A proteo-liposome system for the analysis of the intracellular interactome of membrane proteins using amyloid precursor protein as a model

Transmembrane proteins play crucial roles in many important physiological processes. The intracellular domain of membrane proteins is key for their function by interacting with a wide variety of cytosolic proteins. It is therefore important to examine this interaction. A recently developed method to study these interactions, based on the use of liposomes as a model membrane, involves the covalent coupling of the cytoplasmic domains of membrane proteins to the liposome membrane. This allows for the analysis of interaction partners requiring both protein and membrane lipid binding. This thesis further establishes the liposome recruitment system and utilises it to examine the intracellular interactome of the amyloid precursor protein (APP), most well-known for its proteolytic cleavage that results in the production and accumulation of amyloid beta fragments, the main constituent of amyloid plaques in Alzheimer’s disease pathology. Despite this, the physiological function of APP remains largely unclear. Through the use of the proteo-liposome recruitment system two novel interactions of APP’s intracellular domain (AICD) are examined with a view to gaining a greater insight into APP’s physiological function. One of these novel interactions is between AICD and the mTOR complex, a serine/threonine protein kinase that integrates signals from nutrients and growth factors. The kinase domain of mTOR directly binds to AICD and the N-terminal amino acids of AICD are crucial for this interaction. The second novel interaction is between AICD and the endosomal PIKfyve complex, a lipid kinase involved in the production of phosphatidylinositol-3,5-bisphosphate (PI(3,5)P2) from phosphatidylinositol-3-phosphate, which has a role in controlling ensdosome dynamics. The scaffold protein Vac14 of the PIKfyve complex binds directly to AICD and the C-terminus of AICD is important for its interaction with the PIKfyve complex. Using a recently developed intracellular PI(3,5)P2 probe it is shown that APP controls the formation of PI(3,5)P2 positive vesicular structures and that the PIKfyve complex is involved in the trafficking and degradation of APP. Both of these novel APP interactors have important implications of both APP function and Alzheimer’s disease. The proteo-liposome recruitment method is further validated through its use to examine the recruitment and assembly of the AP-2/clathrin coat from purified components to two membrane proteins containing different sorting motifs. Taken together this thesis highlights the proteo-liposome recruitment system as a valuable tool for the study of membrane proteins intracellular interactome. It allows for the mimicking of the protein in its native configuration therefore identifying weaker interactions that are not detected by more conventional methods and also detecting interactions that are mediated by membrane phospholipids.

Governance in foreign policy-making in Germany and Poland and Polish-German relations:the role of non-state actors

This thesis examines the influence of non-state actors on Polish-German relations by considering foreign policy-making towards Poland in Germany and vice versa. The approach chosen for this thesis is interdisciplinary and takes into consideration literature from domestic politics (Area Studies), Foreign Policy Analysis and International Relations (IR). The thesis argues that IR, by purely looking into the quality of inter-state relations, too often treats these relations as a result of policies emanating from the relevant governments, without considering the policies’ background. Therefore, the thesis argues that it is necessary to engage with the domestic factors which might explain where foreign policies come from. It points out that non-state actors influence governments’ choices by supplying resources, and by cooperating or competing with the government on an issue at stake. In order to determine the degree of influence that non-state actors can have on foreign policymaking two variables are examined: the institutionalisation of the state relations in question; and the domestic structures of the relevant states. Specifically, the thesis examines the institutionalisation of Polish-German relations, and examines Germany’s and Poland’s domestic structures and their effect on the two states’ foreign policy-making in general. Thereafter, the thesis uses case studies in order to unravel the influence of non-state actors on specific foreign policies. Three case studies are examined in detail: (i) Poland’s EU accession negotiations with regard to the free movement of capital chapter of the acquis communautaire; (ii) Germany’s EU 2004 Eastern Enlargement negotiations with regard to the free movement of workers chapter of the acquis communautaire; and (iii) Germany’s decision to establsh a permanent exhibition in Berlin that will depict the expulsions of millions of Germans from the East following WWII.

A gazdasági teljesítmények vállalkozási mérettől függő jellemzői Magyarországon = Changing ownership and business structures in the Hungarian economy

A mögöttünk hagyott két évtizedben – tetszik, vagy sem – a magyar gazdaság 1992. évi mélypontról történő kilábalásában, majd új növekedési pályára állásában meghatározó szerepe volt a hazai forrásokat kiegészítő külföldi befektetéseknek. Ennek természetesen ára volt: a tevékenységi struktúra (termékszerkezet) módosulása, a tulajdonosi összetétel radikális átalakulása, a külgazdasági kapcsolatok irányultságának változása, a lakosság önfoglalkoztatási célú vállalkozásainak szaporodása, a gazdaságfejlesztés irányának és ütemének cikk-cakkos mozgása, az állami szerepkör fokozatos leépülése. Írásunk célja annak áttekintése, hogy a nemzetközi tőkeáramlás tendenciáinak módosulását követően – a Magyarországra érkező külföldi tőkebefektetések jelentős csökkenéséből fakadóan – a kizárólagos és többségi hazai tulajdonú szereplők (kiemelten a hazai közép- és kisvállalkozások) milyen mértékben lehetnek alkalmasak a kieső teljesítmények pótlására, illetve a gazdasági válság lecsengését követően milyen ütemű növekedést képesek biztosítani a magyar gazdaság számára. A válaszok nagy valószínűséggel az Új Széchenyi Terv szempontjából sem közömbösek. Az írást a szerkesztőség vitairatnak szánja és szívesen ad teret a témával kapcsolatos vélemények kifejtésének. / === / The economic performance during the transition period was characterized by the alternations of fulfilled hopes and unrealized expectations. The economic restructuring and changes in market relations took place during the first decade, while new – mostly foreign – investment groups entered the new market. As a result the economy was stabilized and was put on a new growth path. But after the millennium the foreign investment based economy development strategy was no more adequate. The new engine for the growth should have been the domestic small and medium enterprise sector (SME), but despite the subsidies this sector was not strengthened enough to take this role.

A fogyasztói etnocentrizmus új koncepcionális modelljének kialakítása és verifikálása = Forming and verification of a new conceptual model of the customer ethnocentrism

A szerzők cikke az etnocentrikus érzelmek hatását mutatja be a hazai és a külföldi termékek megítélésére. Empirikus kutatásaikra és regressziós modelljeikre támaszkodva felvázolják azt a hatásmechanizmust, amely a szakirodalomba a fogyasztói etnocentrizmus néven vonult be. Megállapítják, hogy másképp hatnak a patrióta és a nacionalista érzelmek a hazai és a külföldi termékek iránti attitűdökre. Míg a hazai termékeknél egy karakterisztikus, többdimenziós kép tárul elénk, addig a cseh, kanadai és német termékek megítéléséből általánosított, külföldi termékek esetében csak a termékkel való azonosulást tudták kiemelni. A megkérdezettek demográfiai jellemzői közül egyedül a férfiak mutattak statisztikailag azonos irányú és erősségű kapcsolatot a hazai és a külföldi termékek megítélésénél. _______________________ The authors’ article presents effects of the ethnocentric emotion of the appreciation of the domestic and foreign goods. Based on their empirical and regressive models they feature that effectmechanism, which is named consumer ethnocentrism in the special literature. They set that the patriot and the nationalist emotions acting differently on attitudes of the domestic and the foreign goods.

A kiskereskedelmi stratégiai szövetségek hatása a kiskereskedelmi marketing tevékenységére és teljesítményére = Effects of the retail strategic alliances to the retailers' marketing activity and performance

A kilencvenes évek második felétől egyre jelentősebb szerepet játszanak a vállalatközi együttműködések, hosszabb távú kooperációk a hazai élelmiszer- és napi cikk kiskereskedelemben. A társulások szintjén a piaci siker egyértelmű, amely jól nyomon követhető az évente megjelenő kiskereskedői rangsorokban. A cikk viszont a tagkereskedők szemszögéből vizsgálja a kérdést, vajon a társuláshoz való csatlakozás ténylegesen javítja-e a kiskereskedő teljesítményét és milyen dimenziókon keresztül. _____________ From the second half of the ’90s the strategic alliances, the long term cooperations have been increasingly role in the domestic food and FMCG retail. On the level of the alliances the market success has been obvious, which has well presented in the annual retail rankings. The article examines the issue from the retailers’ point of view: whether the accession to the alliance has effectively improved the retalier’s performance and which dimensions through.

Rules-based economic governance in the European Union: A reappraisal of national fiscal rules.

The economic and financial crisis of 2007/2009 has posed unexpected challenges on both the global and the regional level. Besides the US, the EU has been the most severely hit by the current economic crisis. The financial and banking crisis on the one hand and the sovereign debt crisis on the other hand have clearly shown that without a bold, constructive and systematic change of the economic governance structure of the Union, not just the sustainability of the monetary zone but also the viability of the whole European integration process can be seriously undermined. The current crisis is, however, only a symptom, which made all those contradictions overt that were already heavily embedded in the system. Right from the very beginning, the deficit and the debt rules of the Maastricht Treaty and the Stability and Growth Pact have proved to be controversial cornerstones in the fiscal governance framework of the European Economic and Monetary Union (EMU). Yet, member states of the EU (both within and outside of the EMU) have shown an immense interest in adopting numerical constraints on the domestic level without hesitation. The main argument for the introduction of national fiscal rules was mostly to strengthen the accountability and credibility of national fiscal policy-making. The paper, however, claims that a relatively large portion of national rules were adopted only after the start of deceleration of the debt-to-GDP ratios. Accordingly, national rules were hardly the sole triggering factors of maintaining fiscal discipline; rather, they served as the key elements of a comprehensive reform package of public budgeting. It can be safely argued, therefore, that countries decide to adopt fiscal rules because they want to explicitly signal their strong commitment to fiscal discipline. In other words, it is not fiscal rules per se what matter in delivering fiscal stability but a strong political commitment.

Vezetői döntéshozatal és versenyképesség (The managerial decision making and the competitiveness)

A tanulmány a vezetői döntéshozatal három lényeges aspektusát tárja fel. A Versenyben a világgal c. kutatási program eredményei alapján arra lehet következtetni, hogy a menedzserek döntéshozatali képességei és megközelítései, a vállalati teljesítménymérés és menedzsment döntéseket támogató szerepe, valamint a vállalatok érintettekhez fűződő viszonya meghatározó lehet a hatékony vezetői döntéshozatal során. A vállalati döntéshozatal jellemzőinek bemutatása után megvizsgáljuk azt is, hogy a különböző teljesítményű cégek döntéseit mennyire támogatja a menedzserek felkészültsége, a teljesítménymérési gyakorlat és az érintettek elvárásai. A szerzők úgy találták, hogy a fenti tényezők mindegyike hozzájárul a hazai cégek versenyképességéhez, általánosságban ugyanis elmondható, hogy a döntéseket támogató vállalati környezet jobb üzleti teljesítményhez és gyorsabb reagálóképességhez vezethet. Az eredmények összegzése mellett ajánlásokkal is éltek a vállalatok számára, amelyek alkalmazásával hatékonyabb döntéseket hozhatnak. _______ This study presents three main aspects of the managerial decision making. Based on the results of the research program In competition with the World it points to the fact that decision making abilities and approaches of the managers, the corporate performance appraisal and the management decision support role, and the corporate relations to the stakeholders will be determinant in the process of the efficient managerial decision making. After presentation of characteristics of the corporate decision making the authors examine that how the decisions of enterprises with different performances are supported by the preparedness of the managers, the performance appraisal practice and the stakeholders expectations. The authors have thought that every factor contributes to the competitiveness of the domestic enterprises, and generally the decision supporting corporate environment can lead to better business performance and faster responsive abilities. Besides the results summary the authors give useful recommendations to the corporations with which they can make more efficient decisions.

Magyar alkalmazkodás az Európai Unió foglalkoztatás és szociálpolitikájához – tanulságok (The experiences from the Hungarian adaption to the common employment and social policy of the European Union)

A tanulmányban áttekintjük az európai foglalkoztatás- és szociálpolitika kialakulását és történetét, valamint a területen alkalmazott speciális koordinációs módszert. Ezt követően a csatlakozási tárgyalások elemzésével bemutatjuk a hazai politika helyzetét a csatlakozás időpontjában. Az elmúlt időszak foglalkoztatási adatai segítségével megvizsgáljuk a hazai és európai foglalkoztatás- és szociálpolitikai intézkedések hatásait. A cikk zárásaként a magyar EU-elnökség prioritásait és az aktuális közösségi terveket vesszük szemügyre. ______ The article gives a review on the history of the common employment and social policy in the European Union, with special attention to the coordination methods used in the field. The article also analyses the accession negotiations and the domestic policy situation at that time of Hungary's accession to the EU. With the data of recent years, the effects of the Hungarian and common EU measures are also examined. Finally, the priorities of the Hungarian Presidency of the European Council along with the current common policy plans are also demonstrated.

The Europe of Elites. A Study into the Europeanness of Europe's Political and Economic Elites

Contents: 1 Introduction: European integration as an elite project, Heinrich Best, György Lengyel, and Luca Verzichelli; 2 Europe à la carte? European citizenship and its dimensions from the perspective of national elites, Maurizio Cotta and Federico Russo; 3 Ready to run Europe? Perspectives of a supranational career among EU national elites, Nikolas Hubé and Luca Verzichelli; 4 National elites’ preferences on the Europeanization of policy making, José Real-Dato, Borbála Göncz, and György Lengyel; 5 The other side of European identity: elite perceptions of threats to a cohesive Europe, Irmina Matonyté and Vaidas Morkevicius; 6 Elites’ views on European institutions: national experiences sifted through ideological orientations, Daniel Gaxie and Nicolas Hubé; 7 Patterns of regional diversity in political elites’ attitudes, Mladen Lazic, Miguel Jerez-Mir, Vladimir Vuletic, and Rafael Vázquez-García; 8 The elites–masses gap in European integration, Wolfgang C. Müller, Marcelo Jenny, and Alejandro Ecker; 9 Party elites and the domestic discourse on the EU, Nicolo Conti; 10 Elite foundations of European integration: a causal analysis, Heinrich Best; 11 Elites of Europe and the Europe of elites: a conclusion, Heinrich Best; 12 Appendix. Surveying elites: information on the study design and field report of the IntUne elite survey, György Lengyel and Stefan Jahr.

EU-s források a vállalkozások tőkeellátottságának javítására - A JEREMIE Kockázati Tőkeprogram (EU funds to improve the capitalization of the companies – JEREMIE Venture Capital Program)

A hazai kis- és középvállalkozások (kkv-k) tőkeellátottságának javítása meghatározó szerepet játszik fejlődésük előmozdításában. Jelen tanulmány az Új Széchenyi Terv (ÚSZT) keretében a vállalkozások rendelkezésére álló pénzügyi eszközök közül a kockázati tőke működését mutatja be. A fejlődésük növekedési ciklusában járó cégek mellett a korai életszakaszukban járó, innovatív tevékenységet folytató, gyors növekedésre képes, de forráshiányos vállalkozások finanszírozásában nyújthat segítséget Magyarországon a 2010-ben elindult JEREMIE Kockázati Tőkeprogram. Az állami és a privát tulajdonban levő piaci szereplők hazánkban újnak mondható együttműködése révén megvalósuló program a magyar kockázatitőke-piac kínálati oldalának bővítését szolgálja, abban az alsó (döntően az 1-1,5 millió EUR/tranzakció alatti) szegmensben, ahol a tisztán piaci alapon működő befektetők korlátozottabb szerepvállalása figyelhető meg, és így a piacon hiány jelentkezik. Az EU-s támogatások ezen új típusú felhasználási formája színesíti és kibővíti a vállalkozások számára elérhető pénzügyi eszközök körét és volumenét, fokozottabb mértékben érvényesül a piaci szemlélet, hiszen verseny van a forrásokért, és verseny van a források kihelyezését végző pénzügyi közvetítő szervezetek között is, mindezek mellett további magánforrások bevonását biztosítja, ösztönzőleg hat a cégek működésére, és a visszaforgó rendszer biztosítja a fenntarthatóságot, a források későbbi újbóli felhasználását is. _______ To improve the capitalization of the domestic small and medium-sized enterprises (SMEs) has a decisive role in promoting development. This study presents the operation of venture capital from the available business financial instruments of the New Széchenyi Plan. In Hungary the JEREMIE Venture Capital Program, which launched in 2010, can help in financing of the rapidly growth, innovative, early life stage companies besides the development cycle of growth companies. This program with new cooperation between the stateowned and private companies enlarge the supply-side of the Hungarian venture capital market, at that the bottom (mostly in the 1 to 1.5 million EUR / transaction below) segment, where can be observed the limited role of the purely market-based investors, and thus there is a shortage in the market. These new type application form of the EU supports enriches and expands the scope and volume of the available financial instruments for the enterprises, the market orientation prevails more broadly, because there is a competition for resources and there is a competition between the resources allocation financial intermediaries,in addition ensures further private resources.

The impacts of trade policy reforms on the Sri Lankan economy

This dissertation presents an analysis of the impacts of trade policy reforms in Sri Lanka. A Computable General Equilibrium (CGE) model is constructed with detailed description of the domestic production structure and foreign trade. The model is then used to investigate the effects of trade policy reforms on resource allocation and welfare.^ Prior to 1977, Sri Lanka maintained stringent control over its imports through rigid quantitative restrictions. A new economic policy reform package was introduced in 1977, and it shifted Sri Lanka's development strategy toward an export oriented policy regime. The shift of policy focus from a restrictive trade regime toward a more open trade regime is expected to have a significant impact on the volume of external trade, domestic production structure, allocation of resources, and social welfare.^ Simulations are carried out to assess the effects of three major policy reforms: (1) a devaluation of the Sri Lanka rupee, (2) a partial or a complete elimination of export duties, and (3) a devaluation-cum-removal of export duties.^ Simulation results indicate that the macroeconomic impact of a devaluation-cum-removal of export duties can be substantial. They also suggest that the resource-pull effects of a devaluation and a devaluation-cum-export duty removal policy are significant. However, the model shows that a devaluation combined with an export duty reduction is likely to be a superior strategy. ^

Eden in the age of the fifth sun: The narrative work of Homero Aridjis

Homero Aridjis (b. 1940) is a major Mexican poet, novelist, essayist and ecological activist whose prolific body of work, ranging over forty years and including more than eleven volumes of poetry and thirteen novels, has yet to be studied as a coherent literary corpus in the context of recent Latin American fiction. The purpose of this dissertation was to analyze the narrative works of this author as both illustrative of the changes that have occurred in Latin American fiction since the 1960s when it first burst onto the world scene, as well as to study the uniqueness of this particular author's view of literature as it relates to historical discourse, apocalypticism. and social commitment. ^ Research showed that in the case of the narrative style of Aridjis, major trends in the contemporary Latin American novel were present in such a profuse and model manner as to confirm this author's importance as a prime example of what is commonly known as “Post-Boom” fiction. However, beyond the mere presence of literary elements, this study showed that the author's unique approach to narrative style has altered and expanded the aesthetic and thematic possibilities of the contemporary novel. The area where this is most clearly seen is in his experimentation with the historical genre. By manipulating the referential techniques of what has lately come to be known as the “new historical novel,” Aridjis has written both a cycle of purely historical novels and a cycle of futuristic ones that attempt to transcend the temporal limits traditionally imposed by these narrative forms, fusing them into one constant questioning of the nature of love, hate and identity. In this manner, he has developed a “simultaneist” narrative approach where distinct historical and imagined periods, places, people, things, and texts coexist and interact, widening almost to delirium the interpretative possibilities of the work. ^ This unique view of time and narrative, together with the author's political activism and millenarian view of history, make the novels of Homero Aridjis an important element in understanding the continuing development and evolution of Latin American fiction at the turn of the century. ^

Political corruption in the Caribbean Basin: A comparative analysis of Jamaica and Costa Rica

Political corruption in the Caribbean Basin retards state economic growth and development, undermines government legitimacy, and threatens state security. In spite of recent anti-corruption efforts of intergovernmental and nongovernmental organizations (IGO/NGOs), Caribbean political corruption problems appear to be worsening in the post-Cold War period. This dissertation discovers why IGO/NGO efforts to arrest corruption are failing by investigating the domestic and international causes of political corruption in the Caribbean. The dissertation's theoretical framework centers on an interdisciplinary model of the causes of political corruption built within the rule-oriented constructivist approach to social science. The model first employs a rational choice analysis that broadly explains the varying levels of political corruption found across the region. The constructivist theory of social rules is then used to develop the structural mechanisms that further explain the region's levels of political corruption. The dissertation advances its theory of the causes of political corruption through qualitative disciplined-configurative case studies of political corruption in Jamaica and Costa Rica. The dissertation finds that IGO/NGO sponsored anti-corruption programs are failing because they employ only technical measures (issuing anti-corruption laws and regulations, providing transparency in accounting procedures, improving freedom of the press, establishing electoral reforms, etc.). While these IGO/NGO technical measures are necessary, they are not sufficient to arrest the Caribbean's political corruption problems. This dissertation concludes that to be successful, IGO/NGO anti-corruption programs must also include social measures, e.g., building civil societies and modernizing political cultures, for there to be any hope of lowering political corruption levels and improving Caribbean social conditions. The dissertation also highlights the key role of Caribbean governing elite in constructing the political and economic structures that cause their states' political corruption problems. ^

From stability to insurgency: The root and proximate causes of the September 2002 civil war in Côte d'Ivoire

This dissertation was an analysis of the root and proximate causes of the September 2002 civil war in Côte d’Ivoire. The central question of this study was: Why did Côte d’Ivoire, which was relatively stable under President Houphouët-Boigny, suddenly begin to experience political violence in the 1990s and an explosion in 2002? Côte d’Ivoire was an interesting case because it was stable for a long period of time, apparently making it an infertile ground for conflict. It was also interesting for comparative purposes because of the fact that several states in West Africa (for instance, Benin, Togo, and Ghana) have experienced military coups but not have civil wars. Finally, this case was an opportunity to revisit the debate on the causes of civil wars in the African context. Chapter one has outlined the entire dissertation project and contextualized the analysis that follows in the subsequent chapters. Chapter two has reviewed the literature on civil wars in general, identified the different types of civil wars, and the type the Ivoiran war is. Chapter three has examined the domestic and international political economy as a source of the civil violence in Côte d’Ivoire. Chapter four has examined the role of ethnicity and region as identities of the war, while chapter five has analyzed the role of the foreign relations in the civil war, as well as the regional political context. Chapter six has distinguished between the root and proximate causes of the Ivoirian civil war, made judgments about the relative weight of the various causes, and the extent to which the weight of the causes can be measured. The study found that the “Ivoirité” was the most important trigger of the civil war in Côte d’Ivoire. The overall conclusion of my dissertation was that the September 2002 crisis in that country was a political crisis which occured in the context of a political reform. It first started with succession problems in 1993 followed by the controversial elections in 1995 and 2000. Later, this electoral politics spread beyond electoral issues, namely citizenship matters.

Proton nuclear magnetic resonance investigation of the native and modified active site structure of heme proteins

Hemoproteins are a very important class of enzymes in nature sharing the essentially same prosthetic group, heme, and are good models for exploring the relationship between protein structure and function. Three important hemoproteins, chloroperoxidase (CPO), horseradish peroxidase (HRP), and cytochrome P450cam (P450cam), have been extensively studied as archetypes for the relationship between structure and function. In this study, a series of 1D and 2D NMR experiments were successfully conducted to contribute to the structural studies of these hemoproteins. ^ During the epoxidation of allylbenzene, CPO is converted to an inactive green species with the prosthetic heme modified by addition of the alkene plus an oxygen atom forming a five-membered chelate ring. Complete assignment of the NMR resonances of the modified porphyrin extracted and demetallated from green CPO unambiguously established the structure of this porphyrin as an NIII-alkylated product. A novel substrate binding motif of CPO was proposed from this concluded regiospecific N-alkylation structure. ^ Soybean peroxidase (SBP) is considered as a more stable, more abundant and less expensive substitute of HRP for industrial applications. A NMR study of SBP using 1D and 2D NOE methods successfully established the active site structure of SBP and consequently fills in the blank of the SBP NMR study. All of the hyperfine shifts of the SBP-CN- complex are unambiguously assigned together with most of the prosthetic heme and all proximal His170 resonances identified. The active site structure of SBP revealed by this NMR study is in complete agreement with the recombinant SBP crystal structure and is highly similar to that of the HRP with minor differences. ^ The NMR study of paramagnetic P450cam had been greatly restricted for a long time. A combination of 2D NMR methods was used in this study for P450cam-CN - complexes with and without camphor bound. The results lead to the first unequivocal assignments of all heme hyperfine-shifted signals, together with certain correlated diamagnetic resonances. The observed alternation of the assigned novel proximal cysteine β-CH2 resonances induced by camphor binding indicated a conformational change near the proximal side.^