No description available.

In-phase and quadrature (I/Q) signal generation is often required in modern transceiver architectures, such as direct conversion or low-IF, either for vector modulation and demodulation, negative frequency recovery in direct conversion receivers, or image rejection. If imbalance between the I and Q channels exists, the bit-error-rate (BER) of the transceiver and/or the image rejection ratio (IRR) will quickly deteriorate. Methods for correcting I/Q imbalance are desirable and necessary to improve the performance of quadrature transceiver architectures and modulation schemes. This thesis presents the design and characterization of a monolithic 5-6 GHz Silicon Germanium (SiGe) inductor-capacitor (LC) tank voltage controlled oscillator (VCO) with tunable polyphase outputs. Circuits were designed and fabricated using the Motorola 0.4 ìm CDR1 SiGe BiCMOS process, which has four interconnect metal layers and a thick copper uppermost bump layer for high-quality radio frequency (RF) passives. The VCO design includes full-wave electromagnetic characterization of an electrically symmetric differential inductor and a traditional dual inductor. Differential effective inductance and Q factor are extracted and compared for simulated and measured inductors. At 5.25 GHz, the measured Q factors of the electrically symmetric and dual inductors are 15.4 and 10.4, respectively. The electrically symmetric inductor provides a measured 48% percent improvement in Q factor over the traditional dual inductor. Two VCOs were designed and fabricated; one uses the electrically symmetric inductor in the LC tank circuit while the other uses the dual inductor. Both VCOs are based on an identical cross-coupled, differential pair negative transconductance -GM oscillator topology. Analysis and design considerations of this topology are presented with a particular emphasis on designing for low phase noise and low-power consumption. The fabricated VCO with an electrically symmetric inductor in the tank circuit tunes from 4.19 to 5.45 GHz (26% tuning range) for control voltages from 1.7 to 4.0 V. This circuit consumes 3.81 mA from a 3.3 V supply for the VCO core and 14.1 mA from a 2.5 V supply for the output buffer. The measured phase noise is -115.5 dBc/Hz at a 1 MHz offset and a tank varactor control voltage of 1.0 V. The VCO figure-of-merit (FOM) for the symmetric inductor VCO is -179.2 dBc/Hz, which is within 4 dBc/Hz of the best reported VCO in the 5 GHz frequency regime. The die area including pads for the symmetric inductor VCO is 1 mm x 0.76 mm. In comparison, the dual inductor VCO tunes from 3.50 to 4.58 GHz (27% tuning range) for control voltages from 1.7 to 4.0 V. DC power consumption of this circuit consists of 3.75 mA from a 3.3 V supply for the VCO and 13.3 mA from a 2.5 V supply for the buffer. At 1 MHz from the carrier and a control voltage of 0 V, the dual inductor VCO has a phase noise of -104 dBc/Hz. The advantage of the higher Q symmetric inductor is apparent by comparing the FOM of the two VCO designs at the same varactor control voltage of 0 V. At this tuning voltage, the dual inductor VCO FOM is -166.3 dBc/Hz compared to -175.7 dBc/Hz for the symmetric inductor VCO -- an improvement of about 10 dBc/Hz. The die area including pads for the dual inductor VCO is 1.2 mm x 0.76 mm. In addition to these VCOs, a tunable polyphase filter with integrated input and output buffers was designed and fabricated for a bandwidth of 5.15 to 5.825 GHz. Series tunable capacitors (varactors) provide phase tunability for the quadrature outputs of the polyphase filter. The die area of the tunable polyphase with pads is 920 ìm x 755 ìm. The stand-alone polyphase filter consumes 13.74 mA in the input buffer and 6.29 mA in the two output buffers from a 2.5 V supply. Based on measurements, approximately 15° of I/Q phase imbalance can be tuned out using the fabricated polyphase filter, proving the concept of tunable phase. The output varactor control voltages can be used to achieve a potential ±5° phase flatness bandwidth of 700 MHz. To the author's knowledge, this is the first reported I/Q balance tunable polyphase network. The tunable polyphase filter can be integrated with the VCO designs described above to yield a quadrature VCO with phase tunable outputs. Based on the above designs I/Q tunability can be added to VCO at the expense of about 6 mA. Future work includes testing of a fabricated version of this combined polyphase VCO circuit. / Master of Science

Submitted by Irvana Coutinho (irvana@ufpa.br) on 2017-06-06T16:44:40Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Tese_InfanciaCriancasExperiencias.pdf: 6030671 bytes, checksum: f20ad5b0e1d74d0e8e89f9b2c74bf332 (MD5) / Approved for entry into archive by Irvana Coutinho (irvana@ufpa.br) on 2017-06-06T16:46:07Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Tese_InfanciaCriancasExperiencias.pdf: 6030671 bytes, checksum: f20ad5b0e1d74d0e8e89f9b2c74bf332 (MD5) / Made available in DSpace on 2017-06-06T16:46:07Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Tese_InfanciaCriancasExperiencias.pdf: 6030671 bytes, checksum: f20ad5b0e1d74d0e8e89f9b2c74bf332 (MD5) Previous issue date: 2017-02-10 / A tese intitulada Infância, crianças e experiências educativas no Educandário Eunice Weaver (1942-1980), insere-se no campo da História da Educação e da História da infância - Pará e tem como objeto a história da infância e as experiências educativas de crianças que viveram isoladas institucionalmente em função da política pública de isolamento compulsório implantada no Brasil, na primeira metade do século XX, para o controle e prevenção da hanseníase. O estudo teve como objetivo central explicitar a infância e as experiências educativas de crianças que viveram institucionalizadas num espaço criado para acolher, manter, educar e instruir crianças que não possuíam hanseníase, mas por serem filhas de pais doentes, deveriam ser afastadas da família para evitar o contágio da doença pelos pais. Os preventórios/educandários foram criados em quase todos os estados brasileiros num momento de notável crescimento do interesse público pela infância, de controle social e intervenção autoritária do poder público sobre a população. Os procedimentos adotados para a aquisição das informações e para o alcance dos objetivos propostos, foram a entrevista em história oral híbrida e temática e a pesquisa documental, pois, nesse tipo de procedimento, valoriza-se o tema pesquisado, e, os dados orais entram em diálogo com outras fontes, que podem ser os documentos e os referenciais de análise. As principais fontes que comporam o corpus da tese foram as narrativas orais de 13 egressos da instituição, o regulamento dos preventórios para filhos de lázaros instalados no Brasil, o livro da Campanha da solidariedade em prol da construção do preventório para filhos sadios dos lázaros no Pará, relatórios da I e II Conferência Nacional de Assistência social aos lázaros, de 1939 e 1945, respectivamente, o regulamento do Departamento Nacional de Saúde Pública de 1923, registros fotográficos, relatórios de governo, ofícios, além de artigos, livros e revistas com assuntos sobre a hanseníase e sobre a instituição. As reflexões empreendidas estão ancoradas nos fundamentos da história cultural. Autores como Michel Foucault, Mikhail Bakhtin e Erving Goffman nos deram aporte para as análises empreendidas. Os resultados da pesquisa revelam uma história de crianças que foram retiradas do convívio com seus familiares e do convívio social, construindo assim uma forma de se vivenciar a infância baseada no isolamento, no controle dos corpos infantis por meio do disciplinamento e da violência física e psicológica. / The thesis entitled Childhood, Children and Educational Experiences in the Educandário Eunice Weaver (1942-1980), is part of the History of Education and History of Childhood - Pará and has as its object the history of childhood and the educational experiences of children who live institutionally isolated due to the public policy of compulsory isolation implanted in Brazil in the first half of the XX century, for the control and prevention of leprosy. The main objective of the study was to explain the childhood and educational experiences of children who lived institutionalized in a space created to host, maintain, educate and instruct children who did not have leprosy, but because they were children of sick parents, they should be removed from the family to avoid the contagion of the disease by the parents. The preventers/educandários were created in almost all the Brazilian states in a moment of remarkable growth of the public interest in childhood, of social control and authoritarian intervention of the public power over the population. The procedures adopted for the acquisition of information and for the achievement of the proposed objectives were the interviews in oral and thematic oral history and documentary research, because, in this type of procedure, the researched topic is valued, and oral data communicate with other sources, which may be the documents and the analysis references. The main sources of the corpus of the thesis were the oral narratives of 13 graduates of the institution, the regulation of the preventers for children of lazarus installed in Brazil, the book of the Solidarity Campaign for the construction of preventory for healthy Lazarus’s children in Pará, reports of the I and II National Conferences of Social Assistance to the Lazarus, in 1939 and 1945, respectively, The National Public Health Department Regulations of 1923, photographic records, government reports, offices, as well as articles, books and magazines with subjects on leprosy and about the institution. The reflections undertaken are anchored in the foundations of cultural history. Authors like Michel Foucault, Mikhail Bakhtin and Erving Goffman gave us input for the analyzes undertaken. The research results reveal the history of children who were removed from their relationship with their families and from social life, thus building a way of experiencing childhood based on isolation, control of children's bodies through discipline and physical and psychological violence. / La thèse intitulé Enfance, enfants et expériences au sein du Educandario(internat) Eunice Weaver (1942- 1980), dans le domaine de l'histoire de l'éducation et de l'histoire de l'enfance- Pará, et a comme objet l'histoire de l'enfance et les expériences éducatifs des enfants que on vécut isolées, sur le plan institutionnel en fonction de la politique publique d'isolement obligatoire déployé au Brésil dans la moitié du XXème siècle pour le contrôle et la prévention de la lèpre. L'étude avait comme objectif centrale clarifier l'enfance et les expériences éducatifs des enfants que on vécut dans ses espaces crées pour accueillir, maintenir, éduquer, et instruire des enfants que ne souffreant pas de la maladie, mais étaient des enfants des parents malades, doivent être éloigner de la famille afin d'éviter le contagion de la maladie par les parents. Les Préventoriums/internats ont été créés dans presque tous les états brésiliens dans un moment de croissance remarquable d'intérêt publique pour l'enfance, de contrôle social et intervention des autorités publiques par rapport à la population. Les procédures adoptées pour l'acquisitions des informations et la réalisation des objectifs proposés, étaient l'entrevue en histoire oral hybride et thématique et la recherche documentaire, parce que dans ce genre de procédure, est valorisée la thématique recherché, et, les données orales, rentrant en dialogue avec d'autres sources, qui peuvent être des documents et références. Les principales sources qui composent le corpus de la thèse étaient les récit oraux des 13 diplômées de l'institution, le règlement des préventoriums pour les enfants en bonne santé de parents atteints de la lèpre installées au Brésil, le livre de la campagne de solidarité en faveur de la construction des préventoriums pour les enfants sains au Pará, les rapports des Conférence Nationale de Aide Sociale Aux lépreux I et II, de 1939 et 1945, respectivement, la règlementation du département National de santé publique de 1923, documents photographiques, rapports gouvernementaux, métiers, en plus d'articles , livres et des magazines avec des sujets sur la lèpre et sur l'institution. Les réflexions menées sont ancrées dans les fondements de l'histoire culturelle. Des auteurs tels que Michel Foucault, Mikhail Bakhtin et Erving Goffman nous ont donné une base pour les analyses effectuées. Les résultats du sondage révèlent une histoire d'enfants qui ont été amenées à vivre éloignées de leurs familles et de la vie en société, créant ainsi une façon de découvrir l'enfance basée sur l'isolement, le contrôle des corps des enfants basées sur la discipline et à la violence physique et psychologique.

Η νόσος του Parkinson χαρακτηρίζεται από τη βαθμιαία, εκλεκτική νευροεκφύλιση των ντοπαμινεργικών νευρώνων της μελαινοραβδωτής οδού. Η μειωμένη δραστηριοποίηση των ντοπαμινεργικών υποδοχέων που προκαλείται από την ανεπάρκεια ντοπαμίνης τροποποιεί τη λειτουργία των βασικών γαγγλίων και αναστέλλει τα κινητικά συστήματα. Ιδανικό πειραματικό μοντέλο αποτελεί το μοντέλο weaver, το οποίο εμφανίζει το ίδιο μοτίβο νευροεκφύλισης με τους παρκινσονικούς ασθενείς καθώς και περισσότερη από 70% μείωση της ντοπαμίνης στο ραβδωτό σώμα. Το γεγονός πως δεν υπάρχει σήμερα αποτελεσματική θεραπεία που να σταματά ή να αναστρέφει την εξέλιξη της νόσου, δημιουργεί την ανάγκη ανακάλυψης ενός φαρμακευτικού σχήματος το οποίο θα έχει νευροπροστατευτική δράση και θα περιορίζει τις παρενέργειες. Προηγούμενα αποτελέσματα της ομάδας μας δείχνουν σημαντική επιβίωση των ντοπαμινεργικών κυττάρων στο μοντέλο weaver μετά από χρόνια χορήγηση του ενδογενούς νευροστεροειδούς DHEAS, του χημικού αναλόγου του ΒΝΝ-50 (το οποίο δε μεταβολίζεται σε οιστρογόνα) και του φαρμακευτικού συνδυασμού του ΒΝΝ-50 με τη Ν-ακετυλοκυστεΐνη (NAC), με το τελευταίο να επαναφέρει πλήρως τον αριθμό των κυττάρων στη μέλαινα ουσία. Στην παρούσα εργασία θελήσαμε να διερευνήσουμε τους μηχανισμούς μέσω των οποίων επιτυγχάνεται η νευροπροστασία που προκαλεί η συγχορήγηση του συνδυασμού BNN-50/ΝAC. Για το σκοπό αυτό, αξιολογήσαμε την αντιαποπτωτική, καθώς και την αντιοξειδωτική δράση του σχήματος BNN-50/NAC. Οι δύο δείκτες επιλέχθηκαν λαμβάνοντας υπόψιν τον κεντρικό ρόλο του αποπτωτικού θανάτου στη διαδικασία της νευροεκφύλισης, καθώς και το ρόλο του οξειδωτικού στρες στην παθογένεια της νόσου. Τα αποτελέσματα μας υποδεικνύουν πλειοτροπική δράση του φαρμακευτικού συνδυασμού BNN-50/NAC, η οποία εκφράζεται μέσω της ισχυρής αντιαποπτωτικής και αντιοξειδωτικής του δράσης. / Parkinson 's disease is characterized by the progressive, selective neurodegeneration of the dopaminergic neurons of the nigrostriatal pathway. The decreased activation of dopamine receptors caused by insufficient dopamine levels, modifies the function of the basal ganglia circuit and inhibits the mobility systems. The weaver model consists an ideal model for neuroprotection studies, which exhibits the same pattern of neurodegeneration as the parkinsonian patients and more than 70% decrease of dopamine in the striatum. The fact that there is currently no effective treatment to attenuate or reverse the disease progression, creates the need for discovery of a drug combination which will exhibit neuroprotective effect and reduce the side effects. Previous results of our group, have shown a significant survival of dopaminergic neurons in weaver mice after chronic administration of endogenous neurosteroid DHEA-S, the chemical analog BNN-50 (which is not metabolized to estrogens) and the combination of the BNN-50 with N-acetylcysteine (NAC,with the latter combination completely rescuing the number of dopaminergic cells of the substantia nigra. The aim of this study was to investigate the mechanisms of neuroprotection induced by coadministration of combination BNN-50/NAC. For this purpose, we evaluated the possible antiapoptotic and antioxidant action of the BNN-50/NAC combination. Our results suggest a pleiotropic effect of the BNN-50/NAC drug combination, that is expressed through strong antiapoptotic and antioxidant activity.

Analysing the repeated debates within American conservatism over the place of Abraham Lincoln within American history.

Cashew, Anacardium occidentale Linnaeus, is an economically important cash crop for more than 300,000 rural households in Tanzania. Its production is, however, severely constrained by infestation by sap-sucking insects such as Helopeltis anacardii Miller, H. Schoutedeni Reuter and Pseudotheraptus wayi Brown. The African weaver ant (AWA), Oecophylla longinoda Latreille, is an effective biocontrol agent of hemipteran pests in coconuts in Tanzania; but its efficacy for the control of sap-sucking insects, especially Helopeltis spp. and P. wayi, has not been investigated so far in cashew crops in Tanzania. Field trials were carried out at the Coast region of Tanzania to evaluate the effect of seasonality and abundance of AWA on Helopeltis spp. and P. wayi. Results showed that AWA abundance expressed, as number of leaf nests per tree, and colonization of trails on main branches varied significantly between cashew-seasons and off-seasons. There was a negative correlation between numbers of nests and pest damage. AWA-colonized cashew trees had the lowest shoot damaged by Helopeltis spp., 4.8 and 7.5% in 2010 and 2011, respectively, compared to 36 and 30% in 2010 and 2011, respectively, in uncolonized cashew trees. Similarly, nut damage by P.wayi was lowest in AWA-colonized trees with 2.4 and 6.2% in 2010 and 2011, respectively, as compared to 26 and 21% in 2010 and 2011, respectively, in uncolonized trees. Interaction between AWA and dominant ant species, namely big-headed ant (BHA), Pheidole megacephala Fabricius, and common pugnacious ant (CPA), Anoplolepis custodiens Smith, was examined because of the implication that the dominant ant species may have on the efficacy of AWA in its control of sap-sucking pests of cashew. Abundance of AWA was significantly negatively correlated to BHA (r(39) = -0.30; P < 0.0001) and CPA (r(39) = -0.18; P = 0.01) at Bagamoyo in 2010. A similar trend was also observed at Mkuranga. The presence of these ant species may therefore hinder effectiveness of AWA to control sap-sucking pests in cashew in Tanzania. Therefore, suppression of these two inimical ant species should be emphasized for effective control of the sap-sucking pests in cashew fields. It was therefore also important to establish the abundance and diversity of ant species occurring in cashew agro-ecosystems. Results from pitfall traps revealed the diversity and abundance of ants in cashew agro-ecosystems: a total of 14001 ants were trapped belonging to six subfamilies, 18 genera and 32 species. The ant species diversity was high in the cashew fields at two of the four sites, namely Mkuranga A and Kibaha during both seasons. CPA was the most abundant ants in the pitfall traps. It is an important aspect that should be addressed for effective control of sap-sucking pests in cashew fields with AWA, since the correlation between AWA and CPA abundance was found to be negative. The effect of alternative fungicides to sulphur dust used for powdery mildew disease (PMD) on AWA was also investigated. No significant difference could be found in the effect ofthe different fungicides on the number of leaf nests and colonization of trails. In order to develop AWA as a component of cashew integrated sap-sucking insect management, strategies for their conservation during cashew off-seasonswas evaluated. The use of fish and hydramethylon (Amdro®) as baits increased the number of leaf nests and colonization trails of AWA over the control during off-season; however, the increase was significantly high when both fish and hydramethylon were used together. Fish and hydramethylon can therefore be used for conservation of AWA during off-season. It can therefore be concluded that AWA effectively controls sap-sucking pests on cashew and can be conserved during off-season using disposal waste such as fish intestines. Fungicides used for the control of PMD did not have detrimental effects on AWA abundance and can therefore be integrated as a component of cashew IPM. / PhD (Environmental Sciences), North-West University, Potchefstroom Campus, 2013

Cashew, Anacardium occidentale Linnaeus, is an economically important cash crop for more than 300,000 rural households in Tanzania. Its production is, however, severely constrained by infestation by sap-sucking insects such as Helopeltis anacardii Miller, H. Schoutedeni Reuter and Pseudotheraptus wayi Brown. The African weaver ant (AWA), Oecophylla longinoda Latreille, is an effective biocontrol agent of hemipteran pests in coconuts in Tanzania; but its efficacy for the control of sap-sucking insects, especially Helopeltis spp. and P. wayi, has not been investigated so far in cashew crops in Tanzania. Field trials were carried out at the Coast region of Tanzania to evaluate the effect of seasonality and abundance of AWA on Helopeltis spp. and P. wayi. Results showed that AWA abundance expressed, as number of leaf nests per tree, and colonization of trails on main branches varied significantly between cashew-seasons and off-seasons. There was a negative correlation between numbers of nests and pest damage. AWA-colonized cashew trees had the lowest shoot damaged by Helopeltis spp., 4.8 and 7.5% in 2010 and 2011, respectively, compared to 36 and 30% in 2010 and 2011, respectively, in uncolonized cashew trees. Similarly, nut damage by P.wayi was lowest in AWA-colonized trees with 2.4 and 6.2% in 2010 and 2011, respectively, as compared to 26 and 21% in 2010 and 2011, respectively, in uncolonized trees. Interaction between AWA and dominant ant species, namely big-headed ant (BHA), Pheidole megacephala Fabricius, and common pugnacious ant (CPA), Anoplolepis custodiens Smith, was examined because of the implication that the dominant ant species may have on the efficacy of AWA in its control of sap-sucking pests of cashew. Abundance of AWA was significantly negatively correlated to BHA (r(39) = -0.30; P < 0.0001) and CPA (r(39) = -0.18; P = 0.01) at Bagamoyo in 2010. A similar trend was also observed at Mkuranga. The presence of these ant species may therefore hinder effectiveness of AWA to control sap-sucking pests in cashew in Tanzania. Therefore, suppression of these two inimical ant species should be emphasized for effective control of the sap-sucking pests in cashew fields. It was therefore also important to establish the abundance and diversity of ant species occurring in cashew agro-ecosystems. Results from pitfall traps revealed the diversity and abundance of ants in cashew agro-ecosystems: a total of 14001 ants were trapped belonging to six subfamilies, 18 genera and 32 species. The ant species diversity was high in the cashew fields at two of the four sites, namely Mkuranga A and Kibaha during both seasons. CPA was the most abundant ants in the pitfall traps. It is an important aspect that should be addressed for effective control of sap-sucking pests in cashew fields with AWA, since the correlation between AWA and CPA abundance was found to be negative. The effect of alternative fungicides to sulphur dust used for powdery mildew disease (PMD) on AWA was also investigated. No significant difference could be found in the effect ofthe different fungicides on the number of leaf nests and colonization of trails. In order to develop AWA as a component of cashew integrated sap-sucking insect management, strategies for their conservation during cashew off-seasonswas evaluated. The use of fish and hydramethylon (Amdro®) as baits increased the number of leaf nests and colonization trails of AWA over the control during off-season; however, the increase was significantly high when both fish and hydramethylon were used together. Fish and hydramethylon can therefore be used for conservation of AWA during off-season. It can therefore be concluded that AWA effectively controls sap-sucking pests on cashew and can be conserved during off-season using disposal waste such as fish intestines. Fungicides used for the control of PMD did not have detrimental effects on AWA abundance and can therefore be integrated as a component of cashew IPM. / PhD (Environmental Sciences), North-West University, Potchefstroom Campus, 2013

There are more than 7000 described rare genetic disorders; however, the molecular basis underlying approximately half of these disorders is unknown, and the majority are currently untreatable. Stature and growth abnormalities are a common clinical feature of many rare disorders including: Floating-Harbor syndrome (FHS), a short stature syndrome characterized by delayed osseous maturation, language deficits, and unique dysmorphic facial features; Weaver syndrome, an overgrowth syndrome characterized by advanced osseous maturation, developmental delay, and macrocephaly; and Sotos syndrome with cutis laxa, an overgrowth syndrome with marked tissue laxity in addition to the typical Sotos characteristics of developmental delay, macrocephaly, and a unique facial gestalt. The genetic basis underlying these three rare stature conditions were unknown at the outset of this study. We utilized high-throughput exome sequencing approaches to investigate the molecular etiology of these rare disorders and identified truncating mutations in the final exon of SRCAP as the genetic cause underlying FHS, missense mutations in EZH2 in Weaver syndrome, and novel mutations in the Sotos syndrome gene NSD1 in Sotos syndrome with cutis laxa. Next, we investigated the spectrum of SRCAP mutations in FHS and established the clustering of truncating SRCAP mutations in the final exon as being highly suggestive of a non-haploinsufficiency mutational mechanism in FHS. Finally, global methylation array analysis identified a unique methylation ‘epi-signature’ in FHS individuals, providing further insight into FHS disease mechanism and a diagnostic signature. These studies have delineated the molecular etiology of these three rare stature/growth disorders, furthered our understanding of the associated clinical spectrum, and provided biological insight into disease pathogenesis.

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Η παρούσα εργασία αφορά στη μελέτη της ανταγωνιστικής αλληλεπίδρασης των Α1/D1 υποδοχέων στο επίπεδο έκφρασης του πρώιμου γονιδίου zif/268 (δείκτης νευρωνικής δραστηριότητας) και της in vivo μεταγωγής σήματος των Α1 και Α2Α υποδοχέων αδενοσίνης κάτω από τη ντοπαμινεργική απονεύρωση στο μυ weaver. Ο μυς weaver αποτελεί ένα γενετικό μοντέλο ντοπαμινεργικής απονεύρωσης, η οποία συμβαίνει σταδιακά, έτσι ώστε το μοντέλο αυτό να προσομοιάζει τη Νόσο Πάρκινσον (ΝΠ) στον άνθρωπο. Στο πρώτο στάδιο της μελέτης προέκυψε το ενδιαφέρον αποτέλεσμα ότι με την ταυτόχρονη ενεργοποίηση των Α1 και D1 υποδοχέων παρατηρήθηκε η αναμενόμενη ανταγωνιστική αλληλεπίδραση (ενδεχομένως μέσω σχηματισμού του ετεροδιμερούς), ενώ με την ενεργοποίηση μόνο των Α1 υποδοχέων στους weaver μύες παρατηρήθηκε αυξημένη ενεργοποίηση των νευρώνων του ραβδωτού σώματος και συγκεκριμένων περιοχών του εγκεφαλικού φλοιού. Η ενεργοποίηση αυτή ήταν μη αναμενόμενη, δεδομένου ότι οι Α1 υποδοχείς (A1Rs) είναι συζευγμένοι με Gi πρωτεΐνες και καταστέλλουν τη μεταγωγή σήματος που οδηγεί στην επαγωγή του zif/268 μέσω του D1R/Gs/cAMP/PKA/pDARPP-32/pCREB μονοπατιού. Η ακόλουθη διερεύνηση του μηχανισμού έδειξε ότι η Α1R-επαγόμενη ενεργοποίηση του zif/268 καταστέλλεται από τον ειδικό ανταγωνιστή των Α2Α υποδοχέων αδενοσίνης (A2ARs) ZM241385 και από τον ειδικό αγωνιστή των D2 υποδοχέων ντοπαμίνης Quinpirole, υποδεικνύοντας την ενεργοποίηση των Α2ΑRs και άρα ενεργοποίηση της έμμεσης οδού. Το αποτέλεσμα αυτό επιβεβαιώθηκε, δεδομένου ότι η διέγερση των Α1Rs προκάλεσε αύξηση της έκφρασης του mRNA της εγκεφαλίνης, αλλά όχι της δυνορφίνης, που αποτελούν δείκτες ενεργοποίησης της έμμεσης και της άμεσης οδού, αντίστοιχα. Το γεγονός ότι ο αγωνιστής των Α1Rs δεν προκαλεί στα φυσιολογικά ζώα ενεργοποίηση του zif/268 mRNA υποδεικνύει την υπερευαίσθητη απόκριση των Α2ARs. Η μελέτη της υπερευαίσθητης αυτής απόκρισης στο μυ weaver έγινε με τη διερεύνηση της μεταγωγής σήματος μετά από in vivo ενεργοποίηση των Α2ΑRs: α) του καθιερωμένου μονοπατιού Α2ΑRs/Gs/AC/cAMP/PKA/pDARPP-32/pCREB, το οποίο οδηγεί στη επαγωγή του zif/268 και β) του μονοπατιού των ΜΑΡΚ. Τα αποτελέσματα έδειξαν αυξημένα βασικά επίπεδα φωσφορυλίωσης της DARPP-32 στη θέση Thr-34. Τα αυξημένα επίπεδα της φωσφορυλιωμένης DARPP-32 πολλαπλασιάζουν τη δράση της ΡΚΑ και άρα διευκολύνουν τη μεταγωγή σήματος μέσω Α2ΑRs/Gs/AC/cAMP/PKA/pDARPP-32/pCREB μονοπατιού. Επομένως, η υπερευαίσθητη απόκριση των Α2ΑRs κάτω από την έλλειψη ντοπαμίνης στο μυ weaver φαίνεται να οφείλεται στα αυξημένα ενδογενή επίπεδα της φωσφορυλιωμένης DARPP-32. Ενδιαφέρον παρουσιάζει το γεγονός ότι τα βασικά επίπεδα φωσφορυλίωσης των πρωτεϊνών ERK1/2(MAPK44/42) είναι αυξημένα στον μυ weaver, αλλά μειώνονται σημαντικά μετά από την ενεργοποίηση των Α2ΑRs. Δεν γνωρίζουμε το μηχανισμό μέσω του οποίου αυξάνονται τα ενδογενή επίπεδα των ERK1/2 και πρέπει να διερευνηθεί περαιτέρω. Το συμπέρασμα όμως που εξάγεται είναι ότι κάτω από τη ντοπαμινεργική απονεύρωση η μεταβίβαση σήματος μέσω των Α2ΑRs δεν ενεργοποιεί την οδό των MAP κινασών. Στην παρούσα in vivo μελέτη αναδεικνύεται ο ρόλος των Α1 και Α2Α υποδοχέων στην λειτουργία των βασικών γαγγλίων κάτω από τη ντοπαμινεργική απονεύρωση. Τα αποτελέσματα αυτά έχουν ιδιαίτερη σημασία δεδομένου ότι εμφανίζονται σε ένα γενετικό μοντέλο παρκινσονισμού, στο οποίο η εκφύλιση των ντοπαμινεργικών νευρώνων είναι σταδιακή και προσομοιάζει τη ΝΠ, και όχι οξεία, όπως σε άλλα τοξικά μοντέλα. Επιπλέον, τα αποτελέσματα αυτά παρουσιάζουν ενδεχομένως κλινικό ενδιαφέρον, δεδομένου ότι η ενεργοποίηση της έμμεσης οδού μέσω Α1Rs από την ενδογενή αδενοσίνη θα επιδείνωνε περαιτέρω τις κινητικές δυσλειτουργίες της ΝΠ. Η πληροφορία αυτή, καθώς και η γνώση για την ενισχυμένη μεταγωγή σήματος μέσω των Α2Α υποδοχέων ενισχύουν την πρόταση για χρήση των Α2Α ανταγωνιστών ως αντιπαρκινσονικά φάρμακα. Δεδομένου ότι σήμερα το ενδιαφέρον είναι στραμμένο στη δημιουργία διμερών προσδεμάτων (bivalent ligands) που μπορούν να δρουν ταυτόχρονα σε δύο υποδοχείς, η συγκεκριμένη πληροφορία θα μπορούσε να χρησιμοποιηθεί για μελλοντική δημιουργία φαρμακευτικού σχήματος που να δρα ταυτόχρονα ως αγωνιστής των D2 υποδοχέων ντοπαμίνης και ως ανταγωνιστής των Α2Α υποδοχέων αδενοσίνης. / The present work studied the antagonistic interaction of A1/D1 receptors at the level of mRNA expression of the immediate early gene zif/268 (used as a marker of neuronal function). In parallel we studied the in vivo signal transduction of A1 and A2A adenosine receptors under dopamine deficiency in weaver mutant. The weaver mutant represents the only genetic animal model of gradual nigrostriatal neuron degeneration, which can be characterized as a pathophysiological phenocopy of Parkinson’s Disease. In the first part of the study, the co-activation of A1 and D1 receptors revealed the well-known antagonistic interaction of these receptors (possibly through the formation of A1/D1 heterodimer) in weaver mutant. An interesting result was that the activation of A1 receptors alone did induce zif/268 mRNA expression in stiatal and specific cortical neurons in weaver mutant. This induction was not expected, since A1 receptors are Gi-coupled and suppress the signal transduction pathway that leads to zif/268 induction through AC/PKA/p-DARPP-32/pCREB cascade. Further study, revealed that the A1 receptor-induced zif/268 mRNA expression is counteracted by the A2A receptor selective antagonist ZM241385 and by the D2 receptor selective agonist Quinpirole, suggesting the activation of A2A receptors and thus the activation of the “indirect pathway”. Moreover, A1 receptors activation induced the expression of enkephalin mRNA, but not of dynorphin, which are considered as marker of neuronal activation of the “indirect” and the “direct” pathway, respectively. The fact that the A1 receptor agonist did not induced zif/268 mRNA expression in +/+ animals indicates that under dopamine deficiency the A2A receptors react with a supersensitive response. This response was analyzed in weaver mouse after in vivo A2A receptor activation: a) by examining the classical signal transduction pathway of A2A receptors/AC/PKA/p-DARPP-32/pCREB, which leads to zif/268 expression and b) by studying the MAPK cascade. Results showed increased basal phosphorylation levels of DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, MW 32kDa) of Thr-34 in weaver compared to control mice. Increased phosphoThr34-DARPP-32 would amplify the effects of the PKA and thus facilitating the signal transduction through A2A receptors/AC/PKA/p-DARPP-32/pCREB. Therefore, the A2A receptors supersensitive response under dopamine deficiency in weaver mutant seems to be due to elevated endogenous phosphorylation levels of DARPP-32. Interestingly, while the basal phosphorylation levels of ERK1/2 (MAPK44/42) are elevated in weaver mutant, they are significantly reduced after A2A receptor activation. Although we do not know the mechanism through which the endogenous ERK1/2 levels are elevated, the conclusion is that, under dopamine deficiency, A2A receptors do not activate MAPK cascade. The present in vivo study demonstrates the role of A1 and A2A adenosine receptors in the function of basal ganglia under dopamine deficiency. Our results are significant since the expreriments were performed in a genetic parkinsonian model, in which the dopaminergic neurons are gradually degenerated and thus simulate the human PD, and not in an acute toxic model. Moreover, these results could be of possible clinical relevance, since the activation of A1 receptors by endogenous adenosine would exaggerate the motor dysfunctions of PD. Furthermore, the enhanced signal transduction pathway through A2A receptors supports the suggestion that the A2A receptor antagonists as antiparkinsonian agents. Given the well-known A2A/D2 antagonistic interaction, new therapeutical prospectives would involve the development of pharmacological bivalent ligands, which can interact with the A2A/D2 receptors and act simultaneously as A2A receptor antagonists and as D2 receptor agonists.