Дисертації з теми "Translational studies"
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1
Kanapathy, M. "Translational studies in wound healing." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/1569432/.
Анотація:
This work explores the role of gap junctional proteins (GJP) in wound healing in two clinical settings: venous disease and epidermal grafting. Chronic wounds and ulcers are common and a feared problem particularly in the elderly, causing pain and disability. Treatment costs are estimated at £2-3 billion to the NHS with a further loss of 2 million workdays per year. Varicose veins are the major contributor to the prevalence of ulcers affecting about 0.3-0.5% of the population at any point of time. The expression of GPJ; connexins 43, 30 and 26 were explored in a cross-sectional study of patients with varicose veins at different stages of venous disease (CEAP stage). A stepwise increase in GJPs overexpression was seen corresponding to the clinical CEAP stage of the disease, supporting their role in the disease mechanism and as a biomarker of wound healing. This is also the first-time varicose veins were shown to be associated with poor wound healing. Concurrently, with the introduction of a new wound healing system for epidermal grafting, a sequential program of research was developed. Initially, a systematic review using Cochrane methodology on epidermal grafting for wound healing, and a pilot case series to evaluate the novel surgical technology. Following positive outcomes; a patient reported outcome measure and cost evaluation study was performed. Combining these data, a pilot randomised controlled trial was performed to compare efficacy of epidermal grafting to standard of care. Alongside, translational studies on GJP were undertaken to outline the cellular mechanism of action of epidermal grafts. These data led to the development of a wound healing group at UCL and subsequent engagement with the MRC UCL clinical trials team to design a novel platform trial to further assess epidermal grafting. This platform will investigate the molecular mechanism of action and explore the most appropriate use for this technology. A NIHR EME and a collaborative industry grant is in progress.
2
Langley, Gareth William. "Studies on collagen post-translational modifications." Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:1f7da2dd-9626-4aba-87ed-ee70736e9bed.
Анотація:
The collagen proteins are the principal component of the extracellular matrix and are the most abundant protein family in humans. Therefore, collagens form the major protein component of bone, tendon and cartilage. During collagen biosynthesis, proline and lysine residues are enzymatically converted to (2S,4R)-hydroxyproline, (2S,3S)-hydroxyproline and (2S,5R)-hydroxylysine by the collagen prolyl-4-hydroxylases (C-P4Hs), prolyl-3-hydroxylases (P3Hs) and procollagen-lysine, 2-oxoglutarate 5-dioxygenases (PLODs) respectively. The C-P4Hs, P3Hs and PLODs are members of the FeII and 2-oxoglutarate dependent oxygenase (2OG oxygenase) superfamily. Despite being amongst the first 2OG oxygenases to be identified, the collagen hydroxylases are poorly understood from structural and biochemical perspectives, a consequence of inefficient recombinant production methods. Initial efforts focussed on developing a robust expression system for recombinant C-P4H. An E. coli expression system was pursued to allow for relatively large quantities of protein to be produced, as required for structural studies. A number of novel expression constructs were generated and used in small-scale expression trials. However, attempts to isolate purified C-P4H tetramer have ultimately proved unsuccessful. A prolyl hydroxylase from Paramecium bursaria Chlorella Virus I (vCPH), was pursued as a model collagen prolyl hydroxylase; production of vCPH in E. coli affords large quantities of high purity recombinant protein for subsequent analyses. vCPH catalyses the formation of (2S,4R)-hydroxyproline at proline 3 and proline 5 of the short 8-mer peptide PAPKPAPK and kinetic analyses have revealed that the ascorbate dependence of vCPH-catalysis at these two positions differs significantly, indicating that ascorbate dependence of the collagen prolyl hydroxylases varies dependent upon the residues adjacent to the target residue. A vCPH inhibition assay was developed and a library of potential inhibitors was screened. This screen included compounds that inhibit a different subfamily of 2OG dependent prolyl-4-hydroxylases, the hypoxia inducible factor prolyl hydroxylases (HIF PHDs), which also catalyse the formation of (2S,4R)-hydroxyproline. The studies revealed that inhibitors of the HIF PHDs that are currently in clinical trials also inhibit vCPH. However, analysis of novel HIF PHD inhibitors and inhibitors of the prolyl-3-hydroxylase OGFOD1 indicate that achieving selectivity between these prolyl hydroxylases is possible. The inhibition studies have been complemented with amino acid analyses of collagen samples. No evidence for the existence of hydroxylated residues other than (2S,4R)-hydroxyproline, (2S,3S)-hydroxyproline and (2S,5R)-hydroxylysine was acquired. These amino acid analysis approaches may be taken further to analyse collagen samples derived from tissue to assess hydroxylation levels in diseased tendon. Additionally, metathesis-derived lysine analogues have been synthesised and used to analyse 2OG-dependent histone demethylase (KDM) catalysis. These analogues have revealed new modes of activity with KDM3A and provided insight into the charge and conformational requirements of 2OG-dependent KDM catalysis. Overall, the work presented in this thesis has provided insight into the biochemistry of a collagen prolyl hydroxylase and demonstrated the potential for the development of selective inhibitors of prolyl hydroxylases. Additionally, novel reactions catalysed by histone demethylases have been observed.
3
Stone, Simon James. "Translational studies to evaluate plaque control interventions." Thesis, University of Newcastle upon Tyne, 2013. http://hdl.handle.net/10443/2218.
Анотація:
Clinical research should aim to broaden and translate the understanding of health and disease by designing and successfully implementing interventions to achieve healthcare improvement. This thesis reports clinical research that moves from laboratory to clinic and investigates the potential challenges of dissemination and adoption into clinical practice. Initially an established gingivitis was used as a model to evaluate a personalised plaque control intervention. The evaluation used traditional clinical monitoring techniques and pioneering laboratory technologies. Subsequently the personalised plaque control intervention was developed further and applied to a new clinical situation, the gingival manifestations of oral lichen planus. The personalised plaque control intervention was then evaluated as part of a randomised controlled trial using traditional clinically observed, patient-centred and health-economic outcome measures. Finally, a qualitative study investigated the potential barriers in disseminating research through continuing education to general dental practitioners. The research findings showed that in the established gingivitis model, sequential plaque control interventions, comprising powered toothbrushing and professional prophylaxis, were effective in reducing the clinical signs of established gingivitis. Changes in clinical signs were associated with a shift in bacterial species, and transient changes were observed in host inflammatory biomarker concentrations. Personalised plaque control was cost-effective and reduced clinical signs of inflammation and brought about improvements in quality of life for patients with gingival manifestations of oral lichen planus. The qualitative study identified barriers to the successful translation and implementation of contemporary clinical research. The plaque control intervention evaluated in the established gingivitis model and successfully implemented in a new clinical situation. Personalised plaque control should form part of the initial management phase for patients with gingival manifestations of oral lichen planus. Researchers should investigate alternative methods for engaging with general dental practitioners in disseminating research to ensure that relevant findings are translated into improvements in healthcare.
4
Samuel, Jesvin John. "Translational studies in B-cell malignancies : studies on TP53 and BRAF." Thesis, University of Leicester, 2015. http://hdl.handle.net/2381/36233.
Анотація:
This thesis contains two distinct parts: Current models of Chronic Lymphocytic Leukaemia (CLL) pathogenesis invoke specialised anatomical microenvironments that harbour proliferating cells. Such proliferating CLL cells are more resistant to current immuno-chemotherapeutic regimens than cells in the peripheral blood and are thought to be the cause of disease relapse. Using a system to recapitulate CLL proliferation centres in vitro, I have observed that CLL cells undergo proliferation. Unexpectedly, under these conditions an induction of wild-type TP53 protein was also observed in all cases of CLL analysed. The results reported here were undertaken to understand how CLL cells upregulate TP53 protein and proliferate. For reasons that remain unclear, TP53 is unable to transactivate its classic target genes to induce cell-cycle arrest or apoptosis. However, it remains able to trigger a full apoptotic response after further DNA damage and a higher threshold of protein levels is reached. We propose a model whereby oxidative stress induced by proliferation in CLL triggers TP53 protein expression. Hairy Cell Leukaemia (HCL) represents approximately 2% of all leukaemias, follows an indolent course and remains an incurable disease. Recently, virtually all HCL patients shown to carry the BRAFV600E mutation, thought to be a disease-defining event. The BRAF V600E mutation results in constitutive activation of the MEK-ERK pathway resulting in aberrant proliferation, and targeted inhibitors have shown efficacy in BRAFV600E positive tumours. We wanted to test whether this efficacy can be extrapolated to HCL. Here we report in vitro studies using PLX4720 and in vivo trial of Vemurafenib in a patient with refractory HCL. While BRAF inhibition showed no effect on HCL survival in vitro, it resulted in rapid loss of viability of hairy cells in vivo. The results obtained show that efficacy of BRAF inhibition achieved did not occur via the expected inhibition of MEK-ERK activation.
5
Hauck, Wendy. "Studies on the translational efficiencies of reovirus mRNA." Thesis, McGill University, 1986. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=66236.
6
Hägg, Olofsson Maria. "Translational studies of drug-induced tumor cell death /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-855-X/.
7
Foukakis, Theodoros. "Basic and translational studies of follicular thyroid neoplasia /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-319-1/.
8
Wilkins, A. C. R. "Translational energy loss studies of electron capture reactions." Thesis, Swansea University, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.636601.
Анотація:
Translational energy spectroscopy is an invaluable tool in the study of ion-neutral processes. By measuring the change in energy of the projectile ion information can be obtained about the initial and final states of the projectile and the final states of the target (presuming that the target possesses only thermal energy and is initially in its ground state) for a wide range of collisional processes. One such process is that of electron capture where the multiply-charged ion will capture one or more electrons from the target. The Wigner spin-conservation rule has previously been studied for binary collision processes, however the applicability to electron capture reactions has not been studied extensively. Over eighty reaction channels for the single-electron capture by N2+, O2+, C2+ and Ar4+ have been identified, all of which conform with the rule. Of equal significance the spin non-conserved channels which lie in the same energy range are conspicuously absent. With the O2+ and Ar4+ collision systems a rare quintet state is also identified in the primary ion beam. The spin rule appears less stringent for double-electron capture reactions where many spin forbidden reaction channels have been identified. These are explained as being allowed through two consecutive spin-conserved single electron capture channels. The importance of the design of the collision cell is often overlooked in a spectrometer. Two novel collision cells have been constructed; the first, a thin collision cell, was utilised to assess and reduce the collisional broadening aberration in a translational energy loss spectrum. A second larger cell was designed to attenuate the ion beam to a high degree so that the metastable content of an ion beam can be measured using the ion beam attenuation method. Metastable ions play a substantial part in many collisional phenomena and these measurements are used to quantify the previously obtained electron-capture spectra.
9
Cronin, BriÌd. "Photofragment translational spectroscopy studies of small organic hydrides." Thesis, University of Bristol, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.440268.
10
Siciliani, Scalco Renata. "Translational research studies in exercise-related muscle disorders." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10060183/.
Анотація:
Translational research is the process that transfers knowledge from basic sciences to the clinical setting. This PhD thesis translates knowledge gained from animal model research in hypokalaemic periodic paralysis (HypoPP) and McArdle disease to humans affected by these conditions to identify new treatment options for both diseases. The efficacy of two compounds, sodium valproate and bumetanide, were assessed for the first time in humans with McArdle disease and HypoPP, respectively. For HypoPP, the role of the McManis test as an outcome measure was explored in a randomised, double-blind, placebo-controlled phase II clinical trial with a cross-over design. For McArdle disease, several outcome measures were explored in an open-label proof-of-concept phase II study. 2 mg bumetanide was not effective to abort a focal attack of weakness in an immobilised hand in the majority of the trial participants with HypoPP, but data presented here supports further studies of bumetanide in this population of patients. Extending the isometric exercise period to 10 minutes increased the sensitivity of the McManis test, and frequent compound muscle action potential (CMAP) amplitude assessments were shown to be useful in assessing both efficacy and safety. 20 mg/kg/day sodium valproate was ineffective in stimulating the expression of the brain glycogen phosphorylase enzyme in skeletal muscle of people with McArdle disease. Based on these results, further research into VPA as a treatment for McArdle disease is discouraged. The combination of several outcome measures contributed to data interpretation and should be considered in future studies exploring treatment efficacy in McArdle disease. The results of this research should contribute to future clinical trials in the field of exercise-related muscle disorders and provide valuable insights for translational research.
11
Holt, Bronno van der. "Translational studies in elderly patients with acute myeloid leukemia." [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 2007. http://hdl.handle.net/1765/10514.
12
Xin, Yan. "Suramin as a chemo- and radio-sensitizer preclinical translational studies /." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1144958112.
13
Galbraith, Susan Mary. "Translational studies on the vascular targeting agent Combretastatin A4 phosphate." Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.367600.
14
Ramarao, Rachana. "Molecular studies of programmed -1 ribosomal frameshifting and translational readthrough." Thesis, University of Cambridge, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.615726.
15
Walters, Julian Roger Ford. "Intestinal malabsorption and diarrhoeal diseases : basic translational and clinical studies." Thesis, Imperial College London, 2017. http://hdl.handle.net/10044/1/55184.
16
Allaj, Viola. "TRANSLATIONAL STUDIES OF TARGETING THE THROMBOXANE A2 RECEPTOR IN CANCER." OpenSIUC, 2014. https://opensiuc.lib.siu.edu/theses/1506.
Анотація:
Thromboxane A2 (TXA2) is an eicosanoid formed by the action of thromboxane A2 synthase (TXS) utilizing the cyclooxygenase product, prostaglandin H2, as the substrate. This prostanoid acts mainly by binding to its cognate thromboxane receptor (TP), a G protein coupled receptor (GPCR). GPCRs convey the majority of signal transduction across cell membranes. They are heptahelical serpentine receptors with many clinical implications. Aberrant expression or deregulated activity of GPCRs contributes to some of the most prevalent human diseases. TP activation can cause platelet activation, vasoconstriction, thrombosis and mitogenesis. A single copy of the TP gives rise to TPα and TPβ isoforms, which share the first 328 amino acids but differ at the carboxy-terminal domains. Previous studies in our lab have shown that the TXA2-TPβ signaling axis pathway regulates tumor cell cytoskeleton by inducing cell contraction during migration. The cytoskeleton reorganization observed was mediated through small RhoA GTPase activation. Metastasis is the major cause of death from cancer and acquisition of motility by cancer cells is a detrimental component in metastasis. Therefore, it is important to identify a natural TP antagonist that will serve as a therapeutic regimen for cancer by inhibiting the TPβ induced cell contraction. Our work has shown that SIU1315, a phytoestrogen, blocks cell contraction induced by the TP agonist U46619. The SIU1315 inhibitory concentration (IC50) of U46619 induced contraction was determined to be 10 uM and treatment with the compound alleviated RhoA activation. Moreover, SIU1315 reduces the migratory capacity and invasiveness of PC3 cells. Utilization of the compound to inhibit TP-mediated tumor cell motility and metastatic progression in an in vivo model of experimental metastasis had an unexpected outcome. Administration of SIU1315 in female SCID mice, that received tumor cells via tail vein injection, did not prevent the metastatic spread of malignant cells. On the contrary, mice that had been treated with SIU1315 were indicative of a higher number of metastatic lung lesions than the non-treated control group. Similar evidence was observed by luciferase readouts in other organs. It is suspected that SIU1315 stimulates the vasodilatory nitric oxide that further interferes with the metastatic process. SIU1315 could be used as an anti-metastatic agent in combination with compounds that would suppress activation of nitric oxide. Furthermore, the quest for TPβ specific antibodies, that would have the potential to distinguish between thromboxane receptor isoforms, led to investigation of a number of purified antibodies. Validation of TPβ specific antibodies demonstrated that none of the examined antibodies was specific for TPβ. Determination of the specific TPβ domain that is responsible for U46619 induced cell contraction proved rather difficult. Generation and utilization of TPβ mutants requires additional optimization studies. The function of TP receptors in lung cancer has not been extensively studied. Kaplan-Meier analysis indicated that patients with high levels of TP expression had significantly shorter disease free survival than patients with low TP expression. Generation of stable lung cancer cell lines expressing TP receptors revealed a higher proliferative advantage of cells expressing TPα when compared to the vector control. U46619 induced activation of TP receptors designated a time dependent stimulation of phosphorylated Erk in stable lung cancer cell lines. Evidence suggested the involvement of phosphorylated Akt in U46619 mediated TP activation. Data indicated differential activation of phosphorylated Erk isoforms. The significance of this observation requires further investigation. TP activation seemed to be positively correlated with β-catenin expression. In conclusion, translational studies on the thromboxane receptor reveal major functions in cancer pathogenesis. Therapeutic targeting of the TP receptor could prove beneficial for cancer patients.
17
Kelly, Leanne. "Studies on the role of post-translational hydroxylation in signalling." Thesis, University of Oxford, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.531965.
18
Grasso, Domenick Gabriel Spremulli Linda L. "Mechanistic and bioinformatic studies of mitochondrial ribosomes and auxiliary translational factors." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2007. http://dc.lib.unc.edu/u?/etd,1459.
Анотація:
Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2007.Title from electronic title page (viewed Apr. 25, 2008). " ... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry." Discipline: Chemistry; Department/School: Chemistry.
19
O'Neill, J. "The translational studies of pain : from spinal neurones to human perception." Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1462470/.
Анотація:
The discovery of new treatments for chronic pain relies on the detection of pre-clinical targets and the progression to successful clinical trials. In order to improve this transition reliable translational models must be identified, based on mechanisms that underlie the symptoms of chronic pain. This thesis aimed to validate the use of 3 potential translational models: topical capsaicin, ultraviolet irradiation (UVB) and UVB rekindling. Furthermore, using a mechanism based approach to treatment, the modulation of capsaicin induced sensitisation was explored in animals and humans. In order to characterise the models in rats, in vivo electrophysiological recordings were made from single unit dorsal horn wide dynamic range neurones. Evoked responses to thermal, mechanical and electrical stimulation were quantified. To complement the animal studies, full QST profiling was undertaken on healthy human volunteers. Assessments of the pain thresholds were made, as well as numerical ratings to sub and supra threshold stimuli, in order to best compare these results with rodent data. All of the models tested evoked similar sensory changes across species, and the symptoms induced in each of the models were used to infer the peripheral and central components. Sensory changes evoked by capsaicin included mechanical hypersensitivity accompanied by a facilitation of responses in the Aδ fibre range. These are reflective of both a peripheral and central sensitisation. Furthermore, these changes were prevented by pre-treatment with the adenosine receptor 1 (A1R) agonist, CPA. UVB appeared to be a strictly peripheral model, resulting in no secondary changes or receptive field expansion. On the other hand, the UVB rekindling model showed clear signs of engaging both peripheral and central mechanisms, including thermal allodynia, secondary brush hypersensitivity and a facilitation of Aβ fibre responses. Overall, we confirmed that similar short-term sensory consequences, that may mimic certain pathophysiologies, could be engaged and quantified in rats and human volunteers in response to topical capsaicin, UVB irradiation and UVB rekindling. The UVB rekindling model induced signs of the engagement of a number of clinically relevant phenomena, such as peripheral inflammation/ sensitisation driving central modifications. As such this model will be useful in investigating mechanisms of inflammatory pain and assessing analgesic efficacy of novel medications.
20
Colombo, Alice. "Reworkings in the textual history of Gulliver's Travels : a translational approach." Thesis, University of Portsmouth, 2013. https://researchportal.port.ac.uk/portal/en/theses/reworkings-in-the-textual-history-of-gullivers-travels(14665966-f5f9-4ff4-b1fd-48ab496fa65d).html.
Анотація:
On 28 October 1726 Gulliver’s Travels debuted on the literary scene as a political and philosophical satire meant to provoke and entertain an audience of relatively educated and wealthy British readers. Since then, Swift’s work has gradually evolved, assuming multiple forms and meanings while becoming accessible and attractive to an increasingly broad readership in and outside Britain. My study emphasises that reworkings, including re-editions, translations, abridgments, adaptations and illustrations, have played a primary role in this process. Its principal aim is to investigate how reworkings contributed to the popularity of Gulliver’s Travels by examining the dynamics and the stages through which they transformed its text and its original significance. Central to my research is the assumption that this transformation is largely the result of shifts of a translational nature and that, therefore, the analysis of reworkings and the understanding of their role can greatly benefit from the models of translation description devised in Descriptive Translation Studies. The reading of reworkings as entailing processes of translation shows how derivative creations operate collaboratively to ensure literary works’ continuous visibility and actively shape the literary polysystem. The study opens with an exploration of existing approaches to reworkings followed by an examination of the characteristics which exposed Gulliver’s Travels to continuous rethinking and reworking. Emphasis is put on how the work’s satirical significance gave rise to a complex early textual problem for which Gulliver’s Travels can be said to have debuted on the literary scene as a derivative production in the first place. The largest part of the study is devoted to textual analysis. This is carried out in two stages. First I concentrate on reworkings of Gulliver’s Travels published in eighteenth- and in nineteenth-century Italy. These illustrate how interlingual translation operated alongside criticism, abridgment, adaptation and pictorial representation to extend the accessibility of Swift’s work and eventually turned it into a popular and children’s book. Then, I examine British reworkings and how the translational processes which they entail contributed to the popularity and the popularisation of Gulliver’s Travels in eighteenth-century Britain.
21
Xu, Ying Jie. "Functional and translational studies of focal adhesion turnover in invasive breast cancer." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=103611.
Анотація:
The progression of primary cancer to metastasis is the main cause of cancer-related death and represents a great clinical challenge since no effective therapies are currently available. Moreover, cellular and molecular mechanisms of metastasis formation remain only partially understood. The acquisition of cancer cell autonomous motile and invasive properties is a fundamental turning point in the progression of a solid tumor from benign to invasive state. This process is driven in part by dynamic assembly and disassembly of multiple focal adhesion (FA) proteins, which mediate cell-matrix attachments and serve as traction sites for cell locomotion. In this thesis work, we demonstrate that overexpression of ErbB2 tyrosine kinase receptor enhanced breast cancer cell migratory and invasive capacity via regulation of FA turnover. Inhibition of the Src-FAK signaling in ErbB2-positive cells by the anti-ErbB2 antibody Herceptin or following expression of RNA interference stabilize FA structures, leading to enhanced number and size of peripherally localized adhesions. Herceptin failed to regulate FA and cell invasion in cells lacking FAK or Src but gains this activity after restoration of these proteins. These results demonstrate a regulation of FA turnover by ErbB2 signaling via the Src-FAK pathway. FA proteins including FAK are coupled to cell cytoskeleton. Unlike the pro-invasive FAK, we identified the actin-binding protein, filamin A, which also regulates FA dynamics, acts as an anti-invasive protein in breast cancer cells. The expression of filamin A in human breast cancer tissues inversely correlates with breast cancer progression. In breast cancer cell lines and orthotopic breast cancer mice models, down regulation of filamin A stimulated cancer cell migration, invasion, and metastasis formation. Time-lapse microscopy and biochemical assays following filamin A silencing and rescue with wild type, or mutant filamin A protein resistant to calpain cleavage, revealed that filamin A regulates FA disassembly at the leading edge of motile cells. Moreover, filamin A downregulation enhanced calpain activity and stimulated the cleavage of FA proteins, including FAK; this mechanism can be rescued by restoration of wild type filamin A, expression of filamin 14-16 repeats containing a calpain targeting sequence, or by inhibition of ERK activation. These results document complex regulatory mechanisms of FA dynamics in invasive breast cancer cells, and open-up future directions for discovery of therapeutic approaches aimed at interfering with FA signaling to tackle invasive breast cancer.La progression de cancer primaire du sein vers des formes métastatiques demeure la principale cause de décès parmi les patients atteint de cette maladie. Ceci représente un défi clinique majeur, étant donné l'absence actuelle de traitements efficaces. De plus, les mécanismes responsables de la formation de métastases ne sont que partiellement compris. L'acquisition de la motilité autonome des cellules cancéreuses et de leurs propriétés invasives représente un point tournant fondamental de la progression d'une tumeur solide du stade bénin au stade invasif. Ce processus est régi en partie par l'assemblage et le désassemblage dynamique de protéines d'adhésion focale (AF); ces dernières assurent les communications entre cellules cancéreuses et la matrice extracellulaire en plus de servir de sites de traction pour la locomotion cellulaire. Dans ce travail de thèse, nous avons démontrés que la surexpression du récepteur de tyrosine kinase ErbB2 augmente la capacité migratoire et le potentiel invasif des cellules cancéreuses du sein en partie due a la régulation de la dynamique de l'assemblage/désassemblage de protéines FA. L'inhibition de la voie de signalisation Src-FAK dans les cellules ErbB2-positives par un anticorps anti-ErbB2 (Herceptin), ou l'expression de l'ARN d'interférence stabilise les structures AF, ce qui conduit à une augmentation du nombre et de la taille des adhésions localisées en périphérie des cellules cancéreuses. L'Herceptin s'est avérée inefficace pour réguler l'AF et l'invasion cellulaire dans les cellules dépourvues de protéines FAK ou Src, mais acquière cette capacité suite à la restauration de ces protéines. Ces résultats démontrent une régulation de la dynamique des AF par le récepteur ErbB2 via la voie Src-FAK. Les protéines AF, incluant FAK, sont étroitement liées au cytosquelette cellulaire. Dans ce contexte, nous avons démontrés que contrairement à la FAK qui est pro-invasive, la protéine filamine A qui lie l'actine et régule aussi la dynamique AF, agit comme une protéine anti-invasive dans les cellules cancéreuses du sein. L'expression de la filamine A dans les tissus cancéreux humains du sein suit une corrélation inverse avec la progression du cancer du sein. Dans les lignes des cellulles cancéreuses et les modèles de cancer chez les souris, l'inhibition de la filamine A stimule la migration des cellules cancéreuses, leur invasion, ainsi que la formation de métastases. L'imagerie microscopique de cellules vivantes combiné avec des études biochimiques à la suite de l'inhibition de la filamine A ou la restauration du type sauvage, ainsi que l'expression de forme mutante de filamine A résistante au coupures la calpaïne, a révélé que la filamine A régule le désassemblage d'AF. De plus, l'inhibition de la filamine A potentialise l'activité calpaïne et stimule les coupures des protéines AF, incluant FAK ; ce mécanisme peut être restaure par l'expression de la filamine A de type sauvage, la filamine mutée contenant une séquence cible (aa 14-16) de calpaïne, ou par inhibition de l'activation ERK. Ces résultats documentent les mécanismes complexes de régulation de la dynamique de protéines d'AF dans les cellules cancéreuses invasives, et ouvrent des horizons pour la découverte future d'approches thérapeutiques visant à interférer avec le signalement de l'AF dans le cancer invasif du sein.
22
Li, Huilin. "Studies of protein post-translational modifications using high resolution tandem mass spectrometry." Thesis, University of Warwick, 2012. http://wrap.warwick.ac.uk/54993/.
Анотація:
Electron capture dissociation (ECD) is a powerful and superior tandem mass spectrometry (MS) fragmentation technique in the study of protein post-translational modifications (PTMs) due to its unique features of preserving labile modifications and providing more detailed sequence information, which has been used to study protein platination and disulfide linked proteins. Cisplatin was found cross-linking multiple methionine (Met) pairs on calmodulin (CaM). The cross–linking of cisplatin to apo–CaM or Ca–CaM can inhibit the ability of CaM to recognize its target proteins as proved by a melittin binding assay. To further establish MS strategies to quickly assign the platinum-modification sites, a series of peptides with potential cisplatin binding sites were reacted with cisplatin and then analyzed by ECD. Radical-mediated side chain losses from the charge-reduced M+Pt species (such as CH3S• or CH3SH from Met, SH• from Cys, CO2 from Glu or Asp, and NH2• from amine groups) were found to be characteristic indicators for rapid and unambiguous localization of the Pt-modification sites on certain amino acid residues. Furthermore, the potential of cisplatin as a protein crosslinking reagent was further explored and demonstrated on other peptides and proteins. Many of the inherent features of cisplatin make it an interesting cross-linking reagent, such as targeting new protein functional groups (thioether and imidazole groups), its unique isotopic pattern, its inherent positive charges, its potential of binding to different functional groups, etc. However, it was found that the distance constraints obtained from NMR structures of CaM are inconsistent with the measured distance constraints by cross–linking. Therefore, a newly developed flexibility simulation method was applied to explore whether the flexibility motions of CaM might contribute to the observed Pt-crosslinking on CaM. The flexibility analysis showed that the structural flexibility of CaM is key to cisplatin crosslinking CaM. ECD mechanism of disulfide bonds is still under debate. To further explore the ECD mechanism of sulfur– containing species, a series of disulfide (S–S), sulfur–selenium (S–Se), and diselenide (Se–Se) bond–containing peptides was studied by ECD. The results demonstrate that the radical has higher tendency to stay at selenium rather than sulfur after cleavage of Se–S bonds by ECD and suggest that direct electron capture at Se–Se and C–Se bonds is the main process during ECD of inter–chain diselenide peptides. Last but not least, a new active ion ECD (AI-ECD) method, named Shots-ECD, was developed and applied to improve Top-down ECD backbone fragmentation efficiency of disulfide-rich proteins. The results show that the Shots–ECD approach can not only cleave multiple disulfide bonds but also significantly improve the backbone cleavage efficiency. This strategy is fast, efficient, and with no need of chemical reduction of samples and instrument modification, and therefore can be a powerful approach to improve top-down ECD efficiency of not only disulfide bonded proteins but all proteins by Fourier transform ion cyclotron mass spectrometry (FTICR MS).
23
Hamirally, Sofia. "Mechanistic studies of the translational readthrough signal of Moloney murine leukemia virus." Thesis, University of Cambridge, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.619933.
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McBride, Sarah Howe. "MULTISCALE MECHANOBIOLOGY OF PERIOSTEAL BONE GENERATION: CELL SCALE STUDIES TO TRANSLATIONAL MODELS." Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1291048293.
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Sekirnik, Rok. "Studies on ribosomal oxygenases." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:9b8d30f1-7401-48f3-9e60-91d4e515272b.
Анотація:
The 2OG oxygenases comprise a superfamily of ferrous iron dependent dioxygenases with multiple biological roles, including in hypoxia sensing, transcriptional control, and splicing control. It was recently proposed that 2OG oxygenases catalyse the hydroxylation of ribosomal proteins in prokaryotes (ycfD) and in humans (NO66 and MINA53), raising the possibility that 2OG oxygenases also control translation. The work described in this thesis concerned investigations on the biochemical and functional aspects of prokaryotic and mammalian ribosomal protein hydroxylases (ROX) in vitro and in cells. An efficient chromatographic system linked to mass spectrometric analysis (LC-MS) was developed for studying the masses of individual ribosomal proteins (>90% coverage of ribosomal proteome) to ±1 Da accuracy. It was demonstrated that ycfD catalyses the hydroxylation of R81 on L16 in E. coli, in a manner dependent on atmospheric oxygen levels. YcfD deletion results in growth phenotype at low temperatures and in minimal medium, and in decreased global translation rates in minimal medium; ycfD deletion does not affect translational accuracy and ribosome assembly. Furthermore, ycfD-deletion results in increased sensitivity to the antibiotics chloramphenicol and lincomycin. Consistent with a 2OG-oxygenase mediated mechanism of antibiotic resistance, chloramphenicol sensitivity of the E. coli wild-type strain could be increased by inhibiting the activity of ycfD by removing co-factors required for catalytic activity (Fe(II) and O2), and, at least in part, by using a ycfD inhibitor, IOX1, which inhibits ycfD with IC50 of 38 μM in vitro. The therapeutic potential of a post-translational modification mediating antibiotic resistance provides an opportunity for medicinal targeting of ribosome-modifying enzymes, for example ycfD, which may be more ‘druggable’ than the ribosome itself. In co-treatment with an existing antibiotic, such as chloramphenicol, a small molecule inhibitor would achieve a potentiated antibiotic effect. Structural aspects of ROX hydroxylation were pursued by characterising a thermophilic ROX-substrate complex; a ycfD homologue was identified in the thermophilic bacterium Rhodothermus marinus and shown to be a thermophilic 2OG oxygenase ycfDRM, acting on R82 of ribosomal protein L16RM. The activity of ycfDRM in cells was limited at high growth temperature and oxygen solubility was demonstrated as a likely limiting factor of ycfDRM activity, thus identifiying a potential 2OG oxygenase oxygen sensor in prokaryotes. A crystal structure of ycfDRM in complex with L16RM substrate fragment was determined to 3.0 Å resolution. Structural analyses suggested that ycfDRM contains 30% more hydrophobic interactions and 100% more salt-bridge interactions than ycfDEC, suggesting that these interactions are important for thermal stabilisation of ycfDRM. The structures reveal key interactions required for binding of ribosomal proteins. Substantial structural changes were observed in the presence of the substrate fragment, which implies induced-fit binding of the L16RM substrate. The work has informed further structural studies on the evolutionarily related human ROX, NO66 and MINA53, for which substrate structures have been obtained since the completion of the work. The LC-MS analysis of ribosomal proteins was extended to mouse and human cells to demonstrate that the human ROX homologue of ycfD, MINA53, hydroxylates the 60S ribosomal protein rpL27a in cells. It was demonstrated that rpL27a hydroxylation is widespread and found in all mouse organs analysed, as well as in cancer cell lines and in clinical cancer tissues. A partial or complete reduction of rpL27a hydroxylation was observed in a number of clinically identified MINA53 mutations from the COSMIC database of cancer mutations. Structural analysis suggested that mutations occur more frequently at structurally important regions of MINA53, including the βIV-βV insert in the core fold of MINA53. The identification of inhibiting clinical mutations suggests that rpL27a hydroxylation level could be used as a cancer mark, and in the future for selective inhibition by ribosomal antibiotics. The work presented in this thesis demonstrates that it is possible to selectively inhibit modified ribosomes; an inhibitor of unhydroxylated rpL27a could therefore, at least in principle, be active against the sub-set of tumours with inactivating mutation(s) of MINA53, but not normal tissue. Future work should therefore focus on identifying a selective inhibitor of unhydroxylated eukaryotic ribosomes which could be applied for treatment of cancers harbouring deactivating MINA53 mutations. The same approach could be applied to other ribosome modifications (to rRNA, ribosomal proteins, and ribosome-associate factors) that are different in cancer compared to normal cells.
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Kennedy, M. A. "Development of TOFMS and GC/TOFMS instrumentation, with fundamental studies using Translational Energy Spectrometry." Thesis, Swansea University, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.637777.
Анотація:
This thesis describes the design, development and testing of two orthogonal acceleration, Time-Of-Flight (oaTOF) mass spectrometers, constructed at Swansea University during the period 1997-2000. The fundamental principles and concepts necessary for the construction of the various forms of the oaTOF instruments (i.e. linear and reflectron) have been incorporated into the relevant sections, with full explanations as to how the systems were developed. This thesis also includes an investigation using the SIMION 7 ion optics program, to evaluate the performance of the two-stage, orthogonal acceleration source, used within the TOF I instrument. The investigation examines the main areas of resolution and sensitivity, due to the current on-source design and evaluates two enhanced oa-source designs. The final investigation to be described within this thesis pertains to an investigation conducted with a high-resolutional translational energy spectrometer. The spectrometer was used to assess the viability of Translational Energy Spectroscopy (TES), as a means to distinguish between structural isomers. To this end, it was found that the TES technique could be used, to distinguish between the structurally dissimilar isomers of acetone and with the aid of several optically forbidden transitions, as discussed in Section 4.5, distinguish between the structurally similar isomers of xylene.
27
Vasant, Dipesh. "Translational studies in the development of neurostimulation based interventions for rehabilitation of dysphagia after stroke." Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/translational-studies-in-the-development-of-neurostimulation-based-interventions-for-rehabilitation-of-dysphagia-after-stroke(39e3cd47-6824-4a53-8ea8-306b310a693e).html.
Анотація:
Neural control of swallowing is hierarchical, involving the cerebral cortex and interactions with several other brain regions including the cerebellum. Cortical control of swallowing exhibits functional asymmetry, whereby brain lesions disrupting the stronger ('dominant') hemisphere are implicated in post-stroke dysphagia. A major breakthrough has been the consistent observation that compensatory changes (neuroplasticity) in the undamaged (contralesional) hemisphere are responsible for swallowing recovery. Whilst existing therapies lack evidence-base, neurostimulation interventions capable of facilitating this natural recovery process have the potential to revolutionise swallowing rehabilitation. Whilst data using several neurostimulation modalities have been promising, translating them into much needed clinical therapies has been hampered by clinical study designs lacking homogeneity. In a series of studies, using three different modalities I describe a step-wise approach for developing neurostimulation interventions from bench-to-bedside. Firstly, in a proof of concept experiment, targeted cerebellar repetitive Transcranial Magnetic stimulation (rTMS) was assessed in healthy subjects (n=17), confirming frequency and duration specific (250-pulses of 10-Hz) induction of long-lasting changes in pharyngeal cortical plasticity, effects which were explored with therapeutic potential in a dysphagic patient. Secondly, in a pre-clinical model of post-stroke dysphagia, optimal parameters of cortical transcranial Direct Current Stimulation (tDCS) were tested, confirming reversal of transient neurophysiological and behavioural swallowing deficits induced by a 'virtual-lesion' (10 minutes, 1-Hz rTMS to the 'dominant' hemisphere) in 15 healthy subjects. Finally, in a randomised trial, optimal parameters and dosage (5-Hz, 10 minutes daily for 3-days) of Pharyngeal Electrical Stimulation (PES) were studied in acutely dysphagic stroke patients (n=36) which despite lower than desired recruitment, trended towards reduced dysphagia severity at 2-weeks, earlier hospital discharge and nasogastric tube removal were observed. These studies have shown for the first time that the cerebellum is a viable target for non-invasive brain stimulation swallowing studies and that cortical tDCS can reverse experimental brain lesions, with both techniques having therapeutic potential for post-stroke dysphagia. These clinical trial data add to the increasing evidence base for PES, the modality with the most evidence to date, with longer-term follow-up. The difficulties encountered in the post-stroke clinical trial in both recruitment and outcome measures highlight the importance of mechanistic studies which have often been lacking, in optimising stimulation specific factors; site, duration, intensity, dosing and controls, prior to clinical trials. An independent, larger, multi-centre, international trial of PES, with greater resources is now required to definitively determine its clinical efficacy. In summary, there may be a role for several different neurostimulation modalities in different patient sub-groups and my preliminary observations lead me to hypothesise that future translation of these therapies will depend on targeting population tailored to specific interventions.
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Sundblom, Jimmy. "Autosomal Dominant Leukodystrophy with Autonomic Symptoms and Rippling Muscle Disease : Translational Studies of Two Neurogenetic Diseases." Doctoral thesis, Uppsala universitet, Neurologi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-162048.
Анотація:
There is a large variety of diseases caused by single-gene mutations. Although most of these conditions are rare, together they impose a significant burden to the population. This thesis describes clinical and genetic studies of two single-gene diseases: 1) Adult-onset autosomal dominant leukodystrophy with autonomic symptoms (ADLD) caused by LMNB1 gene duplications, and characterized by autonomic, pyramidal and cerebellar symptoms. Spinal cords of patients with ADLD were studied by MRI and found to be thin, with high signal intensity in white matter. Histopathology showed loss of myelinated fibres with some reactive gliosis. DNA samples from four different families with ADLD were obtained, and the LMNB1 gene was screened for duplications. Single nucleotide polymorphism array revealed LMNB1 duplications in all ADLD families. LMNB1 mRNA and protein levels were assessed in white blood cells using quantitative polymerase chain reaction and Western blot, and increased levels of LMNB1 mRNA and lamin B1 protein could be demonstrated. We concluded that spinal cord atrophy in patients with ADLD is a valuable differential diagnostic sign, and that increased levels of LMNB1 can be detected in peripheral blood. 2) Rippling muscle disease (RMD) is caused by CAV3 gene mutations. Clinical features are percussion-induced muscle mounding, –rapid contractions and undulating muscle contractions (rippling). The CAV3 gene was sequenced in 38 members of a family with RMD. Twenty-two individuals had clinical features of RMD. No muscle weakness was seen. All patients with signs of RMD carried the p.A46T CAV3 mutation, showing that the p.A46T mutation was benign and that the diagnosis can be made clinically. In vitro contracture test results from 10 of the subjects were collected, but no association between pathological test results and RMD was found.
29
Ilisei, Iustina-Narcisa. "A machine learning approach to the identification of translational language : an inquiry into translationese learning models." Thesis, University of Wolverhampton, 2012. http://hdl.handle.net/2436/299371.
Анотація:
In the world of Descriptive Translation Studies, translationese refers to the specific traits that characterise the language used in translations. While translationese has been often investigated to illustrate that translational language is different from non-translational language, scholars have also proposed a set of hypotheses which may characterise such di erences. In the quest for the validation of these hypotheses, embracing corpus-based techniques had a well-known impact in the domain, leading to several advances in the past twenty years. Despite extensive research, however, there are no universally recognised characteristics of translational language, nor universally recognised patterns likely to occur within translational language. This thesis addresses these issues, with a less used approach in the eld of Descriptive Translation Studies, by investigating the nature of translational language from a machine learning perspective. While the main focus is on analysing translationese, this thesis investigates two related sub-hypotheses: simplication and explicitation. To this end, a multilingual learning framework is designed and implemented for the identification of translational language. The framework is modelled as a categorisation task, the learning techniques having the major goal to automatically learn to distinguish between translated and non-translated texts. The second and third major goals of this research are the retrieval of the recurring patterns that are revealed in the process of solving the task of categorisation, as well as the ranking of the most in uential characteristics used to accomplish the learning task. These aims are ful lled by implementing a system that adopts the machine learning methodology proposed in this research. The learning framework proves to be an adaptable multilingual framework for the investigation of the nature of translational language, its adaptability being illustrated in this thesis by applying it to the investigation of two languages: Spanish and Romanian. In this thesis, di erent research scenarios and learning models are experimented with in order to assess to what extent translated texts can be diff erentiated from non-translated texts in certain contexts. The findings show that machine learning algorithms, aggregating a large set of potentially discriminative characteristics for translational language, are able to diff erentiate translated texts from non-translated ones with high scores. The evaluation experiments report performance values such as accuracy, precision, recall, and F-measure on two datasets. The present research is situated at the con uence of three areas, more precisely: Descriptive Translation Studies, Machine Learning and Natural Language Processing, justifying the need to combine these elds for the investigation of translationese and translational hypotheses.
30
Hunniford, Victoria. "Exploring the Application of a Multicenter Study Design in the Preclinical Phase of Translational Research." Thesis, Université d'Ottawa / University of Ottawa, 2020. http://hdl.handle.net/10393/40030.
Анотація:
Multicenter preclinical studies have been suggested as a method to improve potential clinical translation of preclinical work by testing reproducibility and generalizability of findings. In these studies, multiple independent laboratories collaboratively conduct a research experiment using a shared protocol. The use of a multicenter design in preclinical experimentation is a recent approach and only a handful of these studies have been published. In this thesis, I aimed to provide insight into preclinical multicenter studies by 1) systematically synthesizing all published preclinical multicenter studies; and 2) exploring the experiences of, barriers and enablers to, and the extent of collaboration within preclinical multicenter studies.
In Part One, I conducted a systematic review of preclinical multicenter studies. The database searches identified 3150 citations and 13 studies met inclusion criteria. The multicenter design was applied across a diverse range of diseases including stroke, heart attack, and traumatic brain injury. The median number of centers was 4 (range 2-6) and the median sample size was 133 (range 23-384). Most studies had lower risk of bias and higher completeness of reporting than typically seen in single-centered studies. Only five of the thirteen studies produced results consistent with previous single-center studies, highlighting a central concern of preclinical research: irreproducibility and poor generalizability of findings from single laboratories.
In Part Two, I performed semi-structured interviews with researchers who have been involved in a preclinical multicenter study. Braun and Clarkes’ thematic analysis was used to identify emerging themes, and the extent of collaboration was evaluated using an established theory of collaboration developed by Wood and Gray. Twelve researchers from 6 studies were interviewed. Most participants indicated that funding and the culture of the scientific community were barriers, and that established relationships and transparency with collaborators were enablers to multicenter studies. Some participants felt that a harmonized protocol was optimal, while others stated that variability in the protocol across sites was more appropriate. Most participants indicated that multicenter studies had a purpose and place in preclinical research.
My findings also suggest that multicenter preclinical studies may provide a method to robustly assess therapies prior to considering clinical translation. These insights will allow for more effective planning and execution of future preclinical multicenter projects and may support the development of best practices and guidelines.
31
Quack, Salina [Verfasser]. "Single-molecule studies on the accessibility of chromatin : post-translational modifications and nucleosome remodeler CHD1 / Salina Quack". Ulm : Universität Ulm, 2020. http://d-nb.info/1210557762/34.
32
Hirth, Natalie [Verfasser], and Rainer [Akademischer Betreuer] Spanagel. "The endogenous opioid system in alcoholism: Translational studies in humans and rodents / Natalie Hirth ; Betreuer: Rainer Spanagel." Heidelberg : Universitätsbibliothek Heidelberg, 2017. http://d-nb.info/1178007944/34.
33
Girnary, Roseanne Waheeda. "Structural and functional studies of the stimulatory RNAs involved in programmed -1 ribosomal frameshifting and translational readthrough." Thesis, University of Cambridge, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612716.
34
Mushtaq, Talat. "Translational studies in growth plate research : the effect of glucocorticoids and growth factors on the growth plate." Thesis, University of Edinburgh, 2007. http://hdl.handle.net/1842/29290.
Анотація:
This thesis consists of four major types of studies each utilising different models of growth and chondrocyte biology, which in combination strengthens the understandings of the effects of GC and growth factors on the growing skeleton. The initial in vivo study showed that in children treated with Dexamethasone (Dex) or Prednisolone (Pred) for Acute Lymphoblastic Leukaemia, the effects of Dex on body composition were more apparent in that it was up to 18 times more potent at reducing short term linear growth than Pred. The ATDC5 chondrocyte cell line was fully characterised, which allowed a unique opportunity to study GC effects on a homogeneous population of chondrocytes at the chondrogenesis and terminal differentiation phases. The GCs caused a reduction in cell number, cell proliferation and proteoglycan content whilst stimulating chondrocyte differentiation. These effects were dose dependent and only observed during the chondrogenesis phase when the cells are rapidly dividing. Furthermore these negative effects could be partially reversed with the use of a GC receptor antagonist and completely reversed with IGF-I. These observations were further translated into increasingly physiological models of bone growth. Foetal metatarsal organ explants, where the three dimensional structure and cell connections of the growing bone remain intact, again demonstrated that Dex and IGF-I had opposite effects on bone growth. In contrast to Dex the effects of IGF-I were immediate. IGF-I increased the size of the hypertrophic zone, and this accounted for most of the increase in metatarsal length. Prenatal administration of Dex caused a reduction in birth weight and length and this difference was greater in the female mice. The growth restriction was associated with an elevated IGF-I and IGFBP-2 levels raising the possibility of a state of IGF-I insensitivity, which may explain subsequent growth failure.
35
Hii, John H. "Studies on the synthesis and post-translational modification of measles virus polypeptides in acutely and persistently infected cells." Thesis, McGill University, 1986. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=65393.
36
Hanazono, Yuya. "Structural studies on the mechanism of protein folding." 京都大学 (Kyoto University), 2014. http://hdl.handle.net/2433/188506.
37
Napolitano, Antonio. "Neurotransmitter profiling with high and ultra-high field magnetic resonance spectroscopy : optimization for clinical and translational studies in schizophrenia." Thesis, University of Nottingham, 2011. http://eprints.nottingham.ac.uk/28305/.
Анотація:
Growing interest in the research community has been shown in clinical neuroscience to assess neurotransmitter profiling both in healthy and diseased subjects. A large body of research in this field focuses on schizophrenia to characterise its glutamatergic level according to the most recent hypothesis of NMDA (N-Methyl-D-aspartic acid) receptors hypofunction. Magnetic Resonance Spectroscopy (MRS) is able to detect some of the most common neurotransmitters but a number of issues, such as low signal to noise ratio (SNR), spectra overlapping and line broadening prevents MRS from being clinically relevant for neuropsychiatry. Four important aims were considered relevant for this work. Firstly, we aimed to compare the reliability of conventional and timing-optimized sequences for the detection and measurement of most of the visible metabolites and, in particular, for glutamate (Glu), glutamine (GIn) and gamma-aminobutyric acid (GABA) to assess the best available sequence for a study in schizophrenia. Secondly, we also intended to investigate whether glutamatergic activity might predict the oscillatory activity and how this link might survive or not in schizophrenia. Thirdly, we wanted to study whether the well known animal model of schizophrenia, the rearing in isolation model, exacerbates the effect of ketamine and determines more profound changes on neurotransmitter profile in rats. Fourthly, a further goal focuses on the improved data acquisition and on the data processing to reliably resolve GABA and to be able to quantify a wider range of metabolites. To address those points five studies were performed. The first work (Chapter 3) describes a study of reproducibility on sequences which have been reported in the literature to be capable to detect Glu and GIn. The study was performed on 14 healthy subjects by scanning them twice and repositioning between the two scans. The absolute percentage difference was then computed to assess the accuracy per sequence and metabolite. A good compromise was found in PRESS sequence (TE=80 ms) which was exploited subsequently for the following study on schizophrenic patients (Chapter 4). Twenty-seven early stage schizophrenic patients and twenty-three aged-matched controls were recruited to undergo a protocol including, in two separate sessions, MRS and electroencephalography (EEG). Anterior Cingulate Cortex Glu was found to predict the induced theta activity in healthy controls but not in patients. Furthermore, the NAA values have also been found to be reduced in schizophrenia and linked to N100, an Event Related Potential (ERP) which is well known to be decreased in schizophrenia. Following on from the findings of the study on the early stage of schizophrenia, further investigations were undertaken to study the psychotic state occurring in the disease via a functional MRS, where 25mg/kg of ketamine (NMDA antagonist) injection was administered to two groups of rats. The two groups were group-housed and reared in isolation. This work was able to show increase of prefrontal GIn levels in both groups but showed a selective GABA decrease only in isolated rats. It would have been very interesting to be able to detect GABA changes in the study at 3T but the used protocol did not allow its accurate quantification. Simulations and reliability tests (Chapter 6)were then utilized to optimize a standard sequence to obtain an accurate and reliable GABA concentration. The optimized sequence reproduces the quantification with 12% of accuracy. The preliminary results of the last study (Chapter 7) give an evidence of the potential of combined use of Monte Carlo, Levenberg-Marquardt and NNLS methods embedded in a novel fitting approach for two-dimensional spectra. The three appendices at the end of this work illustrate the details of some of the algorithms and softwares used throughout the studies.
38
Postalcioglu, Aysenaz. "Simone de beauvoir in Turkey: (her)story of a translational journey." Doctoral thesis, Universitat Rovira i Virgili, 2016. http://hdl.handle.net/10803/378645.
Анотація:
Aquest estudi explora i problematitza el viatge de traducció de Simone de Beauvoir a Turquia a través de les dades textuals i paratextuals dels anys 50 endavant, amb una perspectiva conscient de gènere. La primera problemàtica està relacionada amb la (in)visibilitat de Beauvoir i la seva obra dins de l'espai cultural de Turquia. Si bé l'obra de Beauvoir havia estat àmpliament traduïda i llegida des de la dècada de 1960, no existien crítiques publicades de les seves traduccions. La segona problemàtica té a veure amb la seva parcial (i dolenta) representació. Com Beauvoir va ser introduïda per primera vegada a l'espai cultural de Turquia pels mateixos mediadors culturals (masculins) que van introduir Sartre en la intel·lectualitat turca, especialment en els anys 60 i 70, el seu nom es va associar amb el de Sartre i l'existencialisme, fins als anys 80 quan Beauvoir va ser finalment abordada per les feministes turques. La tercera problemàtica està, de fet, relacionada amb la segona, i és el retard en la recepció del vessant feminista de Beauvoir en el sistema cultural de Turquia. Per contextualitzar els resultats, s'argumenta que aquests materials paratextuals i textuals que van tenir un paper significatiu en la “reescriptura” de Beauvoir i la seva obra a Turquia ens donen diverses pistes sobre les postures culturals, socials, patriarcals, i ideològiques respecte “la qüestió de dona”, a l'espai cultural de Turquia.Este estudio explora y problematiza el viaje de traducción de Simone de Beauvoir en Turquía a través de los datos textuales y paratextuales de los años 50 en adelante, con una perspectiva consciente de género. La primera problemática está relacionada con la (in)visibilidad de Beauvoir y su obra dentro del espacio cultural de Turquía. Si bien la obra de Beauvoir había sido ampliamente traducida y leída desde la década de 1960, no existían críticas publicadas de sus traducciones. La segunda problemática tiene que ver con su parcial (y mala) representación. Como Beauvoir fue introducida por primera vez en el espacio cultural de Turquía por los mismos mediadores culturales (masculinos) que introdujeron Sartre en la intelectualidad turca, especialmente en los años 60 y 70, su nombre se asoció con el de Sartre y el existencialismo, hasta los años 80 cuando Beauvoir fue finalmente abordada por las feministas turcas. La tercera problemática está, de hecho, relacionada con la segunda, y es el retraso en la recepción de la vertiente feminista de Beauvoir en el sistema cultural de Turquía. Para contextualizar los resultados, se argumenta que estos materiales paratextuales y textuales que tuvieron un papel significativo en la “reescritura” de Beauvoir y su obra en Turquía nos dan varias pistas sobre las posturas culturales, sociales, patriarcales, e ideológicas respecto “la cuestión de mujer”, en el espacio cultural de Turquía.
This study explores and problematizes the translational journey of Simone de Beauvoir into Turkey through the paratextual and textual data beginning from the 1950s onwards, with a gender-conscious perspective. The first problematic is related to the (in)visibility of Beauvoir and her work within the Turkish cultural space. While Beauvoir’s oeuvre has been extensively translated and read since the 1960s, no reviewers have commented on any translation at all. The second problematic has to do with her partial (mis)representation. As Beauvoir was first introduced into the Turkish cultural climate by the same (male) mediators who introduced Sartre to the Turkish intelligentsia, especially in the 1960s and 1970s, her name was associated with that of Sartre and existentialism, until the 1980s when Beauvoir was finally approached by Turkish feminists. The third problematic is in fact related with the second one, and it is the time lag in the reception of Beauvoir’s feminist side in the Turkish cultural system. To see the big picture and to contextualize the results, it is argued that these paratextual and textual materials which played a significant role in the rewriting of Beauvoir and her work in Turkey give us clues about cultural, social, patriarchal, and ideological stances on “the woman question” within the Turkish cultural space.
39
de, Souza Paul Linus Clinical School St George Hospital Faculty of Medicine UNSW. "Preclinical and phase I studies of phenoxodiol: a translational approach for the development of a novel isoflavone for the treatment of prostate cancer." Awarded By:University of New South Wales. Clinical School - St George Hospital, 2009. http://handle.unsw.edu.au/1959.4/44510.
Анотація:
This work presents an investigation of the potential development of phenoxodiol, a novel isoflavone, for the treatment of prostate cancer. The literature concerning isoflavone epidemiology, pharmacology, clinical use and their effect on prostate cancer is reviewed. Isoflavone impact on signal transduction pathways is also reviewed with a particular focus on the Akt / mTOR signal transduction pathway, a key signaling pathway in prostate cancer cells. In vitro experiments and xenograft nude mice studies show that phenoxodiol inhibits the growth of DU145 and PC3 prostate cancer cells, when used alone and in combination with cisplatin or carboplatin. Phenoxodiol in combination with cisplatin is highly synergistic when inhibiting the growth of DU145 cells in particular. We show for the first time, that phenoxodiol and cisplatin or carboplatin, inhibits phosphorylation of Akt and mTOR in DU145 and PC3 cells. A first-in-human study of single dose phenoxodiol investigating its pharmacokinetic properties in cancer patient volunteers was performed. Extensive conjugation of phenoxodiol and a short half-life was noted in this study. A Phase I study of intravenous phenoxodiol administered weekly to patients with advanced cancer was then performed to assess toxicity of a repeated dose schedule, as well as the maximum tolerated dose. This schedule was well tolerated in patients, with lymphocytopenia noted as the main toxicity. Given the short half-life of phenoxodiol and our preclinical studies suggesting that combination with cisplatin and carboplatin synergistically inhibited prostate cancer cell growth, we also undertook a Phase I dose escalation study of oral phenoxodiol administered in combination with cisplatin or carboplatin to patients with advanced cancer. The main adverse events include hyperglycemia, hypocalcemia, mild transaminase rises, as well as nausea, constipation, infusion site reactions and lethargy. Three patients with ovarian cancer responded to treatment according to CA125 criteria, and there was a 45% reduction in prostate specific antigen level in one man with androgen independent prostate cancer. The bioavailability of the oral formulation of phenoxodiol was calculated to be 17.5%. Phenoxodiol shows promise for further development in the potential treatment of prostate cancer.
40
Boor, Susanne de [Verfasser], Michael [Akademischer Betreuer] Lammers, and Kay [Akademischer Betreuer] Hofmann. "Mechanistic studies on the regulation of Ran-function by post-translational lysine-acetylation / Susanne de Boor. Gutachter: Michael Lammers ; Kay Hofmann." Köln : Universitäts- und Stadtbibliothek Köln, 2015. http://d-nb.info/107396986X/34.
41
Montello, Aaron David. "Studies of Nitrogen Vibrational Distribution Function and Rotational-Translational Temperature in Nonequilibrium Plasmas by Picosecond Coherent Anti-Stokes Raman Scattering Spectroscopy." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1345522814.
42
Devkota, Batsal. "Structural studies of ribonucleoprotein complexes using molecular modeling." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2007. http://hdl.handle.net/1853/22713.
Анотація:
Thesis (Ph. D.)--Biology, Georgia Institute of Technology, 2008.Committee Chair: Harvey, Stephen C; Committee Member: Hud, Nicholas V; Committee Member: McCarty, Nael A; Committee Member: Wartell, Roger M.
43
Siangphoe, Umaporn. "META-ANALYSIS OF GENE EXPRESSION STUDIES." VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/4040.
Анотація:
Combining effect sizes from individual studies using random-effects models are commonly applied in high-dimensional gene expression data. However, unknown study heterogeneity can arise from inconsistency of sample qualities and experimental conditions. High heterogeneity of effect sizes can reduce statistical power of the models. We proposed two new methods for random effects estimation and measurements for model variation and strength of the study heterogeneity. We then developed a statistical technique to test for significance of random effects and identify heterogeneous genes. We also proposed another meta-analytic approach that incorporates informative weights in the random effects meta-analysis models. We compared the proposed methods with the standard and existing meta-analytic techniques in the classical and Bayesian frameworks. We demonstrate our results through a series of simulations and application in gene expression neurodegenerative diseases.
44
Vukmirica, Jelena. "Studies on the role(s) of post-translational modification(s) of human apolipoprotein B during very low density lipoprotein assembly and secretion." Thesis, University of Ottawa (Canada), 2002. http://hdl.handle.net/10393/6397.
Анотація:
The role of two post-translational modifications, N-linked glycosylation and palmitoylation, of human apolipoprotein B (apoB) in the biosynthesis of hepatic apoB-containing very low density lipoproteins (VLDL) was investigated. Working with tunicamycin-treated rat hepatoma McA-RH7777 cells stably expressing human apoB variants, we found that inhibition of N-linked glycosylation decreased the secretion of apoB variants, without affecting translation. Detailed biochemical analysis was performed following site-specific mutagenesis at consensus N-linked glycosylation sites (using asparagine-to-glutamine substitution) within recombinant human apoB variants (i.e. apoB17, -B37, -B48, and -B50). Four notable features associated with the requirement of N-linked oligosaccharides during apoB biosynthesis were observed: (a) N-linked oligosaccharides were required for efficient secretion of the apoB polypeptide. (b) N-linked oligosaccharides were required for the assembly and secretion of the apoB-containing VLDL. (c) Removal of N-linked oligosaccharides was associated with accumulation of total intracellular apoB without specific apoB retention in the ER, and (d) Expression of mutant apoB lacking N-glycans was associated with changes in mass or activity of microsomal triglyceride transfer protein (MTP). Similar biochemical analysis was performed following site-specific mutagenesis at potential palmitoylation sites (using cysteine-to-serine substitution) within human apoB48. The cysteine-to-serine substitution had no effect on the secretion of apoB48-containing lipoproteins or apoB intracellular distribution. Thus, while N-linked glycosylation at the amino terminus of apoB represents an important requisite for proper biogenesis of apoB-containing VLDL, palmitoylation is not required for apoB-containing VLDL assembly and secretion.
45
Thalhammer, Armin. "Functional and inhibition studies on 2-oxoglutarate-dependent oxygenases." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:41c3f967-0dd2-47dd-8dd4-bc543b626221.
Анотація:
This thesis explores roles of 2-oxoglutarate-dependent (2OG) oxygenases as interfaces that modulate steps in the flow of genetic information in cells in response to oxygen availability. Chapter 1 introduces mechanistic, biochemical and physiological aspects of major subfamilies of 2OG oxygenases, and their established regulatory roles in cells. In addition, structural and functional aspects of the ribosome and the translation process are discussed, with a focus on post-translational ribosome modifications. Chapter 2 investigates histone demethylases, which mediate chromatin-dependent regulation of gene expression and provides proof-of-concept for the rational, structure-guided design of small-molecules for selective inhibition of 2OG oxygenases with roles in cancer and inflammatory disease. Chapter 3 suggests regulatory roles for ten-eleven-translocation (TET)- catalysed DNA hydroxylation; calorimetric and thermal analyses reveal a duplex-stabilizing effect of the epigenetic 5-methylcytosine mark that is reversed upon conversion to 5- hydroxymethylcytosine (also termed the ‘sixth’ DNA base), raising the possibility that 2OG oxygenase catalysis might affect transcription via biophysical effects. Chapter 4 investigates fluoride release assays as a technology to enable medicinal chemistry studies on 2OG oxygenases with roles in fat mass regulation and obesity, cancer and inflammation; studies on the ALKBH5 enzyme show that it is a hypoxically upregulated 2OG oxygenase with a substrate preference distinct from previously characterized ALKBH enzymes. Chapter 5 identifies OGFOD1 as a 2OG-dependent ribosomal protein hydroxylase. OGFOD1 catalysis is conserved from yeast to humans. OGFOD1 catalyses formation of trans-3- hydroxy-L-proline in a highly conserved loop of ribosomal protein S23 proximal to the ribosomal decoding centre, possibly to modulate the interactions of eukaryotic ribosomes with tRNA, mRNA and translation factors in an oxygen-dependent manner. OGFOD1 is the functionally most well-conserved protein-modifying 2OG oxygenase; likewise, ribosomal protein S23 hydroxylation is the most well-conserved post-translational ribosome modification in eukaryotes. Some cell lines require OGFOD1 for proliferation, and scaffolds for OGFOD1- selective inhibitors are developed for use as potential antiproliferative agents and probes for cellular function. Chapter 6 shows the development of assays to investigate whether OGFOD1 catalysis affects ribosome assembly and function, including processivity, accuracy of initiation, elongation and termination, in yeast and mammalian cell lines. Chapter 7 concludes that ribosome hydroxylation might present an additional layer of regulatory complexity by which 2OG oxygenases could enable cells to respond to fluctuating oxygen levels.
46
Delotterie, David. "Translational potential of the touchscreen-based methodology to assess cognitive abilities in mice." Thesis, Strasbourg, 2014. http://www.theses.fr/2014STRAJ048/document.
Анотація:
Ce travail visait à évaluer le potentiel d’une méthodologie innovante récemment adaptée à la Souris sur la base de tests neuropsychologiques utilisés en clinique humaine. Après optimisation de 3 tâches (PAL, VMCL, PVD) ciblant différentes fonctions cognitives chez l’animal, nos études ont établi : (1) l’existence possible d’interférences proactives lors d’apprentissages consécutifs ; (2) l’absence de déficit d’acquisition chez les souris de la lignée Tg2576 (modèle transgénique de la maladie d’Alzheimer), quelle que soit l’étendue de la charge amyloïde ; (3) l’implication spécifique du striatum dorsal lors de l’acquisition des tâches de VMCL et PAL, et celle de l’hippocampe lors du rappel de cette dernière tâche. Ces derniers résultats suggèrent qu’en dépit des efforts déployés pour s’assurer du caractère translationnel d’une tâche cognitive dans le paradigme du touchscreen, certaines adaptations inhérentes à chaque espèce influencent profondément les bases neurobiologiques associéesThis thesis work aimed to specify the potential of an innovative methodology latterly adapted in mice from neuropsychological tasks used in Humans. After the optimization of 3 assays (PAL, VMCL, PVD) taxing various cognitive functions in animals, different behavioral studies have gradually revealed: (1) the putative existence of proactive interferences over consecutive learnings in touchscreen tasks; (2) no acquisition deficit in Tg2576 mice (a transgenic model of Alzheimer’s Disease) in these paradigms, whatever the amyloid load considered; (3) the specific involvement of the dorsal striatum during the acquisition of VMCL and PAL tasks and the key role of the hippocampus during the recall of the latter task. As exemplified by the PAL task, our results suggest that despite momentous efforts in order to ensure the translational feature of touchscreen cognitive tasks, certain adaptations inherent to each species deeply influence the nature of underlying neurobiological substrates
47
Jent, Karen Ingeborg. "Making stem cell niches : an ethnography of regenerative medicine in Scotland and the United States." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/279088.
Анотація:
This thesis presents the findings from an ethnography of stem cell science based on fieldwork with researchers in two connected laboratories in Scotland and the United States. It explores stem cell scientists' complicated interactions with live stem cell cultures within national projects of translational regenerative medicine. This analysis both draws upon and contributes to the social studies of biomedicine, reproductive studies and science and technology studies. I examine how stem cell scientists, involved in an international research initiative, navigate the challenging landscapes of translational regenerative medicine and attempt to transform fragile live cell cultures into successful biotechnical, medical and economic products. By considering translational regenerative medicine as an effort to reformulate the relationship between biology and technology in terms of applicability and utility, I illuminate tensions between the specific practices of care that enable stem cell growth in vitro and the elusive goals of national projects of biotechnological innovation. A major focus of this study is the means by which scientists in the two laboratories manage the inherent uncertainties of both cell culture and translational science. By exploring how researchers react to unstable and unpredictable cellular behaviour in the laboratory, while also managing the expectations of government and external funding bodies, I provide a portrait of the complex sociality of contemporary bioscience. In addition to the international collaboration between the two laboratories, I explore scientists' interdisciplinary work with medical specialists and public engagement with stakeholders in regenerative medicine. In doing so, I pay attention to the ways in which scientists themselves deal with and reflect on the relational and interdependent nature of their endeavours. Drawing on twenty-two months of ethnographic fieldwork and fifty qualitative interviews, I show how stem cell scientists' new engagement practices also inform scientific work and the care of stem cells in the laboratory. In short, I argue that translation of science across different sites at once creates and depends on new social relations between stem cells, people and communities. After providing an overview of the literature, central questions and methodology that frame this thesis, I introduce the opportunities and challenges that translational regenerative medicine goals create for the care of stem cells in vitro. From there, I zoom out beyond the tissue culture flask to demonstrate how the necessity for science applicability creates new responsibilities for scientists to connect with stakeholders in regenerative medicine outside of the laboratory. I conclude that a consideration of scientists' ties and societal links is significant for an understanding of the connection between the biological and the technological.
48
Pan, Yu. "Modification of mdmx by ubiquitination and sumoylation." [Tampa, Fla.] : University of South Florida, 2005. http://purl.fcla.edu/fcla/etd/SFE0001114.
49
Moreira, Marcelo Victor de Souza. "Estudos funcionais da tradução: rupturas e continuidades." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/8/8144/tde-27062014-111155/.
Анотація:
O tema desta dissertação é o Funcionalismo, uma abordagem teórica dos Estudos da Tradução que tem em Hans J. Vermeer seu fundador e principal teorizador. Partimos de duas hipóteses de trabalho: por um lado, pressupomos que, a despeito dos relatos historiográficos que enfatizam, com razão, o seu caráter revolucionário, a teoria tenha dado continuidade a importantes princípios de teorias de tradução precedentes. Por outro lado, somos da opinião de que o alicerce teórico tenha sido construído ao longo da década de 1980. Os textos publicados no âmbito da Teoria Funcional de Tradução após esse período consistiriam, assim, na aplicação desses fundamentos teóricos a diversas ramificações da atividade de tradução. Com base nos textos de Reiss e Vermeer (1984), Holz-Mänttäri (1984) e Nord (1988), examinamos o processo de gênese da teoria e seu desenvolvimento ao longo nos anos de 1980, a partir do elenco de seus principais conceitos, com o objetivo de, por um lado, identificar rupturas e continuidades em relação a teorias antecessoras e, por outro, promover uma leitura crítica de textos funcionalistas, pautada em parâmetros bem definidos. Desse modo, adotamos para o presente estudo uma metodologia baseada em quatro etapas. Primeiramente, delimitamos o escopo do trabalho (período e hipóteses), na medida em que foi definido o corpus de análise principal. Posteriormente, descrevemos o contexto histórico, institucional e intelectual de emergência da Teoria Funcional, tendo-nos pautado primeiramente por relatos de testemunhos e crônicas desse tempo, advindos de fontes primárias e secundárias e, em seguida, com vistas à identificação, segundo parâmetros específicos, de conceitos caros a essas propostas, pela análise de textos teóricos anteriores à publicação dos componentes do corpus principal. Numa terceira etapa, lemos e analisamos as obras do corpus principal segundo os mesmos parâmetros utilizados para a análise dos predecessores teóricos, o que nos levou a um mapeamento do desenvolvimento dos conceitos- chave funcionalistas. Finalmente, contrastamos os conceitos funcionalistas e os conceitos defendidos por seus predecessores, o que nos permitiu identificar, com o uso de noções defendidas pela historiografia das ciências para a interpretação dos resultados, rupturas e continuidades entre as duas vertentes. Esse processo nos levou à constatação de que, no plano teórico, as mudanças trazidas pelo Funcionalismo estão, por um lado, em conformidade com o clima intelectual dos estudos sobre a tradução em curso naquele momento e, por outro lado, seguem uma tendência observável no desenvolvimento das próprias teorias pré-funcionalistas de tradução. Ainda assim, constatamos que a vertente teórica trouxe inestimável contribuição no sentido de redefinir o lugar da tradução na Alemanha. A principal ruptura provocada pelo Funcionalismo, fomos levados a concluir, teria sido num plano que não o teórico, qual seja, a constituição de uma disciplina dedicada à tradução na Alemanha Ocidental. Quanto ao desenvolvimento da Teoria Funcional em si, vimos confirmada a hipótese inicial de que ela estabeleceu suas bases ao longo dos anos 1980. O fato de Nord, membro da assim chamada Segunda Geração Funcionalista, utilizar-se especialmente do quadro teórico formulado por Vermeer e Holz-Mänttäri, fazendo por ajustar a retórica funcionalista a uma retórica menos revolucionária, é sinal de que chegara ao fim o momento de revolução, com a abordagem adentrando um estágio de ciência normal.The topic of this thesis is Functionalism, a theoretical approach to Translation Studies which was founded by Hans J. Vermeer, its main theorist. We take two hypotheses as our starting point: on the one hand, we assume that, despite the historiographic studies that rightly emphasize the theorys revolutionary character, it remained in continuity with important theoretical principles of preceding theories. On the other hand, it is our opinion that the theoretical foundation of Functional Translation Studies was established during the 1980s. The essays published in the context of Functional Theory afterward, therefore, would focus on the application of these theoretical principles to the practice of translation in many areas. With reference to the works of Reiss and Vermeer (1984), Holz-Mänttäri (1984) and Nord (1988), we examine the process of the theorys formation and its developments during the 1980s, first determining its main concepts, aiming, on the one hand, to identify departures and continuities between this and prior theories; and, on the other hand, to promote a critical review of functionalistic texts, guided by well defined parameters. Thereby, we adopted a methodology for this study consisting of four stages: first, we established the scope of this study (period and hypothesis), by defining the body of functional theoretical essays to be analysed. Then, we described the historical, institutional and intellectual context in which the emergence of the functional approach took place. In doing so, we were guided firstly by narratives and testimonies of that time, gathered from primary and secondary sources, and also by the analysis of theoretical texts which came prior to the publication of the components of our main corpus, which involved the identification of concepts valuable to this theoretical proposition according to specific parameters. Later on, we read the components of our main body of theoretical texts, and analysed them according to the parameters laid out in the previous stage, thus mapping out the development of the key concepts of Functional Theory. Lastly, we contrasted functionalist concepts with those of the theorys predecessors and, as a result, we identified departures and continuities between both approaches, making use of premises from scientific historiography in order to interpret the results. We found that, in regards to the theoretical field, the changes brought about with Functionalism were, on the one hand, consistent with the intellectual climate of Translation Studies at that time; yet, on the other hand, functional theories followed an observable trend of the further development of the pre-functionalist translation theories. Furthermore, we established that the functional approach provided an invaluable contribution in redefining the place of translation theories in Germany. The most significant change brought about by the functional theory, according to our conclusions, took place outside the theoretical field: the emergence of a new discipline dedicated to translation studies in West Germany. Concerning the development of Functional Theory itself, we came to the conclusion that it, in fact, established its foundations during the 1980s, as we predicted. The fact that Nord, a member of the so-called second generation of functionalists among scholars, made use of the theoretical framework laid out especially by Vermeer and Holz-Mänttäri, yet adjusted the functionalist rhetoric to a less revolutionary one, is a sign that the first revolutionary phase was over, and that the approach was entering a new normal science stage.
50
Cunniffe, Peña Kathleen. "Irlandés in the Americas: Irish Themes and Affinities in Contemporary Spanish American Narrative." Diss., Temple University Libraries, 2017. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/427339.
Анотація:
SpanishPh.D.
This dissertation examines Irish characters, themes and literary affinities in modern and contemporary Spanish American literature (1944-2011), focusing on novels and short stories by eight authors: El otro Joyce by Roberto Ferro, “Dublín al sur” by Isidoro Blaisten, El sueño del celta by Mario Vargas Llosa, selections from Ficciones by Jorge Luis Borges, Entre gringos y criollos and Quema su memoria by Eduardo Cormick, selected stories by Viviana O’Connell, La importancia de llamarse Daniel Santos by Luis Rafael Sánchez, and The Brief Wondrous Life of Oscar Wao by Junot Díaz. As the above list of authors suggests, Irish themes, characters, and intertextualities are present throughout the region’s Spanish-language literature, from some of its most celebrated writers like Borges and Vargas Llosa to contemporary authors such as O’Connell and Cormick. The prologue introduces the historical context of the Irish in Latin America as well as a theoretical framework to support the analyses in subsequent chapters. Each chapter is then dedicated to a different facet of the Irish-Latin American literary connection. Chapter 1 explores the translation of James Joyce into Spanish and the way in which contemporary Argentine writers dialogue with Joyce, problematizing the act of translation. Chapter 2 focuses on the ambiguous nature of Irish characters in Borges’s Ficciones and Vargas Llosa’s historical fiction El sueño del celta. Chapter 3 is dedicated to Latin American writers of direct Irish descendance and their expression of Irishness in the Americas. Finally, Chapter 4 analyzes echoes of Oscar Wilde in Caribbean Latino literature. The central question is how and why these Irish connections manifest themselves in contemporary Spanish American narrative. Ultimately, this dissertation argues that Irish characters and themes present a broader, more hybrid vision of Latin American identity, recognizing the multiplicity of languages, narratives, and selves.
Temple University--Theses