This project sets out to frame and examine the theoretical and practical challenges involved in the process and effect of translating Holocaust testimony, which has been largely overlooked in Holocaust discourses. Research pertaining to the fields of Holocaust memorialisation, historiography, literary theory, and translation studies is drawn together, with a view to shedding light on what it means to write Holocaust testimony, what it means to read it, and how these often conflicting processes affect and are affected by translation. Using a canonical testimonial text by Elie Wiesel as a case study allows the exploration of these questions to be grounded in detailed and wide-ranging textual analysis, demonstrating the extent to which translation impacts Holocaust testimony. The Holocaust is an unparalleled event in the twentieth century and testimony to it is born of a unique desire to relate one’s experiences, coupled with a certainty that these experiences cannot be expressed. This dual set of challenges requires a distinctive approach to reading testimony, which is shaped through a range of textual and paratextual features. Furthermore, the reader’s perception of the author figure is argued here to have a discernible bearing on this reading process. Translation has the potential to unsettle this reading, by undermining the readers’ belief in the author figure and in the referential status of the text. The analysis of Wiesel’s La Nuit in translation demonstrates that translation not only has a marked effect on the content and nature of this piece of testimony, but that the way in which this effect is presented to the readership is a reflection of the text’s shifting target locale and strongly impacts the reading of testimonial texts.

Morphology and syntax have both received attention in statistical machine translation research, but they are usually treated independently and the historical emphasis on translation into English has meant that many morphosyntactic issues remain under-researched. Languages with richer morphologies pose additional problems and conventional approaches tend to perform poorly when either source or target language has rich morphology. In both computational and theoretical linguistics, feature structures together with the associated operation of unification have proven a powerful tool for modelling many morphosyntactic aspects of natural language. In this thesis, we propose a framework that extends a state-of-the-art syntax-based model with a feature structure lexicon and unification-based constraints on the target-side of the synchronous grammar. Whilst our framework is language-independent, we focus on problems in the translation of English to German, a language pair that has a high degree of syntactic reordering and rich target-side morphology. We first apply our approach to modelling agreement and case government phenomena. We use the lexicon to link surface form words with grammatical feature values, such as case, gender, and number, and we use constraints to enforce feature value identity for the words in agreement and government relations. We demonstrate improvements in translation quality of up to 0.5 BLEU over a strong baseline model. We then examine verbal complex production, another aspect of translation that requires the coordination of linguistic features over multiple words, often with long-range discontinuities. We develop a feature structure representation of verbal complex types, using constraint failure as an indicator of translation error and use this to automatically identify and quantify errors that occur in our baseline system. A manual analysis and classification of errors informs an extended version of the model that incorporates information derived from a parse of the source. We identify clause spans and use model features to encourage the generation of complete verbal complex types. We are able to improve accuracy as measured using precision and recall against values extracted from the reference test sets. Our framework allows for the incorporation of rich linguistic information and we present sketches of further applications that could be explored in future work.

Eukaryotic protein translation elongation is tightly controlled by several regulation factors. Eukaryotic translation elongation factor 1B (eEF1B) is the GTP exchange factor for eukaryotic translation elongation factor 1A (eEF1A), which is a G-protein transporting aminoacyl-tRNA to the A site of the ribosome in a GTP dependent manner. The structure of the heavy complex composed of eEF1B and eEF1A (eEF1H) has been widely studied and several models have been proposed, but it is yet not clear how the subunits of the two proteins interact with each other. eEF1B is made up of three subunits, eEF1Bα, eEF1Bδ and eEF1Bγ, and each subunit has been found to be over expressed in different types of cancer. A copy number variant near the eEF1Bδ gene is associated with amyotrophic lateral sclerosis. The two isoforms of eEF1A, eEF1A1 and eEF1A2, are 92% identical, but only eEF1A1 was found to interact with eEF1B subunits in yeast two hybrid (Y2H) experiments. The aims of this PhD project are to investigate the potential involvement of eEF1B in disease, as well as the relationship between eEF1B and eEF1A2. All three eEF1B subunits were present in almost all the cell types and mouse tissues tested. eEF1Bδ showed different variants, the heaviest of which is tissue specific and expressed only in brain and spinal cord. eEF1Bα and eEF1Bδ showed certain abnormalities in transformed cell lines, although in the breast cancer tissues tested no apparent change in eEF1B expression was found. Knockdown of eEF1B did not significantly affect NSC34 cell viability over short periods. In spinal cord sections from motor neurone disease (MND) patients, half of the cases showed a change of eEF1B protein expression compared to normal spinal cord, with either a higher level in glial cells, or a lower level in motor neurones. eEF1B and eEF1A2 were found to be co-expressed in mouse motor neurones, and proximity ligation assay also detected physical interactions between both eEF1A isoforms and eEF1B subunits in mammalian cells, contrary to the previous Y2H study. Experiments in a mouse model with no eEF1A2 expression also support this finding. In heart and skeletal muscle from wasted mice where eEF1A is absent the expression of eEF1Bα and eEF1Bδ was down regulated at both protein and mRNA level, suggesting that eEF1A2 and eEF1B not only physically interact, but also show an interdependence in expression. Overall the results from cultured cells, mouse and human tissues in this study demonstrate the potential involvement of eEF1B in MND, and its interaction with eEF1A, which contributes to the understanding of the non-canonical functions of eEF1B and the structure of eEF1H.

The transmission of Trypanosoma brucei, the causative agent of human African trypanosomiasis, depends upon the development in the bloodstream of 'stumpy forms' from non-transmissible 'slender forms'. In stumpy forms many mRNAs are downregulated and translation is generally repressed. However, a small subset of genes escape this repression and are upregulated, presumably as an adaptation for transmission. To understand the basic of this, regulatory sequences within the 3'UTR of a major stumpy-enriched transcript (an ESAG9 gene) have been characterised. This identified a signal responsible for gene silencing in slender forms and gene activation when cells develop to stumpy forms. An investigation was made of upstream open reading frames (uORFs) as a mechanism for the control of stumpy form gene expression. No evidence was found of uORF control, but one gene investigated was found to produce two transcripts through trans-splicing at different sites. These transcripts, which were found to exhibit some differential abundance between life-cycle stages, would generate a long and short form (from an internal ATG) of the encoded protein. Both are predicted to contain a UBA/TS-N (ubiquitin associated) domain, however, the longer form of the protein is also predicted to contain a transmembrane helix and cleavable signal peptide, suggesting a different localisation. However, ectopic expression of either protein form with a Ty epitope tag resulted in the same protein localisation. Additionally, the transcripts of two translational protein homologues, TbeIF4E4 and TbeIF6, were identified as upregulated in stumpy forms. Radiolabelled-methionine experiments and polysome analysis showed that overexpression or RNAi-mediated ablation of TbeIF6 resulted in a decrease in protein synthesis and decrease in translation. Unlike its archaeal homologue, TbeIF6 protein was not induced by coldshock treatment. Finally, to identify which transcripts escape translational repression in stumpy forms an analysis was made of polysome-associated transcripts by RNA-sequencing. This identified potentially interesting genes for further investigation, and showed that many procyclic-enriched transcripts were also enriched in stumpy form polysomeassociated RNA, confirming these cells as preadapted for transmission. Together, this work has characterised a 3’UTR regulatory element in a stumpy-enriched transcript, examined alternative trans-splicing of another transcript, investigated two translational protein homologues and identified transcripts that escape translational repression in the transmissible life-cycle stage of T. brucei.

This thesis uses a multidisciplinary approach drawing primarily on archival and bibliographical research as well as the fields of children’s literature, book history and translation to explore British translation of Nordic children’s fiction since 1950. Which works of Nordic children’s literature have been published in the UK during the period in question? And how were Nordic children’s authors and texts selected by British publishers, along with British translators and illustrators? Chapter One gives an overview of limited past research in this area, focusing on publishing and book history and Translation Studies (particularly Polysystem Theory). Chapter Two considers bibliographical research already undertaken in Children’s Literature Translation Studies and is followed by a detailed study of the British National Bibliography (1950-2000). This methodological approach has documented for the first time the depth and breadth of the corpus of British translations of Nordic children’s fiction since 1950, enabling key authors, publishers, translators and genres to be identified. A brief analysis is given of the Golden Age of Nordic children’s literature in British translation up to 1975, followed by a decline into the twenty first century. The thesis then goes on to examine the principles and practices of text and translator selection as its second major research element, with extensive use made here of archival sources. Chapter Three explores publishing archives as a research resource and details issues in their distribution and potential use. Chapter Four gives an overview of the key role of the editor as a centre pin in the process of publishing works in translation, drawing on a wide range of publishing archives as well as introducing the case study part of the thesis which examines an independent press and a major international academic publishing house. Chapter Five looks in detail at the role of author-educator-publisher Aidan Chambers in publishing Nordic children’s literature in the early 1990s through small press Turton & Chambers. Chapter Six examines the role of Oxford University Press in publishing Nordic authors from the 1950s to the 2010s, in particular Astrid Lindgren. This thesis aims to make a significant and unique scholarly contribution to the hitherto neglected study of the translation of children’s literature into British English, offering a methodological framework (bibliographical and archival) which has potential for use with other language systems and with adult literature in translation.

Lean has during the past two decades grown to become a worldwide management concept. The purpose of lean is mainly to create value for customers and reduce the downtime for organizations. It origins from the automotive industry and was firstly introduced by Toyota. The concept eventually caught on and spread to other industries, service businesses and most recently to the public sector. A few years ago municipalities in Sweden introduced lean in their organizations and used it as a solution to many of their operational challenges. However, research suggests that the knowledge within the field of lean in the context of municipalities is limited. The study was designed as a single case study of the municipality Södertälje which was one of the first municipalities to adopt the concept of lean. Data was collected through semi-structured interviews with key individuals in Södertälje municipality who had been a part of the introduction of lean or in some way influenced the process. In addition, interviews were held with middle managers who were currently working with lean. Furthermore, text documents such as decisions, objectives and budget documents provided by Södertälje municipality were also analyzed. To get a better understanding of how lean can be used in the context of municipalities the aim of this study was to examine how Södertälje municipality introduced lean, how it was applied and which forms the concept has taken. More specific the study has used institutional and translational theory to investigate how lean has been transferred and translated from the private- to the public context. The empirical data was analyzed through two phases. The first phase was decontextualization which was used to understand how lean was differentiated from the private context by the municipality. The second phase was contextualization which has been used to see how Södertälje municipality introduced lean in their organization and how they interpreted the concept. The findings suggest that the municipality had a problem-oriented approach where lean was considered a possible solution. To transfer lean, Södertälje municipality first recruited Robert Kusén, an executive from Scania, to “carry out” his knowledge and experience from working with lean. Second, the management of the municipality visited Scania and the social district in Copenhagen to “bring in” knowledge about the lean concept. Therefore, the municipality partly used organizational arenas in the same sector and partly organizational arenas in a different and more distant sector than the municipality. The study conclude that the contexts included in the transfer of a concept affects the translation. To translate the concept of lean, Södertälje municipality applied “the translation hierarchical chain” with few exceptions. Further, the municipality developed their lean philosophy and what they thought about lean by what they call “Växthuset”. By doing this and by interlocking lean with their existing vision and values, enrollment rules were used to establish lean in the local context. Using pilot projects also helped creating local references to the idea. Furthermore the municipality used specific rules for translating and reshaping lean. The mainly emphasized instrument was imitation, but there have also been indicators of addition and subtraction. This was expressed through the political context which narrowed the use of long-sightedness and instead resulted in a focus on democratic aspects. The municipality’s use of lean was from the beginning intended to include the entire organization but had instead mainly been practiced by the social welfare department. The poor adaption was largely caused by a lack of interest from the personnel and because key stakeholder had left the organization or had been replaced.

<p>The partitioning of translation to the outer membrane of the endoplasmic reticulum is a problem that has been the subject of inquiry since the discovery of the ribosome. The large degree to which ribosomes were found to be tethered to the membrane led to intense investigation of a series of related questions regarding the identity of those mRNAs that are translated on the endoplasmic reticulum, and the functions of that localization in cell stress. In this dissertation, I approach each of these questions in turn and work to reconcile my observations with those models that have been previously proposed. A theme of this work is the application of modern methods, particularly deep sequencing technology, to address problems that had largely been considered solved. The most prominently featured method is ribosome profiling, which is paired with classical biochemical and cell biological techniques. I arrive at several conclusions: 1) a significant fraction of all mRNAs is well represented on the endoplasmic reticulum membrane, 2) the properties of translation diverge substantially between membrane-associated and free ribosomes, and 3) the compartmentalization of translation can serve as an important variable in cell stress.</p> / Dissertation

published_or_final_version / abstract / Microbiology / Master / Master of Philosophy

Hepatitis C virus NS5A is a multi-functional viral protein essential for viral replication and assembly, although the exact role the protein plays in the viral lifecycle remains unclear. A vast array of functions have been attributed to NS5A in recent years, despite the lack of enzymatic activity. NS5A has been found to interact with over 130 host proteins including many which are central to cellular signaling pathways. NS5A is composed of three domains separated by regions of low complexity. All three domains perform important functions in the viral lifecycle. Domains I and II are essential for viral replication whereas domain III is required for viral assembly. However, the role that NS5A and its individual domains may play in modulating viral translation remains controversial. Previous studies have utilized translation reporter systems that do not accurately reflect the role of the viral 3´-UTR in modulating viral translation. We and others have shown that NS5A binds to the poly-U/UC region of the 3´-UTR. In addition to serving as the initiation site for negative strand synthesis the 3´-UTR functions to significantly enhance viral translation. The mechanism of translation enhancement remains unclear but may involve long range RNA-RNA interaction with the IRES, the binding of cellular proteins which stimulate translation and/or the recycling of ribosomes. Therefore, the protein-RNA interaction between NS5A and the poly-U/UC region has the potential to modulate viral translation. Therefore we set out to determine the role of NS5A and its individual domains in modulating viral translation and the role of the NS5A-poly-U/UC region interaction in this modulation. Utilizing monocistronic RNA reporters which contain the viral 5´- and 3´-UTRs and an internal Renilla luciferase reporter gene, we determined that NS5A specifically down-regulates viral translation in a dose-dependent manner through a mechanism dependent upon the presence of the poly-U/UC region in the viral 3´-UTR. Furthermore, we have re-tested the effect using full-length HCV genomic RNA reporters. These results suggest that NS5A is able to interfere with the stimulation of viral translation exerted by the 3´-UTR. This down-regulatory function of NS5A may function in mediating a switch from translation to replication, a step required in the lifecycle of a positive sensed RNA virus. Having established a role for NS5A in modulating viral translation, we then aimed to determine which region of NS5A was responsible for this effect. We found that each of NS5A domains was capable of this modulatory effect on viral translation independently. Although surprising, this finding is not entirely unexpected as each domain has been shown to retain the ability to bind to the poly-U/UC region. Within NS5A domain I we identified a 61 aa. region sufficient for translation down-regulation. Furthermore, we have identified a number of positively charged residues within this region involved in the modulation of viral translation, in particular arginine 112 (R112). This residue has previously been found to be at the domain I dimer contact interface and to form an intermolecular hydrogen bond with glutamic acid 148 (E148). We found that mutations R112A and E148A individually negate the ability of domain I to modulate viral translation and these mutations impede the formation of domain I dimers. Additionally, the R112A mutation appears to affect the ability of domain I to interact with the poly-U/UC region of the viral 3´-UTR alluding to the possible mechanism of translation modulation. Finally this mutation was lethal in an HCV subgenomic replication, confirming the link between NS5A dimerization, RNA binding and viral replication. These results collectively point to a crucial role for the NS5A arginine 112 residue in the modulation of HCV lifecycle by NS5A. Within NS5A domain II, we identified a 47 aa. region sufficient for translation modulation. Through the mutation of positively charged amino acids within this region, we found that lysine 312 (K312) was essential for this effect. The ability of this domain to modulate viral translation was completely lost when K312 was mutated within a full domain II protein fragment. The mechanism behind this modulation remains unclear but the 47 aa. region identified has been previously found to contain a region proposed to make contact with poly-U RNA and the K312 residue was suspected to interact directly with such RNA. Furthermore, this region interacts with the host protein cyclophilin A, an interaction that enhances the RNA binding ability of domain II. These findings strongly suggest that domain II modulates viral translation by binding within the poly-U/UC region. While investigating the modulation of viral translation by NS5A domain III we determined that the C-terminal 31 aa. are sufficient for the effect of this domain on viral translation. Through alanine scanning mutagenesis we identified glutamic acid 446 (E446) as playing a key role in the modulatory function of this region. Within a domain III protein fragment mutation of this E446 residue abolishes the modulatory function of this domain towards HCV translation. The mechanism behind this modulation and the role of E446 in this effect remains to be determined. These findings suggest that in addition to being essential for viral replication and assembly, NS5A has an important role in modulating viral translation through a mechanism requiring the poly-U/UC region of the viral 3´-UTR. Furthermore, each domain of NS5A appears to contribute to this effect. These results support the description of NS5A as a multi-functional protein and the further characterization of its functions may aid in the development of novel antivirals targeting the numerous functions of this complex, and at times puzzling, viral protein.

La protéine CIRP (Cold Induced RNA binding Protein) est une petite protéine de liaison à l’ARN de 172 acides aminés, qui est constituée du côté amino-terminal d’un domaine de liaison à l’ARN de type RRM (RNA recognition motif), et d’une partie carboxy-terminale riche en glycine et arginine qui comprend plusieurs motifs RGG. Elle a été identifiée comme étant inductible par hypothermie mais aussi par irradiation aux UV et par hypoxie. Nous avons analysé son expression et sa localisation en réponse à différents stress cellulaires. Nous avons montré qu’un traitement à l’arsénite qui induit un stress oxydant n’altère pas l’expression de CIRP provoque sa localisation dans les granules de stress (SG). Les SG sont des structures ribonucléoprotéiques cytoplasmiques contenant des complexes de pré-initiation incompétents pour la traduction, et qui s’accumulent dans les cellules exposées à un stress. Ces structures constituent des sites de triages des ARNm, dans lesquels les ARNm sont soit stockés en attente d’une réinitiation de la traduction une fois le stress surmonté, soit destinés à être dégradés. La protéine CIRP se localise dans les SG que ce soit suite à un stress cytoplasmique ou du réticulum endoplasmique. Nous avons montré également que la localisation de la protéine CIRP dans les SG se déroule indépendamment de la présence de la protéine TIA-1 qui a été décrite comme responsable de l’assemblage des SG. De plus la surexpression de la protéine CIRP conduit à la formation de SG. Nous suggérons donc qu’il existe plusieurs voies qui mènent à l’assemblage de ces structures. En outre, nous avons analysé la localisation de mutants par délétion de la protéine CIRP et avons montré que le domaine RRM et le domaine RGG peuvent indépendamment localiser la protéine dans les SG. Par contre, la méthylation des résidus arginine du domaine RGG est une modification nécessaire à la localisation de CIRP dans les SG. Ensuite, nous avons étudié la fonction de la protéine CIRP dans le métabolisme des ARN messagers. Nous avons montré par une méthode d’adressage, que CIRP est un répresseur de la traduction des ARNm et que le domaine carboxy-terminal est nécessaire et suffisant à cette fonction.