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No description available.

No description available.

No description available.

Early mammalian development before the oocyte-to-embryo transition is under 'maternal control' from factors deposited in the cytoplasm during oocyte growth, synthesized independent of de novo transcription. Maternal mRNAs encode proteins necessary for early embryo development. Two elements in the mRNA 3’untranslated region (UTR), the cytoplasmic polyadenylation element (CPE) and the hexanucleotide (AAUAAA) are involved in the control of translation of specific mRNAs during meiotic maturation. Despite advances in understanding the translational regulation during meiotic maturation, regulation at the 1-cell stage has not been explained. More studies are required to explain this complex mechanism of temporal mRNA recruitment after fertilization. Maternal mRNAs translated at different stages were examined to understand how specific maternal mRNAs are synthesized and stored, what are these maternal mRNAs, which maternal mRNAs are translated, and how these maternal mRNAs are temporally regulated. Polysomal mRNAs from eggs and 1-cell embryos were analyzed by microarray analysis and this indicated that temporally significant biological activities were encoded by mRNAs recruited at different stages of development. The mRNAs recruited in eggs were involved in homeostasis and transport mechanisms and those recruited in zygotes were involved in biosynthesis and metabolic activities. These data indicated that there is a temporal regulation of maternal mRNAs to meet the different biological requirements of the embryos. After the identification of temporally translated mRNAs, experiments were performed to understand the mechanism underlying temporal translation. The prevalence of the CPE differed between the two mRNA populations translated i.e., egg and 1-cell stage polysomal mRNAs. CPEs were present in ~53% of transcripts at the 1-cell stage compared to ~86% at the MII stage. This indicated that novel motifs other than CPEs regulate translation of mRNAs at the 1-cell stage. Truncation and deletion experiments were conducted using chimeric mRNAs based on one mRNA that was enriched in the 1- cell polysomes (Bag4). These experiments led to the identification of two regulatory regions that control translation at the 1-cell stage, an 80 nt region and a 43 nt region with different regulatory motifs. The 80 nt region is involved in activation of translation and the 43 nt region has an inhibitory effect on translation at the MII and early 1-cell stage. These results provide a detailed picture of how specific maternal mRNAs are prevented from undergoing translation at the MII stage and how the effect of inhibition is eliminated by the late 1-cell stage. / Biochemistry

The present study was conducted to determine the effect of a possible selves intervention on self-regulatory efficacy and exercise behaviour. Participants were 19 men and 61 women (Mage= 21.43, SD = 3.28) who reported exercising less than 3 times per week. Participants were randomly assigned to a control condition, a hoped-for possible selves intervention condition, or a feared possible selves intervention condition. Participants in the hoped-for and feared possible selves conditions completed an activity where they imagined themselves in the future as either healthy, regular exercisers or unhealthy, inactive individuals, respectively. Participants in the control group completed a quiz about physical activity. Measures of self-regulatory efficacy (scheduling, planning, goal-setting, and barrier self-efficacy) were taken immediately before and after exposure to the intervention. Participants who received a possible selves intervention reported greater exercise behaviour 4 weeks post-intervention than participants in the control group (p = .05). Furthermore, planning self-efficacy was found to partially mediate the effect of the possible selves intervention on exercise behaviour. These findings suggest that possible selves may play a role in increasing exercise behaviour among inactive individuals. Future research is warranted to examine the role of possible selves interventions in increasing exercise behaviour and to determine which other variables may mediate this intervention-exercise behaviour relationship. / Thesis / Master of Science (MSc)

Yes / The COSMOS Database (DB) was originally established to provide reliable data for cosmetics-related chemicals within the COSMOS Project funded as part of the SEURAT-1 Research Initiative. The database has subsequently been maintained and developed further into COSMOS Next Generation (NG), a combination of database and in silico tools, essential components of a knowledge base. COSMOS DB provided a cosmetics inventory as well as other regulatory inventories, accompanied by assessment results and in vitro and in vivo toxicity data. In addition to data content curation, much effort was dedicated to data governance - data authorisation, characterisation of quality, documentation of meta information, and control of data use. Through this effort, COSMOS DB was able to merge and fuse data of various types from different sources. Building on the previous effort, the COSMOS Minimum Inclusion (MINIS) criteria for a toxicity database were further expanded to quantify the reliability of studies. COSMOS NG features multiple fingerprints for analysing structure similarity, and new tools to calculate molecular properties and screen chemicals with endpoint-related public profilers, such as DNA and protein binders, liver alerts and genotoxic alerts. The publicly available COSMOS NG enables users to compile information and execute analyses such as category formation and read-across. This paper provides a step-by-step guided workflow for a simple read-across case, starting from a target structure and culminating in an estimation of a NOAEL confidence interval. Given its strong technical foundation, inclusion of quality-reviewed data, and provision of tools designed to facilitate communication between users, COSMOS NG is a first step towards building a toxicological knowledge hub leveraging many public data systems for chemical safety evaluation. We continue to monitor the feedback from the user community at support@mn-am.com.

Caulobacter crescentus goes through a classic dimorphic cell division cycle to adapt to the stringent environment and reduce intraspecific competition. Caulobacter mother cell gives rise to two progenies with distinct morphology - a motile swarmer cell equipped with a flagellum and a sessile stalked cell equipped with a stalk. Because of the nature of dimorphic lifestyle, Caulobacter becomes a model bacterium to study the cell differentiation, signalling transduction, stress response, and asymmetry development of prokaryotes. The dimorphic cell cycle of Caulobacter is driven by the elaborate spatiotemporal organization of regulatory molecules through regulations of synthesis, degradation, phosphorelay, and localization. There is a wealth of experimental observations about gene/protein interactions and localizations accumulated in recent decades, while several mathematical models have been proposed to study the cell cycle progression in Caulobacter. However, the specific control mechanisms of stress response and spatial asymmetry establishment are yet clearly elucidated, while these mechanisms are of fundamental importance to understanding the bacterial survival strategy and developing the microbial industry. Here we utilize mathematical modeling to study the regulatory network of cell cycle control in C. crescentus, focusing on the stress response and asymmetry development. First, we investigate the starvation response of Caulobacter through the connection of phosphotransferase systems (PTS) and guanine nucleotide-based second messenger system. We have developed a mathematical model to capture the temporal dynamics of vital regulatory second messengers, c-di-GMP (cdG) and guanosine pentaphosphate or tetraphosphate (pppGpp or ppGpp), under normal and stressful conditions. This research suggests that the RelA-SpoT homolog enzymes have the potential to effectively influence the cell cycle in response to nutrition changes by regulating cdG and (p)ppGpp levels. We further integrate the second messenger network into a temporal cell cycle model to investigate molecular mechanisms underlying responses of Caulobacter to nutrition starvation. Our model suggests that the cdG-relevant starvation signal is essential but not sufficient to robustly arrest the cell cycle of Caulobacter. We also demonstrate that there may be unknown pathway(s) reducing CtrA under starvation conditions, which results in delayed cytokinesis in starved stalked cells. The cell cycle development of Caulobacter is determined by the periodical activation and deactivation of the master regulator CtrA. cdG is an essential component of the ClpXP pro- tease complex, which is specifically responsible for the degradation of CtrA. We propose a mathematical model for the hierarchical assembly of ClpXP complexes, together with modeling DNA replication, transcription, and protein interactions, to characterize the Caulobacter cell cycle. Our model suggests that the ClpXP-based proteolysis system contributes to the timing and robustness of the cell cycle progression. Furthermore, we construct a spatiotemporal model with Turing-pattern mechanism to study the morphogenesis and asymmetry establishment during the cell cycle of Caulobacter. We apply reaction-diffusion equations to capture the spatial dynamics of scaffolding proteins PodJ, PopZ, and SpmX, which organize two distinct poles of Caulobacter. The spatial regulations influence the activity and distribution of key cell cycle regulators, governing the dimorphic lifestyle of Caulobacter. Our model captures major spatiotemporal experimental observations of wild-type and mutant cells. It provides predictions of novel mutant strains and explains the spatial regulatory mechanisms of bacterial cell cycle progression. / Doctor of Philosophy / Cell is the basic unit of life that undergoes a process called 'cell cycle' consisting of DNA replication and cell division to exhibit various functions, abilities, and behaviors. The cell cycle is well organized by complex regulations in time and space that determine when and where changes take place. The regulations behind cell cycle development play important roles for living organisms but are not fully understood. In this dissertation, we utilize mathematical models and focus on a model bacterium, Caulobacter crescentus, to capture characteristics of cell cycle and study the underlying regulations. Caulobacter is widely distributed in freshwater, including environments with poor nutrients. It divides asymmetrically, generating a pair of daughter cells with different appearances and replicative potentials. Therefore, Caulobacter population has the flexibility to save energy by halting DNA replication and to reduce the competition with siblings by settling into different places. We utilize the nature of the asymmetrical division of Caulobacter to quantitatively investigate the control mechanisms of cell cycle development, including how cells detect and respond to external cues and develop different organelles at specific times and locations.

Mathematical modeling of biological systems can be useful to reveal new insights into biological observations. Here we apply mathematical modeling to study the underlying molecular networks driving observed behaviors of two systems. First, we apply systems biology and dynamic systems theory techniques to reveal new insights into the process of hematopoiesis. More specifically, we search the literature to deduce the underlying molecular mechanism that drives cell fate determination in granulocyte-monocyte progenitor (GMP) cells that are exposed to various cytokines. By converting this molecular mechanism into a set of ordinary differential equations (ODEs), we acquired new insights into the behavior of differentiating GMP cells. Next, we explore the cell cycle of the model prokaryotic organism, Caulobacter crescentus. Caulobacter is a uniquely successful oligotrophic bacterium, found abundantly in freshwater systems. While it is not a pathogenic species, Caulobacter is extremely well studied due to its distinguishable asymmetrical morphology and the ability to synchronize populations by cell cycle stage. We built a detailed mathematical model of the molecular mechanism driving the cell cycle. This research suggests a previously unknown role for the unknown form of the master regulator, CtrA, in regulating the G1-S transition. Furthermore, we incorporate a nutrient signaling model into the cell cycle model to investigate how Caulobacter responds to nutrient deprivation. We find that regulation of DivK phosphorylation is an essential component of the nutrient signaling pathway and demonstrate how starvation signals work together in synergy to manifest in observed cell cycle response. / Doctor of Philosophy / Every cell in the human body has the same DNA, yet there are cells of all kinds with different jobs, appearances and behaviors. This simple concept is a consequence of complex regulatory systems within cells that dictate what genes are expressed and when. This dissertation breaks down the molecular mechanisms that regulate gene expression in cells and how these mechanisms result in the interesting behaviors and morphologies that have been observed experimentally. By deriving mathematical equations to describe the molecular mechanisms, we simulate how cell behavior might change under different conditions to make novel discoveries. More specifically, we utilize these techniques to study the freshwater bacterium, Caulobacter crescentus, and human cells of the white blood cell lineage. We utilize our models to identify previously unknown aspects of the molecular mechanisms, develop explanations for mysterious cell behaviors and provide interesting predictions that have not been explored experimentally.

Delay discounting (DD) and self-regulation are important predictors of substance use disorder (SUD) outcomes. Further, regulatory flexibility (RF; i.e., selecting, monitoring, and adapting coping techniques based on contextual demands) is related to psychological resilience. However, studies have yet to examine associations between DD, RF, and remission from SUDs. Individuals (N = 148) in SUD recovery completed the Context Sensitivity Index (CSI), the Flexible Regulation of Emotional Expression (FREE) Scale, and the Perceived Ability to Cope with Trauma (PACT) Scale to assess RF and, an Adjusting Amount Delay Discounting Task. T-tests were used to examine differences in RF and DD by remission status. Univariate linear regressions were used to examine the relationship between RF and DD. Finally, mediation models examined the dynamic relationship between DD, RF, and remission status. Remitted individuals (n=82) had significantly lower DD rates (p<0.001) and higher context sensitivity (p<0.001) and coping flexibility (p<0.001). There were significant negative associations between DD and context sensitivity (p=0.008), coping flexibility (p=0.002), and emotion regulation flexibility (p<0.001). Finally, context sensitivity (p=0.023) and coping flexibility (p=0.007) mediated the relationship between DD and SUD remission. Results suggest that individuals in recovery with broader temporal windows can better identify contextual demands and flexibly cope, contributing to improved SUD recovery outcomes. / M.S. / Preference for immediate gratification (also called delay discounting), and self-regulation (the ability to control one’s emotions) are related to addiction outcomes. Regulatory flexibility - a self-regulation process by which individuals select and adapt their coping strategies based on their situation - is related to improved mental health outcomes. However, research studies have yet to examine the relationship between regulatory flexibility and delay discounting in individuals with a history of drug and/or alcohol dependence. Using a sample from an online addiction recovery research and support community called the International Quit and Recovery Registry, the current thesis examined the relationship between delay discounting and regulatory flexibility grouped by substance use disorder clinical diagnoses amongst 148 individuals. Group comparisons suggested that individuals in remission (i.e., no longer meet criteria for clinical diagnosis of addiction) were better able to delay gratification and were better able to flexibly regulate their emotions compared to individuals who relapsed. When examining the relationship between delay discounting and regulatory flexibility, we found that individuals’ who preferred delayed rewards over immediate rewards were better able to flexibly self-regulate, suggesting that being able to delay gratification is an important component of effective coping, together contributing to improved addiction recovery outcomes.