La pathologie athéromateuse avec ses complications cardio-vasculaires reste aujourd'hui une des principales causes de mortalité dans les pays développés. Dans ce contexte, l'élaboration de nouveaux bio-marqueurs de la maladie athéromateuse occupe une place importante. Les objectifs de ces bio-marqueurs sont : de définir les populations les plus à risque de développer une complication cardio-vasculaire, de stratifier les groupes de patients de manière à optimiser leur prise en charge clinique et thérapeutique , de dévoiler de nouvelles cibles thérapeutiques dans le traitement de la pathologie. Dans ce contexte, nous avons ciblé trois bio-marqueurs d'intérêt à savoir la longueur des télomères leucocytaires (LTL) et le niveau d'expression leucocytaire des gènes c-Fos (impliqué dans les processus inflammatoires et oxydatifs) et OGG1 (nécessaire à la réparation des lésions oxydatives de l'ADN). Nous avons donc dans une première partie de ce travail voulu vérifier l'hypothèse selon laquelle la LTL pouvait être préservée par la prise régulière de statine, une thérapeutique ayant déjà démontré ses bienfaits en terme de prévention primaire et secondaire des maladies cardio-vasculaires. De plus, nous nous sommes intéressés aux possibles relations entre les niveaux d'expression des gènes c-Fos et OGG1 et la LTL. Nous nous sommes placés dans un contexte de patients à haut risque cardiovasculaire que représentent les patients en phase aigue de l'infarctus du myocarde (IDM). Ce travail a permis de montrer que la prise régulière de statine pouvait préserver la longueur des télomères leucocytaires et ce particulièrement chez les sujets les plus jeunes (moins de 64 ans), suggérant un nouvel effet " pléïotrope " des statines. Ce travail a également permis d'identifier les gènes c-Fos et OGG1 comme étant des acteurs potentiels du maintien de l'intégrité des télomères. La seconde partie de notre travail a porté sur une étude plus approfondie du niveau de transcription du gène c-Fos en relation avec l'un des principaux facteurs de risque de la maladie athéromateuse que représente le statut tabagique chez des patients présentant une maladie coronaire. Ce travail a permis de mettre en évidence pour la première fois une relation entre le niveau d'expression de c-Fos et le statut tabagique des sujets, suggérant que l'une des voies possibles de toxicité du tabac pourrait faire intervenir les voies de signalisations impliquant c-Fos. Ainsi, ce travail de thèse a permis de mettre en évidence trois bio-marqueurs intéressants dans le domaine de la pathologie athéromateuse : 1- La longueur des télomères leucocytaires qui peut être une des voies d'action bénéfique des statines en prévention précoce des maladies cardio-vasculaires, 2- Le niveau d'expression du gène OGG1 comme étant un des acteurs potentiels du maintien de l'intégrité des télomères, 3- Le niveau d'expression du gène c-Fos comme marqueur cumulatif d'exposition tabagique et potentiel acteur des effets délétères du tabac. Restent à préciser les mécanismes cellulaires et moléculaires mis en jeu et ainsi développer des stratégies thérapeutiques adéquates afin d'optimiser la prise en charge des patients souffrant de pathologies athéromateuses.

Rationale: Peak initiation of smoking occurs during adolescence and early onset of smoking is associated with a reduced probability of quitting and greater risk of relapse compared to later onset. Considering the epidemiological evidence, adolescents may exhibit a unique biological susceptibility to nicotine taking, in addition to the behavioural and psychosocial factors known to influence adolescent smoking. Objectives: The current series of experiments, using a rat model of adolescent nicotine taking, was designed to investigate age differences in the processes involved in the acquisition and maintenance of nicotine taking that might account for the elevated initiation rates of smoking during adolescence. Methods: We first investigated age differences in the neural response to acute nicotine administration using c-fos mRNA expression. We then examined age differences in the rewarding and aversive effects of nicotine in the conditioned place preference (CPP) and conditioned taste avoidance (CTA) paradigms, respectively. The direct reinforcing effects of nicotine were tested in adolescent and adult rats under a variety of reinforcement schedules in the operant intravenous self-administration paradigm; extinction and nicotine priming-induced reinstatement were also examined. Finally, age differences in nicotine withdrawal precipitated by mecamylamine were assessed. Results: Nicotine had greater activational effects on c-fos mRNA expression in reward-related neural substrates of adolescent compared to adult brain. Adolescent rats were also more sensitive to the rewarding effects of nicotine (CPP) yet less sensitive to its aversive effects (CTA) compared to adult rats. Nicotine was equally reinforcing in adolescents and adults self-administering under simple reinforcement schedules, but adults were more motivated to obtain nicotine under higher reinforcement schedules. Adults were more resistant to extinction, yet both age groups demonstrated similar priming-induced reinstatement of nicotine seeking. Under spontaneous acquisition conditions, adults were more sensitive to the reinforcing effects of a low nicotine infusion dose. The aversive effects of nicotine withdrawal were also more prominent in adults compared to adolescents. Conclusions: These findings have important implications since they demonstrate a unique susceptibility to the conditioned rewarding effects of nicotine that would promote acquisition of smoking behaviour during adolescence, whereas adults may be more vulnerable to processes involved in its maintenance.

近年隨著經濟發展，金融商品之設計日新月異，逐漸打破以往銀行、保險、証劵等行業之區分，金融業者對於其服務逐漸朝向一元化發展。而為因應金融產業之變革，金融監理似乎亦有朝向一元化之趨勢，因此相關監理層面之整合即為客不容緩之要事。 惟我國於金融消費者保護法通過施行前，對於金融消費爭議之各種處理機制尚未統之，因此有管道多元而使消費者無所適從，社會資源浪費、處理程序過長以及品質無法監管等種種問題。而此一問題，於2008年雷曼兄弟倒閉，引發國內多數投資人之損失，並於尋求救濟時產生許多爭議，使前開缺失一一浮上檯面。 本文介紹歐盟替代性紛爭解決機制(ADR)之發展，包含調解人與公評人之相關準則與原則。以及歐盟專門處理金融消費爭議之平台(FIN-NET)之運作方式，並統整FIN-NET各個會員間之制度，觀察其制度內容及差異，進行歸納統整。再以歐盟主要國家，德國、英國與法國之金融消費爭議處理機制為主，對於各國之其制度加以介紹，並進行制度面之比較分析。並藉此評析金融消費者保護法之爭議處理機構。 最後本文認為，我國之爭議處理機構制度上已相當完整，除將各個產業整合由單一爭議處理機構處理外，亦已改善過去部分機構欠缺法律基礎而無資料調閱權限，以及無法中斷時效等之缺失。如同歐盟之多數國家，消費者均無需付費值得肯定，惟若制度運作後濫訴及客訴黃牛之情況嚴重，可仿效歐盟各國向消費者收取部分費用，並給予金融機構每年前三個案件無需收費之優惠。另外，評議有關一定金額拘束力之設計方式，與英國之制度仍有不同，將可能導致評議機制欠缺實效。再者要求消費者親自陳述意見與親自參加調處，雖違反代表原則，然既係在避免有客訴黃牛之情況故尚可容許。且違反資料調閱權之效果倘能有實體法上之效果或許更能幫助紛爭之解決。而能增加當事人對爭議處理機制之損害賠償請求權，惟於違反金保法之人員有故意或重大過失時爭議處理機構對之有內部求償權。最後，仍欠缺就爭議處理品質面之監督機制，亦仍有改善之空間。

Ο καρκίνος της ουροδόχου κύστης είναι η τέταρτη συχνότερη κακοήθεια στους άνδρες και η δέκατη στις γυναίκες και η ετήσια επίπτωσή του αυξάνει συνεχώς στις ανεπτυγμένες χώρες. Oι προγνωστικοί παράγοντες που χρησιμοποιούνται σήμερα δεν μπορούν να προβλέψουν με βεβαιότητα την μακροπρόθεσμη έκβαση του ουροθηλιακού καρκίνου και έτσι προκύπτει η ανάγκη αναγνώρισης δεικτών με δυνατότητα πρόγνωσης της συμπεριφοράς των καρκινωμάτων. Επιπλέον, δεδομένων των περιορισμένων δυνατοτήτων των σημερινών θεραπευτικών επιλογών (χειρουργική αντιμετώπιση, χημειοθεραπεία ή ανοσοθεραπεία και ακτινοθεραπεία), απαιτούνται νέες θεραπευτικές στρατηγικές. Μία τέτοια στρατηγική είναι η στόχευση σε μεταγραφικούς παράγοντες όπως οι πυρηνικοί υποδοχείς και οι upstream ενεργοποιητές τους. Η διαταραχή αυτών των μεταγραφικών παραγόντων είναι κομβικό σημείο της έναρξης και διατήρησης του κακοήθους φαινοτύπου. O πυρηνικός υποδοχέας PPARγ εμπλέκεται στον έλεγχο του μεταβολισμού, την κυτταρική ανάπτυξη, την αγγειογένεση και την ανοσολογική και φλεγμονώδη απάντηση. Επιπρόσθετα, υπάρχουν ενδείξεις ότι ρυθμίζει τους μηχανισμούς καταστολής αλλά και προαγωγής της καρκινογένεσης. Ο RXRα είναι επίσης μέλος της υπεροικογένειας των πυρηνικών υποδοχέων και ετεροδιμερίζεται με τον PPARγ προς σχηματισμό του συμπλόκου που αλληλεπιδρά με το DNA. Οι προσδέτες των RXR υποδοχέων έχουν ήδη χρησιμοποιηθεί στη χημειοπρόληψη διαφόρων μορφών καρκίνου. Ο μεταγραφικός παράγoντας AP-1, απαρτίζεται από διμερή των Fos και Jun πρωτεϊνών και η δράση του σχετίζεται με την πρόοδο της καρκινογένεσης. Υπάρχουν πάντως και ενδείξεις για προ-αποπτωτική δράση του. Η CBP είναι ένας απ’ τους σημαντικότερους ολοκληρωτές σημάτων της μεταγραφής. Ο ανταγωνισμός μεταξύ των PPARγ και AP-1 για τη CBP είναι ένας απ’ τους μηχανισμούς που εξηγούν την αρνητική «συνομιλία» (cross-talk) μεταξύ των PPARγ και AP-1. Στην παρούσα μελέτη εξετάσαμε τόσο ξεχωριστά όσο και σε συνδυασμό μεταξύ τους, την έκφραση των πέντε μοριακών παραγόντων (PPARγ, RXRα, p-c-Jun, c-Fos, CBP) στο φυσιολογικό ουροθήλιο, τις προκαρκινικές αλλοιώσεις και τα ουροθηλιακά καρκινώματα (ΟΚ). Τα ιστικά δείγματα προήλθαν από 88 ασθενείς οι οποίοι υπέστησαν διαγνωστική βιοψία ή θεραπευτική κυστεκτομή, νεφρεκτομή ή ουρητηρεκτομή. Εφαρμόστηκε η ανοσοϊστοχημική μέθοδος σε τομές παραφίνης και εκτιμήθηκε η σχετική έκφραση των μελετώμενων παραγόντων στα ενδοκυττάρια διαμερίσματα, τις ενδοεπιθηλιακές στιβάδες και τις φυσιολογικές ή παθολογικές ιστολογικές βαθμίδες. Όλοι οι παράγοντες παρουσίασαν κυρίως πυρηνική εντόπιση. Η έκφραση του p-c-Jun ελαττώνεται στους ασθενείς άνω των 70 ετών σε σχέση με τους νεώτερους, ενώ κανένα άλλο απ’ τα μελετώμενα μόρια δε φαίνεται να επηρεάζεται από την ηλικία. Η έκφραση των PPARγ, CBP, p-c-Jun και c-Fos σημειώνει αύξηση κατά την πορεία προς τον καρκίνο. Όσο αφορά στα ΟΚ, οι PPARγ και CBP παρουσιάζουν αρνητική συσχέτιση με την αποδιαφοροποίηση. Επιπλέον ο PPARγ συσχετίζεται αρνητικά με την απόκτηση χαρακτήρων διήθησης στα ΟΚ. Αντιθέτως, η έκφραση του RXRα δεν διακυμαίνεται στατιστικώς σημαντικά σε όλη την πορεία της καρκινογένεσης. Η ανάλυση της συνδυασμένης έκφρασης των πέντε παραγόντων έγινε με σκοπό την αποκάλυψη ενδεχόμενων αλληλεπιδράσεων μεταξύ τους. Η προστατευτική δράση του PPARγ στο ουροθήλιο συνοδεύεται από ταυτόχρονη μέτρια ή ισχυρή έκφραση των RXRα, p-c-Jun και c-Fos. Αναλυτικά, η αυξανόμενη έκφραση του p-c-Jun συμπίπτει με ενίσχυση της θετικής συσχέτισης του PPARγ με καλύτερα διαφοροποιημένους, λιγότερο διηθητικούς όγκους, ενώ ο c-Fos φαίνεται να εξασθενίζει ήπια την ευνοϊκή δράση του PPARγ στη διαφοροποίηση του ουροθηλίου. Η αυξανόμενη έκφραση της CBP έδειξε να εξασθενίζει και τελικά να εκμηδενίζει τη στατιστικά σημαντική αύξηση του PPARγ στην πορεία προς τον καρκίνο και την επαγωγή του στους μη διηθητικούς όγκους σε σύγκριση με τους διηθητικούς. Ταυτόχρονα, η αρνητική σχέση της CBP με την αποδιαφοροποίηση και την αύξηση της κακοήθειας των ΟΚ επηρεάζεται από την παρουσία των PPARγ και AP-1, επιβεβαιώνοντας την υπόθεση της συνομιλίας αυτών των μοριακών παραγόντων. Ενδιαφέρουσα είναι η παρατήρηση ότι οι περισσότερες από τις αναφερθείσες πιο πάνω συσχτίσεις μεταξύ των μοριακών παραγόντων ίσχυαν για μεγαλύτερους των 70 ετών αλλά όχι πάντα για τους νεώτερους ασθενείς. Τα αποτελέσματα της παρούσας μελέτης μπορούν πιθανόν να οδηγήσουν σε συμπεράσματα με εφαρμογή σε χημειοπροληπτικές και θεραπευτικές στρατηγικές για τον ουροθηλιακό καρκίνο. / Bladder cancer is the fourth and tenth most common malignancy in men and women, respectively, and its incidence is increasing annually in the developed countries. Current prognostic parameters cannot predict with certainty the long-term outcome of bladder cancer and as a result there is a need to identify markers that may predict tumor behavior. Furthermore, given the limitations of current therapeutic options (surgery, chemotherapy or immunotherapy and radiotherapy), novel treatment strategies are very much needed. One such strategy targets transcription factors such as nuclear receptors and their upstream activators. Disruption of these transcription factors is a key element in the initiation and maintenance of a malignant phenotype. The nuclear receptor PPARγ is involved in controlling metabolism, cell growth, angiogenesis, and immune and inflammatory responses. In addition, it has also been suggested that it regulates tumor suppression as well as tumor promotion. RXRα is another member of the nuclear receptor superfamily, that partners PPARγ to form the DNA-binding complex. RXR ligands are already being used as chemopreventive agents in various types of cancer. The transcription factor AP-1 is formed by dimerization of Jun and Fos proteins and its activity is often associated with tumor progression. On the other hand, there is also evidence that AP-1 may enhance apoptosis. CBP is one of the most important transcriptional integrators. The competition of PPARγ and AP-1 for CBP is one of the multiple mechanisms that explain the negative PPARγ/AP-1 cross-talk. In the present study, we assessed separate and concurrent expression of the five factors (PPARγ, RXRα, p-c-Jun, c-Fos, CBP) in normal urothelium, precancerous lesions and urothelial carcinomas (UC). Clinical samples were derived from 88 patients who had undergone diagnostic biopsy or therapeutic excision of the bladder, the kidney or the ureter. Parafin section immunohistochemistry was utilized and relative expression was estimated in intracellular compartments, intraepithelial layers and histologic categories of urothelium. All five factors had mainly nuclear pattern of expression. P-c-jun was downregulated in patients older than 70 years old compared to younger ones, whereas age did not affect the expression of the rest four factors. PPARγ, CBP, p-c-Jun and c-Fos were upregulated towards tumorigenesis. PPARγ and CBP showed an inverse relationship with carcinoma level of differentiation. Moreover, PPARγ expression downregulated significantly in invasive tumors compared to non-invasive ones. On the contrary, RXRα expression did not vary significantly along the carcinogenesis course. The following correlations were based on coexpression analysis to reveal molecular interactions between the five factors. The established protective effect of PPARγ on urothelium was accompanied by concomitant RXRα, p-c-Jun and c-Fos moderate or strong expression. In detail, p-c-Jun’s increasing expression strengthened the positive relation of PPARγ with better differentiated, less invasive tumors, whereas c-Fos seemed to mildly lessen PPARγ’s favourable effect in urothelium differentiation. Statistically significant PPARγ upregulation in malignant tissues compared to normal urothelium and in non-invasive tumors compared to invasive ones is suppressed and finally cancelled by CBP’s increasing expression. PPARγ and AP-1 seemed to influence the negative relation of CBP with loss of differentiation and increase of malignant potential in UC, an observation that denotes a cross-talk between these molecular factors. Interestingly, most of the aforementioned correlations were noticed in patients older than 70 years old, but not all of them were plausible in younger patients. The results from the present study could lead to conclusions possibly applicable in chemoprevention and therapy strategies for urothelial carcinomas.

Circadian system of mammals is generated in suprachiasmatic nuclei of hypothalamus. This system is synchronized with light conditions through phase shifts that occur after light exposition during the subjective night. Recent studies have shown that activation of endocannabinoid receptors attenuates the light-induced phase shifts and influences the ability of circadian system to light entrainment. The aim of this work is to examine this influence on behavioral level and on light-reactive cellular processes within the suprachiasmatic nuclei. Our results show that the activation of endocannabinoid system via CB1 receptor agonist modulates the light-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and the expression of c-Fos protein in neurons of suprachiasmatic nuclei in the rat's brain; these cellular processes correlate with the attenuation of light entrainment. Keywords: circadian system, suprachiasmatic nuclei, light entrainment, endocannabinoid system, CB1 receptors, extracellular signal-regulated kinase 1/2, ERK1/2, c-Fos

A bacterial and archaeal adaptive immune system, clustered regularly interspaced short palindromic repeats and CRISPR-associated proteins (CRISPR-Cas), has recently been engineered for genome editing. This RNA-guided platform has simplified genetic manipulation and holds promise for therapeutic applications. However, off-target editing has been one of the major concerns of the commonly used Streptococcus pyogenes Cas9 (SpyCas9). Despite extensive enzyme engineering to reduce off-target editing of SpyCas9, we have turned to nature and uncovered a Cas9 ortholog from Neisseria meningitidis (Nme) with high fidelity. In the first part of my thesis, we have systematically characterized Nme1Cas9 for engineering mammalian genomes and demonstrated its high specificity by genome-wide off-targeting detection methods in vitro and in cellulo, and thus provided a new platform for accurate genome editing. Due to its flexibility, CRISPR is becoming a versatile tool not only for genome editing, but also for chromatin manipulation. These alternative applications are possible because of the programmable targeting capacity of catalytically dead Cas9 (dCas9). In the second part of my thesis, we have combined dCas9 with the engineered plant enzyme ascorbate peroxidase (APEX2) to develop a proteomic method called dCas9-APEX2 biotinylation at genomic elements by restricted spatial tagging (C-BERST). Relying on the spatially restricted, fast biotin labeling of proteins near defined genomic loci, C-BERST enables the high-throughput identification of known telomere- and centromere- associated proteomes and novel factors. Furthermore, we have extended C-BERST to map the c-fos promoter and gained new insights regarding the dynamic transcriptional regulation process. Taken together, C-BERST can advance our understanding of chromatin regulators and their roles in nuclear and chromosome biology.

No description available.

<p> One primary focus on internal combustion engines is that these engines create multiple harmful exhaust gases that can cause damage to the environment. There are a number of advanced strategies that are currently being investigated to help reduce the amount of these harmful emissions that are emitted from IC engines. One such method of reducing harmful emission gases focuses on the three-way-catalyst. A three-way-catalyst (TWC) is an exhaust emission control device that is designed in such a way to take harmful exhaust gases and convert them into less harmful gases through various chemical reactions within the TWC. To help further the reduction of these harmful gases in the TWC, a novel two-loop control and estimation strategy is used. This control and estimation strategy involves the use of two loops with an inner-loop controller, outer-loop robust controller, and an estimator in the outer-loop. The estimator consists of a TWC model and an extended Kalman filter which is used to estimate the fractional oxidation state (FOS) of the TWC. This estimated FOS is then used by the robust controller, along with other parameters, to produce a desired engine lambda reference signal, λup. This desired lambda signal is then used by the inner-loop controller to control the engine lambda. Accurate control of lambda is important because the air-fuel-ratio range for a TWC to effectively achieve oxidation and reduction simultaneously is extremely narrow. Another primary focus in the field of internal combustion engines is designing and tuning advanced models within GT-Power that can accurately predict what will happen when running an actual engine. Designing, troubleshooting, and testing a GT-Power model is an extensive but rewarding process. Creating an accurate engine model can not only provide one with primary engine data that is also measurable in a test cell, but can also provide insight into some of the intricate processes and nature of the engine that are difficult or impossible to physically measure. Cummins has an extensive process of tuning GT-Power engine models. This process include items such as initial model calibrations, model discretizations, turbocharger tunings, and other items. Some of these processes are used to calibrate both Cummins Power Systems Business Unit engines as well as a Purdue B6.7N natural gas engine. </p>

Nitric oxide (NO) is an important biological molecule within the body, which over production of this molecule in response to different stimulations can cause various inflammatory diseases. Over production of this molecule is caused by the induction of the inducible nitric oxide synthase (iNOS) enzyme. This enzyme uses L-arginine as a substrate and therefore the presence and transport of this amino acid into the cells can be a key factor in regulating NO over production. Different signalling mechanisms have been implicated in the regulation of this pathway and one of which involves the Mitogen Activated Protein Kinases (MAPK). This family of proteins respond to inflammatory conditions and may mediate effects induced by inflammatory mediators. Of the MAPKs, the role of the c-Jun-N-terminal kinase (JNK) pathway in the induction of iNOS is still controversial. JNK and its downstream target, the transcription factor Activator Protein-1 (AP-1), have shown contradictory effects on iNOS induction leading to controversies over their role in regulating iNOS expression in different cell systems or with various stimuli. The studies described in this thesis have determined the role of JNK/AP-1 on iNOS expression, NO production, L-arginine uptake and also on the transporters responsible for L-arginine transport into the cells. The studies were carried out in two different cell types: rat aortic smooth muscle cells (RASMCs) and J774 macrophages which are both critically associated with the over production of NO in vascular inflammatory disease states. The first approach was to block the expression of the inducible L-arginine-NO pathway using SP600125 and JNK Inhibitor VIII which are both pharmacological inhibitors of JNK. The results from these studies showed that the pharmacological intervention was without effect in RASMCs, but inhibited iNOS, NO and L-arginine transport in J774 macrophages. In contrast, the molecular approach employed using two dominant negative constructs of AP-1 (TAM-67 and a-Fos) revealed a different profile of effects in RASMCs, where a-Fos caused an induction in iNOS and NO while TAM-67 had an inhibitory effect on iNOS, NO, L-arginine transport and CAT-2B mRNA expression. The latter was unaffected in RASMCs but suppressed in J774 macrophages by SP600125. Examination of JNK isoforms expression showed the presence of JNK1 and 2 in both cell systems. Moreover, stimulation with LPS/IFN- or LPS alone resulted in JNK phosphorylation which did not reveal any difference between smooth muscle cells and macrophages. In contrast, expression and activation of AP-1 subunits revealed differences between the two cell systems. Activation of cells with LPS and IFN- (RASMCs) or LPS alone (J774 macrophages) resulted in changes in the activated status of the different AP-1 subunit which was different for the two cell systems. In both cell types c-Jun, JunD and Fra-1 were increased and in macrophages, FosB activity was also enhanced. Inhibition of JNK with SP600125 caused down-regulation in c-Jun in both cell types. Interestingly this down-regulation was in parallel with increases in the subunits JunB, JunD, c-Fos and Fra-1 in RASMCs or JunB and Fra-1 in J774 macrophages. Since, SP600125 was able to exert inhibitory effects in the latter cell type but not in RASMCs, it is possible that the compensatory up-regulation of certain AP-1 subunits in the smooth muscle cells may compensate for c-Jun inhibition thereby preventing suppression of iNOS expression. This notion clearly needs to be confirmed but it is potentially likely that hetero-dimers formed between JunB, JunD, c-Fos and Fra-1 could sustain gene transcription in the absence of c-Jun. The precise dimer required has not been addressed but unlikely to exclusively involve JunB and Fra-1 as these are up-regulated in macrophages but did not sustain iNOS, NO or induced L-arginine transport in the presence of SP600125. To further support the argument above, the dominant negatives caused varied effects on the activation of the different subunits. a-Fos down-regulated c-Jun, c-Fos, FosB, Fra-1 whereas TAM-67 reduced c-Jun and c-Fos but marginally induced Fra-1 activity. Associated with these changes was an up-regulation of iNOS-NO by a-Fos and inhibition by TAM-67. Taken together, the data proposes a complex mechanism(s) that regulate the expression of the inducible L-arginine-NO pathway in different cell systems and the complexity may reflect diverse intracellular changes that may be different in each cell type and not always be apparent using one experimental approach especially where this is pharmacological. Moreover, these findings strongly suggest exercising caution when interpreting pure pharmacological findings in cell-based systems particularly where these are inconsistent or contradictory.

Ce travail s’inscrit dans le cadre de la didactique du Français sur Objectifs Universitaire. Il porte sur l’accueil des étudiants de nationalité étrangère en mobilité en France et les difficultés qu’ils rencontrent pour leur intégration dans le système universitaire français. L’objectif de ce travail est d’analyser les difficultés ressenties par d'étudiants en mobilité en France dans le cadre de leur parcours universitaire. Ces difficultés peuvent être liées aux dimensions linguistiques, culturelles et à l’organisation du système universitaire. Par ailleurs, ce travail cherche à donner des pistes et des alternatives pour améliorer l’intégration d'étudiants de nationalité étrangère en France ; donc nous avons essayé de proposer les bases pour l'élaboration d’un programme de Français sur Objectifs Universitaires (FOU) visant à préparer d'étudiants à l’acquisition de compétences langagières, disciplinaires et méthodologiques de la vie universitaire à partir de l’analyse de leurs besoins spécifiques. / This work is part of the pedagogy of “French as Foreign Language”, and more specifically French for university purpose. It focuses on the reception of foreign students who moved to France and are having difficulties relating to their integration into the French university system.The objective of this work was to analyze the difficulties felt by international students studying in France as part of their university career. The most difficulties were related to linguistic, cultural and organizational aspects of the university system..This work gives leads and alternatives to improve the integration of foreign students in French universities. There fore we propose basis for the development of a program for French university purpose aimed at preparing students to acquire linguistic, disciplinary and methodological skills for university life due to an analysis of their specific needs.