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

Sibling Relationships, Birth Status, and Personality: A Qualitative Study of Asian American and European American College Students

Honors (Bachelor's)PsychologyUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/91780/1/satsun.pd

Rapid onset of hypercalcemia from high-grade lymphoma in the setting of HIV-related immune reconstitution inflammatory syndrome.

Hypercalcemia in HIV patients has been previously reported, but 1,25-(OH)2 vitamin D-mediated hypercalcemia, due to increased activity of extrarenal 1-alpha hydroxylase, is rarely described with HIV-related infections or malignancies. We describe a case of 1,25-(OH)2 vitamin D-mediated hypercalcemia in a patient presenting with progressive cognitive decline and weakness. Initial evaluation revealed a new diagnosis of HIV, for which he was started on antiretroviral therapy (ART). He was also noted to have mild asymptomatic hypocalcemia, likely from his acute illness and malnutrition, which was not further investigated at the time. While the patient's mental status initially improved with ART, he became progressively delirious and was found to be hypercalcemic approximately 4 weeks after the initiation of ART. Possible etiologies for hypercalcemia were vigorously evaluated, including granulomatous disease, infection, and malignancy, in the setting of suspected immune reconstitution inflammatory syndrome (IRIS), due to recent initiation of ART. Infectious workup was unrevealing, but computed tomography (CT) of the chest, abdomen, and pelvis revealed new extensive diffuse lymphadenopathy and hepatomegaly, not present on admission studies. Cytology and flow cytometry of a liver biopsy specimen revealed CD10 positive high-grade B-cell lymphoma. Chemotherapy was not pursued due to poor performance status. Over the next week, spontaneous tumor lysis developed, and the patient expired. Postmortem, his 1,25-(OH)2 vitamin D level returned as markedly elevated. Immunohistochemical staining of his liver biopsy tissue showed strong expression of CYP27B1. 1,25-(OH)2 vitamin D-mediated hypercalcemia is uncommon in a patient with newly diagnosed HIV and, in this case, was likely due to IRIS unmasking an underlying high-grade lymphoma and restoration of immune function (including T-cells and cytokine production). This case emphasizes the importance of including aggressive lymphomas, capable of progressing over days to weeks, in the evaluation of hypercalcemia in HIV patients at risk for developing IRIS and the rapid dynamic changes in mineral homeostasis that can occur with such an aggressive tumor in an immunocompromised host

Control of the Austenite recrystallization in Niobium Microalloyed steels

The use of heavy gauge steel sheets for structural applications very often requires a combination of high yield strength and adequate toughness. The most cost effective way to realize a high yield strength and a high ductility in a low alloyed steel is grain refinement. In industrial practice, this refinement is realized by controlled processing. This process consists of controlling the slab reheating temperature, applying a large amount of hot deformation below the nonrecrystallization temperature (T-nr) and accelerated cooling. A better knowledge of T-nr could optimize the process and the best mechanical properties could be reached against the lowest cost. T-nr can be raised by the addition of microalloying elements such as Nb. Nb can retard the static recrystallization of austenite at low temperatures either by solute drag or by precipitation pinning. In this study, the recrystallization behavior of five Nb-microalloyed model alloys with various Nb contents, was evaluated by double hit compression tests. Further, the precipitation state of the materials was investigated experimentally by Inductively Couples Mass Spectroscopy and X-ray Diffraction. The construction of recrystallization-time-temperature diagrams and precipitation-time-temperature diagrams showed that both mechanisms, i.e. recrystallization and precipitation, strongly influence each other

Analysis of Type Three System transport mechanism in gram-negative bacteria

Das Typ III Sekretionssystem (T3SS) ist ein Proteinkomplex den Gramnegative Bakterien nutzen um in einem Schritt Effektorproteine (Effektoren) aus dem Zytosol über die Doppelmembran zu sekretieren. Für viele Bakterien ist das T3SS ein essenzieller Virulenzfaktor, der es ihnen erlaubt mit ihrem Wirt zu interagieren und diesen zu manipulieren. Charakteristisch für das T3SS ist die strukturelle Komponente, der Nadelkomplex. Dieser ähnelt strukturell einer Spritze, deren Basalkörper die bakteriellen Membranen und das Periplasma durchspannt und einer Nadel, die vom Basalkörper aus dem Bakterium ragt. Basierend auf dem Modell einer Spritze wird angenommen, dass Effektoren entfaltet und anschließend durch Basalkörper und Nadelkanal sekretiert werden. Trotz der kontinuierlichen Forschung an T3SS entbehrt dieses Modell einer experimentellen Grundlage und der Mechanismus ist nicht vollständig erklärt. Ziel der Arbeit war es, eine experimentelle Basis für den Sekretionsmechanismus des T3SS zu schaffen. Um zu verstehen, wie das T3SS Effektoren sekretiert, wurden zunächst Fusionsproteine konstruiert, welche aus einem Effektor und einem stabil gefalteten Knotenprotein bestehen. Aufgrund des Knotens in der Fusion ist davon auszugehen, dass dieser während der Sekretion nicht entfalten kann. Die Effektordomäne wird sekretiert während der Knoten im Kanal verbleibt und diesen verstopft. Nach unseremWissen ist diese Arbeit die erste Visualisierung von Effektorfusionen an isolierten Nadelkomplexen. Die Effektorfusion wird N-terminal voran durch den Kanal sekretiert, wobei der Kanal das Substrat umschließt und gegen Proteasen und chemische Modifikationen abschirmt. Die Ergebnisse dieser Arbeit untermauern eine Grundidee der Funktionsweise des T3SS und liefern eine vielversprechende Strategie für in situ-Strukturanalysen. Dieser Ansatz lässt sich auch auf andere Proteinsekretionssysteme übertragen, bei welchen Substrate vor dem Transport entfaltet werden müssen.The Type III Secretion System (T3SS) is a complex used by Gram-negative bacteria to secrete effector proteins from the cytoplasm across the bacterial envelope in a single step. For many pathogens, the T3SS is an essential virulence factor that enables the bacteria to interact with and manipulate their respective host. A characteristic structural feature of the T3SS is the needle complex (NC). The NC resembles a syringe with a basal body spanning both bacterial membranes and a long needle-like structure that protrudes from the bacterium. Based on the paradigm of a syringe-like mechanism, it is generally assumed that effectors are unfolded and secreted from the bacterial cytoplasm through the basal body and needle channel. Despite extensive research on T3SS, this hypothesis lacks experimental evidence and the mechanism of secretion is not fully understood. This work aimed to provide an experimental basis for the model of the T3SS mechanism. In order to elucidate details of the effector secretion mechanism, fusion proteins consisting of an effector and a bulky protein containing a knotted motif were generated. It is assumed that the knot cannot be unfolded during secretion of the chimera. Consequently, these fusions are accepted as T3SS substrates but remain inside the NC channel and obstruct the T3SS. This is, to our best knowledge, the first time effector fusions have been visualized together with isolated NCs and it demonstrates that effector proteins are secreted directly through the channel with their N-terminus first. The channel encloses the substrate and shields it from a protease and chemical modifications. These results corroborate an elementary understanding of how the T3SS works and provide a powerful tool for in situ-structural investigations. This approach might also be applicable to other protein secretion systems that require unfolding of their substrates prior to secretion

A Cart, a box, a GPS: A Luggage cart and a clip style information device design from the view of universal design

The existing design of the airport luggage cart, which is intended to help travelers carry multiples pieces of luggage, has some issues. Also, the travelers sometimes are challenged to get information or to communicate with the workers at the airports especially when people travel outside of their mother country. These issues show that the airport needs a new luggage cart that is designed under the aspect of Universal Design. Therefore, this study proposed a new luggage cart design and the possibility of it to provide better service for all

Optical Tweezers as a Micromechanical Tool for Studying Defects in 2D Colloidal Crystals

This paper reports on some new results from the analyses of the video microscopy data obtained in a prior experiment on two-dimensional (2D) colloidal crystals. It was reported previously that optical tweezers can be used to create mono- and di-vacancies in a 2D colloidal crystal. Here we report the results on the creation of a vacancy-interstitial pair, as well as tri-vacancies. It is found that the vacancy-interstitial pair can be long-lived, but they do annihilate each other. The behavior of tri-vacancies is most intriguing, as it fluctuates between a configuration of bound pairs of dislocations and that of a locally amorphous state. The relevance of this observation to the issue of the nature of 2D melting is discussed.Comment: 6 pages, 4 figure

Dancing in suits: a performer's perspective on the collaborative exchange between self, body, motion capture, animation and audience.

The motion capture process places unique demands on performers. The impact of this process on the simultaneously artistic/somatic nature of dance practice is profound. This paper explores, from a performer’s perspective, how the process of performing in an optical motion capture system can impact and limit, but also expand and reconfigure a dancer’s somatic practice. This paper argues that working within motion capture processes affects not only the immediate contexts of capture and interactive performance, but also sets up a dialogue between dance practices within and beyond the motion capture studio

The Value of Urban Parklands: A User Study of the Baldwin Hills Park System

Urban parklands are well-documented as critical resources that provide users with extensive benefits and protect open spaces and natural habitat. The Baldwin Hills (BH) urban park system serves residents of Culver City, Los Angeles, Inglewood, local unincorporated counties, and the Larger Los Angeles County, as well as tourists and visitors from other parts of the region. This poster represents the pilot phase of an impending 2-year comprehensive survey of BH park user experiences that aims to inform improvements to quality of urban recreational spaces. The pilot study focused on 6 heavily used parks/ riverways within the BH system. Ten undergraduate research assistants (URAs) were trained according to LMU’s Institutional Review Board policies for human subjects research. URAs visited each park and conducted user surveys that included the following: frequency of park use, demographics, park activity engagement, park accessibility, and health/ disposition. URAs also conducted strategic counts of the number of park visitors. A total of 8 visitor counts and 236 surveys were conducted. This study yielded numerous recommendations on how to improve local urban parks, such as: extending the park grounds to surrounding neighborhoods, adding public transit stops nearer to the parks, installing educational exhibits around the sites to increase environmental awareness, etc. Future efforts will be focused on expanding the scope and scale of the survey assessments and narrowing down the questions to more user- specific topics.https://digitalcommons.lmu.edu/cures_posters/1000/thumbnail.jp