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1
Kingham, Rachel. "The broad-scale impacts of livestock grazing on saltmarsh carbon stocks." Thesis, Bangor University, 2013. https://research.bangor.ac.uk/portal/en/theses/the-broadscale-impacts-of-livestock-grazing-on-saltmarsh-carbon-stocks(a81ba92d-ac40-49c4-ba93-982bffb077d9).html.
Повний текст джерелаАнотація:
In light of recent upward trends in atmospheric carbon dioxide concentration, efforts have turned to methods of sequestering atmospheric carbon into other stable carbon sinks. Enhancing carbon sequestration by natural systems is an effective way of managing carbon sequestration. Due to high productivity and high sedimentation rates, salt marshes are extremely efficient at capturing and storing carbon, and provide the ideal environment for enhancing carbon sequestration rates through the management of livestock grazing, a common use of salt marshes. However, salt marshes are subject to a range of environmental stressors, which can vary considerably over a large spatial scale . It is therefore important to understand the implications of environmental and contextual variability on the use of livestock grazing as a carbon management tool. Twenty-two salt marshes were selected along the coasts of north Wales and north-west England to assess the impact of grazers on above and below-ground carbon stocks and processes in relation to broader contextual variables. The impacts of seasonality on carbon sequestration rates were also assessed by investigating a salt marsh carbon budget over the course of one year. Grazing was found to have a negative impact on several above-ground plant characteristics, but no impact on soil carbon stocks or overall carbon sequestration rates. Instead, below-ground processes were explained more by the broader environmental variables and seasonal changes. While this study does not discount the fact that grazing may affect soil carbon stocks on the small-scale, or after initial introduction, it shows that grazing impacts are insignificant relative to broader contextual factors on marshes with wellestablished grazing regimes.
2
De, Marco Margot. "BAG3 role in cardiomyocytes physiopathology." Doctoral thesis, Universita degli studi di Salerno, 2013. http://hdl.handle.net/10556/896.
Повний текст джерелаАнотація:
2010 - 2011The anti-apoptotic protein BAG3 is expressed at high levels in skeletal and cardiac muscle in vivo. Our group recently focused its interest on BAG3 role in myocardiocyte proliferation, survival and response to stressful stimuli. We found that BAG3 is upregulated during the differentiation of cardiomyoblasts. Our results prompted us to verify whether bag3 silencing could affect the differentiation state of cardiocytes and we found that bag3 silencing resulted in highly reducing the levels of myogenin. Furthermore, we analyzed BAG3 expression and localization following cell exposure to oxidative stress. In particular, we found that epinephrine in vitro increases BAG3 expression in adult human cardiomyocytes. We evaluated whether BAG3 could be involved in the Tako-tsubo cardiomyopathy (or stress cardiomyopathy) pathogenesis that is characterized by left ventricular dysfunction, with symptoms that can mimic an acute coronary syndrome. The absence of significant cardiovascular risk factors in patients affected by stress cardiomyopathy suggested that it might be associated with a possible genetic etiology. Therefore, we sequenced bag3 gene to check for polymorphisms in 29 patients and 1043 healthy donors. Three polymorphism were highly represented among patients (R71Q, C151R, P407L). We also showed for the first time that BAG3 protein is released from stressed cardiomyocytes and is found in chronic heart failure (HF) patients’ sera. Since anti-BAG3 antibodies are also present in patients’ sera, we developed an ELISA test for their specific detection. In serum samples from chronic HF patients, we found significantly higher values of anti-BAG3 antibodies respect to samples from healthy donors. The presence of anti-BAG3 antibodies in chronic HF patients’ sera and the availability of an ELISA test for their detection can contribute a novel tool for diagnostic and prognostic evaluations. [edited by author]
X n.s.
3
D'Auria, Raffaella. "BAG3 extracellulare: target cellulari e molecolari." Doctoral thesis, Universita degli studi di Salerno, 2016. http://hdl.handle.net/10556/2355.
Повний текст джерелаАнотація:
2014 - 2015Bcl-2-associated athanogene 3 (BAG3) belongs to the family of co-chaperone proteins that interact with the heat shock protein 70 (Hsp70) and is involved in a number of cellular processes including proliferation and apoptosis. BAG3 contains the BAG domain which interacts with the ATPase domain of Hsp70. BAG3 is also characterized by the presence of a WW domain, two conserved Ile-Pro-Val (IPV) motifs and a proline-rich (PXXP) repeat that mediate the binding to partners different from Hsp70. These diverse and multiple interactions underlie the ability of BAG3 to modulate major biological processes such as development, cytoskeleton organization and autophagy. In our laboratory, BAG3 has been recently found in a soluble or membrane-associated form and it has been detected in the serum obtained from patients with pancreatic cancer or heart failure. Moreover, we found that BAG3 is able to bind the cell surface of macrophages and activate the production of inflammatory associated components, such as Nitric Oxide (NO) and Interleukin (IL) -6. To identify novel interacting partners of BAG3 an affinity chromatography on nickel-charged resin was performed, in J774A.1 cells, using recombinant BAG3 (rBAG3) followed by mass spectrometry analysis of the rBAG3-containing complexes. Among these, Interferon- Inducible TransMembrane (IFITM) -2 and Neuropilin (NRP) -1 were the only transmembrane proteins and therefore represented good candidates as receptors for BAG3. Our results show that NRP-1 and IFITM-2 are both essential for the binding of rBAG3 to the cell surface of macrophages and its activation for IL-6 release. We then investigated if BAG3 binding activates some of the signaling pathways known to be involved in macrophage activation. In particular we focused on the phosphatidylinositol 3-kinase (PI3K) and on the p38 pathway that are both involved in Cox-2, iNOS and IL-6 induction in macrophages. We demonstrated that BAG3 signaling is mediated by the receptor complex we identified, since IFITM-2 and/or NRP-1 silencing abrogates BAG3- induced phosphorylation of AKT and p38. We than focus our study on human monocytes, rBAG3 binds the cell surface and induces the release of many pro-inflammatory cytokines and chemokines. Furthermore, we have shown that rBAG3 can bind T lymphocytes cells surface after lipopolysaccharide (LPS) stimulus. All together these findings suggest a role for extracellular BAG3 in immune response. [edited by Author]
XIV n.s.
4
Falco, Antonia. "Ruolo della proteina BAG3 nel microambiente tumorale." Doctoral thesis, Universita degli studi di Salerno, 2012. http://hdl.handle.net/10556/293.
Повний текст джерелаАнотація:
2009 - 2010Recenti studi hanno dimostrato che il microambiente tumorale subisce numerosi cambiamenti nel corso dello sviluppo del tumore e influenza l’evoluzione e la progressione del cancro. L'ambiente ipossico del tumore stimola l'angiogenesi che può direttamente promuovere la sopravvivenza delle cellule tumorali e la loro invasione. Anche l'infiltrato infiammatorio, associato a molti tumori solidi, è in grado di modulare il comportamento delle cellule tumorali, con effetti anti- e pro-tumorali. Un ruolo importante è svolto anche dai fibroblasti che circondano il tumore, i quali sono in grado di rilasciare fattori di crescita e citochine che stimolano l’ angiogenesi, la crescita del tumore e l'invasione. Tutti questi componenti sono potenziali bersagli per nuove strategie terapeutiche, e, infatti, diverse molecole che agiscono su tali target, sono attualmente utilizzate nelle sperimentazioni cliniche. Inoltre, dati recenti dimostrano che alcuni componenti del microambiente tumorale sono in grado di fornire importanti informazioni prognostiche e predittive. A tale scopo diventa sempre più evidente che, una caratterizzazione completa delle molecole e delle cellule coinvolte nel microambiente del tumore, è richiesta per una maggiore conoscenza della biologia del tumore. BAG3 è una proteina citoplasmatica che è stata recentemente caratterizzata per il suo ruolo centrale in diversi processi associati al tumore quali la sopravvivenza, la proliferazione, la migrazione e l'autofagia. Il ruolo di BAG3 nel microambiente associato al tumore non è stato caratterizzato finora. Pur non avendo un dominio transmembrana, i nostri studi hanno dimostrato che BAG3 può essere associata alla membrana plasmatica e rilasciata nel mezzo extracellulare di alcune cellule neoplastiche e in particolare cellule tumorali del pancreas. Abbiamo anche confermato la presenza di una forma extracellulare di BAG3 nel siero di pazienti affetti da adenocarcinoma pancreatico. Dopo il rilascio nello spazio extracellulare, BAG3 può legare la superficie di cellule adiacenti al tumore, e in particolare abbiamo cercato di stabilire se BAG3 può avere un effetto sui macrofagi che svolgono un ruolo importante nel microambiente infiammatoria associato al tumore. Abbiamo trovato che BAG3 è in grado di legare la superficie cellulare dei macrofagi e di indurre la produzione di componenti associati al processo infiammatorio. Abbiamo anche individuato un nuovo ruolo per BAG3 intracellulare nella regolazione della neo-angiogenesi. Infatti, abbiamo dimostrato che BAG3 è espressa nelle cellule endoteliali e che è in grado di regolare la proliferazione cellulare interagendo con ERK1/2 e la sua fosfatasi DUSP6. Come conseguenza, la riduzione di BAG3 determina una sostenuta fosforilazione di ERK1/2 e una ridotta crescita delle cellule endoteliali in vitro e in vivo. Questo, a sua volta induce una ridotta crescita del tumore in vivo in conseguenza alla ridotta angiogenesi. Complessivamente questi risultati permettono di individuare per la proteina BAG3 un ruolo nuovo nella regolazione dello sviluppo del tumore. [a cura dell'autore]
IX n.s.
5
Myers, Valerie. "The Role of BAG3 in the Failing Heart." Diss., Temple University Libraries, 2018. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/490584.
Повний текст джерелаАнотація:
Biomedical SciencesPh.D.
Heart disease has been the leading cause of death in the United States for more than 90 years. The leading cause of death in individuals aged 65 and older has remained diseases of the heart from 1950 to the current time. According to the CDC, once diagnosed with heart disease, individuals have an approximately 50% chance of dying within 5 years, regardless of race. Mortality related to heart disease increased dramatically from the start of the 1900s to 1921, but subsequently experienced a steady decline from the mid-1960’s to 2000. However, when the decrease in heart disease is examined at the level of race it is clear that the decrease is not equally shared. While the leading cause of death among both Caucasian American men and women and African American men and women remains heart disease, the decrease in incidence of coronary heart disease among African American men was only half of the decrease in incidence among Caucasian American men. Genetic variants in BAG3 (Bcl-2 associated athanogene 3), a highly evolutionarily conserved gene that has recently emerged as a major dilated cardiomyopathy locus, are prevalent in isolated populations. This led us to hypothesize that variants in BAG3 might contribute to the increased prevalence of IDC in individuals of African ancestry. Expressed predominantly in the heart, the skeletal muscle and in many cancers, BAG3 has pleotropic effects in the heart. It inhibits apoptosis by binding to Bcl-2, facilitates protein quality control by binding to both large and small heat shock proteins, mediates adrenergic responsiveness by coupling the β-adrenergic receptor and the L-type Ca2+ channel, and maintains the integrity of the sarcomere by anchoring actin filaments to the Z disc. However, a paucity of subjects of African ancestry have been included in cohorts of probands with familial dilated cardiomyopathy whose exomes or genomes have been sequenced. Based on our previous observations and reports from other groups we postulated: 1) that mice with haplo-insufficiency of BAG3 will re-capitulate disease seen in humans and serve as a model for studying the pathogenesis of BAG3. 2) The prevalence or identification of specific BAG3 variants will differ by race and/or ethnicity. 3) SNVs of BAG3 may contribute to disease progression and thereby be pathogenic. Our study points out that we cannot understand population-based differences without enhancing the diversity of populations included in genomic studies. Similarly, in the era of big data, efforts must be undertaken to assess the genetic profile of both probands and their family members as without the ability to measure segregation, penetrance and plasticity we can only ascribe associations to functional genetic variants.
Temple University--Theses
6
Engelmann, Ines. "Änderung der Stoffwechselaktivität von BaF3-Zellen durch die Expression von BCR/ABL." Doctoral thesis, Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-163535.
Повний текст джерелаАнотація:
Die vorliegende Arbeit handelt von einer in vitro Untersuchung der Stoffwechselveränderun-gen durch die Expression von BCR/ABL bei BaF3-Zellen, einer murinen, IL-3-abhängigen B-Zelllinie. Die Zellen wurden in nährstoffreichem Standard- und in durch Titrationen ermittel-tem nährstoffarmem Minimalmedium auf unterschiedliche Stoffwechselaktivität in Abhän-gigkeit von BCR/ABL-Expression untersucht sowie auf die zusätzliche Beeinflussbarkeit durch IL-3. Danach wurden vergleichend zwischen den 2 Zelllinien (BaF3 und BaF3-BCR/ABL) im Minimalmedium und im Standardmedium Metabolite wie Glukose, Laktat und Aminosäuren bestimmt, wobei BaF3-BCR/ABL sowohl mit als auch ohne IL-3 kultiviert wur-de. Um den Einfluss von Nährstoffrestriktion auf die Therapie zu zeigen, wurden anschlie-ßend vergleichend in den beiden Medien die Tyrosinkinaseinhibitoren Imatinib und Nilotinib titriert.
Die Ergebnisse zeigen, dass BaF3-BCR/ABL einen Wachstumsvorteil im Minimalmedium hat, welcher im Standardmedium nicht vorliegt. Während die bereits bekannte Verstärkung der Glukoseaufnahme durch BCR/ABL im Standardmedium bestätigt wurde, konnte im Minimal-medium Gegenteiliges gezeigt werden. Zudem wurde ein Unterschied im Aminosäurestoff-wechsel zwischen BaF3 + IL-3 und BaF3-BCR/ABL + IL-3 im Minimalmedium deutlich. Die therapeutische Relevanz des gezeigten Einflusses der Nährstoffrestriktion konnte anschlie-ßend in der Tyrosinkinaseinhibitortitration dargestellt werden, da die Medikamente in Abhän-gigkeit vom Medium unterschiedliche Wirkungen zeigen.
Insgesamt bieten die Ergebnisse einen metabolischen Erklärungsansatz für das Überleben von Tumorstammzellen in nährstoffarmen Arealen des Knochenmarks unter Therapie und Raum für neue Therapieansätze.
7
Korniat, Agathe. "Etude fonctionnelle des variants moléculaires du gène BAG3 associés à la cardiomyopathie dilatée humaine." Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066716.
Повний текст джерелаАнотація:
Le gène BAG3 a été identifié comme étant un nouveau gène responsable de cardiomyopathie dilatée (CMD), première cause d'insuffisance cardiaque (IC). La protéine BAG3 est une co-chaperonne qui participe au contrôle de l'homéostasie protéique via son rôle dans l'autophagie, protégeant ainsi les cellules contre la protéotoxicité induite par les protéines dégradées ou mal repliées. L'hypothèse qu'une inactivation de la voie autophagique contrôlée par BAG3 induirait une protéotoxicité cardiomyocytaire à l'origine de la CMD apparait particulièrement attractive et constitue l'hypothèse centrale de ce travail. Nos résultats indiquent que les mutations de BAG3 abolissent l'interaction avec la chaperonne HSP70, une protéine centrale du contrôle qualité des protéines. Nous avons observé une cytotoxicité des mutants BAG3, une altération de la fonction chaperonne HSP70-dépendante et une absence de réponse autophagique en condition de stress (jeun, choc thermique, expression d'une protéine pro-agrégante). In vivo (modèle poisson-zèbre) l'extinction de l'expression de BAG3 ou la surexpression des mutants conduisent à l'apparition d'un phénotype d'insuffisance cardiaque (¿dème péricardique) chez les embryons injectés. Par édition génomique, nous développons également un modèle de cardiomyocytes dérivés de cellules iPS porteurs ou non de la mutation afin d'explorer plus en avant la fonction contractile de ces cellules. Nos résultats confirment donc le rôle de BAG3 dans la CMD et indiquent que l'altération de la fonction protéostasique serait à l'origine de la maladie. Cette nouvelle voie physiopathologique dans la CMD pourrait s'avérer être, plus généralement, une voie centrale dans l'ICThe BAG3 gene was identified as a novel gene responsible for dilated cardiomyopathy (DCM), a major cause of heart failure (HF). The BAG3 protein is a co-chaperone that participates in the control of protein homeostasis via its role in autophagy, protecting cells against the proteotoxicity induced by degraded or misfolded proteins. The hypothesis that inactivation of the autophagic pathway controlled by BAG3 would induce cardiomyocyte proteotoxicity behind the CMD appears particularly attractive and is the central hypothesis of this work. Our results indicate that BAG3 mutations abolish the interaction with the chaperone HSP70, a central actor of the protein quality control. We observed cytotoxicity of BAG3 mutants, an impaired HSP70-dependent chaperone function and absence of autophagic response under stress conditions (starvation, heat shock, expression of a pro-aggregating protein). In vivo (zebrafish model) the extinction of BAG3 expression or mutants overexpression lead to the occurrence of a heart failure phenotype (pericardial edema) in injected embryos. Through genomic edition, we also develop a model of iPS-derived cardiomyocytes carrying or not the mutation in order to further explore the contractile function of these cells. Our results confirm the role of BAG3 in DCM and indicate that the alteration of the proteostasis function is the cause of the disease. This new pathophysiological pathway in DCM may prove to be more generally, a central line in the IC
8
Manchen, Steven T. "Characterization and subcellular localization of the human BAT3 protein." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/MQ62248.pdf.
Повний текст джерела
9
Isaksen, Katja. "Consumer culture, branding and British adolescents : a vicious cycle? : a comparison between high and low-income adolescents." Thesis, University of Manchester, 2010. https://www.research.manchester.ac.uk/portal/en/theses/consumer-culture-branding-and-british-adolescents-a-vicious-cycle-a-comparison-between-high-and-lowincome-adolescents(94a6b8e2-c339-447b-ba93-110b4dc22755).html.
Повний текст джерелаАнотація:
The growth of consumerism has meant that individuals are increasingly using possessions as a means of developing their personal identities and forming social connections. Specifically, the consumer culture has seen the increase of brands and branded goods as marketers attach emotional attributes to them. Thus, brands have become communicative symbols which display, amongst other things, the owner's values, beliefs and social status. As a result, consumers are attempting to form their identities, social connections and self-worth by consuming (often branded) possessions which they feel are representative of their self or ideal self and will increase their chances of social acceptance. However, psychological studies in consumer behaviour suggest that the increasing propensity to seek inner happiness and social bonds through external means (consumption), has led consumers to be less satisfied with their lives and hence decreases psychological well-being; the focus on external rewards has reduced the importance that individuals place on personal development and intrapsychic developments.This study investigates the relationship between the consumption culture, branding and British adolescents, with a comparison between high and low-income teenagers. Adolescents are particularly prone to assuming consumer orientations (and hence the consequences thereof) due to their stage in identity development, their need for social acceptance and the fact that they are a very profitable market segment. As a result, teenagers are encouraged to turn to consumption for developing their personal and social identities, as opposed to more traditional means such as personal skill development. Although limited studies have investigated adolescent consumption, little attention has been paid to low-income adolescents who are prone to reduced self-worth but have a restricted consumption scope and thus cannot consume their self-worth in the same 'normal' ways as their peers. In light of previous studies, it was necessary to first develop a new measure of self-esteem which included the vital role of possessions (and specifically brands) in feelings of self-worth amongst adolescents. The scale-development process revealed the functional importance of self-esteem as a marker of social inclusion and hence shed light on the reason for the importance that adolescents place on specific brands; they are a promise of fitting-in. A valid and reliable 23-item, self-report measure of self-esteem is presented. Subsequent to developing the new scale, the research provided empirical support for a model of the psychological characteristics of adolescent consumption (including self-esteem). The result is a 'Vicious Cycle' model of consumption which suggests that there is a relationship between the factors which contribute to a consumer orientation and the likely effects of having such an orientation. For example, the model suggests that reduced self-esteem may contribute to consumerism and a consumption orientation may contribute to a reduction in self-esteem. Furthermore, the comparison between high and low-income teenagers showed that low-income teenagers were significantly more materialistic than their high-income counterparts thus supporting the suggestion that low-income teenagers are more prone to consumerism than their high-income counterparts. With reference to the detailed links presented in the Vicious Cycle model, the author proceeds to explore the efficacy of extant consumerist-curbing strategies and highlight the need for more effective methods if we wish future generations to develop in to more than simply shoppers.
10
Peña, Oyarzún Daniel. "Rol de BAG3 en la regulación del metabolismo muscular esquelético." Tesis, Universidad de Chile, 2014. http://repositorio.uchile.cl/handle/2250/134613.
Повний текст джерелаАнотація:
Memoria para optar el título de BioquímicoAutor no autoriza el acceso a texto completo de su documento hasta diciembre de 2015
La proteína co-chaperona Bag3 es un factor clave en el control de la autofagia selectiva, un proceso de degradación de proteínas y organelos activado en respuesta a distintos estresores, en tejidos altamente diferenciados, como el músculo esquelético. Este último tejido transforma la energía química del ATP en energía mecánica para la contracción, por lo que el control del metabolismo de la glucosa resulta fundamental para mantener su función fisiológica. En este sentido, insulina, a través de sus efectores intracelulares Akt y mTORC1, promueve el ingreso y metabolismo de la glucosa. No obstante, en condiciones de estrés nutricional la proteína AMPK activa la autofagia para aumentar el metabolismo celular por degradación de diversas macromoléculas. Prueba de esta relación funcional entre metabolismo y autofagia es que la inhibición de la autofagia lleva a resistencia a la insulina en células musculares esqueléticas. Por otro lado, existe evidencia que los ratones knock-out para Bag3 presentan una disminución en los niveles de glucosa e insulina circulantes, y mueren a las 3 semanas de nacimiento con deterioro muscular progresivo. Sin embargo, hasta hoy se desconoce si Bag3 regula el metabolismo energético de la célula, y si las vías que controlan ese metabolismo se relacionan con la autofagia. En vista de estos antecedentes, se investigó si Bag3 altera la señalización de la vía Akt-AMPK-mTORC1, produciendo efectos metabólicos y de autofagia en miotubos L6 (línea celular: músculo esquelético de rata). A través de ensayos de captura de 3H-2-desoxiglucosa, consumo de oxígeno y detección densitométrica de GLUT4-myc en superficie, se determinó que las células con niveles reducidos de Bag3 (RNA interferente) y sin insulina en el sistema, incorporaron mayor cantidad de glucosa por un incremento de transportadores Glut-4 en la membrana celular junto con una mayor capacidad oxidativa mitocondrial. Lo anterior es debido a un aumento de la activación basal de Akt, evidenciado por Western blot contra Fosfo-Ser-473. Además, estas células presentaron una menor capacidad de activar la autofagia debido a un procesamiento disminuido de LC3, además de una menor activación de AMPK (Fosfo-Thr-172) y una sobre-activación de mTORC1 (Fosfo-Ser-2448). Finalmente, en presencia de insulina (100 nM, 20 min), las células con niveles reducidos de Bag3 presentaron una incorporación deficiente de glucosa para la cantidad de transportador Glut-4 exportado a la membrana, y una menor capacidad oxidativa mitocondrial. En estas condiciones, Akt se activó de forma normal ante insulina, observándose sin embargo que AMPK y mTORC1 se activó e inactivó, respectivamente; comportamiento inverso respecto a lo normal. Con estos datos, se propone a Bag3 como un novedoso regulador del metabolismo y la autofagia muscular esquelética
The co-chaperone protein Bag3 is a key factor for the control of selective autophagy, a degradation process of proteins and organelles activated in response to stress, in highly differentiated tissues, as the skeletal muscle. The role of the latter is to transform the chemical energy from ATP into mechanical energy for contraction, thus the metabolism control of glucose is important to keep its biological function. In that way, the hormone insulin, by its intracellular effectors Akt and mTORC1, promotes the uptake and metabolism of glucose. However, in nutritional stress conditions the AMPK protein activate autophagy in order to increase cellular metabolism by macromolecular degradation. Proof of this functional relationship between metabolism and autophagy is that autophagy abrogation leads to insulin resistance in muscle cells. On the other hand, there is evidence that shows that Bag3 Knock-out mice present diminished glucose and insulin in blood, and die after 3 weeks from birth with progressive muscle wasting. However, it is not known yet whether Bag3 regulates energy metabolism in the cell, nor whether the pathways that control that metabolism are related with Bag3 mediated autophagy. With this in mind, we decided to determine if Bag3 was able to alter the Akt-AMPK-mTORC1 signaling pathway, leading to metabolic and autophagy effects, in L6 myotubes (cell line: skeletal muscle from rat). By 3H-2-desoxyglucose uptake, oxygen consumption and GLUT4-myc surface detection assays, we were able to determine that cells with reduced levels of Bag3 (interference RNA), and without insulin in the system, had increased glucose uptake because of an augmented Glut-4 translocation to the cell membrane, along with an enhanced mitochondrial oxidative capacity. This is explained by an increased Akt basal activation, evidenced by Phospho-Ser-473 western blot. Furthermore, these cells showed a diminished capacity to produce autophagy, because of a decreased LC3 processing, along with a diminished activation of AMPK (Phospho-Thr-172) and an over activation of mTORC1 (Phospho-Ser-2448). Finally, in the presence of insulin (100 nM, 20 minutes), cells with diminished levels of Bag3 showed a deficient glucose uptake for the amount of Glut-4 transporter exported to cell membrane, and a decreased mitochondrial oxidative capacity. Under these conditions, Akt protein increased its activation, as normal, but AMPK was activated and mTORC1 was inactivated, an inverted behavior with respect to normal metabolism. With these data, we propose Bag3 as a novel regulator of metabolism and autophagy in muscle
11
Schröter, Thomas. "Charakterisierung der ba3 Chinoloxidase aus Paracoccus denitrificans." [S.l. : s.n.], 2000. http://deposit.ddb.de/cgi-bin/dokserv?idn=961246944.
Повний текст джерела
12
Sebti, Salwa. "Rôle de la protéine BAT3 dans la signalisation cellulaire de l'autophagie." Thesis, Montpellier 1, 2013. http://www.theses.fr/2013MON1T028.
Повний текст джерелаАнотація:
L'autophagie est un processus d'autodigestion qui se produit dans toutes les cellules eucaryotes et conduit à la dégradation d'éléments du cytoplasme (organites, macromolécules) par le lysosome. Ce mécanisme, qui se produit de manière basale, permet le renouvellement du contenu cytoplasmique mais également la survie cellulaire lorsqu'il est induit par différents stress (carence nutritionnelle, hypoxie…). L'autophagie est alors impliquée dans diverses pathologies comme les maladies neurodégénératives et le cancer car sa dérégulation peut grandement perturber l'homéostasie cellulaire. Le but de ma thèse est de déterminer le rôle de la protéine nucléaire et cytoplasmique BAT3 dans l'autophagie et d'étudier son mécanisme de régulation. Cette protéine de 150 kDa, également appelée BAG6 ou Scythe, est composée de nombreux domaines protéiques (UBL, Prolin-rich, NLS, BAG) qui lui permettent d'interagir avec de multiples partenaires. Sa fonction majeure réside dans le contrôle qualité du cytoplasme mais BAT3 est aussi impliquée dans l'immunité ou l'apoptose. Ce travail identifie la protéine BAT3 comme essentiel pour l'autophagie basale et induite. Nous montrons que son mécanisme d'action passe par la régulation de la localisation de l'acétyltransférase p300 et l'acétylation de ces substrats : p53 et une protéine de la machinerie de l'autophagie : ATG7. En effet, BAT3 (i) limite la présence de p300 dans le cytosol en (ii) maintenant un faible et régulable niveau d'acétylation d'ATG7 et (iii) permet l'acétylation de p53 dans le noyau au cours de la carence nutritionnelle, événement indispensable à l'induction de l'autophagieAutophagy, literally meaning self-eating, is a highly evolutionary conserved process in eukaryotes in which parts of the cytoplasm (organelles, macromolecules) are degraded by lysosomes. Basal autophagy is a quality control mechanism allowing the renewal of the cytoplasm but autophagy is also induced by cellular stress (starvation, hypoxia…) to improve cell survival. Autophagy has been implicated in several physiopathologies such as cancer or neurodegenerative diseases. Deregulations of autophagy may profoundly affect homeostasis.The purpose of my thesis is to explore the role of the nucleo-cytoplasmic shuttling protein BAT3 in autophagy and the mechanism of BAT3-dependent autophagy.Also known as BAG6 or Scythe, this 150 kDa protein is composed of various domain (UBL, Prolin-Rich, NLS, BAG) by which BAT3 interacts with multiple partners. The major of role BAT3 seems to be the protein quality control but BAT3 is also implicated in immunity and apoptosis. Our work demonstrates that the protein BAT3 is essential for basal and starvation-induced autophagy. We show that BAT3 regulation of autophagy is mediated by the modulation of p300 acetyltransferase intracellular localization and acetylation of two subtrates: p53 and the autophagy-related protein ATG7. Indeed, Bat3 allows: (i) the limitation of p300 into cytosol resulting in (ii) the maintenance of a low level of ATG7 acetylation and (iii) the increase of the starvation-induced p53 autophagy leading to the induction of autophagy
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Wördehoff, Judith Friederike [Verfasser]. "Regulation des Cochaperons BAG3 durch Phosphorylierung und Dephosphorylierung / Judith Friederike Wördehoff." Bonn : Universitäts- und Landesbibliothek Bonn, 2020. http://d-nb.info/1225793106/34.
Повний текст джерела
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Rodríguez, Villarroel Andrea Elizabeth. "Estudio de los mecanismos de regulación de la autofagia por BAG3." Tesis, Universidad de Chile, 2015. http://repositorio.uchile.cl/handle/2250/136770.
Повний текст джерелаАнотація:
Doctora en BioquímicaAutor no autoriza el acceso a texto completo de su documento
La macroautofagia (autofagia) es una vía de reciclaje caracterizada por la formación de vesículas de doble membrana denominadas autofagosomas que secuestran estructuras citoplasmáticas marcadas para su degradación. La formación del autofagosoma requiere la actividad de proteínas relacionadas con la autofagia (Atg) que median algunas de las cuatro etapas principales de la autofagia: iniciación, nucleación, expansión y cierre. La proteína MAP1LC3B (referida sólo como LC3) es una de las Atg más importantes ya que ayuda a elongar la membrana y reclutar al cargo. Su forma lipidada (LC3-II) se encuentra en ambas superficies del autofagosoma (externa e interna) donde se degrada con su cargo cuando el autofagosoma se fusiona con el lisosoma. La autofagia se regula principalmente por modificaciones post-traduccionales y modificaciones lipídicas de las proteínas Atg. Además, en algunos escenarios, la inducción de la autofagia se acompaña de aumentos en los niveles de mRNA de ciertos genes asociados a la autofagia, como LC3, ATG5 o ATG12. Sin embargo, prácticamente se desconocen los mecanismos que controlan la traducción de las proteínas Atg. Estudios recientes con la cochaperona Bag3 han mostrado controlar la degradación selectiva de proteínas mal plegadas a través de autofagia, incluyendo huntingtina con expansiones de poli-Q y SOD1 mutante. El mecanismo involucra la asociación de Bag3 a dineína y microtúbulos para el transporte de proteínas mal plegadas a los agresomas, facilitando su eliminación por la autofagia. Además del papel en el plegamiento y degradación de proteínas, recientemente se ha descrito que la chaperona Hsp70 regula la traducción de proteínas. Los últimos trabajos muestran que Bag3 es una proteína que induce la lipidación LC3 pero no hay antecedentes sobre el mecanismo utilizado. En esta tesis se estudió cómo Bag3 controla la autofagia en células HeLa. Para este fin Bag3 se silenció con un siRNA ó shRNA, o se expresó con plasmidios. Los niveles de mRNA, proteínas y estado de fosforilación de varias proteínas Atg, particularmente de LC3I y LC3II, mTOR y AMPK. Además, se determinó si Bag3 es necesaria para la inducción de la autofagia en condiciones de estrés como la privación de nutrientes e inhibición del proteasoma. Los resultados mostraron que Bag3 mantiene los niveles basales de la proteína LC3 en células HeLa, controlando la traducción de su mRNA. El efecto de Bag3 es aparentemente específico para LC3 dado que otras proteínas Atg no fueron afectadas. De hecho, la conversión de LC3I a LC3II por inductores autofagia, como la privación de nutrientes y la inhibición del proteosoma, no se observó afectada. Se concluye que Bag3 regula niveles proteicos totales de LC3, manteniendo su traducción
Macroautophagy (autophagy) is a recycling pathway characterized by the formation of double-membrane vesicles called autophagosomes, which sequester cytoplasmic structures targeted for destruction. Autophagosome formation requires the activity of autophagy-related proteins (Atg), which are shown to participate in the four major steps: initiation, nucleation, expansion and closure. MAP1LC3B (referred only as LC3) is most important Atg protein, aiding to elongate the membrane and recruit the cargo. The lipidated form of LC3 (LC3-II) lies on both surfaces of autophagosome (external and internal) where it degrades with its cargo when the autophagosome fuses with the lysosome. Autophagy is mainly regulated by post-translational modifications and lipid modifications of Atg proteins. Moreover, in some scenarios, the induction of autophagy is accompanied by an increase in the mRNA levels of certain genes associated to autophagy, such as LC3, ATG5 or ATG12. However, less work has done on the study of mechanisms controlling translation of the Atg proteins. In recent studies, Bag3 has shown to control the selective degradation of misfolded proteins by autophagy, including polyQ-expanded huntingtin and mutant SOD1. The mechanism involves Bag3 association to dynein and microtubules to transport misfolded proteins to the aggresomes and facilitates their clearance by autophagy. Besides the role in folding and degradation of proteins, recently has shown a role of the Hsp70 chaperone in the regulation of the translation of proteins. The last reports show that Bag3 is a protein that induces LC3 lipidation but little is known about the mechanisms used. In the present work, we study how Bag3 controls the autophagy pathway in HeLa cells. Bag3 was knockdown with siRNA or shRNA, or expressed with plasmids. mRNA levels, protein levels and phosphorylation status of several Atg, particularly of LC3I and LC3II, mTOR and AMPK were evaluated. In addition, it was determined whether Bag3 is required for the induction of autophagy in stress conditions such as nutrient deprivation and inhibition of the proteasome. Our results showed that Bag3 maintains the basal protein levels of LC3 in HeLa cells, controlling the translation of its mRNA. This effect was apparently specific for LC3 because the levels of other Atg proteins remained unchanged. The LC3I conversion to LC3II did not alter by autophagy inductors such as nutrient deprivation or proteasome inhibition. We concluded that Bag3 maintains the basal protein levels of LC3, controlling the translation of its mRNA
Conicyt Fondecyt Fondap Proyecto Anillo ACT 1111
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Guerriero, Luana. "Studio del ruolo della proteina anti-apoptotica BAG3 nel melanoma umano." Doctoral thesis, Universita degli studi di Salerno, 2016. http://hdl.handle.net/10556/2350.
Повний текст джерелаАнотація:
2014 - 2015BAG3 protein, a member of BAG family of co-chaperones, has a pro-survival role in several tumor types. BAG3 anti-apoptotic properties rely on its characteristic to bind several intracellular partners, thereby modulating crucial events such as apoptosis, differentiation, cell motility and autophagy. In human melanomas, BAG3 positivity is correlated with the aggressiveness of the tumor cells and can sustain IKK-γ levels, allowing a sustained activation of NF-B. Furthermore, BAG3 is able to modulate BRAFV600E levels and activity in thyroid carcinomas. BRAFV600E mutation is the most frequent detected in malignant melanomas and is targeted by Vemurafenib, a molecule used for the treatment of advanced melanoma. However a subset of patients resulted not sensitive or acquired resistance to this molecule. Here we confirmed that BAG3 expression is significantly enhanced in metastasis in respect to primary tumors, than we demonstrated that BAG3 protein expression was significantly enhanced in metastasis of patients carring BRAFV600E mutation. Furthermore we found a significant correlation between BAG3 positivity and patients’ overall survival (OS), disease-specific survival (DSS) and disease-free survival (DFS) from surgery in patients with melanoma metastatic lymph nodes. Moreover here we show that BAG3 down-modulation interferes with BRAF levels in melanoma cells and sensitizes them to Vemurafenib treatment. Furthermore, in an in vitro model of acquired resistance to Vemurafenib, we demonstrated that the down-modulation of BAG3 protein can resensitize this cells to BRAFV600E specific inhibition interfering with BRAF pathway, causing reduction of ERK and its targets phosphorylation. Further studies will be focused in demonstrating our hypothesis that the molecular interactions between BAG3 and mutated BRAF can represent a target for novel multi-drugs treatment design and that BAG3 expression could contribute to prognosis and patient stratification for specific therapeutic approaches. [edited by Author]
XIV n.s.
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Korniat, Agathe. "Étude fonctionnelle des variants moléculaires du gène BAG3 associés à la cardiomyopathie dilatée humaine." Electronic Thesis or Diss., Paris 6, 2015. http://www.theses.fr/2015PA066716.
Повний текст джерелаАнотація:
Le gène BAG3 a été identifié comme étant un nouveau gène responsable de cardiomyopathie dilatée (CMD), première cause d'insuffisance cardiaque (IC). La protéine BAG3 est une co-chaperonne qui participe au contrôle de l'homéostasie protéique via son rôle dans l'autophagie, protégeant ainsi les cellules contre la protéotoxicité induite par les protéines dégradées ou mal repliées. L'hypothèse qu'une inactivation de la voie autophagique contrôlée par BAG3 induirait une protéotoxicité cardiomyocytaire à l'origine de la CMD apparait particulièrement attractive et constitue l'hypothèse centrale de ce travail. Nos résultats indiquent que les mutations de BAG3 abolissent l'interaction avec la chaperonne HSP70, une protéine centrale du contrôle qualité des protéines. Nous avons observé une cytotoxicité des mutants BAG3, une altération de la fonction chaperonne HSP70-dépendante et une absence de réponse autophagique en condition de stress (jeun, choc thermique, expression d'une protéine pro-agrégante). In vivo (modèle poisson-zèbre) l'extinction de l'expression de BAG3 ou la surexpression des mutants conduisent à l'apparition d'un phénotype d'insuffisance cardiaque (¿dème péricardique) chez les embryons injectés. Par édition génomique, nous développons également un modèle de cardiomyocytes dérivés de cellules iPS porteurs ou non de la mutation afin d'explorer plus en avant la fonction contractile de ces cellules. Nos résultats confirment donc le rôle de BAG3 dans la CMD et indiquent que l'altération de la fonction protéostasique serait à l'origine de la maladie. Cette nouvelle voie physiopathologique dans la CMD pourrait s'avérer être, plus généralement, une voie centrale dans l'ICThe BAG3 gene was identified as a novel gene responsible for dilated cardiomyopathy (DCM), a major cause of heart failure (HF). The BAG3 protein is a co-chaperone that participates in the control of protein homeostasis via its role in autophagy, protecting cells against the proteotoxicity induced by degraded or misfolded proteins. The hypothesis that inactivation of the autophagic pathway controlled by BAG3 would induce cardiomyocyte proteotoxicity behind the CMD appears particularly attractive and is the central hypothesis of this work. Our results indicate that BAG3 mutations abolish the interaction with the chaperone HSP70, a central actor of the protein quality control. We observed cytotoxicity of BAG3 mutants, an impaired HSP70-dependent chaperone function and absence of autophagic response under stress conditions (starvation, heat shock, expression of a pro-aggregating protein). In vivo (zebrafish model) the extinction of BAG3 expression or mutants overexpression lead to the occurrence of a heart failure phenotype (pericardial edema) in injected embryos. Through genomic edition, we also develop a model of iPS-derived cardiomyocytes carrying or not the mutation in order to further explore the contractile function of these cells. Our results confirm the role of BAG3 in DCM and indicate that the alteration of the proteostasis function is the cause of the disease. This new pathophysiological pathway in DCM may prove to be more generally, a central line in the IC
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Zeidler, Claudia [Verfasser]. "Functional Characterization of Interaction Partners of the Co-Chaperone BAG3 / Claudia Zeidler." Bonn : Universitäts- und Landesbibliothek Bonn, 2018. http://d-nb.info/116059452X/34.
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Schwarz, Mario [Verfasser]. "Untersuchung autophagischer Prozesse mit Fokus auf BAG3 und seine Interaktoren. / Mario Schwarz." Mainz : Universitätsbibliothek der Johannes Gutenberg-Universität Mainz, 2021. http://d-nb.info/1225796059/34.
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Engelmann, Ines [Verfasser], Thoralf [Akademischer Betreuer] Lange, and Michael [Akademischer Betreuer] Cross. "Änderung der Stoffwechselaktivität von BaF3-Zellen durch die Expression von BCR/ABL : Änderung der Stoffwechselaktivität von BaF3-Zellen durch die Expression von BCR/ABL / Ines Engelmann ; Thoralf Lange, Michael Cross." Leipzig : Universitätsbibliothek Leipzig, 2015. http://d-nb.info/1239564937/34.
Повний текст джерела
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Russo, Alessandra. "Design, synthesis and biological activity of new target selective antitumoral agents." Doctoral thesis, Universita degli studi di Salerno, 2018. http://hdl.handle.net/10556/3037.
Повний текст джерелаАнотація:
2016 - 2017Cancer development is a complex pathological process that exploits a variety of biological actors. The identification of new molecular entities able to interfere with new biological targets, involved in tumorigenesis, is strongly needed, both for the development of new promising drug candidates, and, as chemical probes useful to further investigate less understood biological aspects. Two main targets, involved at different levels, in cancer development, have been thoroughly investigated: Macrodomain proteins, MacroD1 and MacroD2, and the Bcl-2 associated athanogene 3, BAG3 protein... [edited by Author]
XXX ciclo
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Lanoue, Vanessa. "Rôle du récepteur BAI3 dans le développement neuronal - Études in vitro et in vivo -." Phd thesis, Université Pierre et Marie Curie - Paris VI, 2012. http://tel.archives-ouvertes.fr/tel-00865692.
Повний текст джерелаАнотація:
La dendritogenèse et la spinogenèse sont des étapes clés du développement neuronal. Elles impliquent de nombreuses protéines jouant un rôle essentiel dans la réorganisation du cytosquelette d'actine via les RhoGTPases. Des défauts dans ces processus peuvent mener à des maladies neurodéveloppementales comme l'autisme ou la schizophrénie. Les récepteurs BAI appartiennent à la famille des RCPG d'Adhésion et ont été identifiés dans des préparations biochimiques de densités postsynaptiques. BAI1 module la RhoGTPase Rac1 via son interaction avec la protéine ELMO1. De plus, les protéines sécrétées C1q-like ont récemment été identifiées comme ligands du récepteur BAI3 in vitro et cette interaction régulerait la synaptogenèse. Nous avons émis l'hypothèse que le récepteur BAI3 pourrait réguler le développement neuronal, en particulier la dendritogenèse et la spinogenèse, en interagissant avec ELMO1. Nos travaux ont montré que BAI3 est localisé dans les dendrites, et chez les neurones matures dans les épines dendritiques. Des études morphométriques nous ont permis de montrer son rôle dans la croissance et la complexification de l'arbre dendritique des neurones in vitro. Nos données in vivo sont en accord avec un rôle du récepteur BAI3 dans la morphogenèse des cellules de Purkinje du cervelet et la mise en place de leur innervation excitatrice. Le rôle de BAI3 dans la morphogenèse dendritique semble dépendre en partie de son interaction avec ELMO1. Par ailleurs, BAI3 module l'étalement cellulaire, suggérant son implication dans la régulation des RhoGTPases. L'ensemble de nos résultats met en lumière un nouveau rôle des récepteurs BAI comme régulateurs de la dendritogenèse et de la formation des synapses, en partie via la voie de signalisation ELMO1/Rac1. Nos résultats identifient les récepteurs BAI comme de nouveaux acteurs de la morphogenèse neuronale et, au vu du lien génétique existant entre BAI3 et certains symptômes de la schizophrénie, offrent de nouvelles perspectives dans l'étude des maladies neurodéveloppementales.
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Knezevic, Tijana. "TRANSLATIONAL APPROACH TO INVESTIGATE INVOLVEMENT OF BAG3 IN PROTEIN QUALITY CONTROL AND HEART FAILURE." Diss., Temple University Libraries, 2016. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/374885.
Повний текст джерелаАнотація:
BiologyPh.D.
Heart failure continues to be a global problem, even with all the drugs currently available, leading to a need of new therapeutics to decrease incidence of heart failure. Heart failure is the inability of the heart muscle to pump sufficient blood and oxygen to the rest of the body. One of the causes of heart failure is cardiomyopathy, where cardiac muscle becomes larger and weaker. Genetic mutations in genes encoding sarcomeric, structural and cytoskeletal proteins were found in families that developed cardiomyopathy. Our laboratory has indentified a family with heart failure in whom a novel mutation in the BCL2-associated athanogene 3 (BAG3) has been characterized. Among other cardiomyopathy-causing BAG3 mutations reported in various laboratories. Several BAG3 mutations in humans are known to cause familial dilated cardiomyopathy, myofibrilar myopathy, and giant axonal neuropathy. BAG3 is a stress induced co-chaperone protein that interacts with several heat shock proteins and acts as an important regulator of protein quality control. Expression of BAG3 is high in cardiac, skeletal and smooth muscle. BAG3 is localized at the z-disk of cardiomyocytes and was shown to be essential in keeping a normal assembly of z-disk proteins during mechanical stretch. Interaction of BAG3 with actin capping protein CapZbeta1 prevents degradation of CapZbeta1 via proteasome system and maintains the integrity of the z-disk. BAG3 was shown to promote clearance of misfolded proteins, such as filamin C, via autophagy. Not only that BAG3 is able to promote clearance of dysfunctional filamin C, but it was found to enhance synthesis of the new filamin. BAG3 deficient mice develop fulminant myopathy and cardiomyopathy with disorganization of z-disk and die after one month of age. Not only that BAG3 is involved in myofibrilar stability in the cardiomyocytes and that patients with BAG3 mutations develop cardiomyopathy, but our lab showed that patients with heart failure have decrease levels of BAG3. Since heart failure patients have decreased levels of BAG3, the therapy where BAG3 levels are restored to normal levels may improve heart function. Here, I show that in mouse model of heart failure after MI left ventricle function is restored after administration of AAV9 BAG3. BAG3 overexpression in mouse heart helped the stability of z-disk proteins after mechanical stress and myocardial infarction. Overexpressed BAG3 localizes to z-disk and is also able to increase autophagy in cardiomyocytes and help with clearance of misfolded proteins. Taken together, this study shows that BAG3 is a valid and promising new therapeutic target for heart failure patients. BAG3 overexpression is able to induce autophagy and help the heart cope better with stress. Also, AAV9 vector is robustly expressed in the heart after systemic administration, and is a promising vector for gene delivery in the patient heart.
Temple University--Theses
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Iorio, Vittoria. "Determinazione del ruolo della proteina BAG3 nelle isole del Langerhans e suo coinvolgimento nel meccanismo di secrezione dell’insulina." Doctoral thesis, Universita degli studi di Salerno, 2015. http://hdl.handle.net/10556/2041.
Повний текст джерелаАнотація:
2012 - 2013Diabetes is a metabolic alteration due to a decrease in activity of insulin. In particular, it may be a consequence of a reduced availability of this hormone, of an impediment to its normal action, or of a combination of these two factors. The secretion of insulin is a specialized activity of t β cells of the Langerhans islets that are functional endocrine pancreatic part. Diabetes is a widespread disease, particularly in so-called affluent countries, where some risk factors promotes the onset. Actually, it should be considered a syndrome more complex than the simple hyperglycemia. In fact, it is associated to lipid metabolism abnormalities, and increased blood pressure, that, together with abdominal obesity and alterations in glucose homeostasis constitute the so called 'metabolic syndrome': a multifactorial disease that increases the risk of cardiovascular disease. Given to the wide prevalence of this disease, it is therefore necessary a deeper understanding of the normal physiology of β cells and a complete characterization of the molecules involved in the mechanism of insulin secretion. Recently, there has been much progress in this direction, but much remains to be clarified. BAG3 is a protein involved in some of the most important biological processes, such as apoptosis, autophagy, adhesion, migration, and cell invasion. The strong positivity of BAG3 protein in Langerhans islets, recently found in our laboratory, has prompted us to analyze the role of this protein in the β cells physiological functions. To this end, we analyzed BAG3 expression and subcellular localization in the murine insulinoma cell line β TC 6. BAG3 has an apparent mass of 74kDa and is localized in the cytoplasm, here has been shown the presence of a 60 kDa BAG3 form in the insulin- containing granules. The presence in this fraction can be explained by the fact that BAG3 appears to be associated with proteins constitutely expressed on the granules membranes involved in their exocytosis. Indeed, in this work, has been shown the physical interaction of BAG3 protein with t - SNARE SNAP -25 / Syntaxin, which mediate the fusion and exocytosis of insulin vesicles to the plasma membrane. In particular, BAG3 appears to regulate the assembly of the complex allowing a regulated secretion of insulin. In addition, we have shown that BAG3 interacts with the focal adhesion complex FAK / Paxilllin, involved in glucose induced F – actin remodeling. The interaction with FAK, induced by high glucose concentrations, appears to be essential for the phosphorylation of BAG3 by such kinases. BAG3 is also able to sustain ERK phosphorylation, contributing to the destruction of the actin cytoskeleton and increased secretion of insulin. All together these findings disclose a role for BAG3 in regulating insulin release by islet β- cell. [edited by author]
XII n.s.
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Piedallu, Océane. "Physiopathologie d'un modèle murin knock-in d'une mutation du gène BAG3 responsable d'insuffisance cardiaque humaine." Electronic Thesis or Diss., Sorbonne université, 2024. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2024SORUL079.pdf.
Повний текст джерелаАнотація:
Nous avons généré avec succès un nouveau modèle murin récapitulant le phénotype de cardiomyopathie dilatée, y compris le dimorphisme sexuel observé chez l'homme, sans les limitations associées au modèle similaire publié précédemment. Ce modèle knock-in, exprimant la mutation V473M du domaine BAG de Bag3, orthologue à la mutation V468M provoquant une CMD chez l'homme, nous a permis d'étudier les mécanismes physiopathologiques précoces et tardifs impliqués dans le développement de la maladie. Les souris mutantes présentent une déficience de la macroautophagie en condition basale, mais pas en condition de carence nutritionnelle induite par un jeûne, indiquant une altération de la macroautophagie spécifique plutôt qu'en « bulk ». La co-expression d'une desmine mutée protéotoxique pro-agrégante chez les souris Bag3-V473M améliore de manière inattendue la fonction cardiaque et augmente l'ubiquitinylation de la desmine plutôt que d'exacerber le phénotype de CMD. Ceci suggère que la fonction normale de Bag3 peut aggraver la protéotoxicité associée à la desmine mutée à travers une surcharge de la voie agréphagique, tandis que Bag3-V473M, impacté dans son interaction avec HSP70, pourrait être limité dans la prise en charge des agrégats de desmine. Les analyses protéomiques et transcriptomiques ont confirmé une dérégulation de la protéostasie chez les souris mutantes, mais également révélé une altération métabolique. Plus précisément, il s'agirait d'un shift précoce de l'apport énergétique au niveau cardiaque des acides gras vers le glucose, corroboré par des analyses effectuées in vivo et du lipidome cardiaque. En conclusion, nos résultats montrent que la mutation du domaine BAG de Bag3 conduit à une altération de la macroautophagie spécifique, entraînant une dérégulation métabolique cardiaque précoceWe have successfully generated a new mouse model recapitulating dilated cardiomyopathy phenotype, including gender-dependant severity observed in humans, without the limitations associated with the previous similar model. This full knock-in model, expressing the hypomorphic V473M mutation of the BAG domain in Bag3, orthologous to the V468M mutation causing DCM in humans, enabled us to study the pathomechanisms involved both in the onset and later stage of the disease. The mutant mice were deficient in basal macroautophagy yet showed activation upon starvation-induced stimulation, indicating an alteration of specific rather than bulk macroautophagy. Co-expressing a proteotoxic pro-aggregative mutant desmin in Bag3-V473M mice unexpectedly improved cardiac function and increased desmin ubiquitinylation rather than exacerbate DCM features. This suggests that normal Bag3 function may worsen mutant-desmin associated proteotoxicity through aggrephagic pathway overload, while HSP70-interacting deficient V473M mutant may be incompetent in desmin aggregates cargo processing. Proteomic and transcriptomic analyses confirmed proteostasis dysregulation in mutant mice but also witness an early metabolic alteration consistent with a cardiac shift in energy supply from fatty-acids to glucose as an early event in the onset of the disease, supported by in vivo and cardiac lipidomic analyses. To conclude, our results shows that Bag3 BAG domain mutation impaired specific macroautophagy resulting in early cardiac metabolic dysregulation
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Séguin, Samuel. "Le chaperon HSPB8 coopère avec BAG3 pour stimuler la dégradation des protéines à polyglutamine par macroautophagie." Thesis, Université Laval, 2008. http://www.theses.ulaval.ca/2008/25531/25531.pdf.
Повний текст джерела
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Wegehaupt, Oliver Philipp [Verfasser], and Michael [Akademischer Betreuer] Köttgen. "BAG2, BAT3, DNAJB11, GNB2L1 und SERPINH1 interagieren in einem Netzwerk mit dem Polycystin-1-TRPP2-Signalmodul." Freiburg : Universität, 2016. http://d-nb.info/1122647816/34.
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Yu, Yanhua. "Functional characterization of AvrBs3/PthA effectors in Xanthomonas oryzae pv. oryzae strain BAI3 from West-Africa." Thesis, Montpellier 2, 2010. http://www.theses.fr/2010MON20231.
Повний текст джерелаАнотація:
Xanthomonas oryzae pv. oryae (Xoo) est l'agent causal de la bactériose vasculaire du riz (BLB), maladie entraînant des pertes de rendement importantes dans la plupart des régions rizicoles, notamment en Afrique. La virulence des souches Asiatiques de Xoo dépend des effecteurs de la famille AvrBs3/PthA ou TAL (pour Transcription Activator-Like). Des études appro fondies sur le mode d'action des effecteurs TAL ont montré que l'activité de virulence ou d'avirulence que les TAL confèrent à la bactérie dépend essentiellement de leur interaction avec les gènes de sensibilité et/ou de résistance correspondants chez le riz. Les souches de Xoo originaires d'Afrique isolées récemment ne présentent que huit effecteurs de type TAL dans leur génome et leur rôle dans la virulence est jusqu'à présent inconnu. Les travaux de cette thèse ont porté sur la caractérisation des effecteurs de type TAL dans la souche africaine de Xoo BAI3. Une mutagenèse systématique par recombinaison homologue sur l'ensemble des huit gènes tal de la souche BAI3 a été effectuée et a conduit à l'identification et à la caractérisation du gène talC. TalC se caractérise par 21.5 répétitions et est phylogénétiquement proche des TAL de Xanthomonas oryzae pv. oryzicola (Xoc). Le mutant BAI3ΔtalC est incapable de développer les symptômes de la maladie sur plante sensible. Toutefois, les bactéries se multiplient très bien au niveau de l'apex foliaire proche du site d'inoculation, laissant supposer que TalC est requis pour la colonisation du système vasculaire. Parmi les cibles directes potentielles identifiées via l'analyse du transcriptome de feuilles de riz sensible (BAI3 versus BAI3ΔtalC), Os11N3 code une protéine de la famille des noduline-3 MtN3 et est fortement induit durant l'infection par la souche sauvage BAI3. Nous avons identifié dans la région promotrice de Os11N3 une séquence nucléotidique ciblée par TalC et démontré qu'elle était fonctionnelle via des expériences d'expression en trans dans N. benthamiana. Les travaux de cette thèse montrent pour la première fois que les effecteurs de type TAL contribuent de manière importante à la virulence de la souche africaine Xoo BAI3. Ces travaux contribueront à l'amélioration génétique des lignées de riz pour la résistance à la bactériose vasculaire du riz en AfriqueXanthomonas oryzae pv. oryzae (Xoo) is the causal agent of Bacterial Leaf Blight (BLB) on rice, a serious disease causing important yield losses in the main rice growing regions including Africa. The virulence of Asian Xoo strains mainly depends on the type III effectors of avrBs3/pthA gene family, namely TAL (for Transcription Activator Like) effectors. In depth studies on the function of TAL effectors revealed that the virulence and/or the avirulence activities conferred by these effectors requires the binding and the induction of the corresponding S and/or R genes. African Xoo strains was shown to harbor 8 TAL effectors in their genomes. However, the contribution of these TAL effectors to Xoo virulence is still unknown. This work reports on the identification and characterization of TAL effectors in the African Xoo strain BAI3R. A random mutagenesis based on homologous recombination in the genes encoding TAL effector was conducted in Xoo str ain BAI3R and led to the identification of talC. TalC harbors 21.5 repeats in its central domain and is phylogenetically more related to TAL effectors of Xanthomonas oryzae pv. oryzicola (Xoc). The BAI3RΔtalC mutant is seriously impaired in its virulence on susceptible rice varieties. Interestingly, bacteria are still able to grow at wild-type levels in the apex of the leaf, suggesting a requirement of talc for vascular colonization. Potential direct host targets were identified by conducting a transcriptomic analysis of rice leaves challenged with Xoo strain BAI3R vs. BAI3RΔtalC. Among the identified targets, the rice gene Os11N3 was found to be highly induced upon infection by the wild type strain but not the mutant one. A DNA target box for TalC was located in the Os11N3 upstream region and proved to be functional using GUS assays. We also show that the Os11N3 341-bp upstream region is transcriptionnally activated by TalC. Our results demonstrated for the first time that TAL effectors play an important role in the virulence of Xoo strain BAI3R. Our work will contribute to better improve rice for resistance to bacterial leaf blight
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Elders, Christopher Frank. "Caledonian tectonics from stratigraphy and isotope geochemistry of lower palaeozoic successions." Thesis, University of Oxford, 1987. http://ora.ox.ac.uk/objects/uuid:bf48a950-7ffb-4b58-bae3-915a2f7b5a94.
Повний текст джерелаАнотація:
The Southern Uplands of Scotland is interpreted as a Lower Palaeozoic accretionary complex which formed on the northern margin of the Iapetus Ocean. Seven conglomerates which contain detritus derived from the north-west, from sources on the Laurentian continental margin, were studied. Granite clasts in five of the conglomerates have distinct petrographic and geochemical characteristics which indicate that separate source areas supplied detritus to the Southern Uplands at different times. The Llandeilo Corsewall Point and Caradoc Glen Afton conglomerates, which occur in Tracts 1 and 2 of the Northern Belt, contain granite clasts that yield similar Rb-Sr whole-rock isochron ages (c. 1,200 Ma, 600-660 Ma and c. 475 Ma) and similar Sm-Nd model ages. This suggests that the clasts in the two conglomerates were derived from related sources. Some of the granite clasts in the early Ashgill Shinnel Formation conglomerate, which occurs in Tract 3 of the Northern Belt, resemble those in the Corsewall Point conglomerate, but most are petrographically and geochemically distinct, and yield younger Sm-Nd model ages. The lower Llandovery Pinstane Hill conglomerate occurs in Tract 4 of the Central Belt, and contains granitic detritus which yields a Rb-Sr whole-rock isochron age of 458 ± 26 Ma and has similar characteristics to the clasts in the Shinnel Formation conglomerate. The granite clasts in the Corsewall Point and Glen Afton conglomerates are of a different age to the granite intrusions of northern Scotland, and are unlikely to have been derived from this region. Conglomerates in the Midland Valley contain granite clasts with different petrographic and isotopic characteristics to those supplied to the Southern Uplands during the Llandeilo and Caradoc. However, north-west Newfoundland has a similar igneous history to that recorded by the Southern Uplands clasts, which could be derived from this region. The clasts supplied to the Shinnel Formation and Pinstane Hill conglomerates during the Ashgill and Llandovery have more in common with the granitic detritus in the Midland Valley. Thus, the Southern Uplands form a distinct Caledonian terrane which was south-east of Newfoundland in the Llandeilo, and was affected by sinistral strike-slip displacements during and after accretion.
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Dylan, Huw. "The Joint Intelligence Bureau : economic, topographic, and scientific intelligence for Britain's Cold War, 1946-1964." Thesis, Aberystwyth University, 2010. http://hdl.handle.net/2160/6338ec52-6154-47ca-ba92-c6bf092281bf.
Повний текст джерелаАнотація:
This thesis examines the British Joint Intelligence Bureau (JIB), which, between its creation in 1946 and its end in 1964, gathered, collated and processed topographic, economic, scientific, and atomic intelligence. It did so on an inter-service, national level. The thesis examines the creation of the organisation, in the aftermath of the Second World War, exploring what factors and which people supported the creation of the new agency. It then moves on to examine the work of the JIB in several of its key fields of work, namely topography, economics and monitoring the threat from Soviet nuclear forces, before examining some of the JIB’s international connections and how these contributed to its work. It concludes with an examination of how the JIB begat the Defence Intelligence Staff (DIS). It argues that the creation of the JIB was an appropriate response to the need to centralise and retrench in the intelligence machinery after the War, but that the organisation, in essence, represented a compromise between those who wanted to fully centralise military (and military-relevant) intelligence and those who wished to preserve service independence. Over the course of its existence it made important contributions to several key areas of policy – including mapping the Soviet Union for nuclear strike planning, the economic containment of the USSR, as well as China and North Korea during the Korean War, and in monitoring the production of Soviet bombers and missiles – before becoming a central component of the new DIS.
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Oliver, Jacob B. "Birthing Attila." Thesis, Aberystwyth University, 2015. http://hdl.handle.net/2160/3a37bc8b-6a4a-470d-ba90-452dfb823617.
Повний текст джерелаАнотація:
I have termed Birthing Attila a creative-critical project since it is not only a collection of poems, or a critical compendium of methodologies and theories, but an alignment of the two in a mutually illuminating process. My creative work informs my critical, and, reflexively, my critical informs my creative. The Birthing Attila project engages with orthodox narratives of history and ideology, critiquing them, working against linear expectation, and identifying and dramatizing margins of society that are often subordinated or neglected in such discourses. By engaging with New Historicist theory as a creative impetus (see Chapter Three) and exploring other theoretical debates chiefly within feminism and post-colonialism, my poetry is drawn into line with a critical praxis. This critical-creative contact locates Birthing Attila at the confluence of recent work on the 'interfrictions' between theorized inquiry and creative practice. The poems themselves seek to encourage today's readers to look internally and at the world around them, all viewed through a 'time-slipped universe' that adopts three 'worlds' inextricably intertwined - the fall of Rome, the 1980s, and contemporary society. Through the use of a time-slipped space in the creative pieces, fault lines, fractures, and permutations of perception across and embedded within history are explored within poems as well as between them. Birthing Attila fuses time together where clean distinctions between periods and events, and the ability to identify a clear chronology beyond the characters' narrative arcs, are, as with the separation of critical and creative practice in the construction of the project, rendered impossible. Chapter One (Reflections and Influences) explores the range of literary influences on the project and the genesis of the idea of a time-slipped space as a means of critique, focusing principally on the four most central literary figures to the poems' generation: Bret Easton Ellis, Tiffany Atkinson, Charles Bukowski, and Wallace Stevens. Chapter Two (Negotiating Borders and Boundaries) introduces cultural cartography and the ways in which the delineation of borders, boundaries, and 'the other' shape notions of identity, and how, consequently, these often artificial distinctions may be misappropriated for use in nationalist and imperialist dogma in the dominant discourse, particularly as it pertains to the West. Chapter Three (New Historicism and Creative-Critical Practice) seeks to firmly situate the Birthing Attila project along a creative-critical axis and expounds on the reflexive exercise of creative-critical writing. This chapter also explains the decision to employ Marjorie Levinson's New Historicism as a creative springboard, as opposed to viewing New Historicism through a purely critical lens. Chapter Four (Gender and Space) expands on the mapping of the body politic, engages with post-colonial and feminist theory, and investigates notions of time, space, and linearity. Perhaps most crucially, this chapter also explains the role of women in the collection and the choice to consciously exclude them from the poems as a means of critique.
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Beattie, Melissa. "Travelling Torchwood(s) : national and transnational identities, glocalisation and the pseudo-reflexive audience." Thesis, Aberystwyth University, 2017. http://hdl.handle.net/2160/d019a8ca-5018-4cb3-ba9f-47304fa78910.
Повний текст джерелаАнотація:
Telefantasy series Torchwood (2006-2011, multiple production partners) was industrially and paratextually positioned as being Welsh, regardless of its frequent status as an international coproduction. When, for series four, the production (and diegesis) moved primarily to the US as a coproduction between BBC Worldwide and American premium cable broadcaster Starz, fan response was negative from the announcement, with the series being termed 'Americanised' in popular and academic discourse (e.g., Porter 2012, Derhy 2013). This study interrogates these assumptions via textual, industrial/contextual and audience analysis and finds that, in part due to the competing public service and commercial remits of the BBC, Torchwood was a glocalised text from the beginning, despite its positioning as Welsh, which then became glocalised again in series four. This 'second order of glocalisation,' as I term it, has not previously been explored in depth within TV Studies. It leads to a disjuncture between the national 'imaginary' (Tulloch 1995: 151, cf Weissmann 2012)-- as expressed by the text and interpreted by the (fan) audience. The study also develops the concept of a banal diegetic nationalism, drawn from Billig (1995) and adapted to television aesthetics; this includes elements of the mise-en-scène with a special focus on costume drawn from interviews with both costumers for the series. The Bourdieuian concepts of fan and national cultural capitals are also explored in-depth; their interplay creates and impacts a number of potential readings. In addition, by having conducted 42 semi-structured interviews and four focus groups (totalling 16 further participants), this study qualitatively investigates various readings produced by audience members in the US, UK and Canada, as well as transnational viewers who are long-term residents of one of those nations. The study finds that the audience is pseudo-reflexive (cf. Sender 2012) when it comes to interpretation; though all express an awareness and acceptance that national identity is constructed and fluid, they still express an underlying essentialism when discussing national identity in the context of the series. This broadly agrees with Tulloch (1995) and Weissmann (2012) who both note the inflexibility of audience readings with regard to television and national identity (and their attendant connotations) whilst also helping to account for the lack of reading the initial series text as glocalised. The focus upon fan and national cultural capitals also allows for a discussion of performativity in the context of national identity. My work innovatively extends debates surrounding transnational TV drama into audience studies, at the same time demonstrating the ongoing importance of carrying out critical readings of fan interpretations.
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Modh, Sandra Violeta. "Lamaholot of East Flores : a study of a boundary community." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:b7693f46-3a18-4b1a-ba96-0f17e91f0282.
Повний текст джерелаАнотація:
Lamaholot is a population found on Flores and in the Solor Archipelago of Eastern Indonesia. The population is village-based and divided into patrilineal descent groups. Marriage is coupled with bridewealth and follows a pattern of asymmetric marriage alliance between descent groups. This thesis shows that a small group of Lamaholot in the administrative regency of East Flores shares certain traditions with a neighbouring population called Ata Tana ‘Ai. Ata Tana ‘Ai are a sub-group of the Sikka population in the administrative regency of Sikka. Descent group among Ata Tana ‘Ai are matrilineal and households were traditionally based in scattered gardens. Marriage is not coupled with bridewealth and instances of asymmetric marriage alliance between descent groups are here a consequence rather than a cause of marriage. The current fieldsite seems to have been part of the ceremonial system of Ata Tana ‘Ai and also to have shared a tradition of dispersed settlement in the gardens. The descent groups might initially have been matrilineal, but in the recent past there was also a habit of dividing children between the parental descent groups. Recent traditions of dividing children can be found throughout central-east Flores, but seemingly not to same extent as at the fieldsite. The payment of elephant’s tusks was a central feature in the acquisition of group members at the fieldsite and could be paid by both men and women. These payments were not necessarily tied to marriage and did not serve as bridewealth. In the last century outer social factors, such as the Catholic mission and the creation of the Dutch colonial state, have resulted in that many of the traditional practices at the fieldsite have been replaced with traditions from Lamaholot elsewhere. The residence pattern is now village-based, but gardens retain a central social and ritual position. The role of the elephant’s tusks has taken different expressions throughout this period of social change, and alongside the changing role of tusks, the traditional social and material authority of women at the fieldsite has declined, whereas that of men has increased. This thesis examines the current and the traditional practices in and around the fieldsite, and focuses on local definitions of descent group, kinship, and inheritance, looking at both biological and social perspectives.
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Roberts, Thomas C. "Duchenne muscular dystrophy : RNA-based therapeutics and microRNA biology." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:f53ea1f3-92db-4f90-ba95-01f2a56eae8f.
Повний текст джерелаАнотація:
Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder caused by absence of functional dystrophin protein. This thesis describes investigations into the role of small non-coding RNAs in both DMD pathology, and as potential therapeutic molecules. MicroRNAs (miRNAs) are a class of small RNAs that regulate gene expression and are implicated in wide-ranging cellular processes and pathological conditions. This study has compared differential miRNA expression in proximal and distal limb muscles, diaphragm, heart and serum in the mdx dystrophic mouse model relative to wild-type controls. Global transcriptome analysis revealed muscle-specific patterns of differential miRNA expression as well as commonalities between tissues, including previously identified dystromirs. miR-1, miR-133a and miR-206 were found to be highly abundant in mdx serum, suggesting that these miRNAs are promising disease biomarkers. Indeed, the relative serum levels of these miRNAs were normalised in response to peptide-PMO mediated dystrophin restoration therapy. This study has revealed further complexity in the miRNA transcriptome of the mdx mouse, an understanding of which will be valuable for the development of novel DMD therapeutics and for monitoring their efficacy. Myostatin is a secreted growth factor that negatively regulates muscle mass and is therefore a potential pharmacological target for the treatment of muscle wasting disorders such as DMD. This study describes a novel myostatin inhibition approach in which small interfering RNAs (siRNAs) complementary to a promoter-associated transcript induce transcriptional gene silencing (TGS) in cultured myotubes. Silencing was sensitive to treatment with the histone deacetylase inhibitor Trichostatin A, and the silent state chromatin mark H3K9me2 was enriched at the myostatin promoter following siRNA transfection, suggesting epigenetic remodelling underlies the silencing effect. These observations suggest that long-term epigenetic silencing may be feasible for myostatin and that TGS is a promising novel therapeutic strategy for the treatment of muscle wasting disorders. The work in this thesis therefore demonstrates the potential of small RNAs as therapeutic agents and as disease biomarkers in the context of DMD.
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Ahmed, Farrah. "Religious autonomy and the personal law system." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:e8d532c3-be53-4823-ba9d-bb78a9aaefcc.
Повний текст джерелаАнотація:
This thesis examines the Indian system of personal laws (‘the PLS’), under which the state applies a version of religious doctrine to the family matters of citizens whom it identifies as belonging to different religious groups. There has been a lengthy and persistent debate over the PLS, particularly in relation to its discriminatory effects upon women. However, another problem with the PLS has been little commented-upon. Supporters of the PLS emphasise its positive impact on religious freedom to such an extent that there is a pervasive assumption that the PLS is, indeed, good for religious freedom. But there has been surprisingly little critical assessment of the truth of this claim in either academic or political debates. This thesis, a work of applied normative legal theory, attempts to fill this important gap in the literature on the PLS. The thesis addresses the question of how the PLS affects one conception of religious freedom, namely religious autonomy. Its principal findings are that the PLS interferes with the religious autonomy of those subject to it by affecting their religious options (by interfering with their freedom from religion and their freedom to practice religion) and by harming their self-respect (by discriminating on the grounds of sex and religion, and by misrecognising their religious identities). Furthermore, the thesis finds that the PLS cannot be defended in the name of religious autonomy based on the possibility of exit from the system, the advantage of having the ‘option of personal law’, the power it gives people to bind their future selves, the expressive potential of the personal laws, the contribution it makes to membership in a religious community, the contribution it makes to religious group autonomy, or the recognition or validation it provides for religious identities. These conclusions imply that concerns relating to religious autonomy constitute an important set of objections to the PLS. The thesis then considers several reform proposals, including certain modifications of the PLS, a move towards a millet system, ‘internal’ reform of individual personal laws and the introduction of a Uniform Civil Code. It particularly focusses on one reform possibility – religious alternative dispute resolution – which has not been considered closely in the Indian context.
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Bozhilov, Yavor. "Analysis of a gain-of-function mutation that produces a new transcriptional unit in the α-globin locus." Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:c6979237-b318-47a6-ba03-8aab85c33d63.
Повний текст джерелаАнотація:
The expression of the human α-globin locus is regulated by a set of well characterized enhancer elements. Mutations in the α-globin protein coding genes or their regulatory elements can cause a form of anaemia called α-thalassemia which results from the downregulation of α-globin in red blood cells. There are rare cases where this downregulation is caused by genetic defects outside the know elements. This thesis deals with a genetic mutation found in an intergenic region in the α-globin locus outside of any know regulatory site. The individuals with the mutation show the typical features of α-thalassemia but have also acquired the expression of a new transcript in their red blood cells. This transcript originates near a single base pair substitution which has been associated with the phenotype and is located upstream of the α-globin genes. The mutation is a transition from the wild type Thymidine to a Cytosine, which generates a new binding motif for the key erythroid transcription factor GATA1. Previous studies of an affected individual's primary erythroid cells demonstrate enrichment of GATA1 in the region of the mutation, along with the recruitment of TAL1 and RNA Polymerase II and an increase in acetylation of histone H3. The thesis tests the hypothesis that the new transcriptional unit may utilise the established transcription regulatory landscape of the α-globin locus for its own expression. This would result in competition with the α-globin promoters for enhancer activity, thereby causing a downregulation of α-globin transcription. The first objective of this thesis is to recapitulate the previously observed phenotype in a cell line system. This model is then used to address the question of how the normally un-transcribed sequence has acquired the ability to be expressed and lastly, this thesis explores the molecular mechanisms that cause the downregulation of α-globin. To this end an iPSC-based erythroid differentiation system was characterized. This system appears to recapitulate key aspects of erythropoiesis and generates a highly pure culture containing a large number of erythroid-like cells. Next, patient iPSC lines containing the mutation were generated and differentiated along the erythroid pathway. These cells faithfully express the novel transcript and show a reduction in α-globin mRNA levels. Expression of the new transcript is accompanied by the emergence of a new region of open chromatin at the site of the mutation along with the recruitment of GATA1, KLF1 and RNA Polymerase II and the enrichment of the promoter mark H3K4me3. Chromatin conformation analysis was used to assess the proximity between the elements in the α-globin locus in the presence of the mutation. This demonstrates increased interaction between the enhancers and the site of the new transcriptional unit and reduced interaction of the α-globin promoters with their enhancers, suggesting competition for enhancer activity. Finally, to demonstrate that the variant is necessary for the observed phenotype a patient line was genetically engineered to correct the mutation. This rescues the phenotype by reducing the expression of the new transcript, abolishing the accessible region and upregulating α-globin transcription. In addition, the mutation was introduced in a wild type iPSC line to recreate the phenotype. This results in the emergence of the patient-specific region of accessible chromatin, expression of the novel transcript and downregulation of α-globin. These observations prove that the single base pair change is sufficient to cause the formation of the new transcriptional unit and that it is the causal mutation for this form of α-thalassemia.
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Razak, Huzaifah Haritsah Abdul. "Wetting behaviour of colloid-polymer mixtures in confinement." Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:e75a8463-fe02-46f3-ba95-7d7b40c955cb.
Повний текст джерелаАнотація:
We study the wetting behaviour of phase-separating colloid-polymer mixtures in confinement. The phase separation is due to the depletion attraction between the colloids mediated by the polymers and bears similarities to ordinary phase separation of oil and water. We use laser scanning confocal microscopy to investigate the behaviour of our colloidal mixture in the vicinity of different substrates, which serve as the confining walls. The glass walls used are chemically modified with two types of polymer, polyacrylamide and chitosan, and we also use clean glass as a reference. We find that the polymer grafting of the surfaces has a pronounced effect on the wetting behaviour. Here, we observe the formation of colloidal liquid droplets, which implies that the coated walls are partially wet. This geometry allows for the determination of the contact angle. The shape of the droplet is theoretically described by the interplay between gravity and interfacial curvature, with the contact angle entering as a boundary condition. The reconstructed interfacial drop profiles are then fitted to the theoretical model to quantitatively study its variation as a function of colloid-polymer state point, properties of the confining wall, and droplet size. We also visually observe Cahn's wetting transition from partial to complete wetting in three series of state points as we move closer to the binodal. This enables us to estimate the wetting transition line in our phase diagram. In addition, we disperse polyacrylamide-coated silica beads into our colloid-polymer mixtures to observe the wetting effects near curved surfaces. We generate theoretical plots based on the conditions of mechanical equilibrium, and compare to the experiments. Our studies shine light on partial wetting phenomena for systems where the interfacial roughness is comparable to the other relevant lengthscales in the system, such as the droplet size or the curvature of the surface.
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Scaber, Jakub. "The pathophysiological role of TDP-43 in amyotrophic lateral sclerosis due to C9orf72 mutations." Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:c5dd8dcf-c3e0-4ff7-ba9d-bfd3cb9914e8.
Повний текст джерелаАнотація:
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative condition that affects corticospinal and spinal motor neurons and leads to death within 30 months of symptom onset in half of all cases. It remains incurable and treatment is supportive. The genetic and molecular understanding of ALS has gone through a rapid expansion in recent years, notably with the discoveries of TDP-43, a heterogeneous ribonucleoprotein as a major component of neuronal inclusions in ALS, as well as the discovery of the C9orf72 hexanucleotide expansion as the most common genetic cause of this disease. This first part of this thesis addresses the question of which of the various pathological hallmarks of the C9orf72 Hexanucleotide Repeat Expansion (HRE) in autopsy material correlates best with the clinical presentation. The main finding is that TDP-43 distribution, rather than C9orf72 RNA foci or dipeptide aggregation in the brain, corresponds best with the areas relevant to the clinical subtype of ALS-FTD. Subsequently the role of TDP-43 was investigated in induced pluripotent stem cell derived motor neurons, and no evidence of the hallmarks of TDP-43 dysfunction, were seen in this model of the disease. No mislocalisation is found on immunofluorescence, and biochemical analysis shows no differences in insoluble species between the patient and control cell lines. In the final section, RNA sequencing was used to study the transcriptome of a BAC transgenic mouse carrying a human M337V transgene expressed at low levels, to identify early presymptomatic differences in gene expression. Interestingly, no changes were found in genes known to be associated with ALS through mutations, and the constitutive nuclear functions of TDP-43 in the regulation of splicing was maintained, prior to the emergence of a clinical phenotype in the mouse. This favours a gain of function mechanism for TDP-43 mutations in ALS.
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Man, James K. C. "Characterisation of a novel animal model for obsessive-compulsive disorder." Thesis, University of Bristol, 2005. http://hdl.handle.net/1983/6cec00ce-f3c1-4d07-ba98-54c137b7524a.
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Stamatopoulou, Despina. "Aesthetic experience and self-esteem in adolescents." Thesis, University of Bristol, 1993. http://hdl.handle.net/1983/f2b2f32f-0c56-4a7b-baa3-c593aebf2292.
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Ellenrieder, Thomas Jochen. "Investigation of the dynamic wake of a model rotor." Thesis, University of Bristol, 1995. http://hdl.handle.net/1983/13c5bb18-5952-41ae-ba03-08d8d2040d12.
Повний текст джерелаАнотація:
In this study the dynamic induced velocity field of a model helicopter rotor - excited in collective and cyclic pitch at frequencies extending to 1.5 times the nominal shaft speed - is investigated using mainly hot-wire and laser Doppler anemometry. The dynamic induced velocities are found to vary significantly with radial station and frequency. For cyclic excitations, azimuthal variations are also observed. The results point to the dynamic induced flow being influenced by the distribution of shed vorticity in the wake and cannot be explained using simple momentum theory. Vertical variations of the measured inflow response are also observed, with phase changes possibly partly due to transmission type delays. At frequencies above shaft speed a change in character of the induced flow is seen and around shaft speed an increase in the general level of turbulence is found. The available data on the dynamic induced velocity field of a rotor under controlled excitation, are substantially extended. The measured induced flow response was compared to that predicted using the Pitt and Peters dynamic inflow model. In the 'collective' case good agreement was found, suggesting that the primary inflow model parameters such as the inflow gain and apparent mass are correct with some evidence that a higher order inflow representation might be desirable. A novel method is used to infer the aerodynamic hub loading, which could not be directly measured, from the blade flapping data. This is used to isolate the inflow response using the Pitt and Peters dynamic inflow model and the results are compared with experimental measurements. The method shows the Pitt and Peters dynamic inflow representation to be adequate in the 'collective' case. In the 'cyclic' case, the inferred hub loads were very sensitive to the blade model and hence conclusions for this case are limited. A literature survey and review of the Pitt and Peters dynamic inflow model are also given
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Dodds, Klaus-John. "Critical geopolitics and the writing of foreign policy." Thesis, University of Bristol, 1993. http://hdl.handle.net/1983/54c2c69d-717d-4def-ba92-eff80f4d13c6.
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Patsios, Demetrios. "Modelling the dynamic relationship between formal and informal long-term care between 1980 and 1995 in Britain : a multilevel approach." Thesis, University of Bristol, 2001. http://hdl.handle.net/1983/2897487e-5e0d-41e0-ba03-ad3f5d9a8641.
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Hayward, Robert C. "The significance of withdrawal in a multidisciplinary profile of tobacco dependence." Thesis, University of Bristol, 2003. http://hdl.handle.net/1983/fecadd04-2154-439a-baa3-7ba3fa983ecc.
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Dobnik, Simon. "Teaching mobile robots to use spatial words." Thesis, University of Oxford, 2009. http://ora.ox.ac.uk/objects/uuid:d3e8d606-212b-4a8e-ba9b-9c59cfd3f485.
Повний текст джерелаАнотація:
The meaning of spatial words can only be evaluated by establishing a reference to the properties of the environment in which the word is used. For example, in order to evaluate what is to the left of something or how fast is fast in a given context, we need to evaluate properties such as the position of objects in the scene, their typical function and behaviour, the size of the scene and the perspective from which the scene is viewed. Rather than encoding the semantic rules that define spatial expressions by hand, we developed a system where such rules are learned from descriptions produced by human commentators and information that a mobile robot has about itself and its environment. We concentrate on two scenarios and words that are used in them. In the first scenario, the robot is moving in an enclosed space and the descriptions refer to its motion ('You're going forward slowly' and 'Now you're turning right'). In the second scenario, the robot is static in an enclosed space which contains real-size objects such as desks, chairs and walls. Here we are primarily interested in prepositional phrases that describe relationships between objects ('The chair is to the left of you' and 'The table is further away than the chair'). The perspective can be varied by changing the location of the robot. Following the learning stage, which is performed offline, the system is able to use this domain specific knowledge to generate new descriptions in new environments or to 'understand' these expressions by providing feedback to the user, either linguistically or by performing motion actions. If a robot can be taught to 'understand' and use such expressions in a manner that would seem natural to a human observer, then we can be reasonably sure that we have captured at least something important about their semantics. Two kinds of evaluation were performed. First, the performance of machine learning classifiers was evaluated on independent test sets using 10-fold cross-validation. A comparison of classifier performance (in regard to their accuracy, the Kappa coefficient (κ), ROC and Precision-Recall graphs) is made between (a) the machine learning algorithms used to build them, (b) conditions under which the learning datasets were created and (c) the method by which data was structured into examples or instances for learning. Second, with some additional knowledge required to build a simple dialogue interface, the classifiers were tested live against human evaluators in a new environment. The results show that the system is able to learn semantics of spatial expressions from low level robotic data. For example, a group of human evaluators judged that the live system generated a correct description of motion in 93.47% of cases (the figure is averaged over four categories) and that it generated the correct description of object relation in 59.28% of cases.
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Than, Manuel E. "Röntgenstrukturanalyse der Ba3-Cytochrom-c-Oxidase aus Thermus thermophilus und ihres Substrates Cytochrom-c552." [S.l. : s.n.], 2000. http://deposit.ddb.de/cgi-bin/dokserv?idn=959982051.
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Felzen, Vanessa [Verfasser]. "Regulation and function of autophagy in stress resistance and under pathophysiological conditions involves the co-chaperone BAG3 / Vanessa Felzen." Mainz : Universitätsbibliothek Mainz, 2016. http://d-nb.info/110992111X/34.
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Davies, A. C. L. "Accountability : a public law analysis of National Health Service contracts." Thesis, University of Oxford, 1999. https://ora.ox.ac.uk/objects/uuid:7fa277f4-ba95-46e6-bd82-81ab2236acd5.
Повний текст джерелаАнотація:
The thesis takes as its subject the concept of accountability. It examines the use made of the concept in the public law literature, and advances a novel analytical model of the individual accountability mechanism. The model identifies the essential features of that mechanism: setting standards against which an account can be judged; requiring the person being called to account to explain and justify his or her actions; judging the account rendered against the standards set; and responding to the account rendered, where appropriate, with enforcement measures. This analytical approach provides a way of examining, in detail, an individual accountability mechanism, and identifying the main practical problems faced by the parties to it. The approach is applied to an empirical case study of National Health Service (NHS) contracts. (The fieldwork involved an examination of contractual relationships between purchasers (Health Authorities and GP fundholders) and providers (NHS Trusts) in three sample areas, using document analysis, interviews and observation.) The study's main findings fall into three groups. Firstly, purchasers were subject to various pressures and constraints (of time and resources, for example) which affected their actions in calling providers to account. Secondly, the study uncovered some of the complexities of the relationship between the parties to the accountability process. Analytical models of the accountability relationship were developed in order to classify different types of relationship according to the parties' behaviour and their degree of mutual trust. Thirdly, the study examined whether purchasers, as callers to account, could render the accountability process effective. For various reasons, purchasers often lacked the authority to set and enforce the standards they required. The model of the accountability mechanism developed in the thesis also has evaluative potential. Drawing on the public law literature as well as the empirical data, a notion of the good accountability process is evolved. This includes, for example, requirements of maximising the accountability achieved within available resources, maintaining good relationships by using fair procedures, and finding ways of making the whole process effective. Some of these principles may be of more general application to other accountability processes. Possible generalisations are explored, particularly the contribution of the thesis to the development of an explicitly public law concept of contract.
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Katsaroumpas, Ioannis. "Collective labour law in times of economic crisis : theoretical and comparative perspectives." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:1f8bb178-12db-45e6-ba90-0fdcac45429b.
Повний текст джерелаАнотація:
The thesis explores the interaction of the economic phenomenon of 'economic crisis' with the legal phenomenon of Collective Labour Law (CLL). This interaction is the thesis' main problematique. Rather than undertaking an all-encompassing investigation, it seeks to modestly contribute some new theoretical and comparative perspectives on the problematique. These perspectives are of potential value both to the highly underdeveloped area of the theorisation on economic crises and CLL and to the comparative labour law literature. On the theoretical side, the thesis puts forward a novel Marxist-critical theoretical framework for understanding the crisis' operation of CLL. Building successively on the Marxist-critical insights of a fundamental contradiction between the (capitalism) reproductive and (worker) protective function of CLL, the crisis theories' common assertion of economic rationalisation as the primary crisis response and a joint reading of Gramscian counterhegemony and Habermas' theory of legitimation crisis, a theoretical framework is constructed around a proposed concept: crisis (dis)equilibrium. These (dis)equilibria, which arguably determine the course of CLL's crisis developments are composed of two fundamental opposing forces: the force of economic rationalisation, pushing for reforms dictated by the need for intense capitalist restructuring and the opposing counter-legitimation force, which reflects the level of socio-political threat of withdrawal of support to the prevailing economic system or at least to the reforms dictated by economic rationalisation. The comparative side that serves also as a testing empirical ground for the theoretical framework, consists of an extensive interrogation of the recent crisis CLL trajectories in Greece and the UK. For Greece, the analysis observes and accounts for a dramatic collapse of the pre-crisis protective CLL edifice as a result of multiple and abrupt far-reaching CLL reforms bringing about the neo-liberal crisis movement. Subsequently, the thesis offers a response to why the protective constitutionalisation of CLL rights in Greece failed to prevent the de-construction by designating a de-constitutionalisation triangle of normative spheres. The triangle maps and explains how the neoliberal-oriented EU-IMF bailout conditionality prevailed over domestic-constitutional and transnational labour rights normative spheres through identifying a series of 'strong' and 'weak' legal and non-legal interactions. For the UK, the analysis dismisses a suggestion of a complete stasis during the crisis. Instead, it ascertains and accounts for a further -more gradual- neo-liberal consolidating crisis movement of UK's pre-crisis neo-liberal CLL paradigm. Hence the British crisis movement is described as neo-liberal continuity by consolidation. Very importantly, the thesis observes a significant crisis de-constitutionalisation process of CLL in the UK, which takes the shape of a constitutional attack on the political voice of unions by regulatory reforms. Eventually, the thesis finds a comparative crisis pattern of a 'Great Neo-liberal Convergence' between the two previously diametrically opposite CLL systems, since they moved closer and toward the neo-liberal end during the crisis. The 'neo-liberal convergence' finding is situated as a supportive case for the convergence theorists within the convergence/non-convergence debate over whether the European CLL systems are to converge. Moreover, the analysis demonstrates the explanatory value of the Crisis Equilibrium theoretical framework for understanding the crisis trajectories in both countries and suggests that crisis developments confirm the heteronomy of CLL to the theoreticallyidentified dialectic between the capitalist force of economic rationalisation and the social force of counter-legitimation.
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Möller, Stephanie. "Synthese und Untersuchung von Derivaten des Azobenzols mit Silananker zur Darstellung photoschaltbarer Oberflächen." Doctoral thesis, Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2013. http://hdl.handle.net/11858/00-1735-0000-0001-BAB3-A.
Повний текст джерелаАнотація:
Ziel der Arbeit war die Synthese von Derivaten des Azobenzols mit Silananker zur Darstellung photoschaltbarer Oberflächen. Dies ist ein Ansatz zum Aufbau photoschaltbarer Oberflächen, bei der nur ein Reaktionsschritt an der Oberfläche benötigt wird und keine weitere Oberflächenreaktion zur Funktionalisierung der Oberfläche gebraucht wird, wie sie in der Literatur beschrieben werden. In der vorliegenden Arbeit wird eine Vorschrift zur Synthese photoschaltbarer Organosilane mit unterschiedlichen Endgruppen beschrieben. Dieses Verfahren basiert auf der Darstellung photoschaltbarer Organothiole auf Goldoberflächen. Die Charakterisierung der synthetisierten Verbindungen erfolgt mittels 1H-NMR, 13C-NMR, IR, DC und GC-MS. Die analytische Kontrolle der Edukte und der weiteren synthetisierten Zwischenstufen mit endständigen funktionellen Gruppen und aller photoschaltbaren Organosilane zeigt, dass alle photoschaltbaren Organosilane erfolgreich synthetisiert werden, jedoch mit unterschiedlicher Reinheit. Auf Grund der Silanankergruppe wird jede dieser Verbindungen kovalent auf eine SiO2-Oberfläche gebunden. Die Schichtdicke wird mittels Ellipsometrie bestimmt und eine weitere Charakterisierung erfolgte durch die Bestimmung des Kontaktwinkels verschiedener Flüssigkeiten. Die Synthese der Derivate des Azobenzols mit Silananker erfolgt in mehreren Stufen. Im ersten Schritt erfolgt die Darstellung eines Farbstoffs durch ein in para-Stellung substituiertes Anilin über die Azokupplung. Im zweiten Schritt wird eine Alkylkette durch eine nukleophile Substitution mit 11-Brom-1-undecen bzw. 6-Brom-1-hexen erreicht und im dritten Syntheseschritt wird eine Silanankergruppe mittels Hydrosilylierung angebunden. Die Beschichtung von SiO2-Oberflächen wird durch den Prozess der Self-Assembled Monolayer erreicht. Dabei werden monosubstituierte Organochlorsilane verwendet, da diese im Gegensatz zu Trichlorsilanen bessere Monolayer ausbilden. Es werden verschiedene endständige funktionelle Gruppen eingeführt, so dass mit steigender Kettenlänge immer dickere bzw. dichtere Schichten gebildet werden. Die unterschiedliche Ausbildung eines Oberflächenfilms eines photoschaltbaren Azofarbstoffes nach der ersten bzw. zweiten Synthesestufe mit endständiger C10-Kette als funktionelle Gruppe an einer Wasser-Luft-Grenzfläche wird mit der Brewster-Winkel-Mikroskopie in Kombination mit einem Langmuir-Pockels-Trog gezeigt. Der höhere Platzbedarf für die cis-Konfiguration im Gegensatz zur trans-Konfiguration wird nach Bestrahlung der Oberfläche aus den aufgenommenen Schubflächen-Isothermen bestimmt. Die für die Photoisomerisierung benötigten scheinbaren Aktivierungsenergien werden mittels Arrhenius-Gleichung an Hand der UV-/VIS-Spektren bestimmt und diskutiert. Es wird gezeigt, dass diese nicht nur abhängig von dem Substituenten R, sondern auch von den verwendeten Lösungsmitteln sind, wobei diese Abhängigkeit auf der Grundlage der verschiedenen Reaktionsmechanismen der Photoisomerisierung erörtert wird. Bei allen Farbstoffen wird eine trans-/cis-Konfigurations-änderung der chemischen Verbindung bei Bestrahlung mit Licht entsprechender Wellenlängen in verschiedenen Lösungsmitteln beobachtet. Die nachfolgende Rückreaktion (cis-/trans-Konfigurationsänderung) wird nur bei denjenigen Farbstoffen beobachtet, die einen hohen Extinktionskoeffizienten in Lösung besitzen. Die Beeinflussung der Benetzbarkeit wird während der Konfigurationsänderung auf diesen photoschaltbaren Oberflächen durch Kontaktwinkelmessungen untersucht. Diese wird durch die Bildung einer homogenen Oberfläche beeinflusst. Die Homogenität der Oberfläche zeigt die Hysterese, die abhängt von den funktionellen Gruppen der synthetisierten photoschaltbaren Organosilane. Die trans-/cis-Konfigurationsänderung auf einer Oberfläche erfolgte durch Bestrahlung der Oberfläche mit UV- bzw. blauem Licht. Die Einführung einer Alkylkette (C5 bzw. C10) als funktionelle Endgruppe führt zum Teil zu einer Verbesserung der Homogenität der Oberfläche. Durch Mischbeschichtungen von photoschaltbaren und nicht-photoschaltbaren verbessert sich die Änderung des Kontaktwinkels bei der Bestrahlung der photoschalbaren Oberflächen nicht, so dass auch andere Lösungsansätze z.B. die Verwendung anderer Oberflächen, die Erhöhung der Konzentration der photoschaltbaren Verbindungen an der Oberfläche oder der Einsatz hydrophiler Endgruppen in der Diskussion berücksichtigt werden.
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Schweinhardt, Petra. "Neural correlates of clinical pain processing in neuropathic and inflammatory pain patients and comparison with experimental pain." Thesis, University of Oxford, 2006. http://ora.ox.ac.uk/objects/uuid:12e71d31-24f8-47e8-ba83-129575007644.
Повний текст джерелаАнотація:
The goal of this thesis was to examine the processing of clinical pain in two patient groups with well defined primary pathologies, i.e. neuropathic pain patients and patients with rheumatoid arthritis (RA). It was hypothesized that chronic pain is associated with plastic changes in pain processing brain structures that can be detected using functional magnetic resonance imaging (FMRI). The first study, presented in Chapter 3, demonstrates that the neural representation of experimental heat pain is different in neuropathic pain patients than in age- and gender-matched healthy control subjects, although the pain stimulus was applied outside clinically affected areas. Increased activation was found in amygdala and anterior insula in the patient group and was accompanied by increased state anxiety and depression scores. Anterior insula is the focus of Chapter 4 in which it is demonstrated that clinical pain processing is located significantly more anteriorly in the insula than experimental pain processing, in close proximity to neural correlates of highly negative emotions and the conscious perception of bodily sensations. This offers a potential explanation for the shift of clinical pain processing. In Chapter 5, clinical pain is contrasted with experimental pain in the same patient population, i.e. patients with RA. In addition to comparing clinical and experimental pain processing, it was investigated if emotional and cognitive determinates of the pain experience, specifically depression and catastrophizing, exert different influences on the two types of pain. It is shown that clinical pain, but not experimental pain, is likely to be driven partially by depressive symptoms whereas catastrophizing is associated with the same neural activation pattern in both conditions. The cerebral representation of allodynic pain in neuropathic pain patients is presented Chapter 6. Chapters 6 and 7 demonstrate that the FMRI signal encodes the perceived intensity of clinical allodynic pain across subjects and that it reflects longitudinal variations of the perceived intensity within subjects. This thesis illustrates that FMRI can reveal subtle differences in the processing of clinical and experimental pain, despite brain activation patterns being similar on the whole. It also indicates that FMRI can be used to elucidate the origin of these differences, for instance by studying the influence of emotional and cognitive variables. This suggests that neuroimaging methods, in particular FMRI, have the potential to dissect clinical pain into its constituent parts, including central sensitization, brainstem facilitation and amplification by psychological factors. Such knowledge could potentially be exploited to target treatment selectively at different components of clinical pain and to monitor longitudinal changes of these components separately.