Effect of Nedd4 Haploinsufficiency on Insulin Sensitivity, Adiposity and Neuronal Behaviors

The neural precursor cell expressed developmentally down-regulated gene 4 (NEDD4) is a HECT-type E3 ubiquitin ligase that has received broad attention in recent years. Many of its reported substrates are active players in metabolism, implying a potential role of NEDD4 itself in metabolic regulation. Since homozygous Nedd4 deletion leads to embryonic or perinatal lethality, we investigated the function of NEDD4 in metabolic regulation in vivo, using Nedd4- haploinsufficient mice in a high fat diet-induced obesity (HFDIO) model. Our studies show that Nedd4-haploinsufficient mice fed a normal diet (ND) exhibited decreased body weight in both genders and proportionally reduced tissue mass compared to their age-matched wild-type littermates. The heterozygotic Nedd4-deficient mice displayed moderate insulin resistance and mild hyperinsulinemia. These findings are consistent with others’ studies in which depletion of Nedd4 in mouse embryonic fibroblasts (MEFs) led to a decline in insulinlike growth factor I (IGF-1) and insulin signaling. Surprisingly, Nedd4-haploinsufficient mice were partially protected against high-fat diet (HFD) induced obesity. Total weight gain was decreased by 30% in Nedd4-haploinsufficient mice on HFD, which was associated with reduced adiposity, improved insulin sensitivity in white adipose tissue (WAT), alleviated hepatic steatosis and attenuated lipid-induced inflammation. NEDD4 reduction did not affect serum glucose or lipid profile. The energy intake and physical activity were almost indistinguishable between the two groups. We present data indicating that these beneficial effects of Nedd4 haploinsufficiency under conditions promoting obesity or type 2 diabetes (T2D) derive from at least two mechanisms: 1) elevated levels of β- agonist induced lipolysis through stimulation of β-adrenergic signaling as evidenced by enhanced β2 adrenergic receptor (β2-AR) cell surface levels; 2) repressed expression of a key adipogenic regulator, peroxisome proliferator-activated receptor gamma (PPARγ) in Nedd4- haploinsufficient mice in the WAT. Downregulation of NEDD4 in 3T3-L1 preadipocytes impaired the adipogenic response, resulting in decreased PPARγ expression. Thus, the reduced adiposity in Nedd4-haploinsufficient mice fed a HFD compared to littermate wild-type mice may be explained at least in part by their increased lipolysis and suppressed adipogenesis. Our data also imply that NEDD4 may have differential functions in modulating insulin signaling under physiological and pathological conditions. In this study, we tested the possible impact of NEDD4 reduction on cognitive function and anxiety behaviors. Preliminary results showed that Nedd4-haploinsufficient mice had impaired learning and memory performance but increased anxiety compared to wild-type littermates. NEDD4 may modulate different behavioral functions by targeting specific substrates for protein degradation in a brain-region-specific manner. Precise substrates that cause the alteration in such behaviors are yet to be determined by future studies

The Impact of Math Innovations in Elementary Mathematics Classrooms in Georgia Vision Project Districts

The purpose of this dissertation was to study how teachers and school leaders perceived a specific set of classroom math innovations, and how those innovations impacted instruction in relation to the Georgia Vision Project (GVP) standards and recommendations. This was a qualitative study conducted in two GVP districts. The participants in the study were five elementary teachers, two school administrators, and two district leaders. The participants were interviewed to gain an understanding of their perceptions of recent math innovations. The innovations included (a) math instruction using manipulatives (such as counting objects and puzzles) that utilize the Concrete Representational Abstract (CRA) model, which engages students to conceive from the concrete to the abstract; (b) differentiation through flexible student grouping; (c) information about how different subgroups of students learn mathematics; and (d) math professional learning. Previous research had focused on these innovations separately. However, no research study had grouped these innovations together to see how teachers perceived them within the context of a math classroom, and how teachers implemented them in their classrooms in order to increase student achievement. This qualitative case study included schoolteacher and educational leader interviews, observations, and artifacts. The two districts in the study were high performing in the area of mathematics. The results indicated that schoolteachers and educational leaders could not directly relate the math innovations to student success and, moreover, to the GVP standards and recommendations. During the study all GVP standards were analyzed at varying levels. The study primarily focused on the teaching and learning standard, which was a significant initiative for both districts. Both districts had varying levels of implementation concerning the innovations in the study: (a) use of manipulatives, (b) differentiation in classrooms, and (c) professional learning. All participants referenced the innovations as a part of their instruction, but could not directly relate the innovations beneficial to the success of the students

Classification of the approaches to learning adopted by students of architecture in their design coursework

Students’ approaches to learning has been classified through their experiences in the design coursework within the larger context of architectural education. What are the learning approaches being adopted by students in architectural design and how does the introduction of the first year design coursework impact on their approaches to learning in the subsequent years are key to this classification. This research reflects on why learning approaches evolve from the first to the final year of the architecture program. Approaches to learning is well-understood in other disciplines including engineering, information technology, mathematics and sciences to name a few, but less-researched in architectural education. This research endeavours to fill this gap. The students are introduced to design theory as a part of their architectural design coursework. This research vehicle of the architectural design is identified as a more appropriate way of classifying learning approaches instead of history, critical theory and technology as design coursework plays a central role in the studio-based program. The academic context has been reviewed through existing literature with a focus on learning approaches within pedagogical research in architectural education, in addition to other fields and disciplines including established research on ‘surface and deep’ approaches in text-based fields through the qualitative research method of phenomenography. This classification is the further consolidation of the pilot study on students’ learning comparing the first and fourth year of the architecture program through phenomenography. The learning context for this classification includes four architectural institutions from the United States of America, United Kingdom and India. The intention of this research is to present the phenomenographic results as meta-categories by depicting the evolution of the learning approaches in architectural design. This research currently intends to further represent these findings and interpret these meta-categories within real world examples of architectural pedagogy and education through an illustrative account of nine students of architecture and their learning approaches in evolution

Graph-Theoretical Tools for the Analysis of Complex Networks

We are currently experiencing an explosive growth in data collection technology that threatens to dwarf the commensurate gains in computational power predicted by Moore’s Law. At the same time, researchers across numerous domain sciences are finding success using network models to represent their data. Graph algorithms are then applied to study the topological structure and tease out latent relationships between variables. Unfortunately, the problems of interest, such as finding dense subgraphs, are often the most difficult to solve from a computational point of view. Together, these issues motivate the need for novel algorithmic techniques in the study of graphs derived from large, complex, data sources. This dissertation describes the development and application of graph theoretic tools for the study of complex networks. Algorithms are presented that leverage efficient, exact solutions to difficult combinatorial problems for epigenetic biomarker detection and disease subtyping based on gene expression signatures. Extensive testing on publicly available data is presented supporting the efficacy of these approaches. To address efficient algorithm design, a study of the two core tenets of fixed parameter tractability (branching and kernelization) is considered in the context of a parallel implementation of vertex cover. Results of testing on a wide variety of graphs derived from both real and synthetic data are presented. It is shown that the relative success of kernelization versus branching is found to be largely dependent on the degree distribution of the graph. Throughout, an emphasis is placed upon the practicality of resulting implementations to advance the limits of effective computation

Body Image and Anthropometric Measurements in Bariatric Surgery Patients

Purpose: The purpose of this study was to explore body image and anthropometric (body mass index) measurements in bariatric surgery patients over three months. Conceptual framework: The dimensions of body image are body attitude, Appearance Evaluation, body checking, body space, body size, and Appearance Orientation. Body attitude is affective distress related to one’s weight, shape, size, and fatness. Appearance Evaluation is feelings of satisfaction or dissatisfaction with one’s looks. Body checking is the repeated scrutiny of one’s body size, shape, and weight. Perceived body space is the amount of space individuals perceive their bodies to occupy. Perceived body size is body size estimation, measured using silhouettes. Appearance Orientation is self-focus on one’s appearance or grooming. Method: A one group pretest-posttest design was used to study 67 adults before and three months after bariatric surgery. The overall sample included these surgeries: Roux-en-Y gastric bypass (RYGB; n=35), sleeve gastrectomy (SG; n=28), and laparoscopic adjustable gastric band (LAGB; n=4). Six self-report body image measures and anthropometric measures (BMI, percent estimated BMI loss-%EBMIL) were analyzed. Differences in outcomes over three months were examined for the overall sample and within the two surgery groups (RYGB and SG). Differences between the two surgeries were also examined. Comparisons with the LAGB were not made, given the small number of these surgeries. Results: Significant (p\u3c.001) improvements were found in four of six body image measures and in BMI over 3 months for the overall sample and within the two surgery groups. No significant differences were found in body image or BMI between surgery groups. %EBMI loss was 32.8% for the overall sample. Conclusions: This is the first study to examine body image in bariatric surgery patients at 3 months. Changes in body image and anthropometric measures were clinically significant. Body image outcomes not just BMI should be measured at bariatric surgery patients’ clinical appointments

The Concept of Social Ecology as a Means to Integrate Humanities and Science in Landscape Archaeological Research

The relationship between humans, their landscapes, and the natural environment is complex and underlies mutual non-material and material fluxes. Especially challenging is the attempt to reconstruct this relationship in order to understand the role and relevance of Space and Knowledge of Ancient Civilizations, the core theme of the cluster of excellence Exc 264 Topoi, funded from 2007–2019. In this book we present the results of an attempt to use a system-oriented concept of social ecology as tool for interdisciplinary collaboration and integrative research on aspects of human-environmental relationship. In six different interdisciplinary projects the developed social ecological model is applied and critically discussed

The impact of environmental metabolic disruptors on PPARgamma transcriptional regulation of adipocyte differentiation and function

Metabolic homeostasis is controlled, in part, by a family of proteins called nuclear receptors through which lipophilic hormones and hormone-like molecules regulate gene expression. One such nuclear receptor is peroxisome proliferator activated receptor γ (PPARγ). Its activation is essential for white, brite (brown-in-white) and brown adipogenesis, adipocyte function, mature adipocyte maintenance, and insulin sensitivity. PPARγ activation regulates energy homeostasis by both promoting storage of excess energy as lipids in white adipocytes and stimulating energy dissipation in brite and brown adipocytes. Accumulation of white adipocytes significantly increases the risk of obesity and metabolic syndrome. On the other hand, brown and brite adipocytes potentially counteract metabolic disease-related symptoms. The adipocyte differentiation and function as well as insulin sensitizing activities of PPARγ are regulated separately through differential post-translational modifications and/or co-regulator recruitment, with ligands having distinct abilities to activate each of PPARγ’s functions. These provide mechanisms by which a ligand could induce adipogenesis without stimulating PPARγ’s health promoting functions (i.e. insulin sensitivity, energy dissipation). The central hypothesis of this dissertation is that compared to therapeutic PPARγ ligands (i.e. rosiglitazone), environmental PPARγ ligands will activate a distinct PPARγ transcriptional program that disrupts adipose and metabolic homeostasis. Two study aims were developed to test and refine this central hypothesis. The first aim identified genes and pathways that differentiate environmental PPARγ ligands from endogenous and therapeutic chemicals. In primary mouse bone marrow multipotent stromal cells and 3T3-L1 cells, the environmental PPARγ ligands tributyltin (TBT, an antifouling agent and plasticizer) and triphenyl phosphate (TPhP, an organophosphate flame retardant) induced transcriptomic profiles that were distinct from rosiglitazone. All ligands induced adipogenesis; yet, only rosiglitazone strongly enriched pathways related to brown fat differentiation and mitochondrial processes and induced brite adipocyte gene markers (Cidea, Elovl3, Ucp1). Using the transcriptional profiles from 3T3-L1 adipocytes differentiated in the presence of 76 different chemicals, a taxonomy was built to identify environmental chemicals as PPARγ-modifying chemicals distinct from known PPARγ-modifying therapeutics. The second aim investigated the role of phosphorylation of PPARγ in defining environmental ligand-induced changes in adipocyte differentiation and function. In differentiated 3T3-L1 cells, rosiglitazone and TPhP both induced adipogenesis through PPARγ, but only rosiglitazone enhanced mitochondrial biogenesis and mitochondrial respiration, which contribute to healthy energy expenditure. Rosiglitazone, but not TPhP, protected PPARγ from phosphorylation at Ser-273. However, in 3T3-L1 cells in which PPARγ cannot be phosphorylated, TPhP was able to induce mRNA expression of a suite of brite adipocyte genes. In male C57BL/6J mice fed either a low or high fat diet, TPhP caused a significant decrease in brite adipocyte gene expression (Elovl3, Ucp1) in mature adipocytes from inguinal adipose tissue. Together, these studies support our hypothesis that environmental PPARγ ligands (i.e. TBT and TPhP) skew adipocyte differentiation toward white adipogenesis at the expense of brite adipogenesis, potentially because of differential post-translational modification of PPARγ