Il y a presque 20 ans, la mise en évidence de mutations bi-alléliques inactivatrices du gène SMARCB1 dans les tumeurs rhabdoïdes établissait la première démonstration d’altérations du complexe SWI/SNF de remodelage de la chromatine en oncologie. Depuis, l’avènement des techniques d’analyse moléculaire à haut débit appliquées à la cancérologie a permis de montrer que des altérations dans d’autres gènes du complexe SWI/SNF était présentes dans un très grand nombre de cancers. A travers la présentation de plusieurs types de tumeurs SWI/SNF déficientes et de nos modèles d’étude des tumeurs rhabdoïdes, nous montrons que la perte de SMARCB1 est associée à une augmentation de la biosynthèse de la sérine et des voies métaboliques en aval importantes pour l’oncogenèse. Ces résultats pourraient aboutir à une option thérapeutique pour les tumeurs rhabdoïdes voire, plus généralement, pour d’autres modèles de tumeurs SWI/SNF-déficientes. Enfin, la mise en perspective de ces changements métaboliques avec les altérations épigénétiques observées dans les tumeurs SWI/SNF déficientes pourrait se révéler pertinente pour continuer d’approfondir nos connaissances sur ces tumeurs. / Nearly 20 years ago, the demonstration of truncated bi-allelic mutations in the SMARCB1 gene in rhabdoid tumors established the first demonstration of alterations in the SWI/SNF chromatin remodeling complex in oncology. Since then, the advent of high-throughput molecular analysis techniques applied to oncology has shown that alterations in other genes of the SWI/SNF complex are present in a wide variety of cancers. Through the presentation of several types of SWI/SNF deficient tumors and our models of rhabdoid tumors, we show that the loss of SMARCB1 is associated with an increase of the serine biosynthesis pathway and the downstream metabolic pathways important for oncogenesis.These results could lead to a therapeutic option for rhabdoid tumors or, more generally, for other models of SWI/SNF-deficient tumors. Finally, the prospect of these metabolic changes with the epigenetic alterations observed in SWI / SNF deficient tumors may be relevant to continue to deepen our knowledge of these tumors.

Chromatin remodelers are ATP-dependent multisubunit assemblies that regulate transcription and other processes by altering DNA-histone contacts. The mechanism of action is based on the transduction of energy released by ATP hydrolysis to translocation on DNA and ultimately the movement of histones in cis or trans. Though the critical ATP burning and translocation activities are fulfilled by a conserved ATPase domain in the catalytic subunit, there are accessory domains and subunits that are speculated to regulate these activities. Important questions in the field center around the identification of these domains and subunits, whether they affect complex formation, substrate affinity or a critical step in remodeling. If they do affect remodeling, what is the structural basis of the regulatory activity. In this study, these questions have been addressed using the prototype remodeler SWI/SNF from budding yeast. ySWI/SNF is a 12 subunit complex that includes the catalytic subunit Swi2/Snf2. It affects 6% of the yeast genome being primarily involved in gene activation. We employed a systematic protein or domain deletion strategy and characterized the mutant complexes in vitro and in vivo. A key finding was that SWI/SNF is organized in distinct structural modules and that the Snf2 module regulates most of its activities. Snf2 is a central subunit in this module and the function of conserved regions within Snf2 were studied. The N terminus preceding the HSA and ATPase domain has three major roles - complex assembly, recruitment and regulation of catalytic activity. A novel SnAC domain located C terminal to ATPase domain was identified to play critical role in coupling ATP hydrolysis to nucleosome movement by acting as a histone anchor. Finally the tandem AT-hooks between SnAC and bromodomain serve as DNA binding domains but also affect ATPase activity and nucleosome mobilization independent of its binding activity. Taken together, this study provides a comprehensive overview of the function of regulatory domains in SWI/SNF.

Currently, the United States is investigating methods to close the nuclear fuel cycle and increase the use of nuclear power for electricity and cogeneration applications. Congress has called for and held hearings in an attempt to determine an appropriate path forward for reprocessing of nuclear fuel. However, each current proposed method presents a different set of attributes with regards to: Complexity, safety, wastes, and proliferation risks. This thesis provides a decision analysis methodology for approaching the reprocessing issue. The presented methodology builds on the previous work done in the 1970s. Further, current reprocessing technologies which are capable of processing the oxide fuels utilized in the majority of United States reactors are evaluated across ten attributes related to reprocessing performance. A weighted total score is provided for each reprocessing method in order to separate the technological from political or emotional issues related to selection of a process. While it is not the goal of this thesis to select a particular best technology, application of this methodology results in the selection of the COmbined EXtraction (COEX) technology when equal weighting is put on the attributes as defined. It is unlikely that a decision maker will approach this decision with equal weighting; however, actual decision maker weightings are known only to the decision makers. By altering the weightings, different technologies are selected.

Thesis (Ph.D.)--Indiana University, 2009. / Title from screen (viewed on December 1, 2009). Department of Cellular and Integrative Physiology, Indiana University-Purdue University Indianapolis (IUPUI). Advisor(s): B. Paul Herring, Anthony B. Firulli, Frederick M. Pavalko, Simon J. Rhodes. Includes vitae. Includes bibliographical references (leaves 138-149).

Person-centered care (PCC) has been recognized by the Institute of Medicine as a critical element in the redesign of our nations healthcare system. Evidence suggests that the physical environment contributes to a more person-centered inpatient healthcare experience. This study explored the relationships among demographic characteristics of individuals receiving care in skilled nursing facilities, satisfaction with nursing care, perceived ambiance of the healthcare environment, and the perception of PCC. Descriptive statistics, Pearson’s correlation, Spearman’s rho, and hierarchical linear regression were used to analyze the data and answer the research questions. In addition, content analysis was used identify possible themes from the comments by the participants regarding the overall care experience. The sample consisted of 71 individuals (48 women) between the ages of 38 and 97 (M = 71.34, SD = 11.51) having received rehabilitation and/or nursing care in fourteen short-stay SNFs in Texas. A small positive significant relationship was found between the perception of personalized care and years of education (r = .27, p = .012). Moreover, a strong positive significant relationship was found between satisfaction with nursing care and PCC (r = .76, p <. 001), perceived ambiance and PCC (r = .57, p < .001), and satisfaction with nursing care and ambiance (r = .52, p < .001). Hierarchical linear regression only included years of education, satisfaction with nursing care, and ambiance since they were the only variables that had a significant relationship with the outcome variable. The analysis showed that satisfaction with nursing care was the strongest predictor of PCC accounting for 53% of the variance. In addition, ambiance was identified as a significant predictor of the perception of PCC after controlling for education and satisfaction with nursing care. Overall, the three variables accounted for 64% of the variance in the perception of PCC. This was the first study to explore the relationship between perceived ambiance of an inpatient healthcare setting and the perception of person centered care. These findings indicate that the physical environment is an important element that can influence the perception of personalized care in a short-stay SNF setting. / text

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京都大学 / 新制・課程博士 / 博士(医学) / 甲第25183号 / 医博第5069号 / 新制||医||1071(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 遊佐 宏介, 教授 小林 恭, 教授 伊藤 貴浩 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

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In higher eukaryotes, DNA is packaged with histones and other proteins into chromatin. While this is important in the control of unwanted gene expression, chromatin also serves as a barrier to many vital functions in the cell. Therefore, cells have evolved many different types of chromatin remodeling enzymes to contend with this inhibitory structure and enable gene expression and other functions. The Saccharomyces cerevisiae PHO5 gene is triggered in response to phosphate starvation. In this study, I evaluate the chromatin remodeling requirements of this gene with respect to the multisubunit complexes SWI/SNF and SAGA. I show, for the first time, physical recruitment of SWI/SNF to the PHO5 promoter. I also demonstrate the role of promoter occupancy in influencing requirements for chromatin remodeling enzymes. Further, I describe various interactions between these two complexes at the PHO5 promoter. This study presents evidence for the first instance of excess recruitment of an ATP-dependent remodeler potentially compensating for the lack of a histone acetyltransferase.