The p38MAPK-MK2-HSP27 axis regulates the mRNA stability of the pro-tumorigenic senescence-associated secretory phenotype

Protecting the genome is a vital aspect of safeguarding organismal health. Inability to efficiently and effectively replicate the genome or repair damage the genome may encounter can lead to mutational accumulation or senescence, both of which are drivers of multiple diseases including cancer. Understanding the mechanisms by which the genome is maintained, as well as the consequences of repeated rounds of replication or exposure to DNA damaging agents, will allow for greater understanding of the diseases they promote as well as development of targeted therapies aimed at mitigating the detrimental effects of genomic insult. The first section of my work focuses on cellular senescence, a consequence of both aging and DNA damage. Aging is a significant risk factor for the development of cancer. The increase in disease in aged individuals is due in part to the time required for epithelial cells to accumulate mutations necessary to become tumorigenic, and by the increase in senescent cells within their tissues. Senescent cells express a coordinately upregulated family of pro-tumorigenic factors termed the senescence-associated secretory phenotype, or SASP. The SASP is rich in growth factors, immune modulators, and matrix remodelers that together create an environment primed for tumor development. Here, I study the mechanisms that regulate expression of the SASP in response to DNA damage. In cells exposed to a senescence-inducing stimulus but that do not yet display classical senescence markers, SASP expression is reliant upon active transcription for upregulation. However, senescent cells maintain SASP factor upregulation through post-transcriptional stabilization. Previous work demonstrated that this transition is dependent on the stress kinas p38MAPK, and p38MAPK inhibition prevents upregulation and stabilization of SASP factor mRNAs by modulating the binding of AUF1, a protein that binds regulatory sequences in target mRNAs and largely targets them for degradation. AUF1 is not a direct target of p38MAPK activity, however. In this work, I demonstrate that AUF1 regulation and therefore mRNA stabilization of SASP factors occurs through the p38MAPK-MK2-HSP27 pathway. Furthermore, inhibition of MK2 activity abrogates the ability of senescent cells to promote preneoplastic cell growth, suggesting MK2 inhibition is an attractive therapeutic target that warrants further investigation. In the second section of this work, the role of the essential helicase/nuclease Dna2 in DNA replication is investigated. Maintaining genomic stability is essential to preventing mutational accumulation and cancer development, and both elevated Dna2 expression levels in human cancers and heterozygous deletion in mice have been linked to cancer incidence and poor disease outcome. Dna2’s role in DNA replication was initially described in yeast, where it was hypothesized to function in lagging strand DNA replication, namely in Okazaki fragment maturation. However, work described here demonstrates that while shRNA-mediated depletion of Dna2 results in activation of the replication stress checkpoint and phenotypes indicative of replication defects, Okazaki fragment maturation is not measurably affected in human cells. Therefore, Dna2 plays an additional role in DNA replication that is required to ensure high fidelity duplication of the genome during cell division. Together, my work highlights the essential nature of genomic preservation, and consequences that arise when genome stability is threatened

A spatial sampling scheme for a road network

Rabies has been reported in Tanzania, mainly in the southern highland regions, since 1954. To date, rabies is endemic in all districts in Tanzania and efforts are being made to contain the disease. It was determined that mass vaccination of at least 70% of an animal population is most effective, in terms of profitability and cost, in reducing transmission of rabies. The current approach for vaccination in Tanzanian villages takes some features from the EPI method but is rather basic and unreliable. This mini-dissertation proposes using a sampling technique which incorporates the spatial component of the village data and minimises the walking distance between the sampled houses while ensuring the 70% coverage of the animal population.Mini Dissertation(MSc)--University of Pretoria, 2017.STATOMET The Centre for Artificial Intelligence Research (CAIR) National Research Foundation of South Africa (NRF CSUR grant number 90315)StatisticsMScUnrestricte

Extreme radio-wave scattering associated with hot stars

We use data on extreme radio scintillation to demonstrate that this phenomenon is associated with hot stars in the solar neighbourhood. The ionized gas responsible for the scattering is found at distances up to 1.75pc from the host star, and on average must comprise 1.E5 distinct structures per star. We detect azimuthal velocities of the plasma, relative to the host star, up to 9.7 km/s, consistent with warm gas expanding at the sound speed. The circumstellar plasma structures that we infer are similar in several respects to the cometary knots seen in the Helix, and in other planetary nebulae. There the ionized gas appears as a skin around tiny molecular clumps. Our analysis suggests that molecular clumps are ubiquitous circumstellar features, unrelated to the evolutionary state of the star. The total mass in such clumps is comparable to the stellar mass.Comment: 9 pages, 1 figure, to appear in Ap

Identification of communication and coordination issues in the U.S. air traffic control system

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Aeronautics and Astronautics, 2001.Includes bibliographical references (p. 135-136).by Hayley J. Davison.S.M

Modeling the Air Traffic Controller's Cognitive Projection Process

Cognitive projection enables the operator of a supervisory control system, such as air traffic control, to use predicted future behavior of the system to make decisions about if and how to control the system. New procedures and technologies being implemented in the air traffic control system innately affect the information used for projection and the type of projection required from the controller. Because cognitive projection is not well-understood, launching these projection-impacting technologies and procedures could result in the reluctance of the air traffic controllers to accept these advancements or limit the system performance. A Projection Process Model and a Projection Error Concept were proposed to describe the controller’s projection process and the contextual system influences on the projection process. The two primary influences on the projection process were the information/display system and task-based projection requirements. A mismatch between the information/display system states and the task-based projection requirements was described through a cognitive transform concept. The projection process itself is composed of the state mental model and the time into the future over which the projection is made. Hypotheses based on the assumptions of the Projection Process Model and Projection Error Concept were probed through an experiment using an ATC task paradigm. Results were consistent with the proposed models. They suggested that the controllers were able to incorporate higher-level dynamics into the state mental models used for projection and that the quality of the state mental model used was marginally influenced by the error tolerance required in the task. The application of the Projection Process Model and Projection Error Concept was then illustrated through the analysis of the impact on projection from two ATC domain examples of technology and procedure implementation. The Constant Descent Approach Procedure in the TRACON impacted the intent, projection timespan, and abstractions used in the mental model of the controllers. The Oceanic ATC surveillance, communication and workstation improvements resulted in an impact on the states to be projected, intent, projection timespan, and human/automation projection responsibility. Suggestions for improved transition for the projection process were then provided based on the analysis

EVN & MERLIN studies of a new sample of BL Lac objects

The recent Deep X-ray Radio Blazar Survey (DXRBS) has identified a sample of BL Lac objects spanning the intermediate range of spectral energy distributions between “classical” X-ray selected and radio-selected samples of BL Lacs. Detailed studies of such samples are needed to answer some of the currently open questions regarding the nature of BL Lacs and their place in a unified model of AGN. High-resolution radio imaging provides direct information on jet evolution and beaming parameters. We present some preliminary results from EVN & MERLIN observations of sources in the DXRBS BL Lac sample for which little or no high-resolution radio data were previously available

Human Factors Implications of Continuous Descent Approach Procedures for Noise Abatement

Abstract Continuous Descent Approach (CDA) procedures can be effective at reducing aircraft noise in the vicinity of airports. The human factors implications for the air traffic controller of transitioning from conventional to CDA procedures are addressed in this paper. Different types of CDA procedures are introduced and models are developed of the controller tasks undertaken during current approach operations. The models are used to perform cognitive difference analyses to highlight the implications of using CDA procedures, particularly with respect to differences in intent, controllability and structure-based abstractions in the lateral, vertical and speed domains. An experiment is presented which probes the cognitive implications of changing speed profiles during the approach, which was one of the key differences between the procedures identified in the cognitive difference analysis. Based on the results, recommendations are made for CDA procedure design with a view to easing transition and controller acceptance

Time domain studies of Active Galactic Nuclei with the Square Kilometre Array

Variability of radio-emitting active galactic nuclei can be used to probe both intrinsic variations arising from shocks, flares, and other changes in emission from regions surrounding the central supermassive black hole, as well as extrinsic variations due to scattering by structures in our own Galaxy. Such interstellar scattering also probes the structure of the emitting regions, with microarcsecond resolution. Current studies have necessarily been limited to either small numbers of objects monitored over long periods of time, or large numbers of objects but with poor time sampling. The dramatic increase in survey speed engendered by the Square Kilometre Array will enable precision synoptic monitoring studies of hundreds of thousands of sources with a cadence of days or less. Statistics of variability, in particular concurrent observations at multiple radio frequencies and in other bands of the electromagnetic spectrum, will probe accretion physics over a wide range of AGN classes, luminosities, and orientations, as well as enabling a detailed understanding of the structures responsible for radio wave scattering in the Galactic interstellar medium