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El presente trabajo tesis tiene como objetivo mostrar los procesos de: Inicio, planificación, ejecución, monitoreo y control y cierre de los entregables de gestión y construcción dentro del proyecto inmobiliario, Edificio Barcelona 209. El esquema de desarrollo de la tesis se ejecutará en cinco capítulos en los que se pasa por todas los procesos la Guía del PMBOK 5ª edición, partiendo de la configuración del Caso de negocio del proyecto desde el marco referencial de la empresa; marco conceptual en el que se exponen las bases que rigen la dirección de proyectos basada en la Guía del PMBOK 5ª edición; identificando la documentación en los grupos de proceso de: inicio, planificación, ejecución control y cierre y por último se cierra con las conclusiones y recomendaciones. Esta tesis servirá de guía para los proyectos de la empresa aumentando los activos de procesos de la organización. / Tesis

The need of a stable production of At-211 is necessary to continue research in alpha-particle targeted radionuclide therapy. Our objectives were to establish the production of Astatine-211 at Texas A&M Cyclotron Institute, optimize the production methods to reduce the generation of contaminants and maximize At-211 production, and assess the radiological safety aspects of At-211 production. The production of the alpha-particle emitting radionuclide At-211 was performed at the Texas A&M Cyclotron Institute using the K500 superconducting cyclotron following the production reaction Bi-209(α, 2n)At-211 using a thick bismuth target of 500 μm. We carried out two irradiation experiments where the initial energy of the alpha-particle beam, 80 MeV, was degraded using multiple copper and aluminum foils to 27.8 and 25.3 MeV, respectively. The end of beam time was 4 hours for both experiments. The resulting At-211 yields were 36.0 and 12.4 MBq/μA-h, respectively. Several impurities were produced using the 27.8 MeV, which included At-210 and Po-210. However, when the 25.3 MeV beam was used, the impurities At-210 and Po-210 were resolved and other contaminants were minimized to less than 0.8% of At-211 yield. The production yields were in accordance to previous published results. From the success of these initial experiments, additional steps were taken to produce At-211 in excess quantities for distillation purposes. In order to obtain viable quantities of At-211, the gross yield needed to be increased due to losses that are incurred during distillation and radioactive decay. The ability to produce high yields of this isotope required a redesign of the target and use of the K150 cyclotron using a higher beam intensity.

William H. Kautz. / "April 23, 1952." / Bibliography: p. 176-177. / Army Signal Corps Contract No. DA36-039 sc-100 Project No. 8-102B-0. Dept. of the Army Project No. 3-99-10-022.

No abstract available / Old Testament / D.Th. (Old Testament)

Multiple myeloma (MM) is a hematological malignancy of antibody producing plasmablasts/plasma cells. MM is characterized by extensive genetic and clonal heterogeneity, which have hampered the attempts to identify a common underlying mechanism for disease establishment and development of appropriate treatment regimes. This thesis is focused on understanding the role of epigenetic regulation of gene expression mediated by the polycomb repressive complexes 1 and 2 (PRC1 and 2) in MM and their impact on disease biology and therapy. In paper I the genome-wide distribution of two histone methylation marks; H3K27me3 and H3K4me3 were studied in plasma cells isolated from newly diagnosed MM patients or age-matched normal donors. We were able to define targets of H3K27me3, H3K4me3 and bivalent (carry both marks) which are, when compared to normal individuals, unique to MM patients. The presence of H3K27me3 correlated with silencing of MM unique H3K27me3 targets in MM patients at advanced stages of the disease. Notably, the expression pattern of H3K27me3-marked genes correlated with poor patient survival. We also showed that inhibition of the PRC2 enzymatic subunit EZH2 using highly selective inhibitors (GSK343 and UNC1999) demonstrated anti-myeloma activity using relevant in vitro models of MM. These data suggest an important role for gene repression mediated by PRC2 in MM, and highlights the PRC2 component EZH2 as a potential therapeutic target in MM. In paper II we further explored the therapeutic potential of UNC1999, a highly selective inhibitor of EZH2 in MM. We showed that EZH2 inhibition by UNC1999 downregulated important MM oncogenes; IRF-4, XBP-1, BLIMP-1and c-MYC. These oncogenes have been previously shown to be crucial for disease establishment, growth and progression. We found that EZH2 inhibition reactivated the expression of microRNAs genes previously found to be underexpressed in MM and which possess potential tumor suppressor functions. Among the reactivated microRNAs we identified miR-125a-3p and miR-320c as predicted negative regulators of the MM-associated oncogenes. Notably, we defined miR-125a-3p and miR-320c as targets of EZH2 and H3K27me3 in MM cell lines and patients samples.  These findings described for the first time PRC2/EZH2/H3K27me3 as regulators of microRNA with tumor suppressor functions in MM. This further strengthens the oncogenic features of EZH2 and its potential as a therapeutic target in MM. In paper III we evaluated the therapeutic potential of targeting PRC1 in MM using the recently developed chemical PTC-209; an inhibitor targeting the BMI-1 subunit of PRC1. Using MM cell lines and primary cells isolated from newly diagnosed or relapsed MM patients, we found that PTC-209 has a potent anti-MM activity. We showed, for the first time in MM, that PTC-209 anti-MM effects were mediated by on-target effects i.e. downregulation of BMI-1 protein and the associated repressive histone mark H2AK119ub, but that other subunits of the PRC1 complex were not affected. We showed that PTC-209 reduced MM cell viability via significant induction of apoptosis. More importantly, we demonstrated that PTC-209 shows synergistic anti-MM activity with other epigenetic inhibitors targeting EZH2 (UNC1999) and BET-bromodomains (JQ1). This work highlights the potential use of BMI-1 and PRC1 as potential therapeutic targets in MM alone or in combination with other anti-MM agents including epigenetic inhibitors.

Vocal communication allows animals to express distress, territoriality, and most important, to attract mates. In the African Clawed frog, Xenopus laevis, vocal communication is unique, because not only do males advertise for mates using elaborate click vocalizations, but also females are able to advertise their reproductive readiness by eliciting a "rapping" call. Sex differences in vocal repertoire match sex differences in vocal circuitry. During development, the vocal circuitry in the male grows increasingly sensitive to circulating androgens. Androgens induce tremendous growth in the cartilage and musculature of the peripheral vocal organ, the larynx. Net addition of synapses and motor fibers soon follow providing communication from the motor nucleus in the hindbrain to the vocal organ. The laryngeal motor nucleus, n. IX-X, accumulates androgens that serve to protect n. IX-X neurons from programmed apoptosis. Females, who have low levels of circulating androgens, experience a profound net loss on n. IX-X neurons during this developmental critical period. Once the frogs reach sexual maturity males possess larger and more numerous n. IX-X neurons than females, as well as sizable sex differences in laryngeal robustness and physiology. These measurable sex differences yield vastly different vocal programs. Androgens continue to maintain a critical role in governing breeding season trophic effects and mediating call production. Because male X. laevis are so susceptible to the effects of androgens, they may also be sensitive to the actions of endocrine disrupting chemical agents. The vocal system of X. laevis and its androgen sensitivity thus provide an ideal model for studying changes imposed to the anatomy and physiology of the system by the brominated flame retardant, PBDE-209, a putative anti-androgen and common pollutant. The present studies investigate how PBDE-209 affects the male vocal system when animals are exposed during the androgen-sensitive critical period of vocal system development and during adulthood when the tissues are utilizing androgens to vocalize. PBDE-209 effectively reduces male n. IX-X number and size at higher concentrations after exposure during the organizational critical period. Similar dose-dependent effects were observed in adult n. IX-X neurons. Moreover, PBDE-209 inhibited male-typical vocalization by reducing the number of calls elicited as well as the average call amplitude. These data strongly suggest that PBDE-209 has cytotoxic effects that alter n. IX-X anatomy and function, and may be mediated through pathways that include blocking the androgens necessary for proper vocal system development.

The objective of this thesis was to assess the environmental fate and transport of chemicals emitted from consumer products through the development and application of modelling tools. The following hypotheses were tested: i) Multimedia fate models can be applied in a multistage assessment process to emerging chemicals when limited knowledge exists to identify the likely environmental fate and to direct further research; ii) the indoor environment acts as a source of anthropogenic substances in consumer products to the outdoor environment; and iii) chemical removal pathways in the indoor environment are important for the fate of organic chemicals in densely populated areas. The thesis shows that a structured chemical fate assessment strategy can and should be applied at early stages of the evaluation of emerging chemicals to assess their fate and to direct further research. Multimedia fate models play a key role in this strategy. The three‐solubility approach is a simple, rapid method that can be used to estimate physical‐chemical properties for use in early stage evaluation (Paper I). Emissions in the indoor environment affect the urban fate of hydrophobic organic chemicals by providing additional removal pathways and prolonging urban chemical residence times compared to outdoor emissions (Paper III). Emissions of BDE 209, DINP and DEHP to Stockholm indoor air were estimated to be 0.1, 3.4 and 290 mg/capita year, respectively (Paper IV). The contribution of emissions indoors to outdoor air pollution varies between substances. For BDE 209, emissions in the indoor environment added 38 % to the mass entering Stockholm city with inflowing air. For Sweden, the indoor environment was estimated to account for 80 % of BDE 209 emissions to outdoor air (Papers II and IV). For the phthalates, outdoor emissions and/or background inflow are the dominant sources to outdoor air pollution in Stockholm and the influence of the indoor environment is limited (Paper IV). / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript</p>