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Ataxia-telangiectasia mutated gene product (ATM) is a 350 kDa Serine/Threonine kinase belonging to the family of Phosphatidylinositol-3 kinase like kinases. ATM functions as a key element in DNA Damage Response (DDR), a mechanism that maintains genomic integrity within the cells. ATM is activated after double stranded DNA damage and initiates signalling cascades that determine the process of decision-making of cell fate and involves the participation of multiple proteins. This vital protein acts first by sensing double stranded DNA breaks and second by transducing the signal and activating other downstream proteins of the repair pathway via its kinase function. This provides an important link between signals generated after DNA damage, the cell cycle pathway and apoptotic machinery. This function is crucial for mammalian cells which are constantly challenged by genotoxic agents from a variety of sources and therefore require a robust sensing and repair mechanism to maintain cell vitality. Cells lacking ATM are hypersensitive to cytotoxic insults, particularly genotoxic stress, induced through radiation or radiomimetic drugs. This thesis describes the discovery and characterisation of novel autoregulatory feedback loops of ATM kinase in human cells. Firstly, I have discovered that inhibition of ATM kinase activity causes induction of ATM protein expression followed by time dependent oscillations. This novel autoregulatory mechanism was demonstrated in cell cycle independent manner and both in the absence and presence of DNA damage. ATM promoter assay revealed that this autoregulation was governed at the transcriptional level. Furthermore, this autoregulatory induction of ATM was also accompanied by a transient upregulation of P53, pATR and E2F1 levels. Elucidation of the underlying trafficking mechanism of ATM during such autoregulation and in DDR also revealed a novel ATM sub-cellular trafficking mechanism which was dependent on its own kinase activity. This trafficking mechanism involved DNA damage induced Golgi to nuclear transport of phosphorylated ATM S-1981 to elicit DDR. This was found to be a conserved pathway required during the initiation of DDR and was demonstrated in multiple cell lines. Further studies into the sub-cellular transport machinery revealed the involvement of β-COPI coatomer protein in this mechanism of ATM trafficking, which was found to be autoregulated by ATM kinase, and required 387-388 ATM di-Lysine motif. The discovery of these functionally important autoregulatory mechanisms of ATM were further utilised to develop Luciferase reporter based biosensor of DNA damage and single cell fluorescence based ATM inhibition assay to screen for ATM inhibitors. Finally, following the discovery and characterisation of these functional spatio-temporal autoregulations of ATM, quantitative estimations of the kinetics of signalling cascades initiated by it during DDR and its overall outcome on cellular fate were determined to study ATM pathway systematically for employing a quantitative systems biology approach. These novel findings have immensely increased our understanding of ATM regulation and function. Elucidation of the mechanisms of novel autoregulations of ATM provide new dimensions through which DDR pathway could be manipulated, and as such could be utilised for achieving targeted cellular sensitivity in therapeutic intervention of cancer.

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Successful organizational change experience can be easily copied by another organization in the same culture. Residence Administration (R.A.) in Taiwan had a wonderful change experience that can be learned by another public organizations in Taiwan. This paper used Sastry¡¦s(1997) organizational change theory and dynamic feedback loops to research the R.A.¡¦ successful change stories and compare with one health organization for deeper understanding. We know successful change is a dynamic structure, and found some helpful strategies for successful public organizational change: 1. Organizational performance was being influenced by two loops, strategy appropriateness loop and competence establishment loop. 2. Strategy appropriateness loop shows that frequently changing organizational main strategies would lead to bad organizational performance. 3. Competence establisyhment loop shows that there must be enough time to establish new competence for performing new strategies. 4. Change ability loop shows that higher organizational inertia led to lower organizational ability to adapt to its environment. 5. Inertia created loop shows that organizational inertia is highly related to its socialized process. According to the dynamic feedback loops, one organization could figure out its present situation and think its change strategies. This paper showed that Sastry¡¦s theory could explain the R.A.¡¦s change strategies well. Other public organizations can use R.A.¡¦s experience to make their own successful change stories.

The transportation system is vital to the nation’s economic growth and stability, as it provides mobility for commuters while supporting the United States’ ability to compete in an increasingly competitive global economy. State Transportation Agencies across the country continue to face many challenges to repair and enhance highway infrastructure to meet the rapid increasing transportation needs. One of these challenges is maintaining an adequate and efficient agency staff. In order to effectively plan for future staffing levels, State Transportation Agencies need a method for forecasting long term staffing requirements. However, current methods in use cannot function without well-defined projects and therefore making long term forecasts is difficult. This dissertation seeks to develop a dynamic model which captures the feedback mechanisms within the system that determines highway staffing requirements. The system dynamics modeling methodology was used to build the forecasting model. The formal model was based on dynamic hypotheses derived from literature review and interviews with transportation experts. Both qualitative and quantitative data from literature, federal and state database were used to support the values and equations in the model. The model integrates State Transportation Agencies’ strategic plans, funding situations and workforce management strategies while determining future workforce requirements, and will hopefully fill the absence of long-term staffing level forecasting tools at State Transportation Agencies. By performing sensitivity simulations and statistical screening on possible drivers of the system behavior, the dynamic impacts of desired highway pavement performance level, availability of road fund and bridge fund on the required numbers of Engineers and Technicians throughout a 25-year simulation period were closely examined. Staffing strategies such as recruiting options (in-house vs. consultants) and hiring levels (entry level vs. senior level) were tested. Finally the model was calibrated using input data specific to Kentucky to simulate an expected retirement wave and search for solutions to address temporary staffing shortage.

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As some of the most important and widely utilised intercellular signalling molecules, transforming growth factor βs (TGFβs) play critical roles in normal development and in human disease. Establishing appropriate levels of signalling involves positive and negative feedback, driven by the same signal transduction components, but whether or how the two are distinguished has not previously been understood. Here we show that LIM domain binding proteins (Ldbs) drive the Smad6/7-mediated negative feedback of TGFβ signalling, but they are not required for the ligand-driven positive feedback or other downstream transcriptional activation. In Ldb-deficient zebrafish embryos, the homeostasis of TGFβ signalling is perturbed. As a consequence, signalling of TGFβ family members, Nodal and BMP, is stably enhanced, giving rise to excess mesoderm and endoderm, an effect that can be rescued by reducing Nodal and BMP. Later in development, conditional ldb2a knockdown causes defective vascular, angiogenic and haemogenic development, likely also by elevating TGFβ signalling. Thus, Ldbs control the homeostatic regulation of TGFβ signalling and therefore play critical roles in diverse developmental processes.

On the 24th of February 2022, interstate war on a scale unseen since World War II returned to Europe, causing devastating suffering and loss of human life. As of writing, Ukraine’s ability to demonstrate battlefield success is frequently cited as key to sustain Western political willpower to send military aid. This study aims to test presumptions of a positive feedback loop between military assistance and its successful implementation with a mixed-method approach. Regression models analyze time-series data tracking a year of 33 countries’ military aid commitments to Ukraine using random effects (RE) to control for unobserved, country-specific and varying mediating variables. Based on German aversiveness to military solutions, a least-likely case debate analysis analyzes three Bundestag debates to uncover lawmakers’ justifications for approving or rejecting military aid proposals. Applying a theory-generating analysis framework, battlefield successes are confirmed as recurring arguments used to enforce pro-aid narratives, but do not necessarily overcome factors constraining military aid commitments. The RE regression finds a statistically significant positive relationship between Ukrainian battlefield success and military aid commitments. This raises immense implications for Ukrainian decisionmakers, who may be compelled to prioritize short-term military gains to secure future Western support.

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This study examines the impact of academic and personal life on graduate student persistence and transformation. Of particular interest are the relationships, emotions, and life management skills required throughout the graduate experience and how socialization, emotional intelligence, and advising aid students through their academic program. With an average of seven to eight years required to complete a doctoral program, life happens. Students enter and leave relationships, children are born, family members have emergencies, health issues arise, and emotional growth takes place. Therefore, students transform not only academically, but in many ways. These are intertwined as evidenced by the data-derived system representation. The importance of understanding the interconnected links in graduate experience spans academic, social, economic, and societal spheres. Each year hundreds of thousands of students enter graduate school. However, for doctoral students, there is an enormous gap between acceptance and completion. After seven years, approximately 50 percent complete their program and after ten years the rate climbs to only 57 percent (Council of Graduate Schools, 2010). This study offers a systemic representation and a four-stage model of graduate student development, incorporating student-identified factors: Faculty Impact, Life Management, Relationships, Playing the Game, Growth/Transformation, Emotions, and Reward/Purpose. Stage I: Orientation and Socialization Stage II: Adjustment and Transition Stage III: Navigation and Transformation Stage IV: Completion and Advancement The results, presented as a systems-based model, along with analysis, may be used to support faculty, advisors, and administrators in creating better advising, orientation, evaluation, and support systems. Departmental policies may be improved to identify at-risk students, provide mentorship opportunities, or obtain continual feedback to understand the underlying factors that may stop students from progressing. This research might also help identify students during the application/admission process. The methodological framework used to create the system produced in this study is Interactive Qualitative Analysis (Northcutt & McCoy, 2004), a methodology that provides the quantitative rigor of algorithmically generated data analysis, combined with the qualitative descriptiveness of interviews, in order to provide insights into the drivers of graduate school persistence. This methodology uses a systematic, protocol-driven research procedure to construct a unified, descriptive diagram to illustrate the phenomenon. / text