NCube/papyrus huggingface dataset:
Prédire le professionnalisme : une exploration des modèles de la famille de Rasch et de la régression par classes latentes (Étude PERSONA)

The study seeks to draw attention on fundamental issues of any academic admission procedures, specifically on measurement, decision and impact issues. Therefore, it will explore the predictive ability of three non-cognitive variables toward the observed professionalism of PharmD students. Admitting student in the health sciences often rely solely on the student cognitive ability. Taking into account that health sciences program have moved toward competency oriented curriculum, the relevance and validity of traditional admission criteria are challenged. This study proposes to validate the use of personality , values and self-determination measurement scales to pursue effective and equitable admission decisions. The challenges of measuring these variables will be addressed primarily by the dichotomous and polytomous Rasch models. The Strata method will, thereafter, provide methodological basis for decision issues by enabling for student ranking and classification. Then, impact issues will, in turn, be explored by latent class regression analysis. The study demonstrates that the use of such modeling procedures has allowed accurate differentiation, ranking and classification of students. However, the violation of certain basic model requirements and the lack of differentiation made between students on the basis of the criteria of professionalism, made the assessment of the predictive power of personality, values and self-determination hazardous. In fact, the latent class models identified were non conclusive. They showed no marked distinctions useful to guide admission procedures. Although, the Rasch modeling, the latent class regression model and the Strata procedure shows interesting benefits for admission procedures, additional research on the quality of professionalism criteria and non-cognitive variables measurement scales are required.

Keyphrases: Rasch measurement, Latent class, Regression, Prediction, Classification
Travail des chefs d'établissement et pilotage des équipes pédagogiques : analyse de l'activité de chefs d'établissement en collège réseau ambition réussite en France

Headmasters' work has been changing with educational politicies. Headmasters are becoming agents for change or managers in schools wich are independent and under an obligation of results. In France in 2006, headmasters are challenged with the reform of Ambition success networks. An unprecedented situation that raises the question : how to manage heterogeneous teams ? This thesis uses the ergonomic approach to the activity in order to study a paradox : on the one hand, the focus is put on collective work and its impact on performance, on the other hand, the organisation of the work by headmasters and the work of organisation by teachers are ignored. The aim is to show the importance of actual work in order to understand conditions and difficulties of the work of organisation in wich headmasters are engaged.

Keyphrases: headmaster, educational policies, organisation of work, ergonomic approach to the activity, required work, actual work, organisational work
L'accélération de la rigidité vasculaire associée au diabète de type 1 : implication de la protéine Gla de la matrice

Arterial stiffness contributes to the development of isolated systolic hypertension (ISH), the most prevalent form of hypertension in the elderly. Arterial stiffness, due in part to the calcification of large arteries, is accelerated by 15 years in diabetic patients. It is suggested that vascular calcification could be responsible for the resistance to anti-hypertensive agents in patients suffering from ISH, emphasizing the need of developing new therapies directly targeting vascular calcification.  The matrix Gla protein (MGP) is a vitamin K-dependent secretory protein post-transtionnaly modified by the enzyme γ-glutamyl-carboxylase. This post-translational modification renders MGP active, i.e. able to inhibit vascular calcification (cMGP). Another enzyme, the vitamin K oxidoreductase (VKOR) is necessary to ensure the recycling of vitamin K from the epoxide to hydroquinone, the form used by the γ-carboxylase. Recent studies have shown that vascular calcification is associated with increased levels of under-carboxylated MGP (ucMGP), and vitamin K deficiency. However, the modulation of the expression or the activity of the enzymes involved in γ-carboxylation, as well as the impact of this modulation is currently unknown. The goal of this research project was to study the mechanisms involved in the accelerated development of arterial stiffness in diabetes due to increased vascular calcification of large arteries. In a rat model of type 1 diabetes with increased arterial stiffness, we demonstrated that aortic MGP γ-carboxylation was altered. In fact, the amount of active MGP was reduced in the arterial wall, coupled with a marked reduction of γ-carboxylase expression. However, neither VKOR expression nor activity was modified.  This alteration of the γ-carboxylase was reproduced in an ex vivo model of hyperglycemia. In this model, vitamin K supplementation prevented the reduction of γ-carboxylase expression, whereas surprisingly, plasma levels of vitamin K were increased in diabetic rats compared to controls. The PKC signaling pathway has been identified as the pathway involved in the γ-carboxylase alteration. Our results provide multiple new research ideas. For instance, it would be important to study the effect of vitamin K supplementation in an animal model of diabetes-associated arterial stiffness, to gain insight into its impact on γ-carboxylase and MGP γ-carboxylation, and ultimately on vascular calcification. Moreover, it would be very interesting to determine the effect of molecules affecting the PKC pathway on vascular calcification in this model, which would allow for a better understanding of their therapeutic potential. Depending on the results of these experiments, we could have at our disposition new therapeutic options to prevent and treat vascular calcification, which would have the potential to slow down the acceleration of arterial stiffness in diabetic patients and reduce the cardiovascular risk associated with ISH.

Keyphrases: Vascular calcification, Arterial stiffness, Diabetes, Matrix Gla protein
Nanovecteurs pour cibler pseudomonas aeruginosa dans la fibrose kystique

The increased production of viscoid mucus in the lungs of cystic fibrosis (CF) patients hinders the diffusion of therapeutics and favor bacterial infections. Indeed, lung infection by Pseudomonas aeruginosa (PA) relates with increased mortality in CF patients. This work is aimed at developing new antibiotic loaded nanoparticles and liposomes formulations to eradicate PA in CF. Firstly, PEG-g-PLA and PLA-OH polymers were synthesized and characterized. Afterwards, the loading efficiency (LE) of tobramycin, colistin sulfate and levofloxacin was evaluated in PEG-g-PLA and/or PLA-OH nanoparticles (NP). Early stage of optimization showed that levofloxacin NP exhibited increased LE thus this drug was selected for further optimization. However, the highest levofloxacin LE accomplished was 0.02% w/w. Thus, we decided to evaluate the levofloxacin LE into liposomes (LP). In fact, levofloxacin LP exhibited drug loading of 8% w/w with a size and charge suitable for mucus penetration. Preliminary evaluation of free tobramycin, colistin sulfate and levofloxacin against PA showed that the biofilm test was not reproducible. However, the traditional test in the planktonic form of PA showed that the mucoid strain was susceptible to levofloxacin. Thus, we evaluated fresh LP (blank and loaded) and free levofloxacin formulations against the planktonic form of PA (mucoid and non-mucoid strains). Results showed that blank LP did not interfere with the bacterial growth. Loaded LP presented similar minimal inhibitory concentration (MIC) for the susceptible mucoid strain and half MIC for the resistant nonmucoid strain when compared to the free drug. To conclude, LP seemed more appropriate to encapsulate hydrophilic drugs than polymeric PEG-g-PLA nanoparticles. Also, levofloxacin loaded LP seemed to improve the treatment against resistant strain of PA when compared to the free drug. However, further studies need to be performed to conclude whether levofloxacin LP are a promising option for the treatment of CF.

Keyphrases: PEG-g-PLA, liposomes, Pseudomonas aeruginosa, biofilm, Antibiotics, polymeric nanoparticles, PEG-g-PLA, liposomes, Pseudomonas aeruginosa, biofilm, cystic fibrosis
Interactions médicamenteuses et réactions adverses aux soins intensifs: le rôle des sédatifs et des analgésiants

Critically ill patients suffer from co-morbid conditions that impact on their prognosis. Two problems complicate Intensive Care Unit (ICU) stay in 35-50% of patients and are potentially associated with sedatives: delirium, an acute confusional state, and 'iatrogenic' coma, when consciousness is altered pharmacologically. Establishing the association between these clinical syndromes and administering sedatives is key in planning effective prevention of these morbid complications. We studied iatrogenic delirium and coma in 100 ICU patients given midazolam and/or fentanyl, and tallied drug doses, measured plasma levels, genetic variations in metabolism and transport and inflammatory factors. Our data highlight the role drug-drug interactions play in iatrogenic coma, and refute the association between benzodiazepines and delirium. These results clarify the pathophysiology of delirium, corroborate the lack of delirium-benzodiazepine association with a benzodiazepine biological marker, i.e. serum levels, and open the debate as to which agents are useful for treating anxiety and delirium. Recent publications addressing benzodiazepine pharmacokinetics in critical care complement our data in the field of critical care sedation. A chapter on the importance of pharmacogenomics in intensive care, and a published pro-con debate as to benzodiazepine use in critical care are submitted in addition to the clinical study mentioned above as part of this master’s thesis.

Keyphrases: Coma, pharmacologie, cytochrome P-450, Delirium, Sedation, Critical Care or Intensive Care, adverse drug reaction, drug-drug interaction, Pharmacology, Opiates, Benzodiazepines
Feuillets pour un album didactique analyse de quatre œuvres dont 3 fugues et la Fantasia Quasi Variazione

The purpose of this document is to offer a detailed analysis of three fugues and a piece for orchestra, all of which were composed between 2013 and 2014, and who constitutes the summit of a compositionnal approach that was based on a gradation of difficulty in performance and writing. This analysis includes : A detailed explanation of the place these pieces occupy among the album, an explanation of the concept or concepts that underlayed these compositions and a detailed analyses of every section of every composition.

Keyphrases: Fugue, Composition, Analyse, Forms, Analysis, Orchestra
Etude des déterminants génétiques des psychoses à début précoce. Génétique de la schizophrénie et hypothèse glutamatergique

Schizophrenic disorders (SCZ) have high heritability (around 80%), but only a small part has been characterized. Most studies have focussed on common polymorphisms, each having small individual effect, whereas copy number variant and chromosomal abnormalities studies have pointed to the possible involvement of rare and de novo mutations with high penetrance. In the first part of this manuscript, we will present a synthesis on genetic factors of SCZ and then a review of the arguments supporting an involvement of glutamatergic system abnormalities in SCZ, which is the focus of our research. Our work is part of a global project, Synapse to Disease (S2D), that aimed to sequence 1000 synaptic genes in cohort of patients affected with schizophrenia or autism spectrum disorders. We focussed in particular on the glutamatergic system and NMDA receptors. In a first publication we show an association between SCZ and a de novo truncating mutation of kinesin 17, wich has been implicated in the transport of the GRIN2B subunit of NMDA receptors. In a second publication we explore rare and de novo mutations in NMDA receptor subunits. We show an association between de novo mutations in GRIN2A and GRIN2B with cases of SCZ and autism. Our results strengthen the idea that a portion of schizophrenia cases could be related to rare mutations having a high penetrance, an alternative but not contradictory explanation to the hypothesis for an interaction between common variants having a small effect.

Keyphrases: de novo, nmda, glutamate, mutation, genetic
Transient high level mammalian reovirus replication in a bat
epithelial cell line occurs without cytopathic effect

Mammalian reoviruses exhibit a large host range and infected cells are generally killed; however, most studies examined only a few cell types and host species, and are probably not representative of all possible interactions between virus and host cell. Many questions thus remain concerning the nature of cellular factors that affect viral replication and cell death. In the present work, it was observed that replication of the classical mammalian reovirus serotype 3 Dearing in a bat epithelial cell line, Tb1.Lu, does not result in cell lysis and is rapidly reduced to very low levels. Prior uncoating of virions by chymotrypsin treatment, to generate infectious subviral particles, increased the initial level of infection but without any significant effect on further viral replication or cell survival. Infected cells remain resistant to virus reinfection and secrete an antiviral factor, most likely interferon, that is protective against the unrelated encephalomyocarditis virus. Although, the transformed status of a cell is believed to promote reovirus replication and viral “oncolysis”, resistant Tb1.Lu cells exhibit a classical phenotype of transformed cells by forming colonies in semisolid soft agar medium. Further transduction of Tb.Lu cells with a constitutively-active Ras oncogene does not seem cell growth or reovirus effect on these cells. Infected Tb1.Lu cells can produce low-level of infectious virus for a long time without any apparent effect, although these cells are resistant to reinfection. The results suggest that Tb1.Lu cells can mount an unusual antiviral response. Specific properties of bat cells may thus be in part responsible for the ability of the animals to act as reservoirs for viruses in general and for novel reoviruses in particular. Their peculiar resistance to cell lysis also makes Tb1.Lu cells an attractive model to study the cellular and viral factors that determine the ability of reovirus to replicate and destroy infected cells.

Keyphrases: virus, reovirus, interferon, bat
Contribution du globus pallidus lors de la locomotion sous guidage visuel

The breadth of clinical studies on diseases affecting the basal ganglia (BG) showed the great degree of the motor deficits induced by a dysfunction of these structures. Locomotion is especially affected in these patients, suggesting a major role of the BG in its control. However, very few fundamental studies have recorded the activity of neurons in the BG during locomotion in intact models. The globus pallidus, as one of the main output structure of BG, is an ideal target for studying the signal transmitted by these nuclei to the thalamus and brainstem. The aim of our study is to better understand the contribution of the external segment of the globus pallidus (GPe) in the control of visually guided locomotion. This study is the first record of the activity of neurons in the GPe during visually guided gait modifications. Our general hypothesis is that the GPe contributes to the control of locomotion, preferentially during gait modifications. We recorded the activity of neurons in the GPe of cats at rest and then walking on a treadmill and stepping over obstacles. Our results indicated that most cells showed little change during unobstructed locomotion, in comparaison to resting activity. However, half of the recorded neurons showed a significant modulation of their discharge during the step over the obstacle. We observed a majority of these cells that decreased their frequency and a third of the neurons which increased their activity during the modified step, thus suggesting that the GPe has a context-dependant control over the movement, allowing the selective increase or decrease of the motor activity. Furthermore, most cells were modulated during the entire swing phase of the contralateral forelimb, suggesting a contribution of GPe in the timing and duration of this phase. Finally, half of the neurons showed a reciprocal change between the lead and the trail conditions. This result suggests that the GPe may be involved in the action selection of the limb during gait modifications. Our results thus illustrate the great complexity of the activity of GPe neurons during visually guided locomotion and they are compatible with a more general contribution of this structure to movement control than that exerted by the motor cortex.

Keyphrases: globus pallidus, gait modification, action selection, movement control
Implications des canaux K+ sur la régulation génique du canal ENaC, et impact de l'hyperglycémie sur le transport ionique et la réparation de l'épithélium respiratoire

During my Ph.D. training, I studied 3 important functions of respiratory epithelium : regulation of ion transport, liquid clearance and epithelial repair. I focused on potassium channels, because they control these three respiratory epithelial functions. First, I proved that αENaC promoter activity was regulated following K+ channel modulation, in alveolar cells. This regulation of αENaC promoter which might be through a modification of ERK1/2 phosphorylation, was followed by ENaC mRNA and protein expression regulation. I then showed that activation of KvLQT1 and KATP channels increased alveolar liquid clearance, whereas inhibition of these K+ channels decreased the alveolar clearance. I showed that the absence of KvLQT1 channel inhibited the amiloride-sensitive current (ENaC), in tracheal epithelial cells isolated from KvLQT1-KO mice. In the second part of my Ph.D. project, I studied the impact of hyperglycemia on Cystic Fibrosis (CF) and non-CF epithelial cells. I first observed that K+ and Cl- currents were reduced by hyperglycemia. Because we have previously shown that wound-healing process was dependant on K+ and Cl- channels, I then evaluated the impact of hyperglycemia on wound-healing. As expected, hyperglycemia slowed the repair rate of non-CF (CFBE-wt) and CF (CFBE-ΔF508) cell monolayers.

Keyphrases: KvLQT1, KvLQT1, KATP, KATP, ENaC, ENaC, MAPK, MAPK, CFTR, CFTR, DAFK, CFRD, SDRA, ARDS, Wound-healing, Alveolar clearance, Cystic Fibrosis
Impact du stress hyperoxique en période néonatale sur la structure vasculaire : implication des phénomènes de sénescence et rôle possible dans la programmation développementale de l'hypertension artérielle

The scope of this thesis is developmental programming of arterial high blood pressure (HBP) hypertension through early neonatal stimuli that may alter vascular development. Premature newborns have decreased antioxidant defenses compared to term babies and are exposed upon birth to high oxygen (O2) concentration, causing reactive oxygen species (ROS) production. Long term vascular consequences of ROS related damage during the neonatal period and the mechanisms involved remain unknown. Recent data from the laboratory show that neonatal hyperoxic stress leads in adult rat to HBP, endothelial dysfunction and arterial rigidity, characteristic features of vascular aging. We hypothesize that a neonatal hyperoxic stress leads to long term vascular structure alteration explained by an early aging of the vascular system.  We showed a decreased proliferation rate, an altered angiogenic capacity, as well as long term DNA damage and increased expression of senescence proteins at a vascular level following O2 exposure in the animal (male Sprague-Dawley pups kept at 80% O2 from postnatal days 3 to 10 vs. rats remained in room air) and cellular models (embryonic vascular smooth muscle cells from rat thoracic aorta exposed to 40% O2 for 24h or 48h followed by 96h recovery in control conditions). In addition, alterations of vascular structure components indicating vascular remodeling was shown before the onset of the HBP at adult age. Those changes precede the HBP and vascular dysfunction observed in our animal model at adult age and could contribute to them. Study of young adults born before 29 weeks vs. young adults born at term showed that young adults born preterm present indices of arterial stiffness vs. term controls.  Results of the present thesis demonstrate a major role of premature vascular aging in the surge of vascular diseases in adulthood and contribute to a better understanding of the patho-physiological mechanisms involved and could put into practice new prevention strategies among preterm patients.

Keyphrases: Hypertension, Hyperoxie, Arterial stiffness, Aging, Prematurity, Developmental programming, Hyperoxia
Regulation of BAP1 tumor suppressor complex by post-translational modifications

BAP1 is a nuclear deubiquitinating enzyme (DUB) that acts as a transcription regulator and a DUB of nucleosomal histone H2AK119. In the recent years, it has become clear that BAP1 is a major tumor suppressor, inactivated in a plethora of hereditary and sporadic human malignancies. Although, we now accumulated a significant body of knowledge in respect to the occurrence, penetrance and impact of BAP1 disruption in cancer, its mechanism of action and regulation remained poorly defined. This work is dedicated to the biochemical and functional characterization of the BAP1 multiprotein complex and presents one of the first cases regarding its regulation by post-translational modifications.  First, we defined the initial composition of the BAP1 complex and its main interacting components. Second, we specifically focused on two aspects of BAP1 regulation. We described the cross regulation between the two major components of the complex namely HCF-1 and OGT. We found that HCF-1 is important for the maintenance of the cellular levels of OGT. OGT, in turn, is required for the proper maturation of HCF-1 by promoting O-GlcNAcylation-mediated limited proteolysis of its precursor. Third, we discovered an intricate regulatory mechanism of BAP1 mediated by the atypical ubiquitin ligase UBE2O. UBE2O multi-monoubiquitinates BAP1 on its NLS and promotes its exclusion from the nucleus. Importantly, our work emphasises the role of the autocatalytic activity of both enzymes namely the auto-deubiquitination activity of BAP1, required for the maintenance of nuclear BAP1 and the auto-ubiquitination of UBE2O implicated in its nucleocytoplasmic transport. Significantly, we found that auto-deubiquitination of BAP1 is disrupted by cancer-associated mutations, indicating the involvement of this process in tumor suppression.

Keyphrases: Chromatine, O-GlcNAcylation, Ubiquitination, Cancer, O-linked beta-N-acetylglucosamine transferase, Chromatin, Epigenetic mark, Proteolytic processing, Ubiquitination, Deubiquitinase, Atypical ubiquitin ligase, Autocatalytic activity, Host cell factor 1, BRCA1-associated protein 1, UBE2O