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Introduction Triple negative breast cancers are defined by their lack of expression of HER, oestrogen receptors and progesterone receptors. They account for around 10-24% of cases. To define a cancer by the biomarkers it does not express is unsatisfactory. Triple negative breast cancer has been linked to aspects of metabolism and metabolic disorders such as diabetes. There are several biomarkers that are of interest and overlap in both their roles in breast cancer and in aspects of metabolism. Fatty acid binding protein 7 (FABP7) is one of 9 FABPs that is involved in the transport, solubilisation and regulation of metabolism of various fatty acids. Expression profiling and immunohistochemistry (IHC) studies have identified FABP7 to be over-expressed in a subtype of breast cancer that can be considered almost synonymous with triple negative breast cancer; basal-like breast cancer, so called because it expresses cytokeratins that are characteristic of basal epithelial cells. The role of FABP7 in breast cancer is not fully understood and studies have given conflicting results in regards to the relation to prognosis. Evidence suggests that FABP7 can be regulated by methylation acetylation and exposure to fatty acids. Insulin like growth factor binding protein-2 (IGFBP-2) is a member of the IGF-axis that is responsible for altering cell growth and metabolism. IGFBP-2 has been found to be over-expressed in many cancers including those of the prostate and breast. Phosphotensin homolog (PTEN) is a tumour suppressor gene that is responsible for dephosphorylating PIP3 to inhibit the Akt pathway and thus inhibit cell growth and promote apoptosis. IGFBP-2 has IGF independent actions; it can down-regulate PTEN through binding of an integrin receptor and therefore have mitogenic and anti-apoptotic effects. Aims To study the expression of the metabolic biomarkers FABP7, IGFBP-2 and PTEN in clinical cases of Malaysian TN breast cancer. To use appropriate cell lines in order to more fully understand whether epigenetic mechanisms and FAs regulate FABP7 expression. To over-express FABP7 in a breast cancer cell lines and to further understand the role of FABP7 in breast cancer. Methods IHC was used to assess FABP7, PTEN and IGFBP-2 expression in a cohort of triple negative breast cancer cases. FAs, a demethylation agent-AZA and a histone deacetylase inhibitor-TSA were used to investigate what regulated FABP7 in cell lines. Over-expression experiments were used to understand the effect of FABP7 in breast cancer cell lines. Results FABP7 expression in patient samples was associated with lower grade, basal-like phenotype, FAS expression and although not significant, improved patient survival. Treatment of BT-20 and MDA-MB-231 cell lines with AZA and TSA resulted in increases in FABP7 mRNA expression. Fatty acid treatment led to changes in FABP7 mRNA expression. Combinations of AZA and fatty acids gave large increases in FABP7 mRNA expression. Over-expression of FABP7 in BT-20 cells resulted in increased cell viability and although not significant changes in expression of survivin, caspase 9 and their splice variants. IGFBP-2 expression was associated with poor patient survival though this was not significant. PTEN loss was a frequent event in the cohort of triple negative breast cancer cases; 48.3% of cases had PTEN loss. PTEN loss was associated with poor patient survival though this was not significant. PTEN loss was associated with expression of IGFBP-2. Discussion & Conclusions FABP7 is likely to play a role in patient survival as demonstrated in the patient samples. FABP7 over-expressing BT-20 cells tended to have increased survivin FL and ΔEX3 expression. Both increased mitochondrial activity and survivin expression have been found to be associated with improved prognosis in breast cancer and this may explain some mechanisms by which FABP7 results in better prognosis in the TN breast cancer cases in this study. Since FABP7 mRNA expression was not increased to fold changes comparable to oestrogen receptor re-expression after AZA and TSA treatment, it is unlikely that the FABP7 gene is methylated or regulated by acetylation. It is possible that there are genes upstream of FABP7 such as transcription factors that are regulated my methylation and acetylation and therefore impact on FABP7 expression after treatment with AZA and TSA. This is the first study that demonstrates the significant relationship between IGFBP-2 expression and PTEN loss in patient samples. PTEN loss is a frequent event in TN breast cancer. IGFBP-2 and PTEN loss may be useful markers of prognosis in TN breast cancer.

A large amount of research has been conducted into the effects that written emotional disclosure (WED) has on adults' health and well being. Early meta-analyses (e.g. Smyth, 1998) indicated that WED had substantial effects on adults, however recent meta-analyses indicate the effect is small (Frattaroli, 2006) or nonexistent (Mogk, Otte, Reinhold-Hurley, & Kroner-Herwig, 2006). Little research has investigated the effects of WED on children and adolescents. The purpose of the current research was to test whether WED is an effective intervention for early adolescents. The aim of the research was to evaluate the overall effects of WED on adolescents' health and psychosocial functioning, to investigate moderators of the effects of WED, and to explore the content of the emotional writing. To meet these aims two longitudinal studies were conducted. In each study, questionnaires to measure health and psychosocial functioning were administered to participants, aged 12- 13, at baseline. Participants were assigned to a no writing control, factual writing control or emotional writing group. Writing was completed once a week for 3 weeks. The questionnaires were completed again one week after the final writing session and a further 2 months later. Across both studies the writing manipulation was successful: participants in the emotional writing group used more words indicating cognitive and affective processing than participants in the factual writing group did. However, WED was found to have no effects on any of the outcome measures. Moreover, the hypothesised moderators generally did not moderate the effects of WED. A. thematic analysis of the emotional transcripts from Study 2 revealed the perceived purpose of the writing was an important issue to be considered in WED interventions. Together, the results from these studies suggest that WED is not a suitable intervention for early adolescents. It is suggested that adolescents may benefit from alternative interventions and that such interventions should be situated within the curriculum to make them more relevant to teachers, parents and students

This thesis seeks to explore the indirect and direct relationships between food insecurity, concentrated disadvantage, and distribution of violent offenders through the lens of social disorganization. Data gathered by the Little Rock Police Department, American Community Survey, and city business license records are used to test neighborhood-level relationships across Little Rock, Arkansas’ 155 Census block groups. Pearson’s Correlation is used at the bivariate level and negative binomial regression tests multivariate relationships. The results suggest a null relationship between food insecurity and distribution of violent offenders across Little Rock block groups. However, several findings are consistent with prior research and theory– the most salient of which is the impact of concentrated structural disadvantage on the distribution of violent offenders. This thesis contributes original research to the study of food deserts and crime that may be used as a foundation for future studies.

Machine learning is a promising tool for processing complex information, but it remains anunreliable tool for control and decision making. Applying techniques developed for static datasets to real world problems requires grappling with the effects of feedback and systems that change over time. In these settings, classic statistical and algorithmic guarantees do not always hold. How do we anticipate the dynamical behavior of machine learning systems before we deploy them? Towards the goal of ensuring reliable behavior, this thesis takes steps towards developing an understanding of the trade-offs and limitations that arise in feedback settings.In Part I, we focus on the application of machine learning to automatic feedback control.Inspired by physical autonomous systems, we attempt to build a theoretical foundation for the data-driven design of optimal controllers. We focus on systems governed by linear dynamics with unknown components that must be characterized from data. We study unknown dynamics in the setting of the Linear Quadratic Regulator (LQR), a classical optimal control problem, and show that a procedure of least-squares estimation followed by robust control design guarantees safety and bounded sub-optimality. Inspired by the use of cameras in robotics, we also study a setting in which the controller must act on the basis of complex observations, where a subset of the state is encoded by an unknown nonlinear and potentially high dimensional sensor. We propose using a perception map, which acts as an approximate inverse, and show that the resulting perception-control loop has favorable properties, so long as either a) the controller is robustly designed to account for perception errors or b) the perception map is learned from sufficiently dense data.In Part II, we shift our attention to algorithmic decision making systems, where machinelearning models are used in feedback with people. Due to the difficulties of measure- ment, limited predictability, and the indeterminacy of translating human values into mathematical objectives, we eschew the framework of optimal control. Instead, our goal is to articulate the impacts of simple decision rules under one-step feedback models. We first consider consequential decisions, inspired by the example of lending in the presence of credit score. Under a simple model of impact, we show that several group fairness constraints, proposed to mitigate inequality, may harm the groups they aim to protect. In fact, fairness criteria can be viewed as a special case of a broader framework for de- signing decision policies that trade off between private and public objectives, in which notions of impact and wellbeing can be encoded directly. Finally, we turn to the setting of recommendation systems, which make selections from a wide array of choices based on personalized relevance predictions. We develop a novel perspective based on reachability that quantifies agency and access. While empirical audits show that models optimized for accuracy may limit reachability, theoretical results show that this is not due to an in- herent trade-off, suggesting a path forward. Broadly, this work attempts to re-imagine the goals of predictive models ubiquitous in machine learning, moving towards new design principles that prioritize human values.

Globally, increasing human populations have either caused or accelerated several types of environmental change. Symbiotic microbes have powerful effects on plant fitness, yet little study has been done on how microbial-plant relationships are affected by environmental changes. In two different ecosystems I explore how either nitrogen (N) pollution or drought can alter root associated microbe (RAM)-plant relationships using Next Generation Sequencing. In moist-meadow alpine tundra at Niwot Ridge, CO, I examine the relative contribution of host identity, N enrichment, and plant neighborhood on RAM diversity and community composition in two co-dominant plant species; Geum rossii and Deschampsia cespitosa. In New Mexican piñon-juniper woodlands, I sampled roots from a site in which mass Pinus edulis dieback was simulated to mimic the effects of extreme drought events, which are predicted to become more frequent as climate change progresses. I examine the effect of host and neighbor identity, as well as the effect of dead P. edulis neighbors, on root associated fungi (RAF) of P. edulis and Juniperus monosperma. I also compare RAF communities between piñon-juniper woodlands and more arid juniper savanna, a good proxy for what piñon-juniper woodlands will become should these extreme drought events become more frequent.

Introduction and Aims: Breast cancer remains the leading cause of cancer mortality in women globally, despite advances in the development of targeted therapies. Driven by oncogenic signals, cancer cells undergo metabolic reprogramming, upregulating metabolite transporters and shuttling nutrients to promote proliferation and migration. The expression of key metabolic enzymes involved in BCAA metabolism (hBCATc and hBCATm), isocitrate dehydrogenase (IDH1 and IDH2) and serine metabolism (PHGDH) have been demonstrated to be upregulated in breast cancer. However, the expression patterns and the role of these metabolic proteins in breast cancer tumourigenesis remains to be elucidated. This research hypothesises that these metabolic pathways converge in tumour cells, whereby particular metabolic pathways are favoured differentially between breast cancer subtypes, which could lead to the identification of novel therapeutic targets. In breast cancer insulin/IGF-1 signalling has been demonstrated to contribute to tumourigenesis through the activation of growth signalling effectors which is mediated by two chief pathways: Akt/mTOR and RAS/MAPK. As nutrient levels of BCAAs particularly leucine, substrates of hBCAT, regulate the mTOR pathway hBCAT was hypothesised to play a role in the regulation of proliferation and migration of triple-negative breast cancer (TNBC) cells through the IGF-1 and insulin signalling pathways. Methods:Using immunohistochemistry, the expression profile of the metabolic proteins was assessed between breast cancer subtypes. The impact of hBCATc expression on proliferation, migration, invasion, apoptosis and modulation of PI3K/Akt and RAS/MAPK signalling was assessed using molecular biological investigations, Western blot and confocal analysis. Results and discussion:Using serial sections, hBCATm was found to be significantly associated with IDH1 expression, indicating that these two metabolic pathways are activated concomitantly. Expression of hBCATm and IDH1 correlated with luminal A breast cancer and smaller breast tumours, indicating better prognosis. Differentially, hBCATc expression was found to be significantly associated with the more aggressive HER2+ and TNBC subtypes. For the first time, knockdown of hBCATc was demonstrated to significantly reduce insulin and IGF-1-mediated proliferation, migration and invasion in TNBC cells. An analysis of this pathway showed that when overexpressed hBCATc regulates proliferation through the PI3K/Akt/mTO axis, whilst simultaneously attenuating the Ras/MAPK pathway, indicating that hBCATc acts as a conduit between these two pathways. Overexpression of hBCATc ultimately led to the increase in FOXO3a, Nrf2 and GRP78, which play fundamental roles in cell proliferation, cell survival and protein folding. Therefore, hBCATc has been demonstrated to provide TNBC cells with metabolic plasticity to alter dependence on the RAS/MAPK and PI3K/Akt/mTOR signalling cascades, in response to IGF-1/insulin, to promote tumour survival and progression.