La métastase et la chimiorésistance sont les principales causes de mortalité chez les patients atteints d’un cancer. La compréhension des mécanismes moléculaires régissant ces deux processus devient donc un domaine de recherche important pour la conception de nouvelles stratégies thérapeutiques. Dans ma thèse, je me concentre sur la compréhension du rôle du facteur d’initiation de la traduction chez les eucaryotes 4E (eIF4E) dans l’invasion du cancer, et je décris un nouveau mécanisme de résistance que nous avons découvert en étudiant le développement de la résistance à un inhibiteur connu d’eIF4E, la ribavirine. eIF4E est un puissant oncogène qui est connu pour être élevé dans une multitude de cancers comprenant entre autres les sous-types M4 / M5 de la leucémie myéloïde aiguë (AML). Il fonctionne dans la traduction et l'exportation nucléocytoplasmique d'ARNm en se liant à la coiffe m7G des ARNm possédant des codes USER spécifiques dans leur région UTR 5' et/ou 3'. En reconnaissant ces codes USER, le complexe dans lequel se trouve eIF4E régule de manière coordonnée l'expression de gènes essentiels à la croissance, à la prolifération et à la survie, et ainsi, eIF4E a été placée en tant que nœud central d'un régulon d'ARN régissant la prolifération. En analysant les voies dans lesquelles l’export est régulé de façon coordonnée par eIF4E et les effets physiologiques qui en découlent, j'ai trouvé un enrichissement de la voie biosynthétique de l'acide hyaluronique (HA) et de son principal récepteur CD44 qui sont des médiateurs clés connus des métastases cancéreuses. J’ai également démontré que l'élévation d’eIF4E modifie la surface des cellules cancéreuses en les recouvrant de protrusions riches en HA de type microvillus et enrichies d'armes de destruction métastatique. Heureusement, en dégradant le manteau HA ou en utilisant des inhibiteurs de CD44 en combinaison avec la ribavirine, nous pouvons alors nous défendre. Compte tenu de l'avantage prolifératif que confère la surexpression d’eIF4E, il est devenu un talon d'Achille attrayant pour le traitement de cancers ayant un niveau élevé d'eIF4E. En effet, lors d'un essai clinique de phase II parmi des patients atteints de leucémie myéloïde aiguë M4 / M5 réfractaire et récidivante, la ribavirine a conduit au ciblage d'eIF4E et a donné lieu à des réponses cliniques significatives, incluant des réponses complètes ou partielles. Cependant, tel qu’attendu lors d’un traitement monothérapique, les patients ayant répondu finissent par développer une résistance au médicament. Mon analyse a révélé que cette résistance est due à un mécanisme nouveau caractérisé par l'élévation du facteur de transcription Sonic Hedgehog GLI1 qui conduit à la glucuronidation du médicament et donc à la perte de l'interaction entre la drogue et sa cible. Heureusement, ce mécanisme peut être inversé en utilisant des inhibiteurs de la voie Hedgehog. En conclusion, ces découvertes fournissent de nouvelles cibles thérapeutiques pour le traitement des cellules cancéreuses agressives et résistantes. / Metastasis and chemoresistance are the leading cause of mortality among cancer patients. The discovery of molecular mechanisms governing these two processes is becoming an important area of research for the design of novel therapeutic strategies. In my thesis, I focus on understanding the role of the eukaryotic translation initiation factor 4E (eIF4E) in cancer invasion and describe a novel mechanism of resistance that we discovered while studying the development of resistance to a known eIF4E inhibitor, ribavirin. eIF4E is a potent oncogene that is known to be elevated in a multitude of cancers including M4/M5 subtypes of acute myeloid leukemia (AML). It functions in mRNA translation and nucleocytoplasmic export by binding to the m7G cap of mRNAs possessing specific USER codes in their 5’ and/or 3’ UTRs. By recognizing these USER codes, eIF4E complex coordinately regulates the expression of genes essential for growth, proliferation and survival and as such has been placed as a central node of an RNA regulon governing proliferation. When analyzing which pathways have their export coordinately regulated by eIF4E and what physiological effects arise from it, I found an enrichment in the hyaluronic acid (HA) biosynthetic pathway as well as its major receptor CD44 which are known key mediators of cancer metastasis. I demonstrate that eIF4E elevation changes the surface of cancer cells sugar-coating them with HA-rich microvillus-like protrusions that are enriched with weapons of metastatic destruction. Luckily, through degrading the HA-coat or using inhibitors of CD44 in combination with ribavirin we can strike back. Given the proliferative advantage that eIF4E overexpression conveys, this rendered it as an attractive Achilles heel for the treatment of cancers where eIF4E levels are high. Indeed, in a phase II clinical trial in refractory and relapsed poor prognosis M4/M5 AML patients, ribavirin led to eIF4E targeting and resulted in significant clinical responses including complete and partial remissions. However, as it is expected for monotherapy treatment, all responding patients eventually developed resistance to the drug. My analysis revealed that resistance is due to a novel mechanism characterized by elevation of the Sonic Hedgehog transcription factor GLI1 which leads to drug glucuronidation and the subsequent loss of drug-to-target interaction. Fortunately, this mechanism can be reversed using Hedgehog pathway inhibitors. Taken together, these findings provide novel therapeutic venues for the treatment of aggressive and resistant cancer cells.

This dissertation traces the emergence of the air raid shelter as the paradigmatic architecture of air defense under the Nationalist Party government in China during the War of Resistance against Japan (1937–1945). More broadly, it explores how air defense in general became an integral technology for the Nationalists’ “war of resistance and reconstruction” (kangzhan jianguo), a fascist project derived from total war, the globally circulating military-political idea that modern wars would enlist the entire populations and economies of nations in warfare while subjecting national populations and infrastructures to equally comprehensive violence. The Nationalists joined the world in confronting aerial bombing after the Empire of Japan bombed Shanghai in 1932. In response, the government and its military constructed air defense, a political and technological complex combining mass mobilization, through air raid drills and air defense organizations, with material technologies, like searchlights, anti-aircraft guns, and bomb shelters. The Nationalists found in air defense more than a military technology. To them, it also offered a set of tools and resources for fortifying their flailing attempts to unite China in a common national project, and even recasting the substance of that project. Air defense could forge a new society that invested all Chinese people in war as a necessary precondition for overcoming China’s colonial subjection. Where democratic institutions collapsed and appeals to common heritage and customs failed, the Nationalists used air defense to turn survival (shengcun) into the bedrock value of the national community. Meanwhile, a group of young architects associated with the journal Xin jianzhu in Canton identified air defense as an organizing problem for the nascent professional field of architecture. Rather than the stale historicism endorsed in Nanjing, and against China’s craft building traditions, the group championed modernist architecture, especially the International Style, whose principles of simplicity, functionalism, and rationality they saw as necessary for building modern, industrial, and hygienic Chinese cities capable of enhancing human life. Moreover, they argued that the technological instrumentality informing modernism made it the only style capable of preserving Chinese cities and people from modern threats like bombing. After the fall of Canton in 1938, members of the group took their mission to Chongqing, where they joined the Nationalist government in building air defenses in the wartime capital. In particular, this dissertation argues that the air raid shelter and air defense focused contradictions in the Nationalists’ fascist project for uniting and revolutionizing China as it traveled to Chongqing following the Nationalist escape from Japan’s invasion of the coast. Over the course of the War of Resistance, the principal technology of air defense shifted away from mass mobilization, as the Nationalists came to administer refugees and displaced people they had never governed before, and became located in infrastructure like city plans and air raid shelters. Air defense served to exclude surplus populations like women and the elderly, rendered redundant according to the state’s wartime needs for industrial production and conscripts, by dispersing them in satellite settlements outside the city, from which they constantly returned in search of work or material goods. Shoddy air raid shelters, in the meantime, revealed the fragile biology of real bodies beneath the fascist fantasy of the heroic political subject, as shelters failed to provide for basic needs like respiration. Over time, these two problems collided, as the state closed shelters in the city to dispersed people, exposing surplus populations to bombing, while civilians also languished in shelters that could still kill them. The goal of building national unity through survival collapsed into a confusion of inclusion and exclusion, life and death, with disastrous results, like the asphyxiation of around one thousand people in Chongqing’s largest public air raid shelter in June 1941. In these circumstances, professionals like the Cantonese architects and new state regulatory bodies produced proposals and standards for building better shelters, offering a technological resolution of air defense’s political contradictions and consolidating the transformation of air defense into a technical expertise.

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Der cGMP-Signalweg ist als einer der Hauptregulatoren von diversen Funktionen in Eukaryoten bekannt; allerdings ist seine Funktionsweise in Protozoen wenig verstanden. Im Rahmen dieser Arbeit wurde eine Guanylatcyclase, gekoppelt mit N-terminalen P4-ATPase, in intrazellulären Parasiten Toxoplasma gondii gemeldet. Eine in silico-Analyse wies auf eine Aktivierung der Guanylatcyclase durch Heterodimerisierung ihrer Cyclasedomänen hin und ermöglichte wertvolle Einsichten in mögliche Funktionen ihrer ATPase-Domäne. Dieses Protein (477-kDa) bezeichnet als TgATPaseP-GC in dieser Studie, lokalisiert in der Plasmamembran am apikalen Pol des Parasiten. TgATPaseP-GC ist unempfänglich gegenüber genetischer Deletion und seine CRISPR/Cas9 unterstützte Spaltung beendet den lytischen Zyklus von T. gondii vorzeitig. Darüber hinaus reduzierte ein Cre/loxP-vermittelter Knockdown von TgATPaseP-GC die Synthese von cGMP im Tachyzoiten und inhibierte das Parasitenwachstum aufgrund von Beeinträchtigungen Motilitäts-abhängiger Prozesse des Austretens und Eindringens. Trotz seiner zeitlich beschränkten Funktion ist TgATPaseP-GC konstitutiv während des ganzen lytischen Zyklus exprimiert, welches eine post-translationale Regulierung des cGMP-Signalweges bedingt. Nicht zuletzt impliziert das Vorhandensein von TgATPaseP-GC-Orthologen in anderen Alveolata eine divergente Umfunktionierung der cGMP-Signalwege in Protozoen. Darüber hinaus wurde ein optogenetischer Ansatz verwendet, um den cGMP-Weg durch eine photo-aktivierte Rhodopsin-Guanylat-Cyclase (RhoGC) in T. gondii zu exprimiert. Dieses System erlaubte eine kontrollierte Erhöhung von cGMP durch Licht in einer schnellen und reversiblen Weise. Die Anregung von RhoGC stimulierte signifikant die Parasitenmotilität, deren Auswirkung auch mit erhöhten Eindringen und Austreten überwacht wurde; im Gegensatz zum genetischen Knockdown von TgATPaseP-GC. Das System ermöglicht die Vermittler des cGMP-Signalwegs durch Phosphoproteomics zu identifizieren. / cGMP signaling is known as one of the master regulators of diverse functions in eukaryotes; however, its architecture and functioning in protozoans remain poorly understood. In the scope of this thesis, an exclusive guanylate cyclase coupled with N-terminal P4-ATPase was reported in an obligate intracellular parasite Toxoplasma gondii. In silico analysis indicated an activation of the guanylate cyclase by heterodimerization of its two cyclase domains and offered valuable insights into possible functions of its ATPase domain. This bulky protein (477-kDa), termed in this study as TgATPaseP-GC to reflect its envisaged multifunctionality, localizes in the plasma membrane at the apical pole of the parasite. TgATPaseP-GC is refractory to genetic deletion, and its CRISPR/Cas9-assisted disruption aborts the lytic cycle of T. gondii. Besides, Cre/loxP-mediated knockdown of TgATPaseP-GC reduced the synthesis of cGMP in tachyzoites and inhibited the parasite growth due to impairments of motility-dependent egress and invasion events. Notably, despite its temporally restricted function, TgATPaseP-GC is expressed constitutively throughout the lytic cycle, entailing a post-translational regulation of cGMP signaling. Not least, the occurrence of TgATPaseP-GC orthologs in several other alveolates implies a divergent functional repurposing of cGMP signaling in protozoans. Furthermore, an optogenetic approach was utilized to induce cGMP pathway by a photo-activated rhodopsin-guanylate cyclase (RhoGC) in T. gondii. The system enabled a light-control of cGMP elevation on crucial steps of lytic cycle in a fast, spatial and reversible manner. Excitation of RhoGC significantly stimulated the parasite motility of which impact was also monitored with an increased host-cell invasion and egress; as opposed to the genetic knockdown of TgATPaseP-GC. Having an established optogenetic system in the parasite allows to identify downstream targets of cGMP signaling via phosphoproteomic analysis.

Bibliographic note KLIMEŠOVÁ, Tereza. The Implications of the Intervention in Iraq for the United States' Policy of Democracy Promotion. Master thesis. Charles University, Faculty of Social Sciences, Institute of International Studies, Supervisor Ph.Dr. Jan Hornát, Ph.D. Abstract Democracy promotion has been an integral part of US foreign policy for more than a century. Particularly at the end of the 20th century, democracy flourished worldwide as autocratic regimes collapsed at large and scholars talked about the "End of History." Nevertheless, the current situation is very different, and substantial democratic backsliding is observable. Many scholars are tracing the origins of this decline to the Bush's Freedom Agenda, particularly the intervention in Iraq in 2003, arguing that it was the initial turning point for US democracy promotion. However, this thesis argues that the invasion and the subsequent war were pivotal only in part. The most visible implications were within the public perception of democracy promotion. Due to the US engagement in Iraq, domestic support deteriorated substantially. Moreover, the international community's perception of the US as a benign democracy exporter crumbled as well. Another change was observable within the rhetoric of President Obama after taking office in 2009. In...

Orientador: Célio F.B. Haddad / Resumo: Na última década houve um grande desenvolvimento nos Modelos de Distribuição de Espécies (MDE), com diversas aplicações na conservação da biodiversidade. No entanto, apesar dos avanços recentes, a seleção de variáveis preditoras tem sido relativamente negligenciada na construção dos MDE. Este procedimento deveria ser um dos passos cruciais do processo de modelagem, já que as variáveis preditoras estão relacionadas diretamente à capacidade dos modelos de capturar os requisitos ambientais das espécies. Neste contexto, os anfíbios são excelentes organismos modelo para avaliar a importância da seleção de variáveis preditoras ecologicamente significativas no MDE. Isto pode trazer avanços para a biogeografia e biologia da conservação, uma vez que os anfíbios são usados como bioindicadores da qualidade ambiental e da integridade de hábitat. A presente tese de doutorado teve como objetivo principal verificar o efeito da utilização de variáveis preditoras ecologicamente significativas no processo de modelagem dos anfíbios e posteriormente aplicar parte deste conhecimento na comunidade de anfíbios do Estado de São Paulo, visando verificar o potencial desta metodologia para identificar áreas de alto valor de riqueza de anfíbios e verificar também o potencial de invasão de Eleutherodactylus jonhstonei, uma espécie de anfíbio invasora registrada para o Estado de São Paulo. No primeiro capítulo avaliamos a importância da seleção de variáveis essenciais ao MDE usando os anfíbios como estudo... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: In the last decade there has been a great development in the Species Distribution Models (SDM), with several applications in conservation planning. However, despite recent advances, the selection of predictor variables has been relatively neglected in the construction of SDM. This methodological approach should be one of the critical steps of the modeling process, as the predictor variables are directly related to the ability of models to capture the environmental requirements of the species. In this context, amphibians are excellent model for assessing the importance of selecting ecologically meaningful variables in the SDM. This methodology may lead to advances in biogeography and conservation biology, since amphibians are used as bioindicators of environmental quality and habitat integrity. The aim of the work was to verify the effect of the use of ecologically meaningful variables in the amphibian modeling process and to apply part of this knowledge to the amphibian community of São Paulo state, checking the potential of this methodology to identify areas of high amphibian richness value and to verify the potential invasion of Eleutherodactylus jonhstonei, an invasive amphibian species registered in São Paulo state. In the first chapter we evaluated the importance of selecting essential variables in SDM using amphibians as a case study. The second chapter deals specifically with the amphibian modeling protocol of São Paulo state. The central focus of this chapter has been... (Complete abstract click electronic access below) / Doutor

Dans le contexte pathologique de l’athérosclérose, les cellules du muscle lisse vasculaire (CMLV) sont caractérisées par une prolifération et une migration accrue. La stimulation à l’Angiotensine II (Ang II) ou au facteur de croissance dérivé des plaquettes (PDGF) a tendance à promouvoir cette migration anormale. Cependant, ce phénomène seul n’est pas suffisant pour que les CMLV puissent migrer à travers le tissu environnant et envahir l’intima des vaisseaux sanguins. Les CMLV doivent alors dégrader la matrice extracellulaire et développer des structures nécessaires à l’invasion. Ce mouvement cellulaire est à l’origine d’une augmentation de la plaque athéromateuse responsable de nombreuses complications. Des données préliminaires ont montré que des facteurs de croissance ou hormones pouvaient induire l’invasion des CMLV. Dans notre laboratoire, il a été montré que les facteurs d’ADP-ribosylation (ARF) permettent la régulation du remodelage phénotypique des CMLV, et jouent un rôle dans la prolifération et la migration cellulaire. Au cours de cette étude, nous allons donc examiner le rôle de ARF6 dans la formation de structures importantes pour l’invasion et l’activation de métalloprotéinases de la matrice dans les CMLV humaines. En premier lieu, nous avons défini que la stimulation avec du PDGF ou de l’Ang II permet l’activation de la GTPase ARF6. En second lieu, nous avons mis en avant l’impact de la déplétion de ARF6 sur l’invasion cellulaire induite à la suite d’une stimulation avec le PDGF ou l’Ang II. Pour y parvenir, nous avons utilisé deux méthodes d’analyse de l’invasion, tout d’abord de la microscopie sur support gélatineux qui permet d’observer la dégradation de la matrice, ensuite des essais d’invasion sur du Matrigel dans des chambres de Boyden. Pour finir, nous avons voulu définir le mécanisme impliqué dans ce phénomène d’invasion cellulaire chez les CMLV humaines. En somme nous avons montré, l’importance d’ARF6 dans l’invasion induite par des facteurs de croissance ou hormone. Et nous avons soumis l’hypothèse que ce mécanisme passe par l’activation de la voie des MAPK ou PI3K. L’élucidation de ces mécanismes cellulaires pourrait avoir un intérêt quant à l’élaboration de nouvelles stratégies thérapeutiques pour le traitement de l’athérosclérose. / In the pathological setting of atherosclerosis, vascular smooth muscle cells are characterized by an increased proliferation and migration. Stimulation of these cells with Angiotensin II (Ang II) or platelet-derived growth factor (PDGF) usually promotes this abnormal migration. However, this phenotype alone is not sufficient for VSMCs to migrate through surrounding tissues and infiltrate the blood vessels’ intima. VSMCs must also be able to degrade extracellular matrix components and acquire the cellular structures necessary for invasion. The migration of VSMCs to the intima is responsible for the growth of the atherosclerotic plaque which leads to numerous complications. Preliminary data has shown that growth factors and hormones can cause the invasive phenotype of VSMCs. Our group has demonstrated that the ADP-ribosylation factor (ARF) could regulate the phenotypic remodeling of VSMCs and, by extension, their proliferative and migrative capacities. During this study, we will examine the importance of ARF6 in the formation of important invasive cellular structures as well as matrix metalloproteinases activation in human VSMCs. First, we have discovered and defined the connection between agonist stimulation and the activation of the small GTPase ARF6. We have also studied the impact of ARF6 depletion on cellular invasion following PDGF or Ang II stimulation. We have accomplished this using two methods commonly employed to analyze cellular invasion: Gelatine-based matrix degradation assays analyzed by microscopy and invasion assays on Matrigel in Boyden chambers. Lastly, we have tried to uncover the mechanistic behind this invasive phenotype observed in human VSMCs. To summarize, we have demonstrated the importance of ARF6 in growth factors and hormone-induced cellular invasion and we have hypothesized that this activity is mediated by the activation of the MAPK or PI3K signaling pathways. The further characterization of these cellular mechanisms could lead to the discovery of novel therapeutic strategies in atherosclerosis.

Michaela Kubátová Alien species of plants and biotic resistence of invaded communities This study is about problems and questions of alien plants and their relation to native communities in their new range. Ecologists are increasingly aware that soil organisms may affect plant communities because they are part of the processes that affect them. The soil organisms may affect the success of alien species invasion. Each species of plants differ in interaction with soil organisms, these interactions can result in specific feedback that will influence the future growth of other plants. According to Darwin's naturalization hypothesis related species should have similar enemies. This implies less successful invasion of alien plants at home with relatives. The practical part consists of two experiments. Using plant-soil feedback I studied under controlled conditions the importance of kinship of native plants and their soil organisms on the growth of three species of alien plants Impatiens, Parviflora, Stenactis annua and Epilobium ciliatum. There were used soil samples from localities with related and unrelated species; the soil was used as inoculums for growing first-generation plants, where there were original related, unrelated and alien plants. In the second phase only alien species were grown. Part of...

This dissertation traces the emergence of the air raid shelter as the paradigmatic architecture of air defense under the Nationalist Party government in China during the War of Resistance against Japan (1937–1945). More broadly, it explores how air defense in general became an integral part of the Nationalists’ “war of resistance and reconstruction” (kangzhan jianguo), a fascist project derived from total war, the globally circulating military-political idea holding that modern warfare would enlist entire nations and their economies in war while also subjecting them to comprehensive enemy violence. The Nationalists joined the world in confronting aerial bombing after the Empire of Japan bombed Shanghai in 1932. In response, the government and its military constructed air defense, a political and technological complex combining mass mobilization, through air raid drills and air defense organizations, with material technologies, like searchlights, anti-aircraft guns, and bomb shelters. The Nationalists found in air defense more than a military technology. To them, it also offered a set of tools and resources for fortifying their flailing attempts to unite China in a common national project, and even recasting the substance of that project. Air defense could forge a new society that invested all Chinese people in war as a necessary precondition for overcoming China’s colonial subjection. Where democratic institutions collapsed and appeals to common heritage and customs failed, the Nationalists used air defense to turn survival (shengcun) into the bedrock value of the national community. Meanwhile, a group of young architects associated with the journal Xin jianzhu in Canton identified air defense as an organizing problem for the nascent professional field of architecture. Rather than the stale historicism endorsed in Nanjing, and against China’s craft building traditions, the group championed modernist architecture, especially the International Style, whose principles of simplicity, functionalism, and rationality they saw as necessary for building modern, industrial, and hygienic Chinese cities capable of enhancing human life. Moreover, they argued that the technological instrumentality informing modernism made it the only style capable of preserving Chinese cities and people from modern threats like bombing. After the fall of Canton in 1938, members of the group took their mission to Chongqing, where they joined the Nationalist government in building air defenses in the wartime capital. In particular, this dissertation argues that the air raid shelter and air defense focused contradictions in the Nationalists’ fascist project for uniting and revolutionizing China as it traveled to Chongqing following the Nationalist escape from Japan’s invasion of the coast. Over the course of the war, the principal technology of air defense shifted away from mass mobilization, as the Nationalists came to administer refugees and displaced people they had never governed before, and became located in infrastructure like city plans and air raid shelters. Air defense served to exclude surplus populations like women and the elderly, rendered redundant according to the state’s wartime needs for industrial production and conscripts, by dispersing them in satellite settlements outside the city, from which they constantly returned in search of work or material goods. Shoddy air raid shelters, in the meantime, revealed the fragile biology of real bodies beneath the fascist fantasy of the heroic political subject, as shelters failed to provide for basic needs like respiration. Over time, these two problems collided, as the state closed shelters in the city to dispersed people, exposing surplus populations to bombing, while civilians also languished in shelters that could still kill them. The goal of building national unity through survival collapsed into a confusion of inclusion and exclusion, life and death, with disastrous results, like the asphyxiation of around one thousand people in Chongqing’s largest public air raid shelter in June 1941. In these circumstances, professionals like the Cantonese architects and new state regulatory bodies produced proposals and standards for building better shelters, attempting a technical resolution of air defense’s political contradictions and consolidating the transformation of air defense into a primarily technological discipline.

This study of political decision-making stressing the process of decision-making in a group setting is, in part, a reaction against traditional approaches of political analysis. The study of international relations is overburdened with historical studies of the interaction between states. The classic approach to the study of a given decision by one government affecting another might be called the “rational actor model”. This model treats the state as the entity reaching the decision. The decision itself is seen as behavior that reflects a rational purpose or intent. The central concepts of the model center around the calculated weighing of goals, alternatives, consequences, and choices. The “rational actor model” is the dominant method of current political analysis. I will implicitly contend in this paper that the concept of foreign policy as a rational process of gathering information, setting alternatives, and making decisions is not an adequate tool of understanding. In fact, the “rational actor model” does not make sense out of much political phenomenon. I will directly contend in this paper that a process model of political decision-making provides an adequate and helpful tool for the understanding of political decisions.