The B cell population is one of the key components of the adaptive immune system, which protects the host from a tremendous variety of pathogens by producing antibodies. B cells develop from hematopoietic stem cells through a pathway known as B lymphopoiesis. This is a process accompanied by intensive gene expression reprogramming. By the end, genes appropriate for the B lineage are activated and those that are not are continuously repressed. The regulation of lineage gene expression is conferred by a network of transcriptional regulators. Although some key components have been defined, more factors, especially those orchestrating the repression of non-B lineage genes, remain to be identified. Chemically induced mutagenesis is a potent way of identifying genes with critical biological functions. Injection of n-ethyl-n-nitrosourea, a mutagen, has generated a unique point mutation in the mouse Gon4-like (Gon4l) gene that specifically causes a loss of peripheral B cells while maintaining the T cell population. The mutation is therefore named Justy for Just T cells. The goal of this thesis project is to analyze the Justy mice and provide insights into the mechanisms underlying the regulation of B lymphopoiesis. The work presented here demonstrates that the protein encoded by Gon4l is essential for early B lymphopoiesis, which is likely through the repression of non-B lineage genes. Gon4l protein contains conserved domains implicated in transcriptional repression and associates in a complex with the transcriptional repression mediators Yin Yang 1 and Sin3a/HDAC1, after these proteins are transiently expressed in cell lines. When bound to DNA, Gon4l is capable of repressing a nearby promoter and this function correlates with its ability to form a complex. Therefore, these results suggest that Gon4l may function as a transcriptional regulator by employing its associated co-factors in the identified complex. Lastly, a wide spectrum of tumors developed in Justy mice, indicating that Gon4l can also act as a tumor suppressor.

Why does civil conflict spread from country to country? Existing research relies primarily on explanations of rebel mobilization tied to geographic proximity to explain this phenomenon. However, this approach is unable to explain why civil conflict appears to spread across great geographic distances, and also neglects the government’s role in conflict. To explain this phenomenon, this dissertation formulates an informational theory in which individuals contemplating rebellion against their government, or “proto-rebels,” observe the success and failure of rebels throughout the international system. In doing so, proto-rebels and governments learn whether rebellion will be fruitful, which is then manifested in the timing of rebellion and repression. The core of the dissertation is composed of three essays. The first exhorts scholars of the international spread of civil violence to directly measure proto-rebel mobilization. I show that such mobilization is associated with conflicts across the entire international system, while the escalation to actual armed conflict is associated with regional conflicts. The second chapter theorizes that proto-rebels learn from successful rebellions across the international system. This relationship applies globally, although it is attenuated by cultural and regime-type similarity. Finally, the third chapter theorizes that governments are aware of this process and engage in repression in order to thwart it. I further argue that this repression is, in part, a function of the threat posed by those regimes founded by rebels.

Magister Artium - MA / Bettina Wyngaard se misdaadfiksie-trilogie, bestaande uit die romans Vuilspel (2013), Slaafs (2016) en Jagter (2019) het ’n vernuwende uitwerking in die Afrikaanse literatuur gehad. Dit kan hoofsaaklik teruggevoer word na die skrywer se gebruik van ’n (swart) lesbiese protagonis. Wyngaard is ook die eerste swart Afrikaanse vroue-outeur wat haar tot hierdie genre gewend het. Haar misdaadtrilogie toon ’n sentrale bemoeienis met die vroulike subjek se ondergeskikte posisie as deurgaans onderdruk weens verskeie identiteitsaspekte (waaronder ras, gender, klas, seksualiteit, kultuur en nasionaliteit tel). Die simbiotiese verhouding tussen identiteit en mag is dus ’n prominente tematiek in die trilogie. Hierdie bemiddeling tussen identiteit en mag toon raakpunte met die interseksionaliteitsteorie soos voorgestel deur Kimberlé Crenshaw (1989). Sy voer aan dat subjekte onderdruk word deur die tussenspel van identiteitsmerkers en sisteme van onderdrukking wat inherent is daaraan. In hierdie verhandeling word die representasie van die vroulike subjek in Wyngaard se misdaadtrilogie uit ’n interseksionele invalshoek in oënskou geneem. Vanweë die gebruik van literatuur as subjek van analise in hierdie verhandeling, word swart feministiese denkskole oor die letterkunde ingereken as ontledingsinstrumente om Wyngaard se trilogie binne die ruim trajek van swart feministiese fiksie te posisioneer. Terselfdertyd word Wyngaard se subjektiwiteit as swart vroue-outeur krities bekyk omdat sy deur middel van haar tekste verantwoordelik is vir beeldskepping en voorstellings van vroulike subjekte. Aangesien Wyngaard se fiksie dikwels identiteitsaspekte ondervang wat verband hou met haar eie subjektiewe identiteit, sal die wyse bekyk word waarop selfdefiniëring en selfaktualisering in haar trilogie tot stand gebring word.Soos reeds genoem, het Wyngaard grense in die Afrikaanse letterkunde versit deur haar tot misdaadfiksie as genre te wend. As deel van populêre fiksie, staan misdaadfiksie tradisioneel bekend as ’n behoudende genre met ’n resepmatige onderbou wat, só beskou, nie gebruik word om progressiewe argumente in te voer nie. Hierdie aspek van die genre staan dus oënskynlik in kontras met die feministiese aard van Wyngaard se misdaadfiksie-trilogie. In hierdie verhandeling word gevolglik ook die funksionaliteit van genre en die impak daarvan op die beeldskepping van die vroulike subjek bekyk. Maniere waarop Wyngaard gevestigde genrekonvensies oorskry in ’n poging om feministiese benaderings te berde te bring, word in die besonder bestudeer. / South Africa

This paper investigates how changes in states’ repression tactics impact the dynamics of civil protests. Research on the repression-dissident nexus has commonly studied repression as one concept, lacking disaggregation into its different types. In an empirical study of the Gezi Park protest campaign, erupting in late May 2013 in Istanbul, Turkey, this paper focuses on the impact of indiscriminate versus selective repression. Specifically, it examines if the change from an indiscriminate to a more selective state repression strategy had a de-escalatory effect on the protest activity in the Gezi campaign. The study finds support for the hypothesis that this was the case. Further, it concludes that disaggregation of the repression concept is key for capturing the dynamic character of the repression-dissident relationship.

This thesis aims to address how COVID-19 restrictions affected dissent events in autocracies and electoral autocracies. To do so relies on the combination of the grievances and resource mobilization theories. During the COVID-19 pandemic, autocracies and electoral autocracies have implanted restrictive civil liberties policies justified by the necessity to reduce the spread of the virus and the challenging situation. These policies have affected people’s lives and dissent events. The study found a negative relationship between the COVID-19 restrictions and dissent in 2020 compared to 2021. To test this relationship, I used the V-dem v11.1 dataset. Since I wanted to get a bigger picture of the relationship, I used the results of the LNA to select a typical case among countries in Southeast-East Asia. I relied on the Philippines case to test the causal mechanism theorized and tested whether the negative relationship was in place. The results showed that the number of protests in the Philippines decreased in 2020 and 2021 compared to 2019. Using the ACLED dataset, I found that grievances and ICT mobilization were present without leading to an increase in dissent events. Additionally, while ACLED accounted for a digital form of protest, V-dem v11.1 did not. This result leads me to conclude that the results from the LNA might be subjected to a measurement error. Further research is thus required to address the relationship better.

Within hours after its initiation, the severe systemic inflammatory response of sepsis shifts to an adaptive anti-inflammatory state with coincident immunosuppression. This anti-inflammatory phenotype is characterized by diminished proinflammatory cytokine gene expression in response to toll-like receptor (TLR) stimulation with bacterial endotoxin/lipopolysaccharide (LPS), also known as endotoxin tolerance/adaptation. Our and other studies have established that gene-specific reprogramming following TLR4 responses independently represses transcription and translation of proinflammatory genes such as tumor necrosis factor alpha (TNFα). We also previously demonstrated that TNFα and interleukin (IL)-6 mRNA translation is repressed in endotoxin-adapted THP-1 human monocytes by an miRNA-based mechanism involving the argonaute family protein argonaute 2 (Ago2). Here, we further define the molecular nature of reprogramming translation by showing that TLR4-induced microRNA-146 promotes a feed-forward loop that modifies the subcellular localization of the RNA-binding protein RBM4 (RNA-binding motif protein 4) and promotes its interaction with Ago2. This interaction results in the assembly of a translation-repressor complex that disrupts TNFα and IL-6 cytokine synthesis in endotoxin-adapted THP-1 monocytes. This novel molecular path prevents the phosphorylation of RBM4 on serine-309 by p38 MAPK (mitogen-activated protein kinase), which leads to RBM4 accumulation in the cytosol and interaction with Ago2. We further find that microRNA-146a knockdown by antagomirs or protein phosphatase inhibition by okadaic acid increases p38 MAPK phosphorylation and results in RBM4 serine-309 phosphorylation and nuclear relocalization, which disrupts RBM4 and Ago2 interactions and restores TLR4-dependent synthesis of TNFα and IL-6. We conclude that miR-146a has a diverse and critical role in limiting an excessive acute inflammatory reaction.

Within hours after its initiation, the severe systemic inflammatory response of sepsis shifts to an adaptive anti-inflammatory state with coincident immunosuppression. This anti-inflammatory phenotype is characterized by diminished proinflammatory cytokine gene expression in response to toll-like receptor (TLR) stimulation with bacterial endotoxin/lipopolysaccharide (LPS), also known as endotoxin tolerance/adaptation. Our and other studies have established that gene-specific reprogramming following TLR4 responses independently represses transcription and translation of proinflammatory genes such as tumor necrosis factor alpha (TNFα). We also previously demonstrated that TNFα and interleukin (IL)-6 mRNA translation is repressed in endotoxin-adapted THP-1 human monocytes by an miRNA-based mechanism involving the argonaute family protein argonaute 2 (Ago2). Here, we further define the molecular nature of reprogramming translation by showing that TLR4-induced microRNA-146 promotes a feed-forward loop that modifies the subcellular localization of the RNA-binding protein RBM4 (RNA-binding motif protein 4) and promotes its interaction with Ago2. This interaction results in the assembly of a translation-repressor complex that disrupts TNFα and IL-6 cytokine synthesis in endotoxin-adapted THP-1 monocytes. This novel molecular path prevents the phosphorylation of RBM4 on serine-309 by p38 MAPK (mitogen-activated protein kinase), which leads to RBM4 accumulation in the cytosol and interaction with Ago2. We further find that microRNA-146a knockdown by antagomirs or protein phosphatase inhibition by okadaic acid increases p38 MAPK phosphorylation and results in RBM4 serine-309 phosphorylation and nuclear relocalization, which disrupts RBM4 and Ago2 interactions and restores TLR4-dependent synthesis of TNFα and IL-6. We conclude that miR-146a has a diverse and critical role in limiting an excessive acute inflammatory reaction.

An anti-inflammatory phenotype with pronounced immunosuppression develops during sepsis, during which time neutrophils and monocytes/macrophages limit their Toll-like receptor 4 responses to bacterial lipopolysaccharide (LPS/endotoxin). We previously reported that during this endotoxin-tolerant state, distinct signaling pathways differentially repress transcription and translation of proinflammatory cytokines such as TNFα and IL-6. Sustained endotoxin tolerance contributes to sepsis mortality. While transcription repression requires chromatin modifications, a translational repressor complex of Argonaute 2 (Ago2) and RNA-binding motif protein 4 (RBM4), which bind the 3′-UTR of TNFα and IL-6 mRNA, limits protein synthesis. Here, we show that Dcp1 supports the assembly of the Ago2 and RBM4 repressor complex into cytoplasmic processing bodies (p-bodies) in endotoxin-tolerant THP-1 human monocytes following stimulation with LPS, resulting in translational repression and limiting protein synthesis. Importantly, this translocation process is reversed by Dcp1 knockdown, which restores TNFα and IL-6 protein levels. We also find this translational repression mechanism in primary macrophages of septic mice. Because p-body formation is a critical step in mRNA translation repression, we conclude that Dcp1 is a major component of the translational repression machinery of endotoxin tolerance and may contribute to sepsis outcome.

Subjects' reported dream recall frequency, dream content and vividness or recall were discussed and examined in relation to sex of the subject and MMPI Conscious Anxiety, Conscious Repression and Ego-strength scores. Fifty-three Utah State University students, who volunteered to participate in a study of dreaming behavior, were administered the MMPI and asked to complete a dream log diary. The dream log required a daily recording of total number of dreams recalled, the number of vividly and vaguely recalled dreams and a rating of each dream in one of four dream content-process categories. Content-process categories included pleasurable, working, conflict and disorganized/frightening dreams. Relationships and possible interaction effects for the variables measured were tested for significance. No significant relationship was found between Conscious Anxiety, Conscious Repression or Ego-strength and dream recall frequency, sex of the subject, percentage of vivid dreams recalled, or percent of dreams recalled in the positive (pleasurable and working dreams) versus negative (conflict and disorganized/frightening) categories. Several significant differences were found, however, between the percentage of dreams reported in dream content-process categories for male subjects when analyzed according to higher-lower MMPI scale score categories and higher-lower dream recall level. Results of subcategory analysis tended to support an interaction between anxiety, repression and dream process consistent with the continuity and adaptive theories of dreaming. Male subjects with higher Conscious Anxiety reported a significantly greater percent of disorganized/frightening dreams. Higher anxiety tended to produce a higher percentage of working dreams as long as repression of threatening material was low enough to permit the recall of more emotion-laden dream processes. There was also a significant interaction between reported precent of pleasurable dreams, recall level and repression, which was explained as possibly indicating that pleasurable dreams may serve as an escape of integrating process for high repression male subjects. Results of analysis for female subjects indicated that higher recall subjects reported a significantly higher percent of disorganized dreams, which is consistent with the salience theory of recall. Recalled dream processes seemed to be not as strongly tied to personality variables for female subjects. Contentless dreams have been proposed in previous research to reflect repression by the subject. Results showed no significant difference between higher and lower repression subjects on the number of contentless dreams reported.

L’auxine est une hormone végétale impliquée dans presque toutes les étapes du développement des plantes, de la formation de l’embryon jusqu’à la floraison, déterminant la position des organes et donc la structure de la plante. Comme pour les autres hormones, la perception de l’auxine est suivie par une transduction du signal qui produit une série de changements dans les cellules végétales dont des régulations transcriptionnelles. Cette thèse est divisée en 3 chapitres, chacun d’eux étant focalisé sur des aspects structuraux, moléculaires et évolutifs de différentes protéines impliquées dans la régulation des gènes de réponse à l’auxine.Nous avons tout d’abord centré nos études sur TOPLESS (TPL), un corépresseur qui agit au niveau de la répression des gènes de réponse à l’auxine, mais aussi dans d’autres processus végétaux compte tenu de son interaction avec de nombreux répresseurs transcriptionnels. Nous avons déterminé la structure de la partie N-terminale de TPL et compris comment TPL interagit avec différents partenaires au niveau d’un même site de liaison. Nous avons alors démontré que TPL forme un tétramère à l’aide d’une surface de tétramérisation constituée par un nouveau domaine, le domaine CRA, qui fait aussi partie du site de liaison. Les résidus impliqués dans la tétramérisation et l’interaction avec des partenaires sont très conservés depuis des centaines de millions d’années montrant ainsi l’importance du rôle de TPL depuis l’origine des plantes. Enfin, les similarités de structure entre TPL et d’autres corépresseurs qui possèdent des domaines similaires mais possédant une fonction différente montrent un bel exemple de la manière dont l’évolution joue avec des domaines protéiques pour créer de nouvelles fonctions.Nous avons ensuite étudié les préférences de liaison à l’ADN des facteurs de transcription de la réponse à l’auxine (ARF). Pour cela nous avons utilisé une combinaison d’analyses bio-informatiques de données de DAP-seq sur la liaison des ARFs sur le génome, des tests d’interaction ADN-protéine in vitro et de la modélisation de structures. Nos résultats indiquent que les différents ARFs ont des sites préférentiels de liaison sur le génome et que ces préférences sont déterminées par l’orientation et l’espacement entre motifs de liaison. Enfin, ces études suggèrent qu’en fonction du site de liaison, les ARFs pourraient se lier avec différentes conformations à l’aide de surfaces de dimérisation qui ne sont pas encore décrites. Ces résultats permettent d’expliquer comment différents ARFs coexprimés dans la même cellule peuvent fonctionner ensemble pour contribuer à une réponse transcriptionnelle à l’auxine spécifique et robuste.Finalement, nous avons remonté le temps pour positionner l’origine de la voie de signalisation de l’auxine chez les plantes. Pour cela, nous avons recherché des homologues des protéines de la voie de signalisation de l’auxine dans des algues vertes charophytes, les ancêtres les plus lointains (450 Millions d’années) des plantes. Nous avons alors trouvé un homologue des ARFs et TPL chez les premières algues multicellulaires (Chlorokybus atmophyticus). La caractérisation biochimique de l’ARF de C. atmophyticus indique qu’il partageait déjà les mêmes propriétés que les ARFs des plantes terrestres et était aussi capable d’interagir avec TPL comme certains ARFs. L’absence d’homologues du récepteur de l’auxine chez ces algues primitives indique cependant que la dépendance à l’auxine aurait été acquise plus tard avec l’apparition du système corécepteur TIR1/AFB-Aux/IAA après la divergence des charophytes vers les plantes terrestres. / Auxin is a plant hormone implicated in almost all plant developmental stages, since the embryo formation till flowering, determining the position of the organs in the plant and thus, its whole structure. As for any other hormone, auxin perception is followed by a signal transduction that finishes in a series of changes in a plant cell, including transcriptional changes. This thesis is divided in 3 chapters, each with a focus on the structural, molecular and evolutionary aspects of different proteins involved in the regulation of auxin genes response.First, we focused our studies on TOPLESS (TPL), a co-repressor implicated, not only in auxin responsive genes repression, but also in many other plant processes due to its interactions with numerous transcriptional repressors in plants. Our determination of the TPL N-terminal structure allowed us to understand that TPL can interact with different partners through the same binding site. Moreover, it revealed that TPL is a tetrameric protein, with the tetramerization interface formed by a newly identify domain, the CRA domain, that is also part of the binding site. The high residues conservation in both tetramerization interface and TPL binding site since m.y.a indicates the importance of TPL role since the origin of plants. This work also shows that the structural similarities between TPL and other co-repressor with similar domains but different function nicely exemplify how evolution plays with common features for creating new functions.Second, we studied ARF proteins, the transcription factors of the auxin transcriptional response, with a focus on their DNA binding preferences. For this, we used a combination of bioinformatic analyses of DAP-seq ARFs genomic binding, with in vitro DNA binding tests and structure modelling. Our results point out that different ARFs can have different preferential binding sites within the genome, with these preferences being determined by the orientation and spacing of the binding motifs. Moreover, our studies suggest that depending on the binding site, ARFs could bind with different conformations using dimerization interfaces not yet discovered. These results can explain how different ARFs co-expressed inside a plant cell can collaborate to the specificity and robustness of auxin transcriptional response by differential bindings to the genome.Finally, we travelled back in time to position the origin of auxin signalling pathway in the evolution of plants. Here we looked for protein homologues of the auxin signalling pathway in charophyte green algae, the most ancient plants ancestor (450 M years). This search retrieved an ARF and a TPL homologue in the first multicellular charophyte algae (Chlorokybus atmophyticus). The biochemical characterization of C. atmophyticus ARF indicated that it presented already the same properties of the ARFs from land plants and that it was able to interact with TPL protein, as it is the case for some ARFs. The absence of auxin receptor homologues in these primitive algae indicates however that auxin-dependency appeared with the acquisition of TIR1/AFB-Aux/IAA coreceptor system, after charophytes divergence into land plants.