The purpose of the thesis is to explore the role of BMP signaling in developing vertebrate midbrain. BMP signaling plays important roles in various tissues and stages of neural development to regulate cell fate, proliferation, differentiation, morphogenesis and more. We observed that several major BMPs are expressed not only at the roof plate but also the floor plate of the midbrain. This has led us to ask the role of BMP signaling in dorsal and ventral midbrain patterning. Despite ventral experiments, we found that BMP signaling does not regulate ventral cell fate specification in the midbrain. Instead BMPs profoundly influence the shape and early morphogenesis of the midbrain neural plate as it closes into a neural tube. During neural tube closure, one of the early events occurring at the ventral midline is median hinge point (MHP) formation. Failure to form MHP leads to neural tube closure defects, the 2nd most common birth defects in humans. However, the molecular mechanisms underlying MHP formation are not well known. We found that the lowest BMP signaling occurs at the MHP during early neurulation and BMP blockade is necessary and sufficient for MHP formation. Interestingly, we also demonstrated that BMP blockade directs MHP formation by regulating the apicobasal polarity pathway and this regulation may be mediated by biochemical interactions between pSMAD5 and the apical protein, PAR3. Additionally, our time-lapse data suggest that BMP blockade slows cell cycle progression by increasing duration of G1 to S transition and S phase which leads cell nuclei stay at the basal location longer. This mimics basal nuclear migration seen at the MHP where low BMP signaling occurs. Thus, we conclude that BMP signaling regulates neural tube closure via the apicobasal polarity pathway and in a cell cycle dependent manner at the ventral midline. We observed that BMP signaling is necessary and sufficient for the dorsal cell fate specification in a context-dependent manner and ventral BMP signaling affects dorsal cell fates. Taken together, we propose the idea that BMP signaling has distinct roles in different contexts. BMPs regulate tissue morphogenesis in the ventral midbrain and dorsally cell fate specification. / text

Η ηπατική εγκεφαλοπάθεια είναι ένα σύνθετο νευροψυχιατρικό σύνδρομο το οποίο εκδηλώνεται κυρίως σε συνθήκες ηπατικής κίρρωσης. Διάφορες παθολογικές και τοξικές καταστάσεις μπορεί να επηρεάσουν την ηπατική λειτουργία σε τέτοια βαθμό ώστε να προκληθεί ηπατική εγκεφαλοπάθεια. Το οξειδωτικό στρές έχει ενεπλακεί σε διάφορες μελέτες στην παθογένεση της ηπατικής εγκεφαλοπάθειας. Επιπλέον, η ανάπτυξη αυξημένου οξειδωτικού στρές υπό την επίδραση αποφρακτικού ικτέρου έχει μετρηθεί σε διάφορα όργανα πειραματοζώων, συμπεριλαμβανομένου και του εγκεφάλου. Ο σκοπός της παρούσας μελέτης ήταν να ανιχνεύσει της αλλαγές στις αποφρακτικές συνδέσεις των τριχοειδικών αγγείων του εγκεφάλου που συσχετίζονται με την οκκλουδίνη. Για να το επιτύχουμε αυτό χρησιμοποιήσαμε ένα μοντέλο απολίνωσης του κοινού χοληδόχου πόρου (BDL) σε πειραματόζωα (αρουραίους). Στο πείραμα 1 η έκφραση της οκκλουδίνης εκτιμήθηκε μέσω της μεθόδου ποσοτικοποίησης κατά Westernblot. Σε αυτό το πείραμα χρησιμοποιήθηκαν πέντε (BDL) και πέντε ψευδώς χειρουργηθέντα πειραματόζωα (sham). Τα πειραματόζωα θανατώθηκαν δέκα ημέρες μετα το χειρουργείο. Στην κατά Westernblot ποσοτικοποίηση παρατηρήθηκε μεγάλη μείωση της ποσότητας της οκκλουδίνης στα BDL πειραματόζωα σε σχέση με τα sham. Στο πείραμα 2 χρησιμοποιήθηκαν εννέα BDL και εννέα sham πειραματόζωα. Τρία πειραματόζωα από τις δύο παραπάνω ομάδες θανατώθηκαν την πρώτη, την πέμπτη και τη δέκατη μετεγχειρητική ημέρα. Τα επίπεδα οκκουδίνης σε αυτά τα πειραματόζωα συσχετιστήκαν με τις τιμές τηςinvivo μέτρησης των ελευθέρων ριζών οξυγόνο. Τα αποτελέσματα ανέδειξαν ότι η τιμή της οκκλουδίνης στα BDL ζώα ήταν σημαντικά μειωμένη σε σχέση με τα sham όλες τις χρονικές στιγμές που έγιναν οι μετρήσεις, ενώ οι χαμηλότερες τιμές καταγράφηκαν στα πειραματόζωα που παρέμειναν υπό αποφρακτικό ίκτερο για δέκα ημέρες. Επιπλέον καταδείχθη ότι η χρονικά συσχετιζόμενη μείωση των επιπέδων της οκκλουδίνης στα ενδοθηλιακά κύτταρα του εγκεφάλου συσχετίζεται με τα αυξανόμενα επίπεδα ελευθέρων ριζών οξυγόνου της ημέρες μετά το χειρουργείο, φανερώνοντας τη σχέση μεταξύ αυτών των δύο φαινομένων. Συμπερασματικά, η παρούσα μελέτη πρώτη παραθέτει στοιχεία που προτείνουν την εμπλοκή της οκκλουδίνης στην παθοφυσιολογία της ηπατικής εγκεφαλοπάθειας σε συνθήκες εξωηπατικής χολόστασης. Αυτό γίνεται μέσω της μείωσης των επιπέδων τις οκκλουδίνης στις αποφρακτικές συνδέσεις των ενδοθηλιακών κυττάρων του εγκεφάλου υπο την επίδραση του χολοστατικού ικτέρου, η οποία οδηγεί σε άρση του αιματο-εγκεφαλικού φραγμού. / Hepatic encephalopathy in a complicate neuro-psychiatric syndrome which is common under hepatic cirrhosis. Various pathological and toxic lesions can deteriorate liver function in such way, so hepatic encephalopathy can be inflicted. Oxidative stress is involved in pathogenesis of hepatic encephalopathy in several protocols. Moreover the development of increased oxidative stress in the context of obstructive cholestasis has been proven in various rats' organs including the brain. The present study aimed to detect alterations of tight junction-associated occludin in rat brain capillaries. To accomplish that we have used a rats bile duct ligation experimental model (BDL). In experiment 1, occludin expression was evaluated by Western blot analysis. In this experiment were used five BDL and five sham rats. The experimental animals were sacrificed ten days after the operation. Western blot analysis revealed significant decrease of occlidins amount in BDL rats compared to the sham rats. In experiment 2, nine BDL and nine sham animals were used. Three animals from each group were sacrificed during the first, fifth and tenth post-operate day. The results of occludin level to these animals were associated with the in vivo superoxide radical production. The results indicated that occludin level in BDL animals, as opposed to sham-operated, was significantly reduced at every time point studied, being lowest in the rats remaining on BDL condition for 10 days. Moreover, it was demonstrated that the time-dependent reduction of occludin level in the brain endothelial was significantly correlated with the time dependent increase of brain superoxide radical level, implying a relationship between these two abnormalities. In conclusion, the evidence presented herein suggests for first time the implication of occludin in pathophysiology of hepatic encephalopathy under extra-hepatic cholestasis. This phenomenon occur due to the reduce of occludin level to cerebral endothelial cells’ tight junctions under cholestatic jaundice, which drives to lift of brain-blood barrier.

Ο αιματο-εγκεφαλικός φραγμός (ΑΕΦ) παίζει έναν καθοριστικό ρόλο στην ομοιόσταση του Κεντρικού Νευρικού Συστήματος. Οι στενοσύνδεσμοι (TJ) των ενδοθηλιακών κυττάρων των εγκεφαλικών τριχοειδών συνεισφέρουν σημαντικά στη λειτουργία του ΑΕΦ περιορίζοντας την παρακυτταρική διάχυση. Η οκλουδίνη, μια διαμεμβρανική πρωτεΐνη, αποτελεί μείζον συστατικό των TJ και παίζει σημαντικό ρόλο στη ρύθμιση της λειτουργίας τους. Το οξειδωτικό στρες αποτελεί κοινό χαρακτηριστικό πολλών νευροεκφυλιστικών και νευροφλεγμονωδών παθήσεων και η δυσλειτουργία των TJ με τη συνοδό διαταραχή του ΑΕΦ, συνδέονται με αυτό. Το αυξημένο οξειδωτικό φορτίο στα πλαίσια της αποφρακτικής χολόστασης έχει αποδειχθεί σε διάφορα όργανα αρουραίων μεταξύ των οποίων και ο εγκέφαλος. Στην παρούσα μελέτη χρησιμοποιήθηκε ένα πειραματικό μοντέλο αρουραίων με απολίνωση του χοληδόχου πόρου (BDL), για να εξεταστεί η επίδραση της χολόστασης στην εντόπιση της οκλουδίνης στο ενδοθήλιο εγκεφαλικών τριχοειδών με τη χρήση ηλεκτρονικού μικροσκοπίου. Αρσενικοί αρουραίοι Wistar χωρίστηκαν τυχαίως σε δύο ομάδες. Ομάδα Ι ψευδώς χειρουργημένοι αρουραίοι και ομάδα ΙΙ αρουραίοι που υπεβλήθησαν σε απολίνωση χοληδόχου πόρου (BDL) και οι δύο την ίδια ημέρα 0. Την 10η μετεγχειρητική ημέρα, όλα τα επιζήσαντα ζώα θυσιάστηκαν δια αποκεφαλισμού. Μετά από κατάλληλη προετοιμασία για σήμανση με ανοσοχρυσό της οκλουδίνης, δείγματα από το μετωπιαίο λοβό, το μεσεγκέφαλο και την παρεγκεφαλίδα από κάθε ομάδα παρατηρήθηκαν με ηλεκτρονικό μικροσκόπιο για διαφορές στην εντόπιση της οκλουδίνης σε σχέση με τη διενδοθηλιακή σχισμή. Τα αποτελέσματα ανέδειξαν μετακίνηση της οκλουδίνης μακριά από την περιοχή των στενοσυνδέσμων του τριχοειδικού ενδοθηλίου. Σημαντική αύξηση της απόστασης της οκλουδίνης από τη διενδοθηλιακή σχισμή παρατηρήθηκε στο μεσεγκέφαλο και στην παρεγκεφαλίδα και όχι στο μετωπιαίο λοβό, σε σχέση με την ομάδα ελέγχου (control). Τα συγκεκριμένα αποτελέσματα υπαινίσσονται μια εκλεκτική ως προς την περιοχή αποδιοργάνωση της οκλουδίνης σε απάντηση στην ηπατική δυσλειτουργία και ένα σημάδι δυσλειτουργίας των TJ με λογικό συνεπακόλουθο τη δυσλειτουργία και του ΑΕΦ. Προκαταρκτικά δεδομένα της χρήσης αντιοξειδωτικών παραγόντων, όπως η αλλοπουρινόλη, αφήνουν να διαφανεί ένας προστατευτικός ρόλος όσον αφορά τη μετατόπιση της οκλουδίνης σε BDL αρουραίους. Εν συντομία, η παρούσα πειραματική μελέτη παρουσιάζει την επίδραση του οξειδωτικού στρες, στην εντόπιση της πρωτεΐνης των στενοσυνδέσμων οκλουδίνη στο ενδοθήλιο των εγκεφαλικών τριχοειδών αγγείων σε αρουραίους με απολίνωση χοληδόχου πόρου. Για τη μελέτη χρησιμοποιήθηκαν τεχνικές ανοσοσήμανσης συνδυαζόμενες με ηλεκτρονική μικροσκοπία και παρουσιάστηκαν δεδομένα εκλεκτικής ως προς την περιοχή εγκεφαλικής δυσλειτουργίας στην ηπατική πάθηση με δυνητική συσχέτιση με τις κλινικές εκδηλώσεις της ηπατικής εγκεφαλοπάθειας. / The blood–brain barrier (BBB) plays a critical role in central nervous system homeostasis. Interendothelial tight junction (TJ) protein complexes of the brain microvasculature have a major contribution to the BBB function by limiting paracellular diffusion Occludin, a transmembrane protein, is a major component of the TJ which plays a significant role in its regulation. Oxidative stress is a major underlying cause of neurodegenerative and neuroinflammatory disorders while TJ dysfunction leading to BBB disruption is associated with it. The development of increased oxidative stress in the context of obstructive cholestasis has been proven in various rats' organs including the brain. The present study used a rat model with bile duct ligation, to examine the effect of cholestasis, to the localization of occludin in brain capillary endothelium by means of electronic microscopy. Male Wistar rats were randomly divided into Group I, rats subjected to sham operation, and Group II, rats subjected to bile duct ligation (BDL) on day 0 and on post-operative day 10 all surviving animals were sacrificed by instant decapitation. After specific treatment for immunogold labeling of occludin, samples from frontal cortex, midbrain and cerebellum from each group were observed for differences in occludin location in relation to the interendothelial cleft. The results demonstrated a dislocation of occludin away from the tight junction sites of brain endothelial cells. A significant increase of the occludin-interendothelial cleft distance was demonstrated in the midbrain and the cerebellum samples but not in the frontal cortex, compared to the control group samples. These findings imply a brain region selective derangement of occludin in response to liver disease and a sign of TJ impairment and thus, a speculated BBB dysfunction. Preliminary data of use of antioxidant agents, as allopurinol, imply a protective effect concerning the dislocation of occludin in BDL rats. In brief, this experimental study demonstrates the effect of oxidative stress, in the location of TJ protein occludin in brain capillary endothelium of BDL rats. The study used immunolabeling techniques combined with electron microscopy and presented data of region-specific brain abnormalities in liver disease with potential correlation with clinical manifestations of hepatic encephalopathy.

Στην εν λόγω εργασία, έγινε μια προσπάθεια καταγραφής του τεχνολογικού τοπίου της τηλεπικοινωνιακής αγοράς, με έμφαση την διαλειτουργικότητα μεταξύ των Δικτύων Κινητής Τηλεφωνίας και των Ασύρματων Δικτύων Δεδομένων και των σχετικών αλλαγών που έχει επιφέρει αυτή η διαλειτουργικότητα, τόσο στις παρεχόμενες υπηρεσίες, όσο και στα εφαρμοζόμενα επιχειρηματικά μοντέλα από πλευράς εταιρειών της συγκεκριμένης αγοράς. Στα πλαίσια αυτής της προσπάθειας, χρειάστηκε να πραγματοποιηθεί μια λεπτομερής καταγραφή των τεχνολογικών εξελίξεων, σε επίπεδο τεχνικών προδιαγραφών και προτύπων, στις παραπάνω δύο κατηγορίες δικτύων, ώστε να καταλήξουμε σε εκείνα τα πρότυπα που πλέον μπορούν να οδηγήσουν στην υλοποίηση δικτύων τα οποία θα χαρακτηρίζονται από τα παρακάτω: • θα είναι ενοποιημένα ώστε οι διαφορετικές τεχνολογικές πλατφόρμες των εταιρειών να λειτουργούν απρόσκοπτα, • θα χαρακτηρίζονται από χαμηλό κόστος, • ο τελικός χρήστης θα μπορεί να είναι συνεχώς συνδεδεμένος με κάποιο δίκτυο ασύρματης πρόσβασης και να απολαμβάνει τις υπηρεσίες που επιθυμεί, οποτεδήποτε και οπουδήποτε. Η δομή της διπλωματικής εργασίας ακολουθεί τον προαναφερθέντα τρόπο σκέψης. Στο 1ο Κεφάλαιο γίνεται μια σύντομη παρουσίαση του στόχου σε επίπεδο τεχνολογιών αλλά και υπηρεσιών, δηλαδή των αναμενόμενων αποτελεσμάτων αυτών των δικτύων νέας γενιάς, στα οποία έχουμε συνηθίσει να αναφερόμαστε ως δίκτυα 4G (4th Generation) ή δίκτυα B3G (Beyond 3G) ή τέλος ως All – IP ασύρματα δίκτυα. Στο 2ο Κεφάλαιο, γίνεται μια λεπτομερής παρουσίαση των Δικτύων Κινητής Τηλεφωνίας από τις πρώτες τους εκδοχές (1G) έως τις πλέον σύγχρονες (3.5G) που έχουν εμφανιστεί μέχρι σήμερα. Αναλύονται τόσο οι γενιές των δικτύων όσο και τα χρησιμοποιούμενα πρότυπα, σε επίπεδο αρχιτεκτονικής όσο και σε επίπεδο πρωτοκόλλων. Στη συνέχεια του κεφαλαίου υπάρχει η τεχνική περιγραφή των επικρατέστερων δικτύων κινητής τηλεφωνίας, σήμερα, δηλαδή των GSM, GPRS και UMTS, ενώ στο τέλος του κεφαλαίου υπάρχει μια σύντομη περιγραφή της διαδικασίας intersystem handover μεταξύ των GSM και UMTS. Στο 3ο Κεφάλαιο, περνάμε πλέον στα Ασύρματα Δίκτυα Δεδομένων. Γίνεται μια εκτενής περιγραφή των προτύπων που έχουν καθοριστεί και συγκεκριμένα στα πρότυπα IEEE 802.15 Wireless Personal Area Networks (WPANs) με κυριότερους εκφραστές τα δίκτυα βασιζόμενα σε Bluetooth και IrDA, το πρότυπο IEEE 802.11 Wireless Local Area Networks (WLANs) με σημαντικότερος εκπροσώπους τα WiFi και HyperLan/2, το πρότυπο IEEE 802.16 Wireless Metropolitan Area Networks (WMANs) ή αλλιώς γνωστότερο ως WiMAX και τέλος το πρότυπο IEEE 802.20 Wireless Wide Area Networks (WWANs) ή διαφορετικά Mobile Broadband Wireless Access (MWBA) το οποίο είναι υπό διερεύνηση ακόμα και φιλοδοξεί να αποτελέσει το ασύρματο ανάλογο της τεχνολογίας xDSL, καθώς θα προσφέρει ασύρματες ευρυζωνικές υπηρεσίες. Στο 4ο Κεφάλαιο παρουσιάζονται μεθοδολογίες υλοποίησης του integration μεταξύ δικτύων των δύο κατηγοριών και συγκεκριμένα παραδείγματα διαλειτουργικότητας, όπως μεταξύ GPRS ή UMTS και WLANs ή μεταξύ UMTS και WiMAX. Γίνεται εκτενής συζήτηση γύρω από τα προβλήματα που θα πρέπει να αντιμετωπιστούν, όπως η εξασφάλιση ανεκτού επιπέδου QoS, οι μηχανισμοί για handover μεταξύ των δικτύων, η διαχείριση της κινητικότητας των χρηστών και των τερματικών και δίνονται παραδείγματα δημιουργίας ενοποιημένων δικτύων, τόσο με τη τεχνική της χαλαρής όσο και με την τεχνική της ισχυρής ζεύξης. Στο τελευταίο τμήμα του Κεφαλαίου, γίνεται μια εκτενής αναφορά στις αρχιτεκτονικές διασύνδεσης ετερογενών δικτύων με IP δίκτυα κορμού, τα γνωστά All – IP networks. Ιδιαίτερη έμφαση δίνεται στους μηχανισμούς πραγματοποίησης των handovers βάσει πολιτικών (policy based) και η χρήση τεχνικών για micromobility και macromobility σε σχέση με την κινητικότητα των τερματικών. Το 5ο Κεφάλαιο αφορά τις εφαρμογές και υλοποιήσεις ασυρμάτων δικτύων δεδομένων στον Ελληνικό χώρο, στα πλαίσια του Επιχειρησιακού Προγράμματος «Κοινωνία της Πληροφορίας» και πιο συγκεκριμένα τα «Εξοπλισμός και δικτύωση σε όλες τις βαθμίδες της εκπαίδευσης», «Ασύρματα Ευρυζωνικά Δίκτυα ΟΤΑ»και «Μητροπολιτικά Ευρυζωνικά Δίκτυα Οπτικών Ινών ΟΤΑ» και ουσιαστικά αποτελούν παραδείγματα και υλοποιήσεις διασύνδεσης WiFi, WiMAX και IP backbone δικτύων όπως το ΣΥΖΕΥΞΙΣ με δυνατότητες για παροχή VoIP. / In this thesis, an effort of presenting the technological landscape of the telecommunication market takes place, with focus on the interoperability between the Mobile Telephony Networks and the Wireless Data Networks and the relative changes that have evolved through this interoperability, both regarding the provided services and the applied business models by the enterprises of the specific market. Within the frames of this effort, a detailed recording of technological developments is realised, in terms of technical specifications and standards, in the two aforementioned categories of networks, so as to conclude to those standards that are utilized by the next generation networks (4G) which will be: • Networks that will be unified so as the different technological platforms will function smoothly. • Networks that will be characterized by low cost of deployment. • The end user will be continuously connected with a wireless access network, enjoying the preferred services anywhere and anytime. The master thesis structure follows the aforementioned methodology. The 1st Chapter includes a short presentation of expected results, both in terms of technologies and services for next generation networks, which we usually refer to as 4G networks (4th Generation) or B3G networks (Beyond 3G) or finally as All - IP wireless networks (AIPN). In the 2nd Chapter, a detailed presentation of Mobile Telephony Networks takes place, from their first versions (1G) until the most modern (3.5G) that have been presented up to today. The analysis includes both the various generations of networks and the used standards, in terms of modulation and multiplexing techniques. The rest of the chapter focuses on the technical description of the prevailing networks, GSM, GPRS and UMTS, while the chapter ends with a short description of intersystem handover processes between GSM and UMTS. Τhe 3rd Chapter, includes an extensive description of the Wireless Data Networks standards such as: IEEE 802.15 Wireless Personal Area Networks (WPANs) with main representatives networks based on Bluetooth and IrDA, standard IEEE 802.11 Wireless Local Area Networks (WLANs) mainly represented by WiFi and HyperLan/2, IEEE 802.16 Wireless Metropolitan Area Networks (WMANs) standard, widely known as WiMax and finally the IEEE 802.20 Wireless Wide Area Networks (WWANs) standard, namely Mobile Broadband Wireless Access (MWBA) that is still under development and aspires to constitutes the wireless version of the xDSL technology, since it aims to provide wireless broadband services. In the 4th Chapter methodologies for integrating the two types of networks, are presented along with examples of interoperability between GPRS / UMTS and WLANs or between UMTS and WiMAX. Extensive discussion around the problems that should be faced, as the guarantee of bearable QoS level, the mechanisms for handover between the networks and the management of mobility of users and terminals, is held. Moreover, examples of integrated networks with both loose and tight coupling methodologies are presented. The last section of the chapter concerns a detailed description of architectures for interconnecting heterogeneous wireless networks over IP – based backhaul networks, namely All – IP networks, with special focus on policy based handover mechanisms and techniques for managing micromobility and macromobility issues. The 5th Chapter concerns the changes taking place in the telecommunications market deriving from the technological progress in the subject of heterogeneous wireless networks interconnection. New service packets are created, as a result of new business plans that are drawn up by the big telecommunications organizations. Finally, we present the developments in the Greek market and subsidised projects from Information Society AE, via which wireless networks have been materialised, with aim to promote Broadband Services.

No description available.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

The developmental aspect of drug transport across the blood-brain barrier (BBB) was investigated. Microdialysis was used to study unbound morphine BBB transport at different ages in sheep. An in vitro study was performed to find differentially expressed genes in brain capillary-rich fractions of the brain in rats of different ages. Microdialysis and brain-to-plasma ratios were used to study the contribution of breast cancer resistance protein (Bcrp) to the transport of nitrofurantoin (NTF) across the BBB of rats during development as well as in adult rats and mice. A method of analysing morphine and its metabolites in plasma and microdialysis samples was developed and validated. The in vivo recovery of deuterated morphine, used as a calibrator in microdialysis experiments, was not affected by the presence of morphine in the tissue. A net influx of morphine was observed in premature lambs and adult sheep, in contrast to the efflux seen in other species. This influx decreased with age, indicating that the morphine transport across the BBB changes with age. In contrast, the transport of the morphine metabolite morphine-3-glucuronide (M3G) did not change with age. Microarray data indicated that several active transporters are differentially expressed with age. Moreover, the mRNA expression levels of Abcg2 (Bcrp) and Slc22a8 (organic anion transporter 3) changed with age when quantified using real-time polymerase chain reaction. In contrast, the expression of Abcb1 (P-glycoprotein) and occludin (a tight junction protein) did not change with age. In rats, the brain distribution of NTF decreased with age due to increased protein binding in plasma. The concentration ratio of unbound NTF across the BBB was low in the adult rat, due to intra-brain metabolism and/or efflux by other transporters. Bcrp did not appear to have a significant contribution in the developing rat or in knock-out mice compared to wild-type controls with regard to NTF BBB transport. In conclusion, in vitro studies showed that the expression levels of some genes changed with age, presumably affecting subsequent drug distribution to the brain. Further, in vivo studies showed that distribution across the BBB changed with age for morphine but not for M3G or NTF.

Oil is the world’s largest primary energy source. It dominates the transportation sector which underpins the world economy. Yet, oil is a nonrenewable resource, destined not to last forever. In the mid-2000s global conventional oil production stagnated, leading to rising oil prices and fears of permanent oil scarcity. These fears, together with the high prices, receded with the unforeseen emergence of a new supply source: tight oil. This licentiate thesis investigates unconventional tight oil production and its impacts on world oil supply in terms of resource availability and oil market dynamics, and in turn briefly discusses some possible wider economic, political and environmental implications of these impacts. The thesis is based on three papers. The first investigates the usefulness of bottom-up modelling by a retrospective study of past oil projections. The second looks at how unconventional tight oil production can be modelled on the well level using decline curve analysis. The third derives typical production parameters for conventional offshore oil fields, a growing segment of conventional production and a useful comparison to tight oil. The results show that tight oil production has increased resource availability significantly, as well as introduced a fast responding marginal supply source operating on market principles rather than political ones. The emergence of tight oil production has altered OPEC’s strategic options and led to a period of lower and less volatile oil prices. However, this condition of world oil supply can only last as long as the unconventional resource base allows, and, at the same time, total fossil fuel consumption will have to fall to limit climate change. It is concluded that this breathing space with lower oil prices could be used as an opportunity to develop and implement policy for an efficient managed decline of global oil use in order to achieve the dual goals of increased human economic welfare and limited climate change, and in the process preempt any future oil supply shortage. Unconventional tight oil production can both help and hinder in this endeavor. Accurate models and analyses of oil production dynamics and impacts are therefore crucial when maneuvering towards this preferred future.

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Abraços Ronildo on 2018-06-04T18:07:58Z (GMT) / Submitted by Deborah Santos (deborah.araujo89@gmail.com) on 2018-06-04T19:48:12Z No. of bitstreams: 2 Tese - Deborah Santos.pdf: 12203832 bytes, checksum: e193cc5eef9d1f8e0dd6df5a35d4cc55 (MD5) doc PPGQ.pdf: 706491 bytes, checksum: 90df4e7187c05b6824acb979f9f1cafd (MD5) / Approved for entry into archive by Ronildo Prado (ri.bco@ufscar.br) on 2018-06-06T17:46:22Z (GMT) No. of bitstreams: 2 Tese - Deborah Santos.pdf: 12203832 bytes, checksum: e193cc5eef9d1f8e0dd6df5a35d4cc55 (MD5) doc PPGQ.pdf: 706491 bytes, checksum: 90df4e7187c05b6824acb979f9f1cafd (MD5) / Approved for entry into archive by Ronildo Prado (ri.bco@ufscar.br) on 2018-06-06T17:53:10Z (GMT) No. of bitstreams: 2 Tese - Deborah Santos.pdf: 12203832 bytes, checksum: e193cc5eef9d1f8e0dd6df5a35d4cc55 (MD5) doc PPGQ.pdf: 706491 bytes, checksum: 90df4e7187c05b6824acb979f9f1cafd (MD5) / Made available in DSpace on 2018-06-06T17:53:22Z (GMT). No. of bitstreams: 2 Tese - Deborah Santos.pdf: 12203832 bytes, checksum: e193cc5eef9d1f8e0dd6df5a35d4cc55 (MD5) doc PPGQ.pdf: 706491 bytes, checksum: 90df4e7187c05b6824acb979f9f1cafd (MD5) Previous issue date: 2017-12-01 / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Cathepsin L is a lysosomal cysteine protease, that is related to many physiological processes, however overexpression and up- or downregulation may cause several pathologies. Therefore, cathepsin L became an interesting drug target. Peptidyl epoxides and aziridines are reported as potent cathepsin inhibitors.Previously, our research group has synthesized six new epoxi-α-acyloxycarboxamides through one-pot process starting with an organocatalyzed asymmetric epoxidation using catalyst I followed by Passerini reaction. Then, inhibitory assays against cathepsins K, L and V were performed, and the new compounds presented inhibition, mainly against cathepsin L. In order to further evaluate the structure-activity relationship of epoxi-α-acyloxycarboxamides 11 new compounds were synthesized. Among all, LPSN423 exhibited the best inhibitory activity. The mechanistic study showed that LSPN423 is a reversible tight binding uncompetitive inhibitor, which characterized by a high affinity enzyme-inhibitor complex. To further explore the application of 2,3-epoxi-aldehydes in multicomponent reactions, in addition to create a library of compounds to be evaluated against cathepsin L, Ugi reaction were performed sequentially to epoxidation. The 2-step procedure furnished the desired product with yields ranged from 22% to 68%. The new epoxi-α-acylaminocarboxamides were tested against cathepsin L and no significant activity was observed. The organocatalytic aziridination reaction is reported, however some drawbacks are associated with this reaction, such as the use of chlorinated solvents and large excess of base to promote the reaction. Thus, catalyst I allowed the use of the greener solvent mixture ethanol/water and a lower amount of base. Another drawback of this reaction is the unstable product, so to overcome this issue, the one-pot Passerini reaction was performed, right after the completion of the aziridination; the desired products were obtained from moderate to good yields. Preliminary evaluation of the new aziridine peptidomimetics indicates a potential activity of this class of compounds, although further studies are required. / A catepsina L é uma cisteíno protease lisossomal, que está envolvida em vários processos fisiológicos. Entretanto, falhas na sua expressão e regulação desencadeiam processos patológicos, por esse motivo, a catepsina L se tornou um alvo terapêutico interessante. Peptídeos contendo anéis epóxido e aziridina são reportados como inibidores potentes de catepsinas. Em um estudo prévio desenvolvido pelo nosso grupo de pesquisa, 6 epoxi-α-aciloxicarboxamidas foram sintetizadas de maneira one-pot via reação de epoxidação assimétrica organocatalisada utilizando o catalisador I seguida da reação de Passerini. Testes relacionados à atividade dos compostos como inibidores de catepsinas K, V e L mostraram o potencial da nova classe, sobretudo frente à catepsina L. Neste trabalho, a coleção de epoxi-α-aciloxicarboxamidas foi ampliada com a síntese de mais 11 exemplos, a fim de melhor avaliar a relação estrutura-atividade desta classe de compostos frente à catepsina L. De toda a série, o LPSN423 apresentou a melhor inibição. Estudos sobre o mecanismo de inibição demonstraram que o LSPN423 é um inibidor reversível do tipo tight binding incompetitivo. Neste modo de inibição, o complexo enzima-inibidor apresenta elevada afinidade. Com o intuito de explorar a aplicação dos 2,3-epoxi-aldeídos assimétricos preparados pela metodologia desenvolvida no grupo de pesquisa, bem como criar uma biblioteca de compostos candidatos a inibidores de catepsina L, novas epoxi-α- acilaminocarboxamidas foram sintetizadas, desta vez empregando de forma sequencial a reação multicomponente de Ugi. Os rendimentos em duas etapas variaram de 22-68% para os cinco exemplos sintetizados. Os compostos desta série foram avaliados frente à catepsina L, porém, nenhum deles apresentou atividade inibitória significativa. A síntese de aziridinas assimétricas via organocatálise é reportada tendo como desvantagem a utilização de solventes clorados e excessos de base. O emprego do organocatalisador I proporcionou o uso de etanol:água como solvente e diminuição da quantidade de base. Uma limitação na síntese de β-formilaziridinas está na dificuldade de isolar os produtos, por esse motivo, aplicou-se a funcionalização da aziridina na reação de Passerini one-pot, na qual obteve-se o produto desejado com rendimentos moderados. A avaliação preliminar das aziridinas obtidas frente à inibição da catepsina L indica uma potencial atividade dessa classe de compostos, no entanto estudos mais aprofundados serão necessários. / CNPq: 144095/2014-9

abstract: I propose a new communications scheme where signature signals are used to carry digital data by suitably modulating the signal parameters with information bits. One possible application for the proposed scheme is in underwater acoustic (UWA) communications; with this motivation, I demonstrate how it can be applied in UWA communications. In order to do that, I exploit existing parameterized models for mammalian sounds by using them as signature signals. Digital data is transmitted by mapping vectors of information bits to a carefully designed set of parameters with values obtained from the biomimetic signal models. To complete the overall system design, I develop appropriate receivers taking into account the specific UWA channel models. I present some numerical results from the analysis of data recorded during the Kauai Acomms MURI 2011 (KAM11) UWA communications experiment. It is shown that the proposed communication scheme results in approximate channel models with amplitude-limited inputs and signal-dependent additive noise. Motivated by this observation, I study capacity of amplitude-limited channels under different transmission scenarios. Specifically, I consider fading channels, signal-dependent additive Gaussian noise channels, multiple-input multiple-output (MIMO) systems and parallel Gaussian channels under peak power constraints. I also consider practical channel coding problems for channels with signal-dependent noise. I consider two specific models; signal-dependent additive Gaussian noise channels and Z-channels which serve as binary-input binary-output approximations to the Gaussian case. I propose a new upper bound on the probability of error, and utilize it for design of codes. I illustrate the tightness of the derived bounds and the performance of the designed codes via examples. / Dissertation/Thesis / Doctoral Dissertation Electrical Engineering 2015