No description available.

No description available.

Myeloid-derived suppressor cells (MDSC), emerging during tumor growth or chronic inflammation play a critical role in regulating T cell function. However, mechanisms governing the generation of these cells remain unclear, and need to be further defined. Using a DSS-induced colitis and recovery model, we characterized the dynamic changes within myeloid compartments and the emergence of MDSC during active and resolution phases of inflammation. We show that the immature myeloid compartment expands in bone marrow (BM) specifically at the resolution phase of inflammation during colitis transition to recovery. Additionally, we found enhanced levels of IL-17 in the serum of colitis mice tightly correlates with expansion of the IMC compartment, and is likely the factor responsible for expansion of these cells. Our study also determined that the expanded population of myeloid cells underwent a functional reprogramming event. In particular, two major functional changes occurred when colitic mice were allowed to recover: 1) CD11b+Gr-1+ myeloid cells in bone marrow and spleen acquired T cell suppressive functions, and 2) acquired the ability to enter into circulation from BM, confirming previously reported characteristics of MDSC. Additionally, we determined that acquired migratory capability in the low density myeloid cells isolated from resolution time points was due to enhanced surface expression of chemokine receptor CXCR2. Furthermore, we determined that after mobilization of MDSC from the bone marrow, these cells collected in the T cell-rich spleens, where they effectively functioned to suppress T cell proliferation. Through these acquired functions, our study determines a protective role for MDSC during the recovery phase of post-acute inflammation during persistent DSS-induced colitis.

ABSTRACT DNA in the eukaryotic nucleus is complexed with histone and non-histone proteins into chromatin. Nucleosomes, the basic repeating unit of chromatin, not only package DNA but are also intimately involved the regulation of gene expression. All DNA transactions including replication, transcription, recombination and repair take place in such a chromatin environment. Access to packaged nucleosomal DNA in vivo is mediated at least in part by protein complexes that modify or remodel chromatin. Buried sequences in nucleosomes can also transiently become accessible to DNA binding proteins during cycles of partial, reversible unwrapping of nucleosomal DNA from the histone octamer. We have investigated the ability of the human, bifunctional DNA glycosylase, endonuclease III (hNTH1), to initiate base excision repair (BER) of discretely positioned oxidative lesions in model nucleosomes. hNTH1 was able to process a thymine glycol (Tg) lesion almost as efficiently as naked DNA, when the minor groove of the lesion faced away from the histone octamer. Lesion processing did not require or result in detectable nucleosome disruption, as assayed in gel mobility-shift experiments. Instead, hNTH1 formed a slower migrating enzyme-nucleosome ternary complex that was found to contain processed DNA. Processing of an inward-facing Tg residue located just 5 bp away from the outward-facing lesion was much reduced and processing of a sterically occluded Tg residue positioned closer to the dyad center of the nucleosome was even more reduced. Notably, processing of both inward-facing lesions was found to increase as a function of enzyme concentration. Restriction enzyme protection studies indicated that access to these inward-facing lesions did not entail nucleosomal translocation or sliding. Collectively, these observations are consistent with a model in which hNTH1 binds to lesions during cycles of reversible, partial unwrapping of nucleosomal DNA from the histone octamer core. To further investigate this partial unwrapping hypothesis, we studied the kinetics of hNTH1 processing of sterically occluded lesions in greater detail. Our results suggest that efficiency of processing of inward-facing lesions is a function of both DNA unwrapping and rewrapping rates, and enzyme affinity for the lesion. In addition, we determined that APE1 which catalyzes the second step in BER, exhibited an increasing capacity to process inward-facing furan residues as its concentration was increased. Thus as with hNTH1, we hypothesize that APE1 can capture occluded furan residues during cycles of partial DNA unwrapping. We propose that cellular regulatory factors benefit from this intrinsic, periodic exposure of nucleosomal DNA exposure in vivo, which may be amplified by the downstream recruitment of remodeling and / or modifying proteins to facilitate DNA transactions in the cell.

Radiotherapy continues to be a primary modality in the treatment of cancer. DNA damage induced by radiation can promote apoptosis as well as both autophagy and senescence, where autophagy and senescence can theoretically function to prolong tumor survival. A primary aim of this work was to investigate the hypothesis that autophagy and/or senescence could be permissive for DNA repair, thereby facilitating tumor cell recovery from radiation-induced growth arrest and/or cell death. In addition, studies were designed to elucidate the involvement of autophagy and senescence in radiation sensitization by PARP inhibitors and the re-emergence of a proliferating tumor cell population. In the context of this work, the relationship between radiation-induced autophagy and senescence was also determined. Studies were performed using DNA repair proficient HCT116 colon carcinoma cells and a repair deficient Ligase IV (-/-) isogenic cell line. Irradiation promoted a parallel induction of autophagy and senescence that was strongly correlated with the extent of persistent H2AX phosphorylation in both cell lines; however inhibition of autophagy failed to suppress senescence, indicating that the two responses were dissociable. Irradiation resulted in a transient arrest in the HCT116 cells while arrest was prolonged in the Ligase IV (-/-) cells; however, both cell lines ultimately recovered proliferative function, which may reflect maintenance of DNA repair capacity. The PARP inhibitors (Olaparib) and (Niraparib) increased the extent of persistent DNA damage induced by radiation as well as the extent of both autophagy and senescence; neither cell line underwent significant apoptosis by radiation alone or in the presence of the PARP inhibitors. Inhibition of autophagy failed to attenuate radiation sensitization, indicating that autophagy was not involved in the action of the PARP inhibitors. As with radiation alone, despite sensitization by PARP inhibition, proliferative recovery was evident within a period of 10-20 days. While inhibition of DNA repair via PARP inhibition may initially sensitize tumor cells to radiation via the promotion of senescence, this strategy does not appear to interfere with proliferative recovery, which could ultimately contribute to disease recurrence.

Call number: LD2668 .T4 1959 R44

M.Ing. (Engineering Management) / The turbo-generator unit is very important equipment for electric power production, which has a high rate of failure. As the capacity increases, condition monitoring and fault diagnostic play a crucial role to guarantee safe operation and cost efficiency. The Eskom generator fleet is fast approaching the end of the original designed life. Also in view of the recent constrained reserve margin, outage downtime, maintenance costs, resource management, and maintenance inherent problems, a systematic approach is required to optimise scheduled time-based maintenance to improve reliability and availability. The subject of turbo machine condition monitoring requires the development of new technologies to diagnose the turbo-generator problems. Condition is an underlying factor in the performance of machines. It is also an important predictor of future performance that the machine is in a good condition and will be reliable and perform better. It provides a reference for maintenance engineers on the current condition of the turbo-generator. Trends in condition monitoring can be used to determine whether turbo-generators are being maintained and that are meeting their expected service lives or whether their performance is deterioration faster than expected. In the industry, traditional maintenance philosophies have taken two approaches; the first approach is to perform fixed time interval maintenance, where the system engineers take advantage of relaxed production cycles to fully inspect all aspects of the turbo-generator. The second route is for engineers to simply react to the generator failure as and when it happens. All too many utilities operate largely in the reactive run-to-failure mode. The old phrase, “if it aren’t broken don’t fix” is perennial run to failure argument. Nonetheless, making use of today’s technology, a new scientific methodology is becoming popular to maintenance management. For the purpose of investigating the management of condition-based monitoring and diagnostic technology to optimise timed-based maintenance of large turbo-generators, Eskom Units installed with condition monitoring techniques were considered. The minidissertation culminated in the compilation of case histories based on Eskom turbo-generator fleet where the technology is being rolled out. The literature survey looked at current industry practices in areas such as total productive maintenance (TPM), technology management and support systems, return on investment (ROI) and maintenance management to compare what Eskom is doing to what in others in the field are doing. There is no research work currently that has been done that links maintenance to maintenance technology deployment enablers. The research incorporates a number of operational experiences where some Eskom turbo-generator units continue to operate with a known fault. Regular maintenance interventions introduce faults into the machine due to human error, the opening of units and the handling of components. Attention is given to the impact of two-shifting or cyclic operation on turbo-generators that were originally designed for base load condition. The time–based maintenance of these units is not taking advantage of condition monitoring information. Also, the installed condition monitoring techniques fall short of addressing twoshifting monitoring requirements. A number of lessons were learnt from the implementation of the condition-based maintenance technology on Eskom generator fleet. The theory of maintenance management underscores establishment of a good relationship between system engineers, maintenance personnel and the technology provider which is key to success of the technology. It further indicates that this relationship must go deeper than the mere technology provider and the end user of the technology service agreement. The maintenance engineers are taking key business decision for the well-being of machines and maintenance technology needs to demonstrate that it is creating value for the business. From the people perspective attention is required to staff motivation and providing balanced job satisfaction, whilst ensuring that employees feel part of an integrated organisation maintenance strategy rather than of being under thread of disempowered by the technology. A myriad of considerations have been identified to affect the effective execution of conditionbase maintenance strategy on Eskom generator fleet. There are multiple dashboards or standards indicators that can be used for maintenance management improvement. It has been established that the success of the implementation of condition-based maintenance rests in the concept of total productive maintenance approach. Within the ambit of TPM, the entire process of maintenance must be managed on the basis of maintenance programmes plan, which will have function of connecting the various maintenance programmes.

M.Ed. (Curriculum Studies) / Please refer to full text to view abstract

Os modelos de sistemas reparáveis usuais são os de reparo mínimo, perfeito e imperfeito, sendo que, na literatura, o modelo de reparo mínimo é o mais explorado. Em sistemas reparáveis é comum que componentes do mesmo tipo sejam estudados e nestes casos é relevante verificar a heterogeneidade entre eles. Segundo Vaupel et al. (1979), os métodos padrões em análise de dados de sistemas reparáveis ignoram a heterogeneidade não observada e em alguns casos esta deveria ser considerada. Tal variabilidade pode ser estimada a partir dos modelos de fragilidade, caracterizados pela utilização de um efeito aleatório. Propõe-se o modelo de reparo mínimo com fragilidade, afim de estimar a heterogeneidade não observada entre sistemas. Para este modelo foi realizado um estudo e simulação como objetivo de analisar as propriedades frequentistas do processo de estimação. A aplicação em um conjunto de dados reais mostrou a aplicabilidade do modelo proposto, em que a estimação dos parâmetros foram determinadas a partir das abordagens de máxima verossimilhança e Bayesiana. / The usual models in repair able systems are minimal, perfect and imperfect repair, and, in the literature, the minimum repair model is the most explored. In repair able systems it is common that the same type of components are studied and in these cases is relevant to verify the heterogeneity between them. According to Vaupel et al. (1979), the standard methods for analysis of repair able systems data ignore the heterogeneity not observed and in some cases this should be considered. Such variability can be estimated from frailty models, characterized by using a random effect. It is proposed that the minimum repair model with frailty in order to estimate the heterogeneity not observed between systems. For this model it was conducted a simulation study in order to analyze the frequentist properties of the estimation process. The application of a real data set showed the applicability of the proposed model, in which the estimation of the parameters were determined from maximum likelihood and Bayesian approaches.

This dissertation focuses on developing and furthering curation as a mode of inquiry for the discipline of communication, and how concepts can lead to action (praxis) for life. It will contribute to the ongoing repair of communication and media studies by addressing how an emergent interdisciplinary curational approach leads us to reimagine media and materiality, thus redefining communication today. The study presents definitions of the key concepts in communication and media studies. To ground this curational communication research approach, interdisciplinary and integrative accounts are composed using radial category analyses of medium, media, and intermedia, as well as the emergent extensions of information, multimedia, transmedia, and metamedia. Three exemplars are presented to explore the material practices providing evidence of an applied curational approach. They focus on Jane Addams and Ellen Gates Starr’s Hull-House and Museum, the 1893 World’s (Fair) Columbian Exposition, and the collaboration between John Dewey and Albert Barnes at the Barnes Foundation. An argument is made for an embodied aesthetics, ethics, and design built along a Pragmatist line that can contribute to new notions of curation and its relation to communication, embodied meaning, and praxis. The dissertation offers a framework for engaging curation as meliorative, stewarding, and repairing. The pragmatist exemplars demonstrate an orientation to medium/media that embraces embodiment and nature to help us rethink how this mode of inquiry plays out concretely in people’s lives. Overall, the dissertation brings forward marginalized resources of embodied cognition in communication theory to revitalize and ecologize communication theory-practice. We need a novel pragmatist conception of curation, not merely preservation and presentation of artifacts, but as a participatory activity, a melioristic remaking of experience for the better, as a caring for, as a repair of, and as a stewardship supported by pragmatism.