation, continuous flow
Synthèse de sulfilimines et de sulfoximines catalysée par les métaux de transition

Sulfilimines and sulfoximines are interesting building blocks that have found many applications both in medicinal chemistry and agrochemistry. During our work, we have developed new efficient methods for the synthesis of these moieties. A catalytic amount of metal complex is used to enhance the reactivity of an electrophilic nitrogen source towards thioethers and sulfoxides. Our group has developed an expertise in the development of stereoselective C-H bond amination and aziridination reactions using chiral N-mesyloxycarbamate as electrophilic amination reagents. The large scale synthesis of the chiral reagent was first investigated. It was then tested in a diastereoselective dirhodium(II)-catalyzed amination of thioethers and sulfoxides, to produce respectively chiral sulfilimines and sulfoximines in excellent yields and selectivities.  During the optimization process, we have found that some additives proved instrumental to enhance both the reactivity and the selectivity of the reaction. Mechanistic studies has been carried out to elucidate the exact role of the additives. We have observed that Lewis bases, namely 4-dimethylaminopyridine (DMAP), can coordinate to a rhodium(II) dimer catalyst, modifying its structural and redox properties. These studies suggest that a mixed-valent dirhodium Rh(II)/Rh(III) complex is the catalytically active species in the thioether amination process. Moreover, we have discovered that the use of bispyridinium salts is crucial to enhance the selectivity of the amination reaction. Diastereoselectivities were also influenced by the nature of the leaving group of the N-sulfonyloxycarbamate. Based on the results, we hypothetized a rhodium nitrenoïd species as key intermediate in the amination process.  Continuous flow techniques were employed in the development of a very efficient amination process of thioethers and sulfoxides, using azides as electrophilic amination reagents. Based on the photochemical decomposition of azide derivatives with a simple and commercially available iron(III) complex, we were able to produce sulfilimines and sulfoximines in excellent yields. We investigated the design of a new type of capillary photoreactor to further reduce the residence time of the amination process. The technical improvements were pivotal to enhance the efficiency and productivity of the reaction process.

Keyphrases: Sulfilimine, Sulfoximine, Amination, Rh(II) catalyst, Rhodium(II) dimer, N-mesyloxycarbamate, Nitrenoïd, Iron(III) catalyst, Continuous flow, Photochemistry, Photoreactor, Azide
Dispositifs optoélectroniques à base de semi-conducteurs organiques en couches minces

Small p-type low band-gap semi-conducting molecules are rapidly gaining notoriety as potential replacements for conjugated polymers used in organic photovoltaic devices (OPV) along with n-type fullerene derivatives. As these active compounds often tend to crystallize upon coating, homogeneous, smooth thin-film formation is usually not trivial to obtain. We have devised bulk heterojunction OPVs in which various species of semi-conducting polymers or readily available insulating polymers are used as third-component matrices in order to rectify film inhomogeneity and enhance device performances. Polymers of specific molecular weights (MW) were also synthesised via a controlled Wittig type polymerization process by efficiently controlling the monomer and base ratios, and the effects of the MW variation were correlated with the thin-film morphologies and the resulting electroluminescence performances. In order to follow the evolution of the morphologies and the molecular arrangements, scanning and transmission electronic microscopy (SEM and TEM, respectively) was used, together with atomic force microscopy (AFM), and a new technique was introduced for preparing thin-film samples for imaging based on Si-wafer coating. Motivated by the increasing price of indium and the high cost of ITO-coated substrates, we have also examined ways to recover and recycle the tin-doped indium oxide (ITO) substrates used in these studies via environmentally benign methods.

Keyphrases: Organic solar cells, Photovoltaics, Organic light-emitting diodes, Low bandgap materials, Push-pull small molecules, Thin film morphologies, Polymer matrices, Polymer pockets, Polymer molar mass, Electroluminescent polymers, Emission tuning, Quantum yield, Recycling, Tin-doped indium oxide (ITO), Transmission electron microscopy, Focused ion beam, Silicon wafer, NaCl substrates, Organic templates, Nano-patterning
Décentralisation et allocation des ressources : les détours de la municipalisation du système de santé brésilien

In this thesis, we have analyzed the evolution of a process of health system municipalization that was carried out in the Rio Grande do Norte (RN), one of the federated north-east states of Brazil. Bearing in mind the historical context of these developments, we have concentrated our focus on the stakeholders implication in this process, especially in the system’s financial resource allocation.  Beliefs, perceptions, expectations, depictions, knowledge, interests, all these together are contributing factors in the construction of a cognitive capacity of the stakeholders, supporting reflexivity on their actions and the definition of various strategies in order to pursue the definition of strategies in their objectives in the health system.  They are seen as competent and reflexive agents, capable of appropriating structural properties of the health system (rules and resources), in a way that allows them to position themselves in the social sphere of the system which will allow change or at least maintain the status quo. During the restructuring process of the unique Brazilian health system, (SUS), municipalization was the best developed stream of a reform health project. In light of the contextual constraints and the complex dynamics of social spaces of health, the reformers stakeholders could not follow the idealistic utopia, some detours were encountered. In RN, the municipalization of the health system is composed of a complex process where the triad of centralization/decentralization/recentralization continued in the middle of negotiations, conflicts, alliances, disputes, cooperation and competition. Despite these successive contextual constraints, the structural properties of the health system and the social dynamics within the health system, certain changes have taken place: the construction of collective leaderships; the emergence of a spirit of negotiation; the creation of structures and the social spaces, fostering meetings amongst the stakeholders in each municipality and also at the federated state level; collective learning of the structuring process of the SUS; a tremendous growth of primary health care services permitting a reversal of the service delivery model; the first steps towards the rupture of culture of bureaucracy in the system. The SUS is still a prisoner of some institutionalized issues enshrined in the health system: the dependence on the private sector and on some professional groups; on insufficient and unstable financing; and on the human resources situation. The changes that have occurred have been convergent, incremental and slow; the results of these actions have been prescriptive, deliberate and formalized. They have also resulted in some unexpected successes: some informal, some paradoxical, some local, others more generalized; some short term, some long term.

Keyphrases: Municipalization, management, financing, stakeholder, complexity, change, structuring
Implication du domaine intracellulaire du précurseur de la protéine amyloïde dans la modulation de la plasticité synaptique

Alzheimer's disease is the most common type of dementia in the elderly; it is characterized by early deficits in learning and memory formation and ultimately leads to a generalised loss of higher cognitive functions. While amyloid beta (Aβ) and tau are traditionally associated with the development of Alzheimer disease, recent studies suggest that other factors, like the intracellular domain (APP-ICD) of the amyloid precursor protein (APP), could play a role.  In this study, we investigated whether APP-ICD could affect synaptic transmission and synaptic plasticity in the hippocampus, which is involved in learning and memory processes. Our results indicated that overexpression of APP-ICD in hippocampal CA1 neurons leads to a decrease in evoked AMPA-receptor and NMDA-receptor dependent synaptic transmission. Our study demonstrated that this effect is specific for APP-ICD since its closest homologue APLP2-ICD did not reproduce this effect. In addition, APP-ICD blocks the induction of long term potentiation (LTP) and leads to increased of expression and facilitated induction of long term depression (LTD), while APLP2-ICD shows neither of these effects.  Our study showed that this difference observed in synaptic transmission and plasticity between the two intracellular domains resides in the difference of one alanine in the APP-ICD versus a proline in the APLP2-ICD. Exchanging this critical amino-acid through point-mutation, we observed that APP(PAV)-ICD had no longer an effect on synaptic plasticity. We also demonstrated that APLP2(AAV)-ICD mimic the effect of APP-ICD in regards of facilitated LTD.  Next we showed that the full length APP-APLP2-APP (APP with a substitution of the Aβ component for its homologous APLP2 part) had no effect on synaptic transmission or synaptic plasticity when compared to the APP-ICD. However, by activating caspase cleavage prior to induction of LTD or LTP, we observed an LTD facilitation and a block of LTP with APP-APLP2-APP, effects that were not seen with the full length APLP2 protein. APP is phosphorylated at threonine 668 (Thr668), which is localized directly after the aforementioned critical alanine and the caspase cleavage site in APP-APLP2-APP. Mutating this Thr668 for an alanine abolishes the effects on LTD and restores LTP induction. Finally, we showed that the facilitation of LTD with APP-APLP2-APP involves ryanodine receptor dependent calcium release from intracellular stores.  Taken together, we propose the emergence of a new APP intracellular domain, which plays a critical role in the regulation of synaptic plasticity and by extension, could play a role in the development of memory loss in Alzheimer’s disease.

Keyphrases: Alzheimer, APP, APLP2, LTP, LTD, Calcium, Amyloid, plasticity, metaplasticity
Étude de la reconstitution de l’immunité spécifique au cytomégalovirus et au virus de la varicelle suite à la transplantation de sang de cordon ombilical

Umbilical cord blood transplantation (UCBT) is a treatment of choice for a variety of hematological malignancies and non-malignant diseases in children and, in some cases, in adults. UCBT is associated with a slower immune reconstitution and a high incidence of viral infections, especially related to cytomegalovirus (CMV) and the varicella-zoster virus (VZV). As part of this work, we aimed to assess the reconstitution of CMV and VZV-specific T cell responses. Neither pre-transplant serostatus nor disease development is required for development of T cell mediated immunity. Moreover, spontaneous reconstitution detected in some patients who were seronegative for CMV or VZV. Detected especially after 6 months post-transplant, antiviral responses are protective in terms of viral reactivation and development of clinical signs, when a frequency of 150 cells producing d'IFN-γ / million is achieved. However, less than 5% of patients develop an antiviral response during the first 100 following UCBT. Compared to their bone marrow (BM) counterparts, UCB CD8+ T lymphocytes may be functionally impaired, a state commonly called « clonal exhaustion ». Characterization of the inhibitory receptors repertoire expressed by CD8+ T cells following UCBT and BMT showed a significant increase in the frequency of cells expressing PD-1 early after transplantation. This population, mainly characterized by effector phenotype, showed a significant loss of proliferative capacity and produced less IFN-γ, IL-2, TNF-α and CD107a. An improved understanding of the CD8+ T cell compartment following UCBT, as well as biomarkers related to T cell exhaustion will decrease infection, transplant related mortality and correlate with better prognosis

Keyphrases: Lymphocytes T, Umbilical cord blood transplantation, Cytomegalovirus, Varicella-zoster virus, Immune reconstitution, T cells, Clonal exhaustion
Eph kinases and their ligands ephrins act in concert with sex hormones in regulating blood pressure

Erythropoietin-producing hepatocyte (EPH) kinases are the largest family of receptor tyrosine kinases. Their ligands, ephrins (EFNs), are also cell surface molecules. Ephs/EFNs are implicated in many biological processes. Hypertension is a chronic medical condition of high arterial blood pressure (BP). New hypertension therapeutic treatments are of great importance for public health. Until recently, there are only a few studies related to the role of EPHs/EFNs in vascular smooth muscle cell (VSMC) function. In our previous studies, we have found that EPHB6 and EFNB1 function in concert with sex hormones to regulate BP.  In the present investigation, we found that different EPH/EFN family members can either positively or negatively regulate the VSMC contractility and BP: while EPHB4 and EFNB2 belong to the former category, EFNB1, EFNB3 and EPHB6, the latter.  In vivo, male but not female smooth muscle-specific EPHB4 knockout (KO) mice presented decreased BP, compared to WT controls. VSMCs from EPHB4 KO mice in the presence of testosterone showed reduced contractility.  EFNB2 is the major ligand of EPHB4. As expected, smooth muscle-specific EFNB2 KO mice had a similar although not identical BP phenotype as EPHB4 KO mice. Male but not female EFNB2 KO mice on regular or high-salt diet presented reduced BP, compared to WT counterparts. At the cellular level, the KO VSMCs showed reduced contractility compared to WT controls. In a human genetic study, we identified in the EFNB2 gene six SNPs that were significantly associated with hypertension risk in a sex-dependent way, corroborating our findings in mice. On the other hand, EFNB3 gene KO in female mice resulted in elevated BP and small artery resistance in vivo, enhanced small arterial contractility ex vivo, and augmented VSMC contractility in vitro. Male KO mice had normal BP, but castration led to significant BP elevation in KO but not in WT mice. VSMCs from female KO mice showed heightened MLC phosphorylation and reduced MLC kinase phosphorylation. This signaling change was mediated through an adaptor protein Grip1. Indeed, in a genome-wide association study by the International Consortium for Blood Pressure, an SNP in the GRIP1 gene approached the significant threshold p-value for its association with diastolic BP.  Our research for the first time revealed that EPHs/EFNs are novel components in the BP regulation system. Members of the EPH/EFN family may act as Yin and Yang forces to finely tune the vessel tone for BP homeostasis and regulation. Such effects of EPHs/EFNs depend on sex and sex-hormone levels. Based on this new knowledge, we could develop novel personalized hypertension therapy using sex hormone antagonists or sex hormone replacement therapy, depending on the sex hormone levels of the patients and mutations in EPH/EFN genes.

Keyphrases: Erythropoietin-producing hepatocyte (EPH), ephrins, vascular smooth muscle cells, hypertension, sex hormones, Erythropoietin-producing hepatocyte (EPH)
Impact de la cécité sur le système nociceptif

Vision is important for avoiding encounters with objects in the environment that may imperil physical integrity. Since pain also plays a major role in preventing bodily injury, we tested whether, in the absence of vision, pain hypersensitivity would arise from an adaptive shift to other sensory channels. Indeed, a wealth of literature indicates that blindness leads to sensory compensation and crossmodal plasticity. Furthermore, studies have shown that pain perception can be modulated by vision and by temporary visual deprivation. In a first study, we measured innocuous and noxious thermal thresholds using a Peltier-based thermotester in congenitally blind and normal sighted participants. We also assessed their suprathreshold pain ratings using a CO2 laser device and evaluated their attitude towards daily pain encounters using questionnaires on attention and anxiety. Results show that congenitally participants have lower pain thresholds and higher suprathreshold pain ratings. The psychometric data further indicates that they are more attentive to pain compared to their sighted peers. In a second study, we investigated whether visual experience has an impact on pain perception by replicating the first study in late blind participants. Results indicate that individuals who lost sight later in life are similar to the sighted in every aspect of pain perception that we measured. In a third study, we tested whether blind individuals have supranormal skills in detecting small and quick increases in temperature, as these thermal cues of the environment might help identifying and avoiding potentially harmful objects. Results show that congenitally blind participants outperform their sighted peers and that they are more susceptible to spatial summation of heat. In a fourth study, we examined the contribution of A∂ and C-fibres to blind individuals’ nociceptive processing, as these fibres are thought to signal the first and second pain, respectively. Our findings indicate that congenital blindness leads to an enhanced detection to C-fibre mediated sensations and to faster reaction times to these nociceptive inputs. In a fifth and final study, we probed the potential changes in the descending modulation of nociceptive inputs following visual deprivation by measuring the effects of psychological factors like anticipation and anxiety on blind individuals’ pain perception. Results show that congenitally blind participants are more sensitive to pain in response to uncertainty about threat, suggesting that they are more susceptible to top-down modulation of pain. Overall, this work indicates that visual deprivation from birth, but not later in life, causes a leftward shift in the stimulus–response function to nociceptive stimuli and lends new support to a model of sensory integration of vision and pain processing.

Keyphrases: Thermoception, Nociception, Pain Perception, Vision, Blindness, Multisensory Integration, Sensory Compensation, Brain Plasticity
Influence du vieillissement et de la scolarité sur la compréhension du discours : apport de l’imagerie optique

Discourse comprehension, and its evolution through aging, is a subject of importance by its complexity and its place in the preservation of life’s quality. The objectives of this thesis were to evaluate the influence of aging and level of education on discourse comprehension capacities and their related underlying brain activity. To achieve this, three groups (young adults with a university education, elderly adults with a university education and elderly adults with a high school education) carried out a task where they read short stories and answered probes about those stories. Discourse comprehension capacities were evaluated through three processing levels of the Kintsch’s construction-integration model (microstructure, macrostructure and situation model). Using NIRS, the variation of oxyhemoglobin (HbO) and deoxyhemoglobin (HbR) concentrations was estimated through the task. Results indicated that elderly adults were as capable as younger adults to recall the macrostructure (gist of the text), but that they had more difficulties to recall microstructure (details) and the situation model (inference and integration) after reading short texts. While reading, elderly adults also showed greater brain activity in the left dorsolateral prefrontal cortex which could be a compensatory mechanism similar to the one described in the CRUNCH model. No significant difference was observed between participants having a university education and those having a high school education on discourse comprehension capacities and the underlying brain activity. Nevertheless, the two groups had maintained cognitively stimulating life habits, particularly great reading habits. Thus, those habits seem to have a greater influence than education on the performance in comprehension and on the underlying brain activity. Maybe higher education promotes more cognitive habits, and ultimately, it is those habits that seem to have a real impact on cognitive aging.

Keyphrases: discourse comprehension, aging, cognitive aging, education, reading, cerebral plasticity, NIRS, language