Non-homologous end joining (NHEJ) is one of two pathways responsible for the repair of double-strand breaks in eukaryotic cells. The mechanism involves the alignment of broken DNA ends with minimal homology, fill in of short gaps by DNA polymerase(s), and ligation by XRCC4-DNA ligase IV complex. The gap-filling polymerase has not yet been positively identified, but recent biochemical studies have implicated DNA polymerase λ (pol λ), a novel DNA polymerase that has been assigned to the pol X family, in this process. Here we demonstrate that purified pol λ can efficiently catalyze gap-filling synthesis on DNA substrates mimicking NHEJ. By designing two truncated forms of pol λ, we also show that the unique proline-rich region in pol λ plays a role in limiting strand displacement synthesis, a feature that may help its participation in in vivo NHEJ. Moreover, pol λ interacts with XRCC4-DNA ligase IV via its N-terminal BRCT domain and the interaction stimulates the DNA synthesis activity of pol λ. Taken together, these data strongly support that pol λ functions in DNA polymerization events during NHEJ.

Includes abstract. Includes bibliographical references.

The purpose of this study was to explore how counselling teams draw on narrative therapy during intersession break consultations in walk-in counselling. Walk-in counselling is a form of single-session therapy (SST) that allows an individual, couple, or family to meet with a counsellor on a drop-in basis. Walk-in counselling clinics are becoming increasingly popular in Canada and globally, with a particularly high number operating in Ontario. Sessions in walk-in counselling typically involve a break partway through, during which the counsellor meets with a team of colleagues for a brief consultation; this is referred to as the “intersession break”. Narrative therapy is a postmodern therapeutic approach commonly used in walk-in counselling. Data collection occurred at two Ontarian walk-in counselling clinics and involved recording and transcribing a total of six intersession break consultations. Transcripts were examined using discourse analysis as a methodological approach. My analysis process identified four conversational practices counselling teams engaged in that drew on various aspects of narrative therapy theory. These practices are as follows: (a) counsellors engaging in externalization, (b) counsellors orienting to possible alternative narratives, (c) counsellors centring the person visiting the clinic, and (d) counsellors demonstrating tentativeness. This research is most directly relevant to counsellors working in walk-in counselling clinics and agencies offering SST involving intersession breaks. For mental health practitioners interested in postmodern therapeutic approaches, it provides a detailed account of how narrative therapy is being applied within a particular context. Finally, it may be of interest to people accessing walk-in counselling services who are curious about intersession break processes.

La presente investigación se centra en la generación de mapas de peligro por la simulación del vertido de relaves por rotura de la presa del depósito de relaves en estado pulpa ubicada en el distrito de Chocó, en Colombia mediante un modelo hidrológico – hidráulico, y la posterior clasificación de los mapas de inundación y velocidad en niveles de peligrosidad. Este tipo de simulaciones requieren de un modelo numérico capaz de analizar y desarrollar el comportamiento de un flujo hiperconcentrado en la llanura de inundación aguas abajo. Las ecuaciones que controlan el movimiento de estos tipos de flujos son las aplicadas para fluidos no newtonianos, los cuales están controlados por los parámetros reológicos, como: viscosidad dinámica, esfuerzo de fluencia y la tasa de corte. Es por ello que se ha escogido el software FLO-2D el cual cuenta con facilidad de ingreso de datos y geometría, estabilidad de rutina computacional y la facilidad de lectura de archivos de salida. Los resultados obtenidos de la simulación en el distrito de Chocó muestran de manera didáctica la delimitación de zonas de riesgo de acuerdo a la clasificación de peligro en torno a velocidades y tirantes máximos. Eso nos permitió reconocer las estructuras que comprendidas en las zonas de alto riesgo. Estos mapas de peligro servirán como herramientas para evaluaciones de alcance social, ambiental y económico y la consideración y elección de medidas a corto, mediano y largo plazo, y de carácter tanto estructural, como no estructural. / This research focuses on the generation of hazard maps by simulating the discharge of tailings due to breakage of the dam of the pulp tailings deposit located in the Chocó district, in Colombia, using a hydrological-hydraulic model, and the subsequent classification of the flood and speed maps in danger levels. These types of simulations require a numerical model capable of analyzing and developing the behavior of a hyperconcentrated flow in the downstream floodplain. The equations that control the movement of these types of flows are those applied for non-Newtonian fluids, which are controlled by the rheological parameters, such as: dynamic viscosity, creep stress and the shear rate. That is why the FLO-2D software has been chosen which has ease of data entry and geometry, computational routine stability and ease of reading output files. The results obtained from the simulation in the Chocó district didactically show the delimitation of risk areas according to the hazard classification around maximum speeds and braces. This allowed us to recognize the structures included in high risk areas. These hazard maps will serve as tools for evaluations of social, environmental and economic scope and the consideration and choice of short, medium and long-term measures, both structural and non-structural. / Tesis

Spatial ability represents our ability to mentally arrange, rotate, and explore objects in multiple dimensions. This ability has been found to be important for engineers and engineering students. Past research has shown that many interventions can be created to boost an individual’s spatial ability. In fact, past research has indicated that engineering students significantly increase in spatial ability without an intervention while they are enrolled in certain engineering courses. Some researchers have claimed that the spatial ability boosts are permanent after an intervention. However, most researchers do not check the validity of that claim with continued assessment after more than a week past the end of an intervention. Additionally, if engineering education researchers are trying to measure the impact of their separate spatial ability intervention while the participating engineering students are actively enrolled in engineering courses, a confounding variable is introduced as the courses can impact students’ spatial ability. To resolve this, the work presented in this paper reflects research on engineering students’ spatial ability maintenance during the winter break between semesters. It was found that newer students exhibit spatial ability improvement during the break, while older students maintain their spatial ability at the same level. A deeper statistical analysis revealed that there are other factors that play a role in spatial ability changes over the break that are more significant than how far students had progressed in their studies. Those factors include with academic performance, the sex of the students, playing music during the break, and prior life experiences.

Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism utilized by a subset of cancers to promote replicative immortality. The ALT mechanism is driven by increased replication stress and persistent DNA damage response signaling that leads to a homology-directed repair mechanism called break-induced telomere synthesis (BITS). In particular, ALT cells are hypersensitive to inhibition of ataxia telangiectasia Rad3-related (ATR), a DNA damage response kinase implicated in telomere mobility and recruitment of repair proteins for telomere elongation in ALT. However, little is known about what regulates ATR activity at ALT telomeres. Given the importance of ATR in the ALT mechanism, we hypothesized that known ATR activators, ETAA1 and TopBP1, regulate ALT activity and telomere synthesis. Here, we show that ETAA1 and TopBP1 localize to ALT telomeres at sites of ALT activity and telomeric damage. Furthermore, depletion of ETAA1 and TopBP1 leads to defects in ATR signaling, a decrease in BITS and compensatory engagement of telomeric MiDAS (spontaneous mitotic telomere synthesis) for replication stress resolution. Taken together, our findings show that both ETAA1 and TopBP1 are important for mediating BITS at ALT telomeres and may better inform our efforts in targeting the ATR signaling pathway in ALT-positive cancers.

No description available.

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第18083号 / 理博第3961号 / 新制||理||1571(附属図書館) / 30941 / 京都大学大学院理学研究科地球惑星科学専攻 / (主査)教授 千木良 雅弘, 教授 釜井 俊孝, 准教授 松四 雄騎 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18879号 / 医博第3990号 / 新制||医||1008(附属図書館) / 31830 / 京都大学大学院医学研究科医学専攻 / (主査)教授 髙田 穣, 教授 平岡 眞寛, 教授 小松 賢志 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(人間・環境学) / 甲第19068号 / 人博第721号 / 新制||人||173(附属図書館) / 26||人博||721(吉田南総合図書館) / 32019 / 京都大学大学院人間・環境学研究科相関環境学専攻 / (主査)教授 小松 賢志, 教授 宮下 英明, 准教授 三浦 智行 / 学位規則第4条第1項該当 / Doctor of Human and Environmental Studies / Kyoto University / DFAM