MECHANISMS OF THE DOWNREGULATION OF PROLACTIN RECEPTOR AND THEIR ROLE IN CELL PROLIFERATION

Cells react to diverse stimuli by expressing specific receptors that recognize these stimuli and initiate specific signaling pathways that enable a cell to change with the environment. Downregulation of these signaling receptors represents the most direct method for limiting the magnitude and duration of downstream signal transduction. For cell surface transmembrane receptors, ligand-stimulated endocytosis is a major mechanism by which the ability of a cell to react to a ligand is restricted. In order to investigate the downregulation of the prolactin receptor (PRLr), we investigated the mechanism and key determinants in the endocytosis and downregulation of PRLr. In Chapter 2, we show that the endocytosis of PRLr is a ligand-induced process which requires the catalytic activity of the constitutively bound Janus kinase Jak2. In Chapter 3, we show that PRLr is internalized by a clathrin-dependent mechanism which requires phosphorylation of the conserved phosphodegron motif (DS349GRGS) at Ser 349 and an active SCFβ-TrCP E3 ligase complex. Optimal PRLr endocytosis is shown to be achieved via K63-linked polyubiquitination of the receptor. In Chapter 4, we show that PRL signaling promotes cell growth in 2-D and 3-D culture systems where PRLr levels are increased/stabilized. In Chapter 5, we identify pyruvate kinase M2 (PKM2), a glycolytic enzyme whose role in tumorigenesis has been described, to be a novel interactor of PRLr. We show that prolactin (PRL) signaling works to inhibit PKM2 activity by the propagation of tyrosine-phosphorylated proteins. This inhibition of PKM2 prevents progression through glycolysis and allows PKM2 to take a pro-tumorigenic role. We show that the interaction between PRL signaling and PKM2 is required for optimal prolactin-dependent cell growth. In this thesis (model shown in Model 1), we show that there is a defined mechanism of PRLr downregulation which works to limit PRL signaling. If this mode of receptor downregulation is not properly executed, it can result in aberrant signaling whereby prolactin-mediated inhibition of pyruvate kinase M2 mediates the pro-tumorigenic effect of prolactin

Roadway-Embedded Transmitters and Multi-Pad Receivers for High Power Dynamic Wireless Power Transfer

Electric vehicles (EVs) offer considerable economic and environmental benefits to society. Despite the decreasing vehicle costs and increasing range of newer EVs, the problem of range anxiety still exists. Range anxiety, at its core, is an issue of charging speeds rather than a concern about the driving range. Dynamic wireless charging of EVs is seen as a potential solution to this issue of range anxiety. Further, wireless charging technology also helps the push towards level 5 autonomy and opens new opportunities for how an EV can be utilized. Dynamic wireless power transfer (DWPT) systems typically require a high initial investment due to the scale of deployment needed and require a certain level of EV adoption before they become economically viable. The challenges facing DWPT technologies are broadly categorized into development, deployment and operation challenges. To address the deployment challenges, this dissertation presents the pavement integration of DWPT systems, and the design and validation of concrete-embedded wireless charging pads. To improve infrastructure utilization and address the operation challenge, different vehicle classes need to recharge from the same charging infrastructure. This is made possible by the use of multi-pad receivers, which allow different vehicle classes to receive different power levels using the same charging infrastructure. This work presents a scaled-down version of a multi-pad receiver system to demonstrate the operation and scalability of these modular receivers. To help further reduce the cost of development and implementation of DWPT systems, finite element method (FEM) and circuit simulation models are presented. The time-domain simulations can be used to develop and validate various control and communication schemes without the need for expensive hardware implementation. Finally, leakage magnetic field reduction to ensure safety and compliance for DWPT systems is discussed, and an example system is analyzed using FEM simulations

Land, labour and migrations : understanding Kerala's economic modernity

This paper seeks to map out the historical trajectory leading to a series of migrations in and from the erstwhile princely state of Travancore during 1900-70 in order to acquire and bring land under cultivation. It argues that these migrations undertaken with a moralistic and paternal mission of reclaiming ‘empty’ spaces into productive locations were a result of a specific form of economic modernity in Kerala as beckoned by colonialism and appropriated by a resolute local agency through a process of translation. The attempt is to disentangle the intertwining history of colonialism, capital and ‘native’ agency and thereby to capture the complex circumstances that unleashed a new discourse of development with land and hard work at the centre of its scheme. The transition was facilitated by a conforming social imaginary that not only dissented radically with the idea of leaving landscape empty and being idle but also advocated passionately the idea of using the opulent natural resources for the development of the self and the nation. Leading the transition the Syrian Christians were successful in wielding a new subjectivity of development with a specific authority over the modernity of Kerala as purogamana karshakar (forward-looking peasants). Key words: Economic modernity, translation, objectification, social imaginary, migration, modernisation, development discourse. JEL Classification: N5, P16, O13, O1

Model based methodology development for energy recovery in ash heat exchange systems

Flash tank evaporation combined with a condensing heat exchanger can be used when heat exchange is required between two streams and where at least one of these streams is difficult to handle (in terms of solid particles content, viscosity, pH, consistency etc.). To increase the efficiency of heat exchange, a cascade of these units in series can be used. Heat transfer relationships in such a cascade are very complex due to their interconnectivity, thus the impact of any changes proposed is difficult to predict. In this report, a mathematical model of a single unit ash tank evaporator combined with a condensing heat exchanger unit is proposed. This model is then developed for a chain of the units. The purpose of this model is to allow an accurate evaluation of the effect and result of an alteration to the system. The resulting model is applied to the RUSAL Aughinish Alumina digester area

To survive or to flourish? : minority rights and Syrian Christian community assertions in 20th century Travancore/Kerala

The arrival of modernity not only constituted communities but also impelled them in competition against each other in Kerala. Modern politics of the state as a result is inextricably liked with intense community politics. The success of community politics for rights and resources varied across communities, so also strategies of assertion. This paper will focus on different instances of community assertions by the Syrian Christians in twentieth century Travancore/Kerala. The confrontation of the community with the Hindu state and the then Dewan in the 1930s, the ‘Liberation Struggle’ against the Communists during late 1950s and the anti-eviction movements of 1960s testifies to its lack of primordial adherences and openness to heterogeneous strategies as required by different historical circumstances. It moves freely from secular to non-secular, minoritarian to majoritarian and lawful to unlawful, with claims to a greater citizenship. The hegemonic developmentalist ideology to which the community subscribes, along with reiteration of a righteous and industrious citizenship, ensured the transformation of the ‘unlawful’ into ‘lawful’. Using even ‘state secularism’ in Travancore of the 1940s as a route of sectarianism, Syrian Christian politics resorted to no permanent self-representation, resulting in unfixed community constellations. The paper also suggests that the recent recourse of the community to minority rights may hint at an internal crisis and a loss of moral weight it possessed earlier. Keywords: Syrian Christian, community, minority, secularism, communalism, communitarianism, citizenship, developmentalism

Transition to the ultimate regime in two-dimensional Rayleigh-B\'enard convection

The possible transition to the so-called ultimate regime, wherein both the bulk and the boundary layers are turbulent, has been an outstanding issue in thermal convection, since the seminal work by Kraichnan [Phys. Fluids 5, 1374 (1962)]. Yet, when this transition takes place and how the local flow induces it is not fully understood. Here, by performing two-dimensional simulations of Rayleigh-B\'enard turbulence covering six decades in Rayleigh number Ra up to $10^{14}$ for Prandtl number Pr $=1$, for the first time in numerical simulations we find the transition to the ultimate regime, namely at $\textrm{Ra}^*=10^{13}$. We reveal how the emission of thermal plumes enhances the global heat transport, leading to a steeper increase of the Nusselt number than the classical Malkus scaling $\textrm{Nu} \sim \textrm{Ra}^{1/3}$ [Proc. R. Soc. London A 225, 196 (1954)]. Beyond the transition, the mean velocity profiles are logarithmic throughout, indicating turbulent boundary layers. In contrast, the temperature profiles are only locally logarithmic, namely within the regions where plumes are emitted, and where the local Nusselt number has an effective scaling $\textrm{Nu} \sim \textrm{Ra}^{0.38}$, corresponding to the effective scaling in the ultimate regime.Comment: 6 pages, 4figure

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