The novel E3 ligase of PPAR?? TRIM25 regulates adipocyte differentiation

Department of Biological SciencesPeroxisome proliferator-activated receptor ?? (PPAR??) is a ligand-dependent transcription factor which regulates glucose homeostasis and adipocyte differentiation. Its transcriptional activity is regulated by not only ligands but also post-translational modifications (PTMs). In this study, we demonstrate a novel E3 ligase of PPAR??, TRIM25 directly induces ubiquitination of PPAR?? followed by proteasome-dependent degradation. During the adipocyte differentiation, both mRNA and protein expression of TRIM25 significantly decreased and negatively correlated with the expression of PPAR??. Stable expression of TRIM25 reduces PPAR?? protein levels, but not mRNA expression, and suppressed adipocyte differentiation in 3T3-L1 cells. In contrast, specific knock-down of TRIM25 increases PPAR?? protein levels and stimulates adipocyte differentiation. Furthermore, TRIM25 knock-out mouse embryonic fibroblast (MEFs) shows an increased ability for adipocyte differentiation compared with wild-type MEFs. Taken together, these data indicate that TRIM25 is a novel E3 ubiquitin ligase of PPAR??, and depict TRIM25 as a novel target for PPAR??-involved metabolic diseases.ope

Geometry and Analysis of some Euler-Arnold Equations

In 1966, Arnold showed that the Euler equation for an ideal fluid can arise as the geodesic flow on the group of volume preserving diffeomorphisms with respect to the right invariant kinetic energy metric. This geometric interpretation was rigorously established by Ebin and Marsden in 1970 using infinite dimensional Riemannian geometry and Sobolev space techniques. Many other nonlinear evolution PDEs in mathematical physics turned out to fit in this universal approach, and this opened a vast research on the geometry and analysis of the Euler-Arnold equations, i.e., geodesic equations on a Lie group endowed with one-sided invariant metrics. In this thesis, we investigate two Euler-Arnold equations; the Camassa-Holm equation from the shallow water equation theory and quasi-geostrophic equation from geophysical fluid dynamics. First, we will prove the local-wellposedness of the Camassa-Holm equation on the real line in the space of continuously differentiable diffeomorphisms, satisfying certain asymptotic conditions at infinity. Motivated by the work of Misio{\l}ek, we will re-express the equation in Lagrangian variables, by which the PDE becomes an ODE on a Banach manifold with a locally Lipschitz right-side. Consequently, we obtain the existence and uniquenss of the solution, and the topological group property of the diffeomorphism group ensures the continuous dependence on the initial data. Second, we will construct global weak conservative solutions of the Camassa-Holm equation on the periodic domain. We will use a simple Lagrangian change of variables, which removes the wave breaking singularity of the original equation and allows the weak continuation. Furthermore, we obtain the global spatial smoothness of the Lagrangian trajectories via this construction. This work was motivated by Lenells who proved similar results for the Hunter-Saxton equation using the geometric interpretation. Lastly, we will study some geometric aspects for the quasi-geostrophic equation, which is the geodesic on the quantomorphism group, a subgroup of the contactomorphism group. We will derive an explicit formula for the sectional curvature and discuss the nonpositive curvature criterion, which extends the work of Preston on two dimensional incompressible fluid flows

Enhancing Oral Communications for Korean English-as-a-Foreign Language (EFL) Students in Business Settings

This project is intended to help adult EFL students in Korea familiarize themselves with the sounds of words and expressions that are used in everyday conversation, especially in business settings or workplaces. This project, with help of technology, focuses on customizing learnings and feedbacks for each student to meet their unique needs and maximizes the effectiveness and efficiency of learning process and outcomes. Also, the project emphasizes the importance of intonations and point of stress in spoken English that most Korean students have difficulty in distinguishing and recognizing in real-life conversations. It also introduces diverse accents of English since many Korean students consider American Standard English as the only “norm” of English language sound, which is not the case, especially when they interact with diverse people from many different countries or geographical backgrounds in business settings

THE DEVELOPMENT OF NOVEL PROTEASOME INHIBITORS FOR THE TREATMENT OF MULTIPLE MYELOMA AND ALZHEIMER’S DISEASE

Over a decade, proteasome inhibitors (PIs), bortezomib, carfilzomib (Cfz) and ixazomib, have contributed to a significant improvement in the overall survival for multiple myeloma (MM) patients. However, the response rate of PI was fairly low, leaving a huge gap in MM patient care. Given this, mechanistic understanding of PI resistance is crucial towards developing new therapeutic strategies for refractory/relapsed MM patients. In this dissertation work, we found H727 human bronchial carcinoid cells are inherently resistant to Cfz, yet susceptible to other PIs and inhibitors targeting upstream components of the ubiquitin-proteasome system (UPS). It indicated H727 cells may serve as a cell line model for de novo Cfz resistance and remains UPS dependent for survival. To examine the potential link between proteasome catalytic subunit composition and cellular response to Cfz, we altered the composition of proteasome catalytic subunits via interferon-γ treatment or siRNA knockdown in H727 cells. Our results showed alteration in composition of proteasome catalytic subunits results in sensitization of H727 cells to Cfz. It supported that proteasome inhibition by alternative PIs may still be a valid therapeutic strategy for patients with relapsed MM after having received treatment with Cfz. With this in mind, we designed and synthesized a small library of epoxyketone-based PIs by structural modifications at the P1′ site. We observed that a Cfz analog, harboring a hydroxyl substituent at its P1′ position was cytotoxic against cancer cell lines with de novo or acquired resistance to Cfz. These results suggested that peptide epoxyketones incorporating P1′-targeting moieties may have the potential to overcome Cfz resistance mechanisms in cells. The immunoproteasome (IP), an inducible proteasome variant which is harboring distinct catalytic subunits, LMP2, MECL1 and LMP7 of the proteasome typically expressed in cells of hematopoietic origin, plays a role in immune response and is closely linked to inflammatory diseases. It has been reported that the IP is upregulated in reactive glial cells surrounding amyloid β (Aβ) deposits in brains of Alzheimer’s disease (AD) patients and AD animal models. To investigate whether the IP is involved in the pathogenesis of AD, we examined the impact of IP inhibition on cognitive function in AD mouse models. We observed that YU102, an epoxyketone peptide targeting the IP catalytic subunit LMP2, improved cognitive dysfunction in AD mice without clearance of Aβ deposition or tau aggregation. Our cell line model study also showed a potential mode of action of YU102 which is suppressing pro-inflammatory cytokine production in microglial cells. It suggested that LMP2 contributes to microglia-mediated inflammatory response. These findings supported that LMP2 may offers a valuable therapeutic target for treatment of Alzheimer’s disease, expanding the therapeutic potential of the LMP2-targeting strategy

ROLE OF THE N-END RULE PATHWAY IN CARDIOVASCULAR DEVELOPMENT, SIGNALING, AND HOMEOSTASIS

The N-end rule pathway relates the in vivo half-life of a protein to the identity of its N terminal residue. In this pathway, a substrate bearing N-degron is recognized and ubiquitylated by a family of E3 ubiquitin ligases named UBR proteins. The N-end rule pathway is implicated in various physiological and pathological processes including cardiac development and angiogenesis. It has been previously shown that mice lacking ATE1, which mediates N-terminal arginylation, die during embryogenesis associated with various defects in cardiovascular development. The goal of my graduate research was to understand the function of the N-end rule pathway in cardiovascular development, signaling, and homeostasis. In my first project, I employed a genome-wide functional proteomic approach to identify physiological substrates of ATE1, that potentially underlie the above cardiovascular phenotypes. I found that RGS4, RGS5, and RGS16 are in vivo substrates of the N-end rule pathway, the first to be identified in mammals. These RGS proteins, emerging regulators for cardiovascular G protein signaling, were degraded through sequential N-terminal modifications including N-terminal exposure of their Cys 2, its oxidation, and arginylation. In the second project, to understand the physiological meaning of ATE1-mediated RGS proteolysis in cardiac development and signaling, I characterized ATE1-/- mice and embryonic cardiomyocytes with an emphasis on GPCR signaling. I found that cell-autonomous function of ATE1 regulates the proliferation of cardiomyocytes and the homeostasis of Gq-dependent cardiac signaling. In the third project, I explored a model of heterovalent interaction by developing RF-C11, a small molecule inhibitor of the N-end rule pathway. Its two heterovalent ligands were designed to cooperatively target two cognate sites of N-recognins. RF-C11 showed higher inhibitory efficiency than its homovalent controls, providing molecular basis of designing multivalent inhibitors for specific intracellular pathways. Moreover, the treatment of RF-C11 reduced cardiac proliferation and hypertrophy in cardiomyocytes, unveiling a previously unknown function of the pathway in cardiac proliferation and signaling. In summary, my graduate research contributes to comprehensive understanding of the function of the N-end rule pathway in the cardiovascular system

Analytical Models of Exoplanetary Atmospheres. II. Radiative Transfer via the Two-stream Approximation

We present a comprehensive analytical study of radiative transfer using the method of moments and include the effects of non-isotropic scattering in the coherent limit. Within this unified formalism, we derive the governing equations and solutions describing two-stream radiative transfer (which approximates the passage of radiation as a pair of outgoing and incoming fluxes), flux-limited diffusion (which describes radiative transfer in the deep interior) and solutions for the temperature-pressure profiles. Generally, the problem is mathematically under-determined unless a set of closures (Eddington coefficients) is specified. We demonstrate that the hemispheric (or hemi-isotropic) closure naturally derives from the radiative transfer equation if energy conservation is obeyed, while the Eddington closure produces spurious enhancements of both reflected light and thermal emission. We concoct recipes for implementing two-stream radiative transfer in stand-alone numerical calculations and general circulation models. We use our two-stream solutions to construct toy models of the runaway greenhouse effect. We present a new solution for temperature-pressure profiles with a non-constant optical opacity and elucidate the effects of non-isotropic scattering in the optical and infrared. We derive generalized expressions for the spherical and Bond albedos and the photon deposition depth. We demonstrate that the value of the optical depth corresponding to the photosphere is not always 2/3 (Milne's solution) and depends on a combination of stellar irradiation, internal heat and the properties of scattering both in optical and infrared. Finally, we derive generalized expressions for the total, net, outgoing and incoming fluxes in the convective regime.Comment: Accepted by ApJS. 23 pages, 11 figures, 3 tables, 158 equations. No change from previous version except for title (to match ApJS convention