Дисертації з теми "HAdFA"
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Enklaar, Arnold Helmig. "The Hadra vases /." Amsterdam : Universiteit van Amsterdam, 1992. http://catalogue.bnf.fr/ark:/12148/cb357429858.
Повний текст джерелаDoležilová, Huangová Jo-Chih. "Historický vývoj hry na harfu na Novém Zélandu." Master's thesis, Akademie múzických umění v Praze.Hudební a taneční fakulta. Knihovna, 2018. http://www.nusl.cz/ntk/nusl-391620.
Повний текст джерелаUlehlová, Kateřina. "Harfa a její uplatnění v komorní hudbě." Master's thesis, Akademie múzických umění v Praze. Hudební fakulta AMU. Knihovna, 2006. http://www.nusl.cz/ntk/nusl-78748.
Повний текст джерелаStankovic, Katarina. "Preludes Op. 28 for piano by Chopin played on harp - A Comparison." Master's thesis, Akademie múzických umění v Praze.Hudební a taneční fakulta. Knihovna, 2018. http://www.nusl.cz/ntk/nusl-391645.
Повний текст джерелаFitzpatrick, Katherine. "Foraging and menstruation in the Hadza of Tanzania." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/275062.
Повний текст джерелаUPC, Alumnos de Periodismo, and Universidad Peruana de Ciencias Aplicadas (UPC). "Absenta: el vuelo del hada en Lima." Universidad Peruana de Ciencias Aplicadas (UPC), 2015. http://hdl.handle.net/10757/344538.
Повний текст джерелаSiala, Mourad. "La Hadra de Sfax : rite soufi et musique de fête." Paris 10, 1994. http://www.theses.fr/1994PA100083.
Повний текст джерелаSince few decades, after the extinction of the religious brotherhood’s manifestations in sax, the Hadra, which is the music of these brotherhoods, is no longer played except in profane context that is family parties. My first intention was then to historically review this music and examine its organization, its activities, and its influence on its auditors in the past and in the present. My second intention was to show the originality of this music by analyzing its musical system and the transcription of its repertoire, its musical text and words in native language. The Hadra, as a musical concert, goes back at the latest to the end of the XIXth century, the period during which the main mystic edifices of major brotherhoods were found. Other than its main function of dancing, the Hadra is known for its magic influence on certain people who, when listening to some of its musical airs, loose control of themeselves and become in a state of France. The behavior of these subjects, during this trance state, is related to possession, but this is not recognized as such by the society. A subject, as said has the "ahwal" - i. E. Has a predisposition to the trance by listening to its predilection air - is not considered as posseded even if he really is, and that he enters this state for therapeutic purposes. The rhythmic system represent the strongest and the most important side of the musical system, in general, which explains the predominance of percussion instruments in the instrumental constitution of the Hadra
Sandoval, Ccancce Benjamín Abhat. "Campos figurativos en ¡Oh hada cibernética!de Carlos Germán Belli." Bachelor's thesis, Universidad Nacional Mayor de San Marcos, 2015. https://hdl.handle.net/20.500.12672/4659.
Повний текст джерелаTesis
Gaibar, Constansó Vanessa. "Cruzando fronteras: parejas palestino-judías en el barrio del Carmel (Haifa, Israel)." Doctoral thesis, Universitat Autònoma de Barcelona, 2017. http://hdl.handle.net/10803/457431.
Повний текст джерелаIn the State of Israel, relationships between Palestinian and Jewish population are a controversial issue that provokes a great social expectation. A taboo that grew especially strong in the context of the conflict of the summer of 2014. Through the study of everyday experiences of Palestinian-Jewish couples that live in Haifa, I will try to show how the social perceptions and reactions about these couples are microcosms of the dynamics of the current Israeli society. To explain why these relationships are so problematic in the country, this thesis analyze the historical and political context of the region, the social and spatial segregation in the country, the legal system and the regulation of the marriages, the identitarian discourse building processes and the gender relationships, amongst other aspects. In this context, the Palestinian-Jewish couples should face difficulties and limitations, so they will need to develop several strategies to confront them. The ethnographic data collected in the fieldwork, the conceptual analysys of the terms used in the country to define the Israeli population and another complementary sources will allow to present a picture of the social, legal and political reality of the State of Israel
Geva-Kleinberger, Aharon. "Die arabische Stadtdialekte von Haifa in der ersten Hälfte des 20. Jahrhunderts /." Wiesbaden : O. Harrassowitz, 2004. http://catalogue.bnf.fr/ark:/12148/cb39983009n.
Повний текст джерелаIntroduction et commentaires en allemand. Glossaire arabe transcrit-allemand-hébreu. Bibliogr. en allemand, en arabe et en hébreu. Bibliogr. p. 347-357. Notes bibliogr.
Hidalgo, Mendieta Fidel Julio. "Ventilación de minas Catuva, Hada y Esperanza, Cía. Minera Raura S.A." Universidad Nacional de Ingeniería. Programa Cybertesis PERÚ, 1991. http://cybertesis.uni.edu.pe/uni/1991/hidalgo_mf/html/index-frames.html.
Повний текст джерелаAl, Mutary Hayfa Hamed A. "Exploring symptom clusters in people with chronic kidney disease." Thesis, Queensland University of Technology, 2017. https://eprints.qut.edu.au/103986/1/Hayfa%20Hamed%20A_Al%20Mutary_Thesis.pdf.
Повний текст джерелаBen-Ze'ev, Efrat. "Narratives of exile : Palestinian refugee reflections on three villages, Tirat Haifa, 'Ein Hawd and Ijzim." Thesis, University of Oxford, 2000. http://ora.ox.ac.uk/objects/uuid:66344f8f-5b2f-4824-9719-37b642325bc2.
Повний текст джерелаRifai, Ghada Issa Said. "British economic policy in Palestine, 1919-1935 : the construction of Haifa harbour : a case study." Thesis, Queen Mary, University of London, 2017. http://qmro.qmul.ac.uk/xmlui/handle/123456789/24736.
Повний текст джерелаLAHMER, ABDERRAHIM. "Le rituel therapeutique de la "hadra" dans la confrerie marocaine des jilala a el jadida." Paris 7, 1986. http://www.theses.fr/1986PA070067.
Повний текст джерелаThe jilala are brotherhood in el jadida, morocco. The therapeutic rituel is organised in some occasion. The ceremony begin by a sacrifice, then men and women are invited to dance all the night. The music instruments are "bendir" and "qasba". The ecstatic dance is invocation of spirits named "m'luk"
Abdou, Mahmoud Amir, and Ted Dahlqvist. "Ånghuvud för steamer." Thesis, Halmstad University, School of Business and Engineering (SET), 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:hh:diva-4631.
Повний текст джерелаFöljande examensjobbs rapport bygger på examensjobbskursen i CAD-teknikerprogrammet årskurs två.
Arbetet som rapporten bygger på är utfört i samarbete med Hafa badrum i Halmstad. Arbetet innefattar utvecklingen av ångmunstycke för steamrar, en slags ångdusch som är en blandning av ångbastu samt dusch. Skälet bakom utvecklingen är att passa in ångmunstycket med Hafas övriga design, samt att försöka få så lite överskottsvatten som möjligt.
Det kom fram en gemensam idé att integrera ångmunstycket, under ett möte med Hafa, som sedan spann vidare och blev den första prototypen.
Prototypen visade sig vara lyckad, även om skydd för ångan var tvunget att tillverkas då den kom ut för starkt i duschen, främst då lite spillvatten skapades och för att prototypen endast hade en tredjedel av materialmängden jämfört med den modell Hafa har idag.
Metoden som följdes var den samme som användes av oss i princip-, primär-, och tillverkningskonstruktions kurserna.
The following report is for CAD-technicians 2nd year.
The task that the report is built on is done in collaboration with Hafa AB. The task is to develop a new steam nozzle for steamers, a sort of combination of steam sauna and a shower. The reasoning behind the development is to make the steam nozzle match with Hafa’s current design and to gain as little wasted water as possible.
There came forth a mutual idea to integrate the steam nozzle into the shower column, during a meeting with Hafa, which we developed further and became the first prototype.
The prototype showed to be a success, even though protection for the steam had to be made since it flowed into the steamer at a rate which was not acceptable, mainly because little water was wasted and because the prototype was just a third of the original steam nozzle’s size.
The method that we used was the same that was used by us during earlier courses in the CAD-technicians programme.
Haffa, Daniel [Verfasser], and Jörg [Akademischer Betreuer] Schreiber. "Tailored online diagnostics for a laser-driven plasma ion source prototype / Daniel Haffa ; Betreuer: Jörg Schreiber." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/1198112506/34.
Повний текст джерелаBorbara, Anna. "The impact of societal culture on leadership in Arab secondary school in Haifa area in Israel." Thesis, University of Leicester, 2005. http://hdl.handle.net/2381/30893.
Повний текст джерелаBrateljevic, Ana. "Významní harfisté 20. století." Doctoral thesis, Akademie múzických umění v Praze.Hudební a taneční fakulta. Knihovna, 2016. http://www.nusl.cz/ntk/nusl-253670.
Повний текст джерелаTarzi, Zemaryalai. "Hadda a la lumiere des fouilles afghanes de tapa-e-shotor et tapa-e-top-e -kalan." Université Marc Bloch (Strasbourg) (1971-2008), 1991. http://www.theses.fr/1991STR20026.
Повний текст джерелаArchaeological site of afghanistan famous for the discovery of countless buddhist statues moulded in stucco, clay or cut in schist or limestone characterized by an art definitly of hellenistic inspiration, hadda and its artistic school are tought of an essential link in the history of the relations between the west and the indian world in the fertile plain of the present djallalabad (nagarahara of ancient times), hadda owes part of its prosperity to its geografical position, advantage by the roads connecting the great towns and the holly places of buddhism. Being itself an important place where relics of buddha were kept, it became a well knowed artistic center. Every where all around of hadda the hi-lo (hidda) of the chines straveller, tens of buddhist monastries saw the light from the 1st-2nd to 5nd centuries and the 8-9nd centuries a. D. The six years of excavations of hadda and specially the sites of tapa-e-shotor (tsh) and tapa-e-top-e-kalan (ttk) allowed the candidate to get cnough knowledge so that he considers the art of hadda not as a descendant of the artistic school called "greco-buddhic art" of gandhara (north-west of india which sat astride between the present afghanistan and pakistan) but like a parallel evolution to the last one becauses the difference was mainly due to materials used
Crittenden, Alyssa Noelani. "Allomaternal care and juvenile foraging among the Hadza implications for the evolution of cooperative breeding in humans /." Diss., [La Jolla] : University of California, San Diego, 2009. http://wwwlib.umi.com/cr/ucsd/fullcit?p3356207.
Повний текст джерелаTitle from first page of PDF file (viewed July 2, 2009). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 119-138).
Perrier, Pierre. "Étude des schémas actanciels des verbes agglomérés en -hada, -tweda et -sikhida en coréen moderne." Thesis, Sorbonne université, 2020. http://www.theses.fr/2020SORUL131.
Повний текст джерелаThe aim of this descriptive study is to carry out a morphosyntactic analysis, with semantic correlates, of the actancial patterns of the agglomerated verbs of modern Korean, with pattern [ N - V ], N being an action noun constituting the lexical base and V a grammaticalized verb which can be hada, to͡eda or çikhida. The examination of linguistic data leads to consider the following paradigm of verbs of a certain productivity : hada, to͡eda, patta, taŋhada and çikhida. The study is based on a sample of 35 lexical bases compatible with at least three of these grammaticalized verbs cited, including hada. It also analyses a corpus of statements extracted from the Web, based on aggregated verbs including these bases and attesting to their use in the formal register of oral lan-guage. The corpus of utterances allows a contrastive study of the utterances that were based on verbs with the same lexical base. The results obtained are interpreted according to Lazard's actance model. The results show that the grammaticalized verbs quoted allow actance variations of three orders: differential marking of the ob-ject, indirect construction and diathesis variation. These diathesis variations use two operations of transfor-mation of the actancian scheme associated with the lexical base, diathesis and transitivation according to Creis-sels' terms. The set of facts examined shows that the actance variations observed mainly depend on the follow-ing factors: communicative aim, telicity of the process, semantic type of process and semantic characterization of the arguments in terms of animosy and intentionality
Mousa, Bacha Hedvika. "Francouzští harfový virtuózové a jejich skladatelský přínos." Master's thesis, Akademie múzických umění v Praze.Hudební a taneční fakulta. Knihovna, 2012. http://www.nusl.cz/ntk/nusl-156032.
Повний текст джерелаEl, Kilani Haifa [Verfasser], and Christian [Akademischer Betreuer] Betzel. "Structural Characterization of Cell Wall and Plasma Membrane Proteins of Arabidopsis thaliana / Haifa El Kilani ; Betreuer: Christian Betzel." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2017. http://d-nb.info/1148650539/34.
Повний текст джерелаBonamy, Alice. "En quête d'une citoyenneté palestinienne, études des élites arabes palestiniennes à Jaffa et Haïfa dans la première moitié du XXè siècle." Thesis, Nantes, 2017. http://www.theses.fr/2017NANT2056.
Повний текст джерелаThe thesis is mainly based of Arab Palestinian sources, considered from a historical and socoloqícaí perspective. lt descríbes the paths taken by several members of the Palestinian elites, who wrote and published thetr Memories: 'Isa aí-Tsa who was both the owner of the newspaper Filas _!In and a businessman in Jaffa, Rasïd al-l;Jäjj 'roräntm. a banker and a resistant. in Haifa. or Khayrï 'Abü al-Jabayn, a young student who was the he.ir of a great family of orarqes-exporters in Jaffa Apart from those writtten Memories, this dissertation is based on the study of a collection ot oral sources and on the study of the archives of Filas .t:rn and al-KarmiJ; that were the two main newspapers, respectively printed in Jaffa and Haifa during much of the period of the British mandate in Palestine, The combination ot tnose different sauces allows the work of reconstructing the territories of the urban and coastal elites: the scholar and university territories. the leisure iermores, the ,economical territories, tt1e cultural and political territories, Those elites are multifaceted social groups, fitted with « muitipJekJyal.ûes )> (to use Rashid Khalidi's words). They alternate resistance and accomoeaton towards the different occupiers, obedience of emancipation towards the national networks of patronage controlled try the great families from Jerusalem. Through their economical and intellectual activities, the eines formulate society projects. in the hopes of a nypothecal national independence. While considering their careers, training and background, sociability networks, professional and intellectual activities, we can .implicitely describe the different forms of a Palestinian citizenships present in their mind : for the emes are influenced ln that matter by both their Arab and/or Palestinianidentity and the Ottoman or European models
Hindi, Hanan. "Postcolonial Palestinians in Ghassan Kanafani's Works: Men in the Sun, All That's Left to You and Returning to Haifa." Kent State University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=kent1532086829180848.
Повний текст джерелаCarrara, Simona. "Neznámý harfový manuskript od Elias Pari sh Alvarse v archivu Českého muzea hudby v Praze." Master's thesis, Akademie múzických umění v Praze.Hudební a taneční fakulta. Knihovna, 2012. http://www.nusl.cz/ntk/nusl-156120.
Повний текст джерелаAves, León Wilmer, López Adela Miranda, Morey Diana Moro, Robles Elena Rodríguez, and Shimon Farja. "Las relaciones Arabe-Israelíes : condiciones actuales para una negociación de paz : entrevista a Shimon Farja, profesor de la Universidad de Haifa, Israel." Derecho & Sociedad, 2015. http://repositorio.pucp.edu.pe/index/handle/123456789/118479.
Повний текст джерелаFelipe, Fernanda Pereira de. "Avaliação do potencial tóxico das microalgas Heterosigma akshiwo (Hada) e Prorocentrum minimum (Pavillard) schiller sobre copépodes planctônicos do gênero Acartia." reponame:Repositório Institucional da UFPR, 2013. http://hdl.handle.net/1884/30279.
Повний текст джерелаKöhler, Hadia Sabine Verfasser], Marlies [Akademischer Betreuer] Schulz, Harald A. [Akademischer Betreuer] [Mieg, and Martin [Akademischer Betreuer] Lanzendorf. "Kopplungen am Arbeitsort : ein synchronischer Vergleich der Aktivitätenkopplungen Erwerbstätiger an ihrem Arbeitsort / Hadia Sabine Köhler. Gutachter: Marlies Schulz ; Harald A. Mieg ; Martin Lanzendorf." Berlin : Humboldt Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät II, 2013. http://d-nb.info/1035234823/34.
Повний текст джерелаKöhler, Hadia [Verfasser], Marlies Akademischer Betreuer] Schulz, Harald A. [Akademischer Betreuer] [Mieg, and Martin [Akademischer Betreuer] Lanzendorf. "Kopplungen am Arbeitsort : ein synchronischer Vergleich der Aktivitätenkopplungen Erwerbstätiger an ihrem Arbeitsort / Hadia Sabine Köhler. Gutachter: Marlies Schulz ; Harald A. Mieg ; Martin Lanzendorf." Berlin : Humboldt Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät II, 2013. http://nbn-resolving.de/urn:nbn:de:kobv:11-100209585.
Повний текст джерелаAdel, Abdelrehim Mohamed Soliman Hadya [Verfasser], Wolfgang [Gutachter] Lenhard, and Peter [Gutachter] Marx. "Structural Equation Modeling of Factors Influencing EFL Reading comprehension: Comparative study between Egypt and Germany / Hadya Adel Abdelrehim Mohamed Soliman ; Gutachter: Wolfgang Lenhard, Peter Marx." Würzburg : Universität Würzburg, 2019. http://d-nb.info/1194313892/34.
Повний текст джерелаFigueiredo, Carolina Ferreira de. "Traços de uma haifa vermelha : um estudo sobre a cultura visual da sociedade palestina/israelense através de charges e ilustrações do artista palestino Abed Abdi (1972-1982)." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2016. http://hdl.handle.net/10183/142947.
Повний текст джерелаThis work aims to analyze the visual culture presented in Israel and Palestine during the 1970s and 1980s, through the unique interaction between the images spectrum and the political struggle in Palestine. The study is concerned to understand territories and the scope of Palestinian visuality, especially due to the disruption caused since 1948 - the birthdate of the State of Israel, known as Nakba - and its various developments. To deepen the understanding of visual reverberations in the political experience of artists (and) Palestinians, it will be explored images of everyday appeal and far-reaching, specifically cartoons and illustrations produced by the Palestinian artist Abed Abdi between the years 1972 and 1982: the first ones published in the Al-Ittihad newspaper (1972-1981), and the second ones produced for the literary magazine Al-Jadid (1980-1982). The time frame chosen is set in a moment of a rich production of the artist, also due to his leftist ideological position, filiation to the Communist Party of Israel and the formal studies taken in Dresden, underlying elements to Abdi´s biography. His critical production, markedly political, provides pictures of a complex scenario of relations between Israel, Palestine, other Middle Eastern countries and the rest of the world in the period. Therefore, in between history and art, visuality and politics, it is addressed themes such as identity and historiographical construction of the Nakba, the artistic productions of the Nakba, the construction of the Nation, the insertion of Communism, the nature of the journals, the presence of Palestinian intellectuals, among others. The problem, finally, consists in the hypothesis of the centrality of the visual in the processes of afirmation, discussion, confrontation and expression of the Palestinian causes in the twentieth century. In this scenario, the images produced by Abed Abdi during the 1970s and 1980s are relevant because they provide a visual repertoire in discussing Palestine politically, not only in its relations with Israel and an Arab World, but from their own terms.
Hesko, Branislav. "Aktivní kontury pro segmentaci ultrazvukových dat." Master's thesis, Vysoké učení technické v Brně. Fakulta elektrotechniky a komunikačních technologií, 2015. http://www.nusl.cz/ntk/nusl-221388.
Повний текст джерелаEsseili, Fatima A. "Deictic Reference: Arabs vs. Arab Americans." University of Toledo / OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1147284821.
Повний текст джерелаSilva, Ana Cibartira Bernardo da. "O conto de fada Cinderela: uma análise dos tempos verbais." Universidade Presbiteriana Mackenzie, 2010. http://tede.mackenzie.br/jspui/handle/tede/2310.
Повний текст джерелаEste trabajo objetiva analizar los tiempos verbales en tres versiones del cuento de hada Cenicienta, llevándose en consideración que los tiempos, en esos cuentos, no indican Tiempo Cronológico ni Tiempo Real, pero desempeñan importante función, dado que presentan al lector/oyente un mundo diferente del suyo y, por lo tanto, no le concierne. Esta pesquisa se fundamenta en los postulados de Harald Weinrich, sobre los dos grupos temporales que focalizan el mundo narrado y el mundo comentado. Esos grupos determinan qué actitud el lector/oyente debe tener en cuanto a lo que está leyendo o escuchando. Para ello, en las tres versiones, se ha elaborado un levantamiento de los símbolos que guían ese tipo de narrativa fantástica, con los respectivos tiempos verbales, como estratégia de análisis.
Este trabalho objetiva analisar os tempos verbais em três versões do conto de fada Cinderela, Tendo em vista que os tempos, nesses contos, não indicam Tempo Cronológico ou Tempo real, mas desempenham importante função, visto que apresentam ao leitor/ouvinte um mundo diferente do seu e, portanto não lhe diz respeito. Esta pesquisa fundamenta-se nos postulados de Harald Weinrich, sobre os dois grupos temporais que focam o mundo narrado e o mundo comentado. Esses grupos determinam que atitude leitor/ouvinte deve ter em relação ao que está lendo ou escutando. Para tal, nas três versões, foi elaborado um levantamento dos símbolos que norteiam esse tipo de narrativa fantástica, com os respectivos tempos verbais, como estratégia de análise.
Al-Ali, Haifa Kathrin [Verfasser], Christoph [Gutachter] Baerwald, and Thomas [Gutachter] Berg. "The impact of the age of HLA-identical siblings on mobilization and collection of PBSCs for allogeneic hematopoietic cell transplantation : The impact of the age of HLA-identical siblings onmobilization and collection of PBSCs for allogeneichematopoietic cell transplantation / Haifa Kathrin Al-Ali ; Gutachter: Christoph Baerwald, Thomas Berg." Leipzig : Universitätsbibliothek Leipzig, 2015. http://d-nb.info/1239566492/34.
Повний текст джерелаK, GAYATHRI DEVI. "SCHEDULING IN FLEXIBLE MANUFACTURING SYSTEM (FMS) USING SOFT COMPUTING TECHNIQUES." Thesis, 2023. http://dspace.dtu.ac.in:8080/jspui/handle/repository/20197.
Повний текст джерелаDay, David D. "Hafa nu ond geheald husa selest: Jurisdiction and justice in "Beowulf"." Thesis, 1992. http://hdl.handle.net/1911/16549.
Повний текст джерелаHussein, Khadra [Verfasser]. "Palästinensische Studentinnen an israelischen Hochschulen : untersucht an der Universität Haifa / von Khadra Hussein (Kablawie)." 2006. http://d-nb.info/98171255X/34.
Повний текст джерелаFerreira, Andreia Sofia da Costa de Mónica. "Oxidoreductase protein family interaction with DJ-1 and oxidative stress-induced modulation of HADHA interactome." Master's thesis, 2016. http://hdl.handle.net/10316/33519.
Повний текст джерелаA doença de Parkinson (DP) é a segunda doença neurodegenerativa mais comum, sendo a mais incidente dentro das doenças do movimento, e caracterizada por uma drástica perca de neurónios dopaminérgicos na região cerebral substantia nigra pars compacta (SNpc), levando à degeneração dos circuitos dopaminérgicos nigroestriatais. Várias evidências apontam para diversas disfunções celulares importantes na patogénese da DP, incluindo o stress oxidativo. Apesar de vários estudos na área terem sido realizados para uma maior elucidação sobre a doença, a etiologia e patogénese da Doença de Parkinson continuam por estar esclarecidas. No entanto, é sabido que a causa da maioria dos casos de DP são esporádicos, e que alguns casos raros têm uma componente genética, hereditária. De facto, diversas mutações em diversos genes têm sido identificadas como causadoras da forma hereditária da doença, o que contribuiu com importantes conhecimentos sobre os mecanismos moleculares que levam à neurodegeneração. O gene dj1, associado às formas genéticas da DP, foi identificado como sendo um gene autossómico recessivo responsável pela DP familiar, que se desenvolve em idades mais novas, o que o torna um candidato para ser estudado de forma a fornecer importantes conhecimentos sobre os mecanismos moleculares da doença. Várias funções foram atribuídas à proteína DJ-1, no entanto o seu papel de neuroprotecção é o mais relevante, provavelmente devido ao seu envolvimento na proteção contra o stress oxidativo. Estudos indicam que a proteína DJ-1 opera em diversos níveis interagindo, direta ou indiretamente, com várias proteínas. Apesar dos mecanismos através dos quais a proteína exerce a sua função neuroprotetora não serem completamente conhecidos, esta aparenta ter uma importante função na mediação de vias de sinalização e na modelação do metabolismo oxidativo. Vários estudos demonstraram que de facto o stress oxidativo é a condição que despoleta a função neuroprotectiva da DJ-1, alterando a conformação da proteína para uma forma oxidada, que é considerada a sua forma ativa. Além do mais, a estabilidade da maioria das interações estudadas entre a DJ-1 e outras proteínas é influenciada pelo seu estado oxidativo. Tendo isto em mente, o interatoma dinâmico da DJ-1 foi anteriormente estudado, de forma a fornecer uma caracterização abrangente dos interatores da proteína em condições do stress oxidativo. Este estudo possibilitou a identificação de diversas proteínas que interagem com a DJ-1, nomeadamente proteínas pertencentes à família das oxidoredutases, que estão relacionadas com a resposta celular ao stress oxidativo, como a NDUFA4, PGDH e a HADHA. No entanto, as interações da DJ-1 com essas proteínas estão ainda por serem validadas. Dentro deste contexto, diversas análises complementares foram realizadas de forma a validar a interação da DJ-1 com as proteínas pertencentes à família das oxidoredutases, incluindo imunoprecipitação, pull down e imunocitoquímica seguida de uma análise por microscopia confocal, em condições fisiológicas e de stress oxidativo. através do ensaio de imunocitoquímica seguido de análise por confocal das células SH-SY5Y, foi possível validar a interação entre as proteínas in situ, o que parece confirmar que tanto a HADHA como a PGDH são interatores da DJ- 1. Além disso, os resultados obtides através da análise por pull down sugerem uma interação das proteínas HADHA e PGDH com a proteína DJ-1 recombinante, na sua forma nativa, sendo essa interação aparentemente modelado pelo stress oxidativo, o que vem corroborar a os esukltados anteriores.foi utilizado de forma a estudar o interatoma da proteína em células SH-SY5Y em células expostas ao stress oxidativo ou em condições fisiológicas, de forma a aferir o envolvimento desta proteína na resposta celular ao stress oxidativa, e para expandir o interactoma dinâmico da DJ-1. Com esta metodologia, foi possível concluir que a proteína HADHA tem um interatoma dinâmico que é modelado pelo stress oxidativo. Diversas proteínas foram identificadas como interatores, pertencendo a diversos grupos funcionais, tais como proteínas do citoesqueleto, proteínas motoras, proteínas envolvidas na reparação do DNA e expressão de genes, e proteínas envolvidas em diferentes vias de sinalização. Além disso, muitas das proteínas identificadas como potenciais interatores da HADHA foram também anteriormente identificadas como interatores da DJ-1. A generalidade das proteínas quantificadas apresentou um aumento de interação com a HADHA em condições de stress oxidativo, fornecendo informações fundamentais sobre as suas funções biológicas associada à resposta celular a essa patologia, apontando para uma nova função da proteína HADHA relacionada com a proteção neuronal contra o stress oxidativo. Estes resultados contribuíram também para o aprofundar dos conhecimentos sobre a patogénese da doença de Parkinson, as potenciais vias envolvidas no despoletar da doença e a sua progressão, podendo fornecer novos potenciais alvos para o prognóstico, terapia e progressão da DP.
Parkinson’s disease (PD) is the second most common neurodegenerative disease and the most common movement disorder, characterized by massive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), leading to degeneration of nigrostriatal dopaminergic pathways. Evidence suggest several cellular dysfunctions important for pathogenesis in PD, including oxidative stress. Even though several efforts have been made to obtain a deeper knowledge of this disease, the etiology and pathogenesis still remain unclear. Nevertheless, there is an agreement that the majority of PD cases are sporadic and some rare cases have familial background. Indeed, mutations in several genes have been reported to cause hereditary forms of the disease, leading to valuable insights into the molecular mechanisms of neurodegeneration. Among the genetic forms, Dj1 gene was identified as an autosomal recessive gene responsible for familial early-onset PD, meaning that deeper knowledge on its physiological functions will provide important insights into molecular mechanisms of PD. Several functions have been attributed to DJ-1 protein, being its putative role in neuroprotection the most relevant, probably due to its involvement in protection against oxidative stress. Evidence indicate that DJ-1 operates at multiple levels and interact, directly or indirectly, with several partners. Although the mechanisms through which DJ-1 mediates neuroprotection is not fully understood, it seems to play a pivotal role in the mediation of signaling pathways and modulation of the oxidative metabolism. Several studies reported that indeed oxidative stress is the trigger condition for DJ-1 neuroprotective function, in a way that conformational changes to an oxidized form were pointed out as protein’s active form. Moreover, the stability of the majority of the interactions reported is also influenced by the oxidation state of DJ-1. A dynamic DJ-1 interactome screening was previously made in order to provide a comprehensive characterization of DJ-1 binding partners under oxidative stress conditions, leading to the identification of several binding partner. From those, proteins belonging to oxidoreductase family were identified, which are mainly associated with cellular response to oxidative stress, such as NDUFA4, PGDH and HADHA. However, such interactions still require validation. Based on this, complementary assays were performed to validate DJ-1 interaction with oxidoreductase proteins, such as immunoprecipitation, pull down assay, and immunocytochemistry followed by confocal analysis, in normal and oxidative stress conditions. iImunocytochemistry assay followed by confocal analysis of SH-SY5Y cells revealed that DJ-1 interacts with both PGDH and HADHA proteins in situ, thus confirming they are indeed binding partners. Moreover, pull down approach results suggested an interaction between HADHA and PGDH with recombinant WT DJ-1, which is modulated by oxidative stress., thus corroborating previous assumptions. After confirming HADHA as a DJ-1 bindings partner, an AP-SWATH approach was used to study HADHA interactome in SH-SY5Y cells exposed to normal and oxidative stress conditions, to assess this protein’s involvement in cellular response to oxidative stress, and to expand DJ-1’s dynamic interactome. With this methodology, it was possible to conclude that HADHA has a dynamic interactome that it is modulated by oxidative stress conditions. Several proteins were identified as binding proteins, like cytoskeleton proteins, motor proteins, proteins involved in DNA repair and gene expression, and in different signaling pathways. Moreover, some of the identified HADHA putative interactors were previously also identified as DJ-1 interactors. The majority ofproteins quantified showed an increased interaction with HADHA in oxidative stress conditions, thus providing insights into their biological functions in cellular response to such insult, pointing to a new HADHA role in neuronal protection against oxidative stress. Such results, also contribute to deeper knowledge on PD pathogenesis, the distinct pathways involved in the establishment and progression of the disease, highlighting potential new targets for PD prognosis, therapy and prevention.
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