This thesis investigates two contemporary theories of radical democracy, Jürgen Habermas’s deliberative and Chantal Mouffe’s agonistic democracy. By bringing the two scholars together and constructing a debate between them, their respective strengths and weaknesses are highlighted and the similarities and differences are pointed out. Habermas and Mouffe are seldom dealt with simultaneously as they represent different theoretical traditions, critical theory and post-structuralism respectively. This thesis argues that we can learn from both of them. The aim of the thesis is to clarify and critically assess Chantal Mouffe’s and Jürgen Habermas’s versions of radical democracy, their disparate visions of democratic politics and subjectivity, in order to clear the ground for a third position that draws inspiration from both of them. The methodological inspiration comes from the deconstructive approach to interpretation, and thus the study aspires to a ‘just reading’ while being conscious of the elements of violence inherent to any instances of reading. The main bulk of the thesis is dedicated to an analysis of the two authors’ theories of democracy and subjectivity, which leads on to the third position situated beyond the two. From Habermas I take the stress on political communication and intersubjectivity, while both these concepts are extensively reformulated. The elements I reject from his position are the orientation to consensus and the strong requirements of coherence and transparency of the subject. From Mouffe I take the accent on the agonistic spirit of democracy, while setting aside the ontological status of antagonism. Her conception of split subjectivity is included, but supplemented with a more explicit theorization of the unity of the subject in the element of intersubjective meetings. The third position on radical democracy embraces the fundamental status of undecidability, which calls for an ethos of questioning.

Os receptores acoplados à proteína G (GPCRs), também chamados de receptores 7TM, são conhecidos por regular virtualmente todos os processos fisiológicos em mamíferos e cerca de 40% de todas as drogas comerciais agem através destes receptores. A sinalização mediada por eles é classicamente atribuída à proteína G, que é ativada pela troca de GDP por GTP, promovendo a separação das subunidades G e G, e leva à produção de mensageiros secundários como cAMP, Ca2+ e DAG. Após a resposta os GPCRs são fosforilados pelas quinases de GPCRs (GRKs), sinalizando para recrutamento das -arrestinas citoplasmáticas, que por sua vez desencadeiam a formação de endossomos internalizando e dessensibilizando o receptor. Entretanto, estudos mostram que este endossomo, contendo o complexo ligante-receptor--arrestina, pode interagir com proteínas sinalizadoras no citoplasma desencadeando vias de sinalização independentes de proteína G. Recentemente foram descritos para diferentes receptores, ligantes capazes de ativar seletivamente uma das duas vias, proteína G ou -arrestina, chamados agonistas seletivos. O receptor AT1 é um GPCR particularmente interessante no estudo do agonismo seletivo, tanto por sua vasta expressão em tecidos quanto pelo conhecimento de agonistas seletivos já estabelecidos, tais como os ligantes SII e TRV120027. O objetivo deste trabalho foi analisar comparativamente os perfis de sinalização decorrente da ativação de AT1 por SII ou TRV120027 através do uso de arranjos de quinases e da modulação de genes relacionados a sinalização de GPCRs. Ang II que é ligante natural e total (ativa via dependente de proteína G e de -arrestina) neste receptor foi usada como controle para fins de comparação. Nossos dados mostraram que o perfil da sinalização mediada pelo receptor AT1 varia não só entre AngII e os agonistas seletivos, mas também entre os dois ligantes seletivos SII e TRV120027, mostrando que a interação receptor-ligante pode influenciar a sinalização em um grau mais refinado, além da ativação dependente de -arrestina ou proteína G. Estes dados mostram que existem perspectivas para o desenvolvimento futuro de ligantes com ainda maior grau de seletividade. / G protein coupled receptors (GPCRs), also known as 7TM receptors, are known to regulate virtually all physiological processes in mammals and approximately 40% of all current clinical drugs act by modulating such receptors. The signaling mediated by them is classically by coupling to G protein, which is activated by exchanging bound GDP for GTP, dissociation of G and G subunits, then leading to production of second messengers such as cAMP, Ca2+, and DAG. After the signal transduction, GPCR are phosphorylated by GPCR kinases (GRKs), followed by recruitment of cytoplasmic -arrestins, which initiate the endosome formation with consequent internalization and desensitization of the receptor. However, is has been demonstrated that the endosome assembling the ligand-receptor--arrestin complex can interact with cytoplasmic signaling proteins, therefore activating signaling pathways independently of G protein coupling. Recently, for different receptors, it has been described ligands capable of selectively activating one of these signaling pathways, G protein or -arrestin, called biased agonists. The AT1 receptor is a particularly interesting GPCR for the study of biased agonism, either due to its wide tissue expression as well as also due the existence of known and established biased ligands, such as SII and TRV120027. The aim of our study was to comparatively analyze the AT1 receptor signaling pathways profiles after activation by SII or TRV120027, using kinases arrays, and expression modulation of genes related to GPCRs signaling. AngII is the natural and full agonist of this receptor (activates both G protein and -arrestin signaling pathways) was used for comparison. Our data show that the signaling profile mediated by AT1 receptor can be distinct not only when comparing the profiles from AngII and the biased agonists, but also when comparing the profiles from the two biased ligands SII and TRv120027; revealing that the complex ligand-receptor can influence the downstream signaling pathways in a fine-tune way, further to the activation of -arrestin or G-protein. This data show that there are perspectives for the future development of ligands with even higher degree of selectivity.

Os receptores acoplados à proteína G (GPCRs) são proteínas integrais de membrana caracterizados por possuírem sete alfa-hélices transmembranares. Esses receptores são importantes alvos de estudos biomédicos e aproximadamente 40% dos medicamentos atualmente comercializados agem sobre estes receptores. O receptor de Angiotensina II do tipo 1 (AT1) é um GPCR e o principal mediador do Sistema Renina-Angiotensina que tem como principal efetor o octopeptídeo Angiotensina II (AngII). Recentemente foi descrito que as mutações A244S e I103T-A244S no receptor AT1 podem estar relacionadas com a predisposição à fibrilação atrial. Neste trabalho foi realizada a construção, caracterização bioquímica e farmacológica destes mutantes, bem como do mutante I103T, com o objetivo de compreender como a funcionalidade desses receptores mutantes poderiam contribuir para a predisposição à fibrilação atrial. Os mutantes I103T e I103T-A244S revelaram ser mais eficientes e potentes que o receptor selvagem em aumentar os níveis de cálcio intracelular em resposta à AngII. Todos os mutantes estudados apresentaram baixa eficiência quanto à ativação da via das MAPKs e apresentaram comportamento diferente do receptor selvagem quando bloqueados com o antagonista Losartan, seletivo para o receptor AT1 e muito usado na clínica como medicamento anti-hipertensivo. Esses dados ressaltam a relevância do estudo tanto em termos de melhor compreender as bases moleculares da relação entre as mutações e a doença, bem como possível prevenção ao uso de medicamentos que possam interagir e agir diferentemente em receptores com essas mutações. / G-protein coupled receptors (GPCRs) are integral membrane proteins characterized by having seven transmembrane alpha-helices. These receptors are important targets of biomedical studies and approximately 40% of currently marketed drugs act on such receptors. The angiotensin II type 1 receptor (AT1) is a GPCR and the main mediator of the Renin-Angiotensin System whose main effector is the octapeptide Angiotensin II (Ang II). It was recently described that I103T and A244S mutations in the AT1 receptor may be related to the susceptibility to atrial fibrillation. In this study we carried out the construction of these mutants and their biochemical and functional characterization. The I103T and I103T/A244S mutants were shown to be more efficient and potent than the wild-type receptor on the increase of intracellular calcium levels. All mutants showed lower efficcacy for MAPK pathway activation and showed different behavior when compared to the wild-type receptor after antagonism with Losartan. These data highlight the relevance of the present study concerning a better understanding of the molecular basis of cardiovascular diseases and showing that conventional therapies for certain diseases may lead to adverse effects on patients carrying point mutations on the receptor sequence.

Syftet är att ta reda på hur samhällskunskapslärare kan hantera kontroversiella frågor i undervisningen. Detta genom att undersöka vilka perspektiv som förekommer inom forskningen. Uppsatsen ämnar vara en kunskapsöversikt över relevant pedagogisk forskning. I resultatet framgår det att deliberativa perspektivet och agonism är de mest framträdandeperspektiven när det kommer till hur lärare bör förhålla sig kring kontroversiella frågor. Uppsatsen landar i slutsatsen att båda perspektiven ger svar på arbetets frågeställning men att perspektiven lämpar sig olika väl beroende på om läraren vill att eleverna ska skapa en kollektivviljebildning eller om de ska öva på att tycka olika.

The prokaryotic Erwinia chrysanthemi ligand-gated ion channel (ELIC) is competitively inhibited by acetylcholine (Pan et al., 2012). Acetylcholine is the native agonist of the structurally related family of eukaryotic acetylcholine receptors, which like ELIC are pentameric ligand-gated ion channels. To understand the opposite effect upon acetylcholine binding between ELIC and acetylcholine receptors, we used statistical coupling analysis to predict mutations necessary for installing acetylcholine agonism into ELIC. Statistical coupling analysis was performed on the acetylcholine binding protein from Lymnaea stagnalis. This protein is a structural surrogate for the agonist binding domain of acetylcholine receptors, for which a high-resolution structure in complex with acetylcholine is available. Our analysis identified a group of statistically coupled residues that comprises several amino acids previously implicated in acetylcholine agonism of acetylcholine receptors. Mapping these residues onto ELIC revealed 15 residue discrepancies, 4 of which were chosen for initial mutagenesis based upon their proximity to the known agonist binding site. Electrophysiological characterization of ELIC mutants indicates that the potency of the native agonist, cysteamine, is decreased, highlighting the optimized role wild-type residues serve in native agonism. None of the mutants were activated by acetylcholine, however the double mutant A75D/F133W abolished competitive antagonism by acetylcholine, and instead led to acetylcholine dependent potentiation of cysteamine-induced currents. This work demonstrates the ability of statistical coupling analysis to identify functionally important residues in pentameric ligand-gated ion channels and reveals that acetylcholine can be converted from a competitive antagonist into a potentiator, by installing two residues present in acetylcholine receptors.

Over the course of history, we have become increasingly aware of values possessed by individuals and collectives alike not to be taken as being beyond all questioning, yet these values are often perceived as inevitable from the perspective of the individual. This gives rise to a conflict eternal and evident throughout social life, in the form of value clashes. Within the framework of the thesis, such conflict is referred to as the meta-crisis. As the, in the West, increasing polarisation and subsequent inability to understand and tolerate individuals whose values clash with out own, revealed as a permeating layer riding along with other ongoing crises. Discussion between individuals possessing different values has the proven potential to mitigate the meta-crisis. However, current spaces for discussion, within meatspace and the virtual alike, are turning excessively prone to producing echo chambers. This echoing characteristic is actively degrading potential discussion into antagonistic conflict furthering the meta-crisis. The Radical Middle sets out to discover the role of architecture and urbanism in preventing echo chambers from occuring in our increasingly pluralistic cities, in setting up clashes between different spaces of logic, and ultimately constructing conditions for perpetually mitigating the accelerating meta-crisis through discussion between different-minded individuals. A set of principles are discovered, including but not limited to how information spreads, an individual's propensity to congregate with like-minded individuals in particular spaces and relationships between class status and living condition as a model for predicting values across averages. The thesis concludes with a theoretical framework for the conceptualization and actualization of the Radical Middle - as a synthesis of its principles, wherein the whole comes to exceed the sum of its parts, perpetually mitigating the meta-crisis both within and without.

Vi har undersökt hur samhällskunskapslärare på gymnasiet förhåller sig till kontroversiella frågor. Ämnesområdet valdes med tanke på samhällskunskapens potential för diskussioner i frågor som kan upplevas som kontroversiella. Syftet blev därför att undersöka hur samhällskunskapslärare upplever och hanterar kontroversiella frågor. Såväl skolmyndigheter som forskningsfältet är positivt inställda till kontroversiella frågor eftersom de kan utveckla elevers demokratiska kompetens samt hjälper läraren att göra ämnesinnehållet mer levande. Samtidigt existerar en aktuell debatt om i vilken utsträckning lärare uppmuntrar till diskussioner eller ifall de undviker att lyfta och bemöta kontroversiella frågor i klassrummet.        För att uppfylla ovan nämnda syfte utforskade vi först ämnesområdet genom relevant internationell och nationell forskning. Detta för att därefter klargöra begreppsdefinitionen och presentera våra teoretiska glasögon i form av de deliberativa och agonistiska samtalsteorierna. Resultatet visade att lärarnas tolkning av kontroversiella frågor låg nära de vi identifierat från forskningsfältet och att lärarna vi intervjuat generellt är positivt inställda till att arbeta med kontroversiella frågor. Vårt empiriska material för att utforska ämnesområdet består av sex kvalitativa semistrukturerade intervjuer med sju olika samhällskunskapslärare.

The longstanding framing of accountability in principal-agent terms has encouraged adversarial and oppositional interactions and ways of thinking amongst nonprofit and funding agency practitioners within government-nonprofit relationships. These interactions are deeply rooted in the accountability claims made by government funders and responded to by nonprofit practitioners. This dissertation outlines the implications of nonprofit-government contracting for participating nonprofit organizations and explores various strategies practitioners in those institutions utilize to respond to the challenges raised by their relationship to public funders. To understand the tensions surrounding government accountability claims, I provide an overview of the emergence of the contracting regime and an exploration of the understanding of accountability that has attended its evolution. Through an in-depth qualitative case study, constructed on the basis of interviews, observation, and document analysis and following a grounded theory approach to analysis, I explore various nonprofit manager responses to the norms and pressures of the contracting regime. I chronicle nonprofit practitioners\' responses to contracting regime pressures, including accepting those norms, even when arguably inimical to their organization\'s mission, ignoring them in favor of serving clients, or leaving the employ of organizations altogether. I also explore examples of practitioner efforts to navigate outside of the contracting regime\'s antagonistic framing and engage both with powerful stakeholders and others in their organizations to negotiate changes. Drawing on the theoretical lens of agonism, I examine the context and characteristics of those responses to provide insights into how nonprofit managers might move beyond antagonistic accountability frames. / Ph. D.

yes / Pharmaceutical manipulation of cAMP levels exerts beneficial effects through the regulation of the exchange protein activated by cAMP (EPAC) and protein kinase A (PKA) signalling routes. Recent attention has turned to the specific regulation of EPAC isoforms (EPAC1 and EPAC2) as a more targeted approach to cAMP-based therapies. For example, EPAC2-selective agonists could promote insulin secretion from pancreatic β cells, whereas EPAC1-selective agonists may be useful in the treatment of vascular inflammation. By contrast, EPAC1 and EPAC2 antagonists could both be useful in the treatment of heart failure. Here we discuss whether the best way forward is to design EPAC-selective agonists or antagonists and the current strategies being used to develop isoform-selective, small-molecule regulators of EPAC1 and EPAC2 activity.

Abstract  The following essay will discuss conflict- ridden situations in the classroom and how the teachers’ leadership can strengthen the pupils’ democratic development to resolve these situations. Furthermore, we analyzed how deliberative dialogue could be of use to the teacher when these situations occur, as well as how, through civics education, the pupils could learn how to resolve conflicts in a controlled and peaceful environment. This study will, in particular, discuss several concepts concerning, among others, intersubjectivity, agonism and phronesis and how these takes place in the classroom. We will explore the teachers’ leadership ability and approach to the resolvement of conflicts through deliberative conversations. Our method when searching for relevant scientific articles was a systematic use of several databases and scientific journals, including ERIC, ERC, and Taylor & Francis online, where we found a vast variety of articles. Most of the articles show the difficulties the teacher might encounter when teaching, and we strove to examine if deliberative conversations are a useful method when facing sudden conflict-ridden situations in the classroom. We found a lack of knowledge in reference to deliberative conversations as a method in these situations, as well as, the teacher’s insecurity facing sudden conflict-ridden situations.