Dissertations / Theses on the topic 'Restrictions de domaine'

Depuis sa découverte il y a sept ans, les recherches intensives sur SAMHD1 en ont fait un facteur cellulaire important qui limite la réplication du virus de l’immunodéficience humaine de type 1 (VIH-1) à l’étape de transcription inverse dans les cellules immunitaires non-cyclantes. Le VIH-2 et certains virus de l’immunodéficience simienne (VIS) surmontent cette restriction en exprimant la protéine Vpx, qui conduit SAMHD1 à sa dégradation protéasomique. De nombreuses données expérimentales indiquent que l’activité triphosphohydrolase (dNTPase) de SAMHD1, qui diminue les niveaux cellulaires de dNTP, est responsable de la restriction. Cependant, la seule expression de SAMHD1 ne suffit pas à rendre les cellules résistantes à l’infection par le VIH-1 et ce quel que soit le type cellulaire. De plus, il n’existe pas de corrélation stricte entre la fonction neutralisante de SAMHD1 et sa capacité à dégrader les dNTP. Il a été suggéré que la phosphorylation du résidu T592 puisse inhiber les fonctions antivirales de SAMHD1 dans les cellules en division. Cependant, l’étude de mutants phospho-mimétiques ou phospho-ablatifs mène à des résultats contradictoires. Ces données permettent d’envisager que l’activité antivirale de SAMHD1 ne repose pas exclusivement sur son activité dNTPase et que sa régulation ne peut pas être expliquée que par la phosphorylation. Nous avons démontré que SAMHD1 est modifiée par la SUMOylation, i.e. une modification post-traductionnelle consistant en la conjugaison réversible des protéines SUMO ; et avons identifié les sites principaux modifiés. Nos résultats indiquent que les mutations empêchant la SUMOylation de SAMHD1, particulièrement celle du résidu K595 adjacent au résidu phosphorylable T592, invalident sa fonction antivirale sans affecter son activité dNTPase. Un phénotype similaire est observé après suppression de la région C-terminale de SAMHD1 (résidus 595-626). Nous suggérons donc que les résidus K595 SUMOylé et T592 phosphorylé font partie d’une interface responsable du recrutement d’un co-facteur méconnu, dépendant du type cellulaire, et pouvant jouer un rôle dans le mécanisme de restriction de l’infection par le VIH-1. Notre travail permet d’entrevoir un nouvel aspect de la régulation de SAMHD1 et contribue à la caractérisation des mécanismes moléculaires sous-jacents à son pouvoir antiviral. L’identification d’un ou plusieurs partenaires cellulaires de SAMHD1 permettra de mieux comprendre le mécanisme de restriction et pourra servir de cible thérapeutique pour combattre l’infection par le VIH-1<br>Since its discovery seven years ago, SAMHD1 has emerged as an important cellular factor that limits the replication of the Human immunodeficiency virus type 1 (HIV-1) at the reverse transcription step in non-cycling immune cells. HIV-2 and some SIV overcome this restriction by encoding the Vpx protein, which bridges SAMHD1 to the proteasomal degradation pathway. A wealth of experimental evidence indicates that SAMHD1 triphosphohydrolase (dNTPAse) activity, which is responsible for cellular dNTP pools depletion, accounts for the premature termination of viral replication. Notably, SAMHD1 expression is not sufficient to render any tested cell type resistant to HIV-1. Besides, there is no strict link between SAMHD1 capacity to deplete dNTP pools and its neutralizing function. Phosphorylation of residue T592 is proposed to downregulate the antiviral function of SAMHD1 in cycling cells. However, the analysis of phosphomimetic or unphosphorytable mutants of SAMHD1 leads to contradictory results. Altogether, these data suggest that SAMHD1-mediated restriction may neither exclusively rely on its dNTPase activity, nor solely depend on the phosphorylation status of T592.We have demonstrated that SAMHD1 undergoes SUMOylation, i.e. a post-translational modification consisting in the reversible conjugation of SUMO on a target protein; and have identified the major sites of modification. Our results show that mutations preventing SAMHD1 SUMOylation, in particular at residue K595 that lies close to the phosphorytable T592 site, inhibit its antiviral properties without impairing its dNTPase activity. Notably, an analogous phenotype is observed upon deletion of SAMHD1 C-terminus (Δ595-626). Based on these data, we speculate that phosphorytable T592 and SUMOylated K595 residues are part of an interface in SAMHD1 C-terminal tail that is responsible for the recruitment of still unknown cofactor(s) involved in the mechanism of HIV-1 infection restriction. Our work highlights a novel aspect of SAMHD1 regulation and participates to the characterization of molecular basis underlying its antiviral function. The identification of one or several cellular partners will allow a better understanding of retroviral restriction mechanism and could serve as new therapeutic targets to fight HIV-1 infection

Suite au théorème d'Arrow (1963), l'une des voies de recherche envisagées a été de modifier les conditions posées : remise en cause de la condition de domaine universel par exemple (Black (1948), Kalai, Muller et Satterthwaite (1979), Bordes et Le Breton (1989) ou encore Le Breton et Weymark (1996, 2002)), ou modification des hypothèses faites sur les préférences par la prise en compte de préférences floues (Barret, Pattanaik et Salles (1986, 1992), Banerjee (1994), Dutta (1994), Richardson (1998) entres autres). Néanmoins, aucun résultat positif satisfaisant n'émerge de ces voies de recherche. Cette thèse présente ces différents travaux et étudie l'agrégation de ces préférences floues lorsque le domaine est restreint à des domaines économiques

Positive-stranded (+)RNA viruses replicate inside cells and depend on many cellular factors to complete their infection cycle. In the meanwhile, (+)RNA viruses face the host innate immunity, such as cell-intrinsic restriction factors that could block virus replication. Firstly, I have established that the plant DDX17-like RH30 DEAD-box helicase conducts strong inhibitory function on tombusvirus replication when expressed in plants and yeast surrogate host. This study demonstrates that RH30 blocks the assembly of viral replicase complex, the activation of RNA-dependent RNA polymerase function of p92pol and viral RNA template recruitment. In addition, the features rendering the abundant plant DEAD-box helicases either antiviral or pro-viral functions in tombusvirus replication are intriguing. I found the reversion of the antiviral function of DDX17-like RH30 DEAD-box helicase and the coopted pro-viral DDX3-like RH20 helicase due to deletion of unique N-terminal domains. The discovery of the sequence plasticity of DEAD-box helicases that can alter recognition of different cis-acting elements in the viral genome illustrates the evolutionary potential of RNA helicases in the arms race between viruses and their hosts. Moreover, I discovered that Xpo1 possesses an anti-viral function and exports previously characterized cell-intrinsic restriction factors (CIRFs) from the nucleus to the replication compartment of tombusviruses. Altogether, in my PhD studies, I found plant RH30 DEAD-box helicase is a potent host restriction factor inhibiting multiple steps of the tombusvirus replication. In addition, I provided the evidence supporting that the Nterminal domain determines the functions of antiviral DDX17-like RH30 DEAD-box helicase and pro-viral DDX3-like RH20 DEAD-box helicase in tombusvirus replication. Moreover, I discovered the emerging significance of the Xpo1-dependent nuclear export pathway in tombusvirus replication.

Esta dissertação apresenta uma análise semântica, no paradigma da Semântica Formal, da (i) restrição de domínio no DP e da (ii) expressão kar, que veicula a ideia de totalidade, no dialeto paranaense da língua Kaingang, do tronco Macro-Jê, família Jê, falada nas regiões sul e sudeste do Brasil. Num primeiro momento, o artigo definido parece ter, no Kaingang Paranaense, uma distribuição não trivial: aplica-se primeiro a um determinante quantificacional e restringe, via essa combinação, o domínio do quantificador, tal como no Basco, Grego e Státimcets (Giannakidou 2003, Etxeberria 2005 e Etxeberria & Giannakidou 2009), línguas muito parecidas com o Kaingang no domínio nominal. Alguns dados, contudo, apontaram a análise em outra direção. Entendemos que certos padrões de comportamento semântico e sintático apresentado por kar nas sentenças, tal como sua neutralidade quanto à propriedade de distributividade e a possibilidade da conjunção de duas sequências de [NP+kar] sob um mesmo artigo definido (ao contrário do Basco, no qual a mesma estrutura é agramatical, sugerindo que os quantificadores universais em Basco criam um QP), são algumas das evidências que, no conjunto, dão suporte para a hipótese, defendida nesta dissertação, de que kar, no Kaingang Paranaense, parece ser um modificador - à la Lasersohn (1999) -, não tendo, por isso, uma força quantificacional própria. A função semântica de kar seria de controlar o quanto de desvio da verdade é pragmaticamente permissível. Como consequência desta análise, no Kaingang Paranaense o artigo definido não operaria sobre um determinante quantificacional, mas sim sobre um NP. O que aponta no sentido de que os artigos definidos ag/fag (os/as) no Kaingang Paranaense, em contextos em que eles co-ocorrem com kar, não perderiam a sua função max, i.e., de formadores de indivíduo a partir de um conjunto, para funcionar meramente como um operador preservador de tipo e restritor de domínio adjungido ao determinante quantificacional, como proposto por Giannakidou 2003, Etxeberria (2005) e Etxeberria & Giannakidou (2009) para o Basco e o Grego. Ag/fag continuariam sendo artigos definidos clássicos ocupando o núcleo de uma projeção DP e kar um modificador. Também discutimos brevemente algumas das vantagens e problemas de se tentar estender esta análise para o Basco, Grego e Státimcets. E, por último, investigamos o comportamento de kar na sentença, as possíveis leituras quando da sua interação com indefinidos, numerais, tipos de predicados e o operador distributivo introduzido via reduplicação verbal. Com base nos dados, nossa proposta é de que - em função de a leitura distributiva, na maioria dos exemplos, ser permitida pelos informantes somente quando houve reduplicação verbal - kar é neutro quanto à propriedade da distributividade e que o operador distributivo introduzido por reduplicação verbal tem escopo sobre todo o VP.<br>This dissertation presents, in the paradigm of formal semantics, a semantic analysis of both (i) the phenomenon of domain restriction in the DP and (ii) the expression kar, which conveys the idea of totality, in a dialect of the Kaingang language, a Brazilian language from the Macro-Jê Stock, Jê family, spoken in southern and southeastern Brazil. Although, at first, the definite article in Kaingang seems to have a non-trivial distribution: it applies first to a quantificational expression, and via such combination restricts the domain of quantifier, such as in Basque, Greek and Státimcets (Giannakidou 2003, Etxeberria 2005 and Etxeberria & Giannakidou 2009), some data pointed the analysis in another direction. Patterns of semantic and syntactic bevavior presented by kar in some sentences, such as its neutralite regarding the property of distributivity and the possibility of conjoining two [NP + kar] sequences under the same definite article (unlike Basque, which does not allow such structure, suggesting that in Basque the universal quantifier creats a QP), seem to be as a whole evidences for the hypothesis, advocated in this thesis, that the expression kar may be a modifier - à la Lasersohn (1999) - and as such would not have a quantificational force of its own. The semantic function of kar would be to control how much deviation from the truth conditions of the sentences is pragmatically allowed. As a result of this analysis, the definite articles ag/fag in Kaingang do not operate on a quantificational expression, as in Basque and Greek, but on the NP. Such fact suggests that the definite articles in Kaingang, in contexts they co-occur with kar, do not lose their max function in order to work merely as a type preserver and a domain restrictor combined with a quantificational expression, as proposed by Giannakidou 2003, Etxeberria (2005) e Etxeberria & Giannakidou (2009) for Basque and Greek. Ag/fag would still be a classical definite article occupying the head of a DP projection and kar a modifier, instead of a universal quantifier. We also discuss briefly some of the advantages and problems of trying to extend this analysis to the Basque, Greek and Státimcets languages. And lastly, we investigated the behavior of kar in the sentence, its interaction with indefinites, numerals, types of predicates and the distributive operator introduced via verbal reduplication. Based on such data, once distributive readings were permitted by the informants only via verbal reduplication, our proposal is that kar is neutral regarding the property of distributivity and that the distributive operator introduced via verbal reduplication has scope over the VP.

The aim of this study is to analyse a part of a model that describes the relationship in land administration. The model is both international and Swedish standard and is named, The Land Administration Domain Model (LADM). The model describes how a natural or legal person, property unit or joint property unit is affected by the legislation, exercise of authority and agreements within an administrative entity, such as a property unit or joint property unit. A part of the model has been analysed in a case study in Valbo, Gävle.  The study has been delimited to investigate the part that describes land administration that manifests itself as zoning plan, area regulations, Real Property Register and digitalised available cadastral dossiers. The information has been decoded by the part of the model rights, restrictions, and responsibilities (RRR). This is a more detailed way of describing how land administration affects a property unit or person. As far as the author knows has the model not been practiced in Sweden, despite of that the model has been of Swedish standard since 2012.  The study shows that LADM can be used in Swedish legislation and fills a void when describing land administration, the main focus is to describe the relationship between property units and persons. The cross-border collection of property related information generates an overview of what exists in a land area. This makes it possible to see when information is duplicated or absent. LADM has the capacity to gather information from different land administration systems. By gathering information to a system so an overview is created and better conditions for exercise of authority or inhabitant to identify which factors affect a land area.<br>Den här studien syftar till att analysera en del av en modell som beskriver relationer vid markanvändning och markägande. Modellen är både internationell och svensk standard och heter The Land Administration Domain Model (LADM), på svenska Modell för markanvändning och markägande (LADM). Modellen beskriver hur en fysisk eller juridisk person, fastighet eller samfälld mark påverkas av lagar, myndighetsutövning och avtal inom en registrerbar enhet, som en fastighet eller samfälld mark. En del av modellen har analyserats genom att använda metoden fallstudie i Valbo, Gävle.  Studien har avgränsats till att undersöka den del som beskriver markanvändning och markägande som tar sig uttryck som detaljplaner, områdesbestämmelser, fastighetsregistret och digitalt tillgängliga förrättningsakter. Informationen har tolkats enligt modellens rättigheter, restriktioner och skyldigheter (RRR), vilket ger en mer detaljerad beskrivning hur lagar, myndighetsutövning och avtal påverkar en fastighet eller person, mer än förmån och belastning. Vad författaren känner till har inte modellen tillämpats i Sverige tidigare, trots att den varit svensk standard sedan år 2012.  Studien visar att LADM fyller ett tomrum vid beskrivning av markanvändning och markägande, då den fokuserar på att beskriva relationer mellan fastigheter och personer. Insamlingen av fastighetsinformation kan ske gränsöverskridande och därmed skapar modellen en överblick av vad som finns inom ett område. Det skapar möjligheten att se när information finns upprepad hos olika register och när information uteblivit. LADM har kapacitet att samla den information som finns inom markanvändning och markägande. Genom att samla information till ett system skapas en översikt och ger bättre förutsättningar för myndighetsutövning eller invånare att identifiera vilka påverkande faktorer som finns inom ett geografiskt område.

EcoP15I gehört zu den heterooligomeren Typ III Restriktionsendonukleasen. Der multifunktionale Enzymkomplex ist aus zwei Modifikations- und zwei Restriktions-Untereinheiten aufgebaut und katalysiert sowohl die Spaltung als auch die Methylierung der DNA. Für die effektive Spaltung der doppelsträngigen DNA benötigt EcoP15I zwei invers orientierte Erkennungsorte mit der DNA-Sequenz 5’-CAGCAG. Die Spaltung erfolgt im oberen Strang 24 bis 26 Basen in 3’-Richtung nach dem Erkennungsort und im unteren Strang 26 bis 28 Basen in 5’-Richtung nach dem Erkennungsort. Aufgrund des bislang größten definierten Abstandes zwischen Erkennungs- und Spaltort ist EcoP15I ein wichtiges Werkzeug in der funktionellen Genomanalyse. Die Aufklärung der Domänenstruktur beider EcoP15I-Untereinheiten durch limitierte Proteolyse zeigte, dass die Restriktions-Untereinheit modular aufgebaut ist. Sie besteht aus zwei stabil gefalteten Domänen, der N-terminalen Translokase- und der C-terminalen Endo-Domäne. Beide Domänen sind durch einen flexiblen Linker verbunden. In der Modifikations-Untereinheit dagegen wurden keine Domänen identifiziert. Durch Insertion von Aminosäuren in und um den Linkerbereich konnten Enzymmutanten hergestellt werden, die bevorzugt die Positionen mit größten Abstand zum Erkennungsort spalteten. Wurden dagegen in dieser Region Aminosäuren deletiert, verloren die Enzymmutanten ihre DNA-Spaltaktivität. Die photochemische Vernetzung von EcoP15I mit spezifischer DNA ergab, dass EcoP15I drei Kontakte zum Phosphatrückgrat des ersten Adenins im Erkennungsort ausbildet. Ein Kontakt wird dabei über die Aminosäure S635 im C-terminalen Teil der Modifikations-Untereinheit hergestellt, zwei weitere entstehen durch die Aminosäuren Y248 und K421 der Restriktions-Untereinheit. Die transmissionselektronenmikroskopische Abbildung des negativ kontrastierten EcoP15I-Enzym zeigte einen symmetrischen Aufbau und stellt somit eine Grundlage für die Entwicklung eines dreidimensionalen Modells dar.<br>EcoP15I belongs to the hetero-oligemeric type III restriction endonucleases. The multifunctional enzyme complex consists of two modification and two restriction subunits and catalyses both the cleavage and methylation of the DNA. For effective cleavage of the double stranded DNA EcoP15I needs two inversely oriented recognition sites with the DNA sequence 5’-CAGCAG. The cleavage occurs 24 to 25 bases in 3’-direction from the recognition sequence in the top strand and 26 to 28 bases in 5’-direction from the recognition sequence in the bottom strand. Because of the largest known distance between recognition and cleavage site so far EcoP15I is an important tool in functional genomics. The elucidation of the domain structure of EcoP15I restriction as well as the modification subunit by limited proteolysis showed that the restriction subunit has a modular structure. It consists of two stable folded domains, the N-terminal translocase domain and the C-terminal endonuclease domain. Both domains are connected by a flexible linker. In contrast to the restriction subunit no domains could be detected in the modification subunit. Enzyme mutants that were constructed by insertion of amino acids in and around the linker region cleaved preferentially the position with the largest distance between recognition and cleavage site. The enzyme mutants lost their DNA cleavage activity when the amino acids in this region were deleted. The photochemical crosslinking of EcoP15I with specific DNA showed that EcoP15I forms three contacts to the phosphate backbone of the first adenine of the recognition site. One contact is made by amino acid S635 in the C-terminal part of the modification subunit. Two others are made by amino acids Y248 and K421 of the restriction subunit. The transmission electron microscope picture of the negatively stained EcoP15I enzyme showed a symmetric form and therefore it constitutes a basis for the development of a three dimensional model.

L’intérêt public imprime aux ports une organisation juridique et institutionnelle spéciale. Les installations portuaires doivent fonctionner sans désemparer et aucun usager ne doit en être privé au-delà des restrictions nécessaires à la satisfaction de tous. À ce titre, elles sont traditionnellement soumises au régime de la domanialité publique et les activités qui s’y déroulent à celui du service public. Les deux régimes étant, par leur essence même, exorbitants, leur application simultanée génère une surprotection préjudiciable à la compétitivité des ports.L’objet de cette étude est de démontrer l’inadaptation de la domanialité publique portuaire, tant du point de vue de sa cohérence générale, que de du point de vue de son impact sur le développement des sites portuaires. L’adoption du CGPPP et les réformes postérieures n’ont pas permis de résoudre le problème de l’hypertrophie du domaine public portuaire, pas plus qu’elles n’ont consacré un régime domanial véritablement adapté.L’émergence du régime des conventions de terminal constitue une évolution majeure, mais insuffisante. S’il favorise un certain partage des risques entre autorités portuaires et opérateurs privés, il n’a, malheureusement, pas résolu le problème de la précarité des occupations domaniales. L’insécurité juridique demeure ; ce qui n’encourage pas l’investissement privé.Face aux contraintes du droit de la concurrence et à la généralisation de la libre circulation des biens et des personnes au sein de l’UE, les modalités de gestion des installations portuaires doivent s’adapter aux enjeux modernes de l’économie de marché<br>Public interest gives harbours a specific legal and institutional framework. Harbour facilities must work continuously and stay available to every user, according to the limitations required to satisfy everybody. As such, they are traditionally subject to the state ownership system and their related activities are subject to the public service one. Both systems are exorbitant by nature. Applying them simultaneously triggers off an overprotection detrimental to harbours competitivity.This study aims at showing the harbour state ownership system is unsuitable, both in terms of overall consistency and its impact on the harbour site growth. Adoption of the general code ruling the public ownership and posterior reforms did not allow to resolve the harbour state ownership hypertrophy issue, nor did they establish an ownership system truly appropriate.Appearing harbour terminals contracts constitute a major but still insufficient evolution. If they do allow to share risks between harbour authorities and private operators to some extent, unfortunately they did not resolve the ownership activities precarity issue. Legal insecurity remains, which does not stimulate private investment.Against competition law obligations and the free movement of goods and people spreading within the EU, harbour facilities management terms need to adapt to today’s market economy challenges

L'activació sostinguda de Hog1 porta a una inhibició del creixement cel·lular. En aquest treball, hem observat que el fenotip de letalitat causat per l'activació sostinguda de Hog1 és parcialment inhibida per la mutació del complexe SCFCDC4. La inhibició de la mort causada per l'activació sostinguda de Hog1 depèn de la via d'extensió de la vida. Quan Hog1 s'activa de manera sostinguda, la mutació al complexe SCFCDC4 fa que augmenti l'expressió gènica depenent de Msn2 i Msn4 que condueix a una sobreexpressió del gen PNC1 i a una hiperactivació de la deacetilassa Sir2. La hiperactivació de Sir2 és capaç d'inhibir la mort causada per l'activació sostinguda de Hog1.<br/> També hem observat que la mort cel·lular causada per l'activació sostinguda de Hog1 és deguda a una inducció d'apoptosi. L'apoptosi induïda per Hog1 és inhibida per la mutació al complexe SCFCDC4. Per tant, la via d'extensió de la vida és capaç de prevenir l'apoptosi a través d'un mecanisme desconegut.<br>Sustained Hog1 activation leads to an inhibition of cell growth. In this work, we have observed that the lethal phenotype caused by sustained Hog1 activation is prevented by SCFCDC4 mutants. The prevention of Hog1-induced cell death by SCFCDC4 mutation depends on the lifespan extension pathway. Upon sustained Hog1 activation, SCFCDC4 mutation increases Msn2 and Msn4 dependent gene expression that leads to a PNC1 overexpression and a Sir2 deacetylase hyperactivation. Then, hyperactivation of Sir2 is able to prevent cell death caused by sustained Hog1 activation.<br/> We have also observed that cell death upon sustained Hog1 activation is due to an induction of apoptosis. The apoptosis induced by Hog1 is decreased by SCFCDC4 mutation. Therefore, lifespan extension pathway is able to prevent apoptosis by an unknown mechanism.

This dissertation investigates the ways in which natural language restricts the domains of quantifiers. Adverbs of quantification are analyzed as quantifying over situations (instead of being unselective quantifiers). The domain of quantifiers is pragmatically constrained: apparent processes of "semantic partition" are treated as pragmatic epiphenomena. The introductory Chapter 1 sketches some of the background of work on natural language quantification and begins the analysis of adverbial quantification over situations. Chapter 2 develops the central picture of "semantic partition" as a side-effect of pragmatic processes of anaphora resolution. I argue that the apparent effects of topic/focus articulation and presuppositional information on the interpretation of quantifiers are not the result of a direct and local mechanism of sentence grammar. Instead, I develop an analysis where the link is established via the anaphoric dependence of quantifier domains on the discourse context. Chapter 3 discusses the analysis of conditional clauses as quantifier restrictors, concentrating on the question whether conditional clauses restrict quantifiers directly (like common noun phrases restrict determiner-quantifiers) or indirectly (like topic/focus restrict quantifiers). A treatment is explored which has if-clauses constrain the value of the hidden domain variable of the restricted quantifier. Chapter 4, on unless-clauses, and Chapter 5, on only if- and even if-clauses, present some issues in the compositional analysis of complex conditional clauses. These chapters significantly expand the data coverage of the theory of A-quantification. Building on previous work of mine on exceptives, I analyze unless-clauses as exceptive operators on A-quantifiers. The analysis of only if-clauses, treated as conditional clauses that combine if with the focus adverb only, unearthes some interesting new properties. Chapter 6, finally, examines the phenomenon of donkey-anaphora in the light of the results of the previous chapters. I show that a solution to the proportion problem may become possible once we combine the situation-semantic approach to adverbial quantification with the pragmatic theory developed in Chapter 2 and further elaborated in the analysis of donkey anaphora in complex conditionals.

Tesi hau euskarazko zenbatzaileen gaineko tesi bat da. Bertan proposatzen den analisiak Zenbatzaile Orokortuen Teoria zuzena dela erakusten digu eta hizkuntza naturaletako kuantifikazioa azaltzeko ahalmena duela, teoria hau auzitan jarri duten analisien kontra. Zenbatzaile Orokortuen Teoria zuzena izateko zenbatzaileen domeinua beti murriztuta egon behar dela proposatzen da; murriztapen hori euskara bezalako hizkuntza batean azaleko sintaxian burutuko da euskal artikuluaren bitartez. Proposamen honek euskarako artikuluaren analisi jakin bat egitera eramaten gaitu, elementu honek determinatzaile definituaren funtzioa beteko du beti, ‘type-shifting' egiteko erreztasuna izango duelarik eta honek azaltzen ditu euskal artikuluak jaso ditzakeen irakurketak.

In this thesis, I investigate the properties of determiners in Sk̲wx̲wú7mesh (Squamish) Salish. Determiners in Sk̲wx̲wú7mesh behave significantly differently from the definite determiner “the” in English. Sk̲wx̲wú7mesh lacks a definite/indefiniteness distinction; all DPs can be used in both familiar and novel contexts, and are not required to refer to a unique entity. Instead, Sk̲wx̲wú7mesh determiners are split along deictic/non-deictic lines. I argue that deictic features on the determiners have consequences for the grammar in terms of (i) scope and (ii) implicature of uniqueness. If a DP is deictic, (i) it can take wide scope and (ii) any sentence containing it will carry an implicature of uniqueness. If a DP is non-deictic, (i) it must take narrow scope and (ii) any sentence containing it does not carry an implicature of uniqueness. I claim that non-deictic DPs are composed via Restrict and deictic DPs via Specify (cf. Chung and Ladusaw 2004). There is therefore no correlation between more structure and wide scope, but rather a correlation between features and wide scope. Deictic features allow DPs to take wide scope; the lack of features prevents DPs from taking wide scope. Determiners in Sk̲wx̲wú7mesh are quite different from determiners in better-known languages. Do determiners share anything in common cross-linguistically? I argue that Sk̲wx̲wú7mesh determiners and English “the” are both associated with domain restriction (cf. von Fintel 1994). Both non-deictic and deictic DPs are sensitive to the context in which they are used; in familiar contexts, they (usually) refer to the set of entities under discussion. Non-deictic DPs, which in terms of scope behave like bare nouns, must differ from bare nouns in this respect. Bare nouns (in languages which use articles) cannot be used in familiar contexts. They can only introduce new discourse referents. Non-deictic DPs can introduce new discourse referents, but can also refer to previously introduced discourse referents, and can also be used partitively. Sk̲wx̲wú7mesh determiners must be associated with domain restriction, whereas bare nouns cannot be. I propose there is a strict correlation between the syntax and semantics: if a determiner occupies D, it has domain restriction in its representation.<br>Arts, Faculty of<br>Linguistics, Department of<br>Graduate

The APOBEC3 (Apo3) family of proteins are single stranded (ss) DNA cytosine deaminases (C → U). They are grouped into two different structural groups, the single catalytic domain Apo3 enzymes (Apo3A, Apo3C, and Apo3H) and the double catalytic domain Apo3 enzymes (Apo3B, Apo3D, Apo3F, and Apo3G). Apo3G has been implicated in protection from HIV proliferation by becoming encapsidated into budding HIV virions and subsequently mutationally inactivating the synthesized provirus. This largely occurs in the absence of HIV viral infectivity factor (Vif) which mediates the ubiquitination and degradation of Apo3G. Apo3G is a processive enzyme, able to catalyze numerous deaminations in a 5'CCC motif in a single interaction with a substrate. There is a paucity of biochemical data on other Apo3 family members. We performed basic biochemical assays that determined the relative specific activities, processivity, cytosine motif preferences, and binding affinities for DNA, of Apo3A and Apo3H using synthetic DNA substrates in deamination assays. We found Apo3A to be an enzyme with low processivity and Apo3H to be a highly processive enzyme; both of which deaminate a 5'TC motif. Using a reconstituted HIV replication assay we assessed if processivity is needed for efficient restriction of HIV. We were able to demonstrate that each, Apo3G, Apo3A, and Apo3H were able to catalyze deaminations during in vitro reverse transcription. The mutation profile of both Apo3A and Apo3H showed that the 5'TC motif preference was less effective compared to Apo3G in triggering missense and nonsense mutations in the HIV protease active site coding sequence. Nuclear DNA can become deaminated by the related Apo3 family member activation-induced deaminase (AID), when it is present in the nucleus of activated B cells. Apo3A and Apo3H are located in the nucleus but the extent of the damage they cause has only recently been investigated. Here we used an in vitro transcription assay to determine the efficiency of Apo3A and Apo3H deamination during transcription and found that, like AID, they are highly capable of causing deaminations during transcription. Taken together, the results presented here demonstrate that processivity is not necessary for an Apo3 enzyme to catalyze deaminations during HIV reverse transcription and that Apo3A and Apo3H can catalyze deaminations during DNA transcription that could damage host genomic DNA. These results imply a potential cost for maintaining nuclear deaminases.

Type I restriction-modification (R-M) enzymes recognize specific sequences on foreign DNA invading the bacterial cell. At a first sight, also host DNA containing the specific target site for Type I R-M enzyme would cleavage, too, but this doesn't happen as the enzymes are able to distinguish between hostband foreign DNA. Normally the specific sequence on host DNA is either fully methylated or the Type I R-M enzyme recognizes the hemi-methylated state of the DNA, switches to the modification mode and methylates the second strand of the hemi-methylated DNA. Recognition of unmethylated foreign DNA invading the bacterial cell from the outer environment leads to a switching to the restriction mode, initiating endonuclease activity. The R-M complex tightly bound to the recognition sequence on foreign DNA then starts to translocate dsDNA in an ATP-dependent manner towards the stationary enzyme over up to several thousand base pairs. When DNA translocation is finally stalled, the enzyme complex introduces a double strand break, seemingly in a random site distant from the recognition sequence. Multi-subunit structure determines complex behavior of Type I R-M enzymes. The fully assembled Type I R-M enzyme consists of five subunits which are encoded by hsd genes (host specificity for DNA): one copy of HsdS subunit together with two copies of HsdM subunit form the trimeric HsdS1-HsdM2 methyltransferase complex which recognizes and binds to a specific DNA sequence and bears the methylation function. The fully assembled HsdS1-HsdM2-HsdR2 complex possesses ATP-dependent DNA translocation and endonuclease activities located on its HsdR subunits. The X-ray crystal structure of HsdR of EcoR124I with bound ATP gives a first insight of structural/functional correlation in the HsdR subunit. In this work the involvement of the endonuclease domain in interdomain communication within the HsdR motor subunit of EcoR124I is probed experimentally, confronted with computational predictions and discussed in the light of the fully functional pentameric complex.

This thesis is concerned with the description and analysis of two semantically different types of definite articles in German. While the existence of distinct article paradigms in various Germanic dialects and other languages has been acknowledged in the descriptive literature for quite some time, the theoretical implications of their existence have not been explored extensively. I argue that each of the articles corresponds to one of the two predominant theoretical approaches to analyzing definite descriptions: the 'weak' article encodes uniqueness. The 'strong' article is anaphoric in nature. In the course of spelling out detailed analyses for the two articles, various more general issues relevant to current semantic theory are addressed, in particular with respect to the analysis of donkey sentences and domain restriction. Chapter 2 describes the contrast between the weak and the strong article in light of the descriptive literature and characterizes their uses in terms of Hawkins's (1978) classification. Special attention is paid to two types of bridging uses, which shed further light on the contrast and play an important in the analysis developed in the following chapters. Chapter 3 introduces a situation semantics and argues for a specific version thereof. First, I propose that situation arguments in noun phrases are represented syntactically as situation pronouns at the level of the DP (rather than within the NP). Secondly, I argue that domain restriction (which is crucial for uniqueness analyses) can best be captured in a situation semantics, as this is both more economical and empirically more adequate than an analysis in terms of contextually supplied C-variables. Chapter 4 provides a uniqueness analysis of weak-article definites. The interpretation of a weak-article definite crucially depends on the interpretation of its situation pronoun, which can stand for the topic situation or a contextually supplied situation, or be quantificationally bound. I make a specific proposal for how topic situations (roughly, the situations that we are talking about) can be derived from questions and relate this to a more general perspective on discourse structure based on the notion of Question Under Discussion (QUD) (Roberts 1996, Büring 2003). I also show that it requires a presuppositional view of definites. A detailed, situation-semantic analysis of covarying interpretations of weak-article definites in donkey sentences is spelled out as well, which provides some new insights with regards to transparent interpretations of the restrictors of donkey sentences. Chapter 5 deals with so-called larger situation uses (Hawkins 1978), which call for a special, systematic way of determining the situation in which the definite is interpreted. I argue that a situation semantic version of an independently motivated type-shifter for relational nouns (shifting relations (⟨e, ⟨e, st⟩⟩) to properties (⟨e, ⟨st⟩⟩)) brings about the desired situational effect. This type-shifter also applies to cases of part-whole bridging and provides a deeper understanding thereof. Another independently motivated mechanism, namely that of Matching functions, gives rise to similar effects, but in contrast to the type-shifter, it depends heavily on contextual support and cannot account for the general availability of larger situation uses that is independent of the context. The anaphoric nature of the strong article is described and analyzed in detail in chapter 6. In addition to simple discourse anaphoric uses, I discuss covarying interpretations and relational anaphora (the type of bridging expressed by the strong article). Cases where uniqueness does not hold (e.g., in so-called bishop sentences) provide crucial evidence for the need to encode the anaphoric link between strong-article definites and their antecedents formally. The resulting dynamic analysis of strong-article definites encodes the anaphoric dependency via a separate anaphoric element that is incorporated into a uniqueness meaning. Finally, remaining challenges for the analysis are discussed, in particular the existence of strong-article definites without an antecedent and a puzzling contrast between the articles with respect to relative clauses. The final chapter discusses some loose ends that suggest directions for future work and sums up the main conclusions.

Bacterial type I restriction-modification systems are composed of three different subunits: one HsdS subunit is required for identification of target sequence and anchoring the enzyme complex on DNA; two HsdM subunits in the methyl-transferase complex serve for host genome modification accomplishing a protective function against self-degradation; two HsdR (or motor) subunits house ATP-dependent translocation and consequent cleavage of double stranded DNA activities. The crystal structure of the 120 kDa HsdR subunit of the Type I restriction-modification system EcoR124I in complex with ATP was recently reported. HsdR is organized into four approximately globular structural domains in a nearly square-planar arrangement: the N-terminal endonuclease domain, the RecA-like helicase domains 1 and 2 and the C-terminal helical domain. The near-planar arrangement of globular domains creates prominent grooves between each domain pair. The two helicase-like domains form a canonical helicase cleft in which double-stranded B-form DNA can be accommodated without steric clash. The helical domain, probably involved in complex assembly, exhibits only a few specific interactions with helicase 2 domain. Molecular mechanism of dsDNA translocation, cleavage and ATP hydrolysis has not been yet structurally investigated. Here we propose a translocation cycle of the restriction-modification system EcoR124I based on analysis of available crystal structures of superfamily 2 helicases, strutural modeling and complementary biochemical characterization of mutations introduced in sites potentially inportant for translocation in the HsdR motor subunit. Also a role of the extended region of the helicase motif III in ATPase activity of EcoR124I was probed.