Mass production of translationally optimized bacteriophages (hereafter referred to as phages) is the need of the hour in the application of phages to therapy. Understanding translational efficiency of phages is the major preliminary step for mass producing efficient phages. The objective of this thesis is to understand factors affecting translational efficiency of phages. In chapter two, we hypothesized that weak translation initiation efficiency is responsible for weak codon concordance of Escherichia coli lambdoid phages with that of their hosts. We measured the strength of translation initiation using two indices namely minimum folding energy (MFE) and proportion of Shine-Dalgarno sequence (PSD). Empirical results substantiate our hypothesis suggesting lack of strong selection for improving codon adaptation in these phages is due to their weak translation initiation. In chapter three, we measured codon usage concordance between GC-rich and GC-poor Aeromonas phages with their GC-rich host Aeromonas salmonicida. We found low codon usage concordance in the GC-poor Aeromonas phages. We were interested in testing for the role of tRNAs in the GC-poor phages. We observed that the GC-poor phages carry tRNAs for codons that are overused by the phages and underused by the host. These findings suggest that the GC-poor Aeromonas phages carry their own tRNAs for compensating for the compositional difference between their genomes and that of their host. Previously several studies have reported observed avoidance of stable secondary structures in start site of mRNA in a wide range of species. We probed the genomes of 422 phage species and measured their secondary structure stability using MFE. We observed strong patterns of secondary structure avoidance (less negative MFE values) in the translation initiation region (TIR) and translation termination region (TTR) of all analyzed phages. These findings imply selection is operating at these translationally important sites to control stable secondary structures in order to maintain efficient translation.

The liquidation is a topic which is not properly defined by the Czech legislation. There is no dedicated law, which would bring a complex description of the liquidation. The actual law regulation does not address the whole complexity and brings many questions. Therefore this thesis is concerned with problems of the liquidation in accordance with the Czech legislation. The aim of the thesis is to provide sufficient information which would give a comprehensive picture of the liquidation. The introductory part of the thesis focuses on a general description, definitions and law regulation of the liquidation. The main part of the thesis describes the process of liquidation involving the beginning, course, distribution of the liquidation balance, and its termination. The thesis is supplemented by several examples of documents utilized during the liquidation and tables presenting liquidation statistics in past years.

S v Mshumpa dealt with the very controversial issue of third party foetal violence that terminates prenatal life. The decision of the Eastern Cape Division emphasised that, until live birth, a foetus is not a legal subject with constitutional rights. As a result of its position in the law, a foetus cannot be the victim of criminal conduct. The court refused to develop the common law crime of murder to include a foetus and referred this issue to the legislature to address. Concerns raised by the research task relate to the most effective method of law reform and the implications of law reform for well established legal principles concerning legal subjectivity, vestment of constitutional rights and female reproductive rights. In order to avoid these concerns, the introduction of a statutory crime is determined as the preferred method for law reform. The aim of the study is to develop a suitably defined statutory crime, with definitional elements that conform to the Constitution and criminal law principles. Before embarking on the mission of exploring possible grounds that justify law reform, the research first examines the extent of inability of the law to impose criminal liability in cases of third party violence that terminates prenatal life. Aspects that are specifically investigated include the common law crime of murder, contravention of the Choice on Termination of Pregnancy Act, attempting the impossible and the common law crime of abortion. A further purpose of this examination is to determine the reasons why foetal interests are not taken into account. Appreciating the lack of criminal remedy, private law principles are considered in order to determine whether there are any principles available to supplement the deficiencies in criminal law. This research found that the value of dignity established by the founding principles of the Constitution and applied in the Choice on Termination of Pregnancy Act demonstrates that the state has an interest in prenatal life. The value of dignity serves as the foundation for law reform. Having established the existence of a sound legal basis which justifies law reform, the research requires an investigation into foreign jurisdictions where the crime of third party foetal violence exists as a result of a state interest in foetal life. The purpose of the investigation is to determine whether the crime is effectively implemented. The United States of America is the selected country to study because third party foetal violence receives attention at both state and federal level. The research found that the implementation of foetal homicide laws in the United States infringes on female reproductive rights and to a certain extent, the foetal homicide laws also grants a foetus legal subjectivity. The United States fails to effectively implement the crime of third party foetal violence in line with its own established legal principles. The research benefits from the study conducted on the United States in that the United States demonstrates the definitional elements the proposed crime should contain in order for the statutory crime to be harmonious with established constitutional and criminal law principles. The study concludes with the recommendation that a statutory crime be developed in the context of female reproductive rights rather than considering the foetus as the victim of crime. The statutory crime is a response to unauthorised third party violence that terminates a woman’s pregnancy. The definitional elements include foetal viability for purposes of causation and will only be applicable to intentional conduct. The value of dignity in relation to prenatal life serves as a support structure for the driving force of female reproductive rights. / Dissertation (LLM)--University of Pretoria, 2011. / Public Law / unrestricted

Maude es un lenguaje de programación declarativo basado en la lógica de reescritura que incorpora muchas características que lo hacen muy potente. Sin embargo, a la hora de probar ciertas propiedades computacionales esto conlleva dificultades. La tarea de probar la terminación de sistemas de reesctritura es de hecho bastante dura, pero aplicada a lenguajes de programación reales se concierte en más complicada debido a estas características inherentes. Esto provoca que métodos para probar la terminación de este tipo de programas requieran técnicas específicas y un análisis cuidadoso. Varios trabajos han intentado probar terminación de (un subconjunto de) programas Maude. Sin embargo, todos ellos siguen una aproximación transformacional, donde el programa original es trasformado hasta alcanzar un sistema de reescritura capaz de ser manejado con las técnicas y herramientas de terminación existentes. En la práctica, el hecho de transformar los sistemas originales suele complicar la demostración de la terminación ya que esto introduce nuevos símbolos y reglas en el sistema. En esta tesis, llevamos a cabo el problema de probar terminación de (un subconjunto de) programas Maude mediante métodos directos. Por un lado, nos centramos en la estrategia de Maude. Maude es un lenguaje impaciente donde los argumentos de una función son evaluados siempre antes de la aplicación de la función que los usa. Esta estrategia (conocida como llamada por valor) puede provocar la no terminación si los programas no están escritos cuidadosamente. Por esta razón, Maude (en concreto) incorpora mecanismos para controlar la ejecución de programas como las anotaciones sintácticas que están asociadas a los argumentos de los símbolos. En reescritura, esta estrategia sería conocida como reescritura sensible al contexto innermost (RSCI). Por otro lado, Maude también incorpora la posibilidad de declarar atributos. / Alarcón Jiménez, B. (2011). Towards a Framework for Proving Termination of Maude Programs [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/11003 / Palancia

La transcription bactérienne est un processus dans lequel l'information codée dans l'ADN est transféré à l'ARN messager (ARNm). Au cours de la dernière étape de ce procédé, la terminaison de la transcription, l'ARNm est libéré et peut être utilisé pour la synthèse des protéines. Un type de terminaison de la transcription décrit chez les bactéries est la terminaison Rho-dépendante. Le rôle de Rho a été largement étudié dans le modèle à Gram négatif bactérie, Escherichia coli dans laquelle Rho est une protéine essentiel est abondant. En revanche, la connaissance de Rho chez les bactéries qui il ne sont pas essentiels et est présent en faibles quantités: par exemple Gram-positif Bacillus subtilis reste limité..Pour étudier le rôle de Rho dans le contrôle de l'expression des gènes chez B. subtilis plusieurs analyses à grande échelle ont été réalisées, y compris des tests d'interactions physiques et fonctionnelles et une analyse globale des changements observés dans l'expression des gènes en corrélation avec la production de protéines.En effet, un ensemble des Rho-spécifiques interactions physiques et fonctionnelles ont été établies. En outre, de nouveaux phénotypes de mutant dépourvu de rho ont été décrits ce qui élucider le rôle de Rho dans le contrôle des différents aspects de la physiologie cellulaire. / Bacterial transcription is a process in which the information encoded in DNA is transferred to messenger RNA (mRNA). During the final step of this process, transcription termination, mRNA is released and can be used for protein synthesis. One type of transcription termination described in bacteria is Rho-dependent termination. The role of Rho has been widely investigated in model Gram-negative bacterium, Escherichia coli in which Rho is essential an abundant protein. In contrast, the knowledge about Rho inbacteria in which it is not essential and is present in low amounts, i. e. Gram-positive Bacillus subtilis remains limited.To investigate the role of Rho in control of gene expression in B. subtilis several large-scale analysis were performed. In effect, a set of Rho-specific physical and functional interactions were established. Additionally, new phenotypes of rho-null mutant were described unraveling the role of Rho in control of different aspects of cell physiology.

While real-time applications are nowadays routinely used in visualizing large nu- merical simulations and volumes, handling these large-scale datasets requires high-end graphics clusters or supercomputers to process and visualize them. However, not all users have access to powerful clusters. Therefore, it is challenging to come up with a visualization approach that provides insight to large-scale datasets on a single com- puter. Explorable images (EI) is one of the methods that allows users to handle large data on a single workstation. Although it is a view-dependent method, it combines both exploration and modification of visual aspects without re-accessing the original huge data. In this thesis, we propose a novel image-based method that applies the concept of EI in visualizing large flow-field pathlines data. The goal of our work is to provide an optimized image-based method, which scales well with the dataset size. Our approach is based on constructing a per-pixel linked list data structure in which each pixel contains a list of pathlines segments. With this view-dependent method it is possible to filter, color-code and explore large-scale flow data in real-time. In addition, optimization techniques such as early-ray termination and deferred shading are applied, which further improves the performance and scalability of our approach.

1 ABSTRACT Implications of Termination of International Investment Agreements The international investment arbitration proceedings under the Washington Convention on the Settlement of Investment Disputes between States and Nationals of Other States ("ICSID arbitration proceedings" and "ICSID Convention") represents predominantly used mechanism of Investor-state dispute settlement. The adjudicative system of investment arbitration resolving disputes concerning breaches of foreign investment protection within the territory of the host states granted by bilateral investment treaties ("BITs") faces increasing criticism. The reluctance to abide by the binding awards of the arbitral tribunals on behalf of the host states and evolving displeasure towards the ICSID arbitration system triggered the wave of terminations of international investment agreements initiated by the states of the Latin America. Termination of international investment agreements significantly disturbs the procedural protection of foreign investments and ultimately deprives the foreign investors of the right to have their claims against the host states heard in designated arbitration forum. The ICSID arbitration proceedings are characteristic for the interconnection between international investment agreements, particularly the ICSID Convention...

Les mutations non sens introduisent un codon stop prématuré dans une phase ouverte de lecture. Ce type de mutation est retrouvé chez environ 11% des patients atteints de maladies génétiques et dans de nombreux cancers. En effet, entre 5 et 40% des mutations affectant des gènes suppresseurs de tumeurs sont des mutations non sens. La conséquence de la présence d’une mutation non sens dans un gène est la dégradation rapide de l’ARN messager correspondant, par l’activation d’un mécanisme de surveillance des ARN appelé NMD (pour nonsense-mediated mRNA decay) conduisant à une absence d’expression du gène mutant. Dans le cas des cancers, l’absence d’expression d’un gène suppresseur de tumeurs tel que TP53, perturbe un ensemble de processus biologiques dont l’apoptose, facilitant ainsi la progression tumorale.En utilisant un système de criblage moyen débit permettant d’identifier des molécules capables de ré-exprimer des gènes porteurs d’une mutation non sens en inhibant le NMD et/ou en activant la translecture, plusieurs molécules ont été identifiées. La translecture est un mécanisme naturel conduisant à l’incorporation d’un acide aminé à la position du codon stop prématuré au cours de la traduction. Parmi les molécules identifiées, je me suis intéressée à un extrait végétal nommé H7 et au composé CNSM1 (pour corrector of nonsense mutation 1) qui permettent une ré-expression très efficace du gène TP53 lorsqu’il est porteur d’une mutation non sens. J’ai caractérisé ces composés en montrant notamment la ré-expression du gène TP53 porteur d’une mutation non sens dans différentes lignées cellulaires issues de différents cancers. J’ai montré également la très faible toxicité de ces molécules, validant leur potentielle utilisation en clinique. Mon étude a aussi permis de montrer que la protéine p53 synthétisée est fonctionnelle puisqu'elle est capable d’induire l’activation transcriptionnelle d’un de ses gènes cibles, le gène TP21.En permettant la ré-expression du gène suppresseur de tumeur mutant, des molécules comme CNSM1 ou H7 restaurent la capacité des cellules à entrer en apoptose et pourraient aussi réduire certaines résistances à la chimiothérapie.De plus, par une approche d’édition du génome, j’ai confirmé le lien existant entre le blocage du cytosquelette et l’inhibition du NMD. J’ai aussi identifié deux protéines impliquées dans le réarrangement du cytosquelette qui pourraient être ciblées pour inhiber le NMD en thérapie et ré-exprimer une protéine tronquée fonctionnelle. L’utilisation de H7 ou de CNMS1 pourrait ainsi être couplée à une inhibition du NMD pour optimiser la correction des mutations non sens. Ces molécules correctrices de mutations non sens représentent de nouvelles approches thérapeutiques ciblées du cancer et des maladies rares liées aux mutations non sens. / Nonsense mutations generate premature termination codons (PTC) within an open reading frame. This type of mutation is found in about 11% of patients with genetic disorders. Concerning cancer, 5 to 40% of mutations affecting tumor-suppressing genes are nonsense mutations. The presence of a PTC in a gene leads to rapid degradation of its mRNA mediated by the RNA surveillance mechanism named NMD (Nonsense-mediated mRNA decay) preventing the synthesis of truncated proteins. In cancer, the absence of expression of tumor suppressing genes such as TP53 interferes with many biological pathways including apoptosis enabling tumor progression.A screening system that allows identifying molecules capable of re-expressing genes harboring nonsense mutations by inhibiting the NMD system and/or by activating readthrough has been developed in the lab. Readthrough is a natural mechanism, which occurs during translation, leading to the incorporation of an amino acid at the PTC position. Among the molecules that have been identified thanks to the screen, a natural extract named H7 and a compound named CNSM1 efficiently rescues the expression of the nonsense-mutated TP53 gene carrying a PTC.CNSM1 and H7 induces the expression of full-length proteins from PTC-containing genes indicating that these compounds are capable of activating readthrough. I validated the screen results on several cancer cell lines harboring an endogenous nonsense mutation in TP53 gene and showed that the function of p53 was restored in the presence of CNSM1 or H7. I also investigated the cellular toxicity related with the use of CMNS1 on cultured cells and the in vivo effect of H7 in a mouse model harboring a nonsense mutation in dystrophin gene. My results demonstrate that these compounds have a mild cellular toxicity. In addition, using a genome editing approach I confirmed the relationship between the cytoskeletal blockage and the NMD inhibition. I identified two proteins that are implicated in the cytoskeletal rearrangement, which might be targeted to induce NMD inhibition and then the expression of truncated but functional protein from the mutated mRNA. H7 or CNMS1 might be coupled to an NMD inhibition strategy to improve the nonsense mutation correction. Knowing CNSM1 and H7 are so far the most efficient molecule capable of rescuing the expression of PTC-containing genes, these compounds represents a realistic hope for a new-targeted therapy for pathologies associated with nonsense mutations.

Inledning: Inom psykodynamisk teori är den psykoterapeutiska ramen ett centralt begrepp. Syftet med studien är att undersöka hur psykodynamiskt inriktade psykoterapeuter förhåller sig till den psykoterapeutiska ramen med fokus på tidsdimensionen i avslutet av terapitimmen.  Frågeställningar: Hur gör terapeuten för att avsluta en terapitimme? Hur ser terapeuten på avslutet av terapitimmen? Vilka känslor och reaktioner väcker avslutet hos terapeuten? Är avslutet av terapitimmen ett område som man kan prata med andra terapeuter om? Metod: Datainsamlingen genomfördes genom strukturerade intervjuer med kvalitativ forskningsmetod. Studien har en hermeneutisk ansats och resultatet har analyserats tematiskt. Resultat: Undersökningen visar att fyra av de fem intervjuade psykoterapeuterna förbereder patienten på terapitimmens avslut. Denna praktik har inte stöd i den psykodynamiska psykoterapeututbildning som ges vid S:t Lukas utbildningsinstitut. Under utbildningen betonas vikten av att hålla tidsramen noga, i betydelsen att arbeta psykoterapeutiskt tills den överenskomna tiden är slut. Diskussion: Samtliga intervjuade psykoterapeuter delar uppfattningen att de psykoterapeutiska tidsramarna i allmänhet inte tillämpas lika strikt idag som tidigare. Fyra av de fem terapeuterna har erfarenhet av att arbeta med andra terapimetoder än den psykodynamiska, vilket kan påverka deras förhållningssätt till avslutet av terapitimmen. / The psychotherapeutic framework is a central idea in psychodynamic theory. The purpose of the study is to examine how psychodynamically oriented psychotherapist relate to the psychotherapeutic framework with focus on the time dimension at the end of the therapy session. Questions: How does the therapist act to end a therapy session? How does the therapist regard the end of the therapy session? What feelings and reactions does the termination evoke in the therapist? Is the termination of the therapy session a subject you can talk to other therapists about?  Method: The data collection was conducted through structured interviews with a qualitative research method. The study has a hermeneutic approach and the result has been analysed thematically. Result: The study shows that four out of five interviewed psychotherapists prepare the patient for the end of the psychotherapy session. This practice lacks support in the psychodynamic psychotherapist education at St Lukas educational institution. The importance of holding the time frame, in the sense of working psychotherapeutically until the agreed time is over, is emphasized during the training. Discussion: The interviewed psychotherapists share the view that the psychotherapeutic timeframes are generally not applied as strictly today as before. Four out of five therapists have experience of working with other methods of therapy than the psychodynamic, which may affect their approach to the end of the therapy session.

Le complexe condensine est le moteur de la condensation mitotique des chromosomes, un processus essentiel à la stabilité du génome au cours de la division cellulaire. De nombreuses données publiées indiquent qu’il existe des liens fonctionnels étroits entre le processus de transcription des gènes et le processus d’organisation des chromosomes par condensine. Ces données sont toutefois souvent contradictoires et aucun modèle ne fait actuellement consensus pour expliquer les liens entre transcription et condensine. Au cours de cette thèse, nous avons montré chez la levure Schizosaccharomyces pombe qu’en l’absence de l’hélicase à ADN/ARN Sen1, condensine s’accumule spécifiquement à proximité des gènes transcrits par l’ARN Polymérase III. Nous avons utilisé ces observations pour mieux comprendre les liens entre transcription par l’ARN polymérase III et le positionnement de condensine. Nos données montrent que Sen1 est un cofacteur de l’ARN Polymérase III impliqué dans la terminaison de la transcription. Ce résultat est important car il démontre que les modèles existants qui affirment que l’ARN polymérase III termine de transcrire de façon autonome sont erronés. Nous avons ensuite démontré que les défauts de terminaison de l’ARN polymérase III observés en l’absence de Sen1 suffisent entièrement à expliquer l’accumulation de condensine en ces sites. Cette observation importante démontre que le contrôle de qualité de la transcription est directement impliqué dans le positionnement de condensine sur les chromosomes en mitose. Nos résultats nous permettent de proposer qu’au-delà d’un certain seuil, la densité en ARN polymérases est un obstacle à la translocation de condensine sur les chromosomes. / The condensin complex is a key driver of chromosome condensation in mitosis. The condensin-dependent assembly of highly compacted chromosomes is essential for the faithful transmission of the genome during cell division. Many independent studies have established that gene transcription impacts the association of condensin with chromosomes, but the molecular mechanisms involved are still unclear. This is especially true as a number of sometimes contradictory mechanisms have been proposed so far. Here, we show in Schizosaccharomyces pombe that condensin accumulates specifically in the vicinity of a subset of RNA polymerase III-transcribed genes in the absence of the conserved DNA/RNA helicase Sen1. We demonstrate that Sen1 is a cofactor of RNA polymerase III (RNAPIII) required for efficient transcription termination. These results are important because they fundamentally challenge the pre-existing view that RNAPIII terminates transcription autonomously. Strikingly, we show that the RNAPIII transcription termination defects are directly responsible for the accumulation of condensin in the absence of Sen1. This indicates that the quality control of transcription impacts the distribution of condensin on mitotic chromosomes. We propose that above a certain density threshold, the accumulation of RNAPIII constitutes a barrier for the translocation of condensin on chromosomes.