In this study, we aim to develop new likelihood based method for estimating parameters of ordinary differential equations (ODEs) / delay differential equations (DDEs) models. Those models are important for modeling dynamical processes that are described in terms of their derivatives and are widely used in many fields of modern science, such as physics, chemistry, biology and social sciences. We use our new approach to study a distributed delay differential equation model, the statistical inference of which has been unexplored, to our knowledge. Estimating a distributed DDE model or ODE model with time varying coefficients results in a large number of parameters. We also apply regularization for efficient estimation of such models. We assess the performance of our new approaches using simulation and applied them to analyzing data from epidemiology and ecology.

Application of chemotherapeutic agents in current cancer treatment has been limited by adverse effects as poor selectivity results in systemic toxicity; most chemotherapy approaches also experience inherited or acquired drug resistance which lead to reduced treatment outcome. Research efforts have focused on the discovery of novel chemotherapies that overcome the limitations mentioned above. Ru(II) polypyridyl complexes with anti-cancer properties have been extensively studied as traditional cytotoxic agents and photodynamic therapy agents due to their photophysical and photochemical characteristics. Most research has focused on the design of Ru(II) polypyridyl complexes that have affinities to nucleic acids as inspired by the classic small molecule metal complex cisplatin. Though modifying the structures of ligands on the ruthenium metal center, the hydrophilicity, charge state and photochemical properties can be tuned, resulting to Ru(II) polypyridyl complexes that act through cellular targets other than DNA. Understanding the mechanism of action and identifying functional targets remain the challenging and complex research topic in the design and study of novel medication or candidates. With the development of semi-high throughput cytological profiling in a bacterial system, rapid investigation of the mechanism of action can be achieved to distinguish anti-cancer agents which possess different mechanisms of actions. Ru(II) polypyridyl complexes with different scaffolds have been studied and suggested to have anti-cancer properties through DNA damage response, and/or translational inhibition.

Positive community-police relations, which are based on mutual trust, are key to equitable and just policing. Use of force that is perceived as unfair and biased can quickly undermine relations between the police and the public. In an attempt to understand what psychological factors contribute to police use of force decisions and potentially racially biased use of force application, this study proposed masculinity threat as an important psychological factor that influences police behavior. Masculinity threat occurs when a man's status as a man is threatened, and threats to masculinity are often associated with increased aggression and dominance as a way of restoring the threatened status. Policing is a male-dominated field, and because most victims of officer use of force are men, the current research examines how threats to male police officers' masculinity, including verbal and physical manifestations of threat, contribute to officer force against civilians. Past research has explored how high levels of trait masculinity threat (as measured by the Male Gender Role Stress scale; Goff, Martin, & Gamson-Smiedt, 2012) in police officers is associated with higher levels of force against racial minority suspects, however, no such research has examined state level masculinity threat (e.g., in the moment threats) as they occur in real world police-suspect interactions. Focusing on understanding the associations between use of force and state level masculinity threat, it was predicted that officers who have their masculinity explicitly and publicly threatened by male suspects will use more force against suspects compared to interactions where no such masculinity threat has occurred. It was also predicted that minority suspects who threaten officers' masculinity will receive more force than White suspects. To test these hypotheses, reporting officers' (RO) narratives of use of force interactions (excluding lethal force) from a large police department on the West Coast were coded and analyzed. Contrary to the hypotheses, results suggest that masculinity threat within an officer-suspect interaction may relate to lower levels of average officer force and higher number of sequences (e.g., back and forth exchanges) between suspect and officer. While results are in the opposite direction of the hypotheses, they provide new information regarding the association between personal threats to officer manhood and their subsequent actions. Specifically, results suggest that masculinity threat has a more complicated relationship with force than previously predicted and future research would do well to investigate a potential interaction effect of trait level and state level masculinity on police use of force decisions. Several other areas of further research are outlined, such as the need to examine other suspect-level and officer-level variables such as age and tenure. Overall, the results of this study suggest the need for continued clarifying research.

Previous researchers have found mass murderers characterized as loners, victims of bullying, goths, and individuals who had a psychotic break. A gap in the literature that remained concerned the motive and mindset of mass murderers before their attack, particularly those who seek fame, and why they are motivated by such violent intentions. The purpose of this study was to provide a deeper analysis of the characteristics of fame-seeking individuals who have completed or attempted mass murder, as well as insight into their behavior on social media. The conceptual framework consisted of a constructivist model, which guided the exploration the purposeful sample of 12 Americans who completed or attempted mass murder. The research questions aligned with themes provided by Bandura's social learning theory, Sulloway's theory of birth order and family dynamics, Millon and Davis's psychopathy theories, O'Toole's findings on the copycat effect, and Lankford's criteria for fame-seeking mass murderers, and guided an analysis of open-source data. Six main themes among fame-seeking individuals in the United States who had completed or attempted mass murder emerged: (a) fame as primary motivation, (b) preoccupation with violence, (c) presence of specific role models/copycat behavior, (d) strong opinions about society/racial groups, (e) symptoms of narcissism/mood disorder/personality disorder, and (f) failed relationships. These findings add to the knowledge about mass murder and fame seeking. Social change may occur through recommended evaluation of and improvements in current mental health approaches, improved threat assessment, expanded education on characteristics of mass murderers, and dissemination of information related to mass murder.

Approximately 35.1% of live births for the state of Georgia were delivered by the cesarean delivery procedure with significant variation among hospitals. The purpose of this research was to develop a population-based hospital profiling methodology for study of the cesarean delivery procedure. This was a retrospective, observational design, using a 2012 linked dataset that included maternity deliveries from all nonfederal hospitals. The research was guided by Robson 10 Group Classification System, propensity score methodologies, and ethical precepts, for the development of hospital profiles and the study of variations in the cesarean delivery procedure. Key research questions aimed to determine whether hospital profiling methodologies differed according to risk adjustment methods and statistical techniques. Propensity score matching with stratification methods aimed to determine whether there were differences in patient treatment effects on the cesarean delivery outcome. Findings suggested there was a significant difference in hospital ranks and model effects according to the statistical technique and the risk adjustment methods applied. Propensity score matching with stratification demonstrated an increased risk of the cesarean delivery procedure across strata, with the majority of high risk patients situated in the 90th percentile ranges and questionable utilization practice among other strata. Applying profiling methodologies at the facility and population level could advance statewide quality improvement programs for the timely reduction in the variation of inappropriate utilization of the cesarean delivery procedure.

Apomixis, asexual or clonal seed production in plants, can decrease the cost of producing hybrid seed and enable currently open pollinated crops to be converted to more vigorous and higher yielding hybrids that can reproduce themselves through their own seed. Sexual reproduction may be triggered by a programmed stress signaling event that occurs in both the meiocyte, just prior to meiosis, and later in the egg just prior to embryo sac maturation. The prevention of stress signaling and the activation of a pro-growth signal prior to meiosis triggered apomeiosis, the first half of apomixis. The same approach was used prior to embryo sac maturation to trigger parthenogenesis, the second half of apomixis. This discovery suggests that apomixis exists as a program that can be activated by the appropriate metabolic signal at the appropriate developmental stages. Therefore, apomixis may be alternative mode of reproduction rather a ‘broken’ form of sexual reproduction.

In this dissertation, I utilize digital holographic microscopy (DHM) to study the motility of biological cells. As an important feature of DHM, quantitative phase microscopy by digital holography (DH-QPM) is applied to study the cell-substrate interactions and migratory behavior of adhesive cells. The traction force exerted by biological cells is visualized as distortions in flexible substrata. Motile fibroblasts produce wrinkles when attached to a silicone rubber film. For the non-wrinkling elastic substrate polyacrylamide (PAA), surface deformation due to fibroblast adhesion and motility is visualized as tangential and vertical displacement. This surface deformation and the associated cellular traction forces are measured from phase profiles based on the degree of distortion. Intracellular fluctuations in amoeba cells are also analyzed statistically by DH-QPM. With the capacity of yielding quantitative measures directly, DH-QPM provides efficient and versatile means for quantitative analysis of cellular or intracellular motility. Three-dimensional profiling and tracking by DHM enable label-free and quantitative analysis of the characteristics and dynamic processes of objects, since DHM can record real-time data for micro-scale objects and produce a single hologram containing all the information about their three-dimensional structure. Here, I utilize DHM to visualize suspended microspheres and microfibers in three dimensions, and record the four-dimensional trajectories of free-swimming cells in the absence of mechanical focus adjustment. The displacement of microfibers due to interactions with cells in three spatial dimensions is measured as a function of time at sub-second and micrometer levels in a direct and straightforward manner. It has thus been shown that DHM is a highly efficient and versatile means for quantitative tracking and analysis of cell motility.

Despite improvements in the clinical management of soft tissue sarcomas (STS), 50% of patients will die of metastatic disease that is largely unresponsive to conventional chemotherapeutic agents. The aims of this study were to identify genes and pathways that are dysregulated in progressive and metastatic STS. In addition to this, cell lines from fresh tumours were initiated and established, thus increasing the repository of cell lines available for functional studies. Recent advances in the understanding of the molecular biology of STS have thus far not resulted in the use of molecular markers for clinical prognostication. Identifying novel genes and pathways will lead to molecular diagnostic methods to better stratify prognostic groups and could identify cellular targets for more efficacious treatments. Gene expression profiling of sarcoma cell lines of increasing metastatic potential revealed over-expression of genes involved in the epidermal growth factor (EGF) and transforming growth factor beta (TGFb) pathways. Factors involved in invasion and metastasis such as integrins and MMPs were over-expressed in the cell lines with higher metastatic potential. The developmental Notch pathway and cell cycle regulators were also dysregulated. NDRG1 was significantly over-expressed in the high grade sarcoma cell line, a novel finding in sarcomas. The expression of EGFR, NDRG1 and other genes from the above pathways was validated using quantitative RT-PCR in real time (qRT-PCR). A tissue microarray (TMA) comprising STS of varying tumour grades was constructed for high throughput assessment of target proteins. EGFR, its activated form and its signal transducers were investigated using immunohistochemistry (IHC). Activated EGFR (HR 2.228, p < 0.001) and phosphorylated Akt (HR 2.032, p = 0.003) were found to be independent predictors of overall survival and both correlated with tumour grade. Of the several STS cultures initiated and maintained, two of these cell lines were fully characterised in terms of cytogenetics, telomerase and alternate lengthening of 5 telomeres (ALT) status, KIT and TP53 mutation and the expression of certain biomarkers using both qRT-PCR and IHC. In summary, transcript profiling identified several potential biomarkers of tumour progression and metastasis in STS. Crucially, activated EGFR and pAkt were found in a cohort of STS samples to correlate with clinical outcome, identifying them as potential diagnostic and therapeutic targets in the treatment of STS. Activated EGFR can be used as a diagnostic marker for patient selection, as well as for target effect monitoring. Furthermore, the cell lines established in this project will serve as valuable tools in future preclinical studies.

La traduction est une étape critique de la régulation de l'expression des gènes. Chez l'oursin, la fécondation induit une augmentation de la synthèse protéique, qui dépend essentiellement de la traduction d'ARN messagers maternels. Cette synthèse protéique est indispensable au déroulement des cycles cellulaires du développement précoce. Le développement embryonnaire de l'oursin constitue ainsi un modèle de choix pour étudier la régulation de la traduction. Dans le cadre de cette thèse, le contrôle de la traduction a été étudié chez l'oursin dans deux situations : le contexte physiologique de la fécondation et le contexte de l'induction de l'apoptose. Nous nous sommes interrogés d'abord sur les mécanismes régulateurs impliqués dans la synthèse protéique après fécondation. L'une des étapes limitantes de la traduction est l'initiation. Dans ce cadre, le facteur d'initiation eIF2 joue un rôle clé. eIF2 est responsable de l'apport de la méthionine initiatrice au niveau du ribosome. Lorsque la sous-unité alpha d'eIF2 est phosphorylée, la synthèse protéique globale est inhibée et la traduction sélective de certains ARNm est stimulée. Dans les ovules non fécondés d'oursin, eIF2alpha est physiologiquement phosphorylé et la fécondation provoque sa déphosphorylation. En micro-injectant dans les ovules non fécondés un variant d'eIF2alpha mimant l'état phosphorylé, nous avons montré que la déphosphorylation d'eIF2alpha est nécessaire pour la première division mitotique chez l'oursin. Nous nous sommes intéressés au lien entre la phosphorylation d'eIF2alpha et l'induction de l'apoptose chez l'oursin. En effet, la traduction d'ARNm codant pour des protéines pro- ou anti- apoptotiques influence directement la survie des cellules. L'embryon d'oursin possède la machinerie nécessaire pour le déclenchement de l'apoptose, après induction par l'agent génotoxique MMS. Le traitement au MMS des embryons provoque la phosphorylation d'eIF2alpha. Dans cette situation, nous avons trouvé que la kinase GCN2 est impliquée dans la phosphorylation d'eIF2alpha. En fin, dans le but d'étudier comment la machinerie traductionnelle module le recrutement polysomal, nous avons analysé le traductome en réponse à la fécondation et après le traitement au MMS. Nous avons effectué une approche de séquençage à haut-débit des transcrits purifiés par gradients de polysomes. L'analyse de ces transcrits nous permettra d'appréhender le réseau des gènes régulés au niveau traductionnel lors de la fécondation et de l'induction de l'apoptose dans les embryons d'oursin.

<p>Excessive memory use may cause severe performance problems and system crashes. Without appropriate tools, it may be difficult or impossible to determine why a program is using too much memory. This applies even though Python provides automatic memory management --- garbage collection can help avoid many memory allocation bugs, but only to a certain extent due to the lack of information during program execution. There is still a need for tools helping the programmer to understand the memory behaviour of programs, especially in complicated situations. The primary motivation for Heapy is that there has been a lack of such tools for Python.</p><p>The main questions addressed by Heapy are how much memory is used by objects, what are the objects of most interest for optimization purposes, and why are objects kept in memory. Memory leaks are often of special interest and may be found by comparing snapshots of the heap population taken at different times. Memory profiles, using different kinds of classifiers that may include retainer information, can provide quick overviews revealing optimization possibilities not thought of beforehand. Reference patterns and shortest reference paths provide different perspectives of object access patterns to help explain why objects are kept in memory.</p>