The field of material microstructural design to achieve a set of targeted mechanical and functional properties has become a mainstay of new material development strategies. Structural materials, which by their very nature are intended to carry mechanical loads in service, can be designed to provide additional performance-enhancing functions through tailoring of meso-, micro-, or nano-structures. Structural materials with these performance-enhancing capabilities have been termed “synthetic multifunctional materials.” Structural composites, by their multiphase nature, offer many opportunities for the design of performance-enhancing multifunctional materials. Recently, a new class of structural materials has been developed at the University of California, San Diego, termed metallic-intermetallic laminate (MIL) composites.2 The goal of this materials development effort was to extrapolate upon the positive engineering properties exhibited by hierarchical multiphase complex natural composites, such as mollusk shells,3,4 to design and synthesize multifunctional composites to optimize specific structural properties while facilitating low-cost, designable, and functional microstructures.

G protein-coupled receptor (GPCR) signaling regulates cancer cell proliferation, invasion, migration and survival at metastatic sites. However, despite the success and promise of GPCRs as therapeutic targets, there are currently no FDA-approved drugs targeting GPCRs for cancer. Protease-activated receptor-1 (PAR1) is a GPCR that promotes breast cancer progression. PAR1 is overexpressed in breast cancer patient tissue biopsies and in breast carcinoma cell lines, and correlates with increased rates of metastasis and poor prognosis and increased invasion and metastatic potential, respectively. One mechanism that leads to PAR1 aberrant over-expression is defective lysosomal trafficking and degradation of the receptor, leading to persistent G protein signaling. Our lab recently showed that arrestin domain containing protein-3 (ARRDC3), an adaptor protein for E3 ubiquitin ligases, functions in regulating proper lysosomal trafficking and degradation. ARRDC3 has been identified as a tumor suppressor in aggressive breast cancer and I further examined the role of ARRDC3 in PAR1 trafficking in invasive breast carcinoma cells. The Hippo pathway, which converges on the transcriptional co-activators YAP and TAZ, is a well-established mediator of tumorigenesis and cancer progression and is also activated by GPCR stimulation, including through PAR1, in breast carcinoma. However, the mechanisms by which ARRDC3 regulates GPCR-stimulated Hippo signaling to promote breast cancer metastasis remains unknown. In the work described in this thesis, I discovered that ARRDC3 displays a multifunctional role in suppressing breast cancer growth and invasion: 1) by controlling proper PAR1 trafficking and degradation, thus inhibiting persistent G protein signaling and 2) by interacting with TAZ, thus sequestering TAZ in the cytoplasm and blocking downstream Hippo pathway gene transcription to occur. I used a tetracycline-inducible pSLIK lentiviral vector to restore expression of ARRDC3 in highly invasive, basal-like MDA-MB-231 cells, which exhibit high PAR1 and low ARRDC3 expression. Re-expression of ARRDC3 restored agonist-induced PAR1 degradation, attenuated JNK and Hippo-YAP signaling, and further inhibited PAR1-mediated breast carcinoma cell invasion. Thus, the dysregulation of PAR1 trafficking due to loss of ARRDC3 expression leads to persistent JNK signaling and promotes breast cancer invasion. ARRDC3 re-expression in invasive breast carcinoma cells also attenuates GPCR-stimulated Hippo signaling and invasion that is mediated by activation of TAZ but not YAP. Furthermore, siRNA-targeted depletion of TAZ, but not YAP, inhibits GPCR-induced Hippo signaling and invasion. Our studies suggest a crucial role for ARRDC3 and TAZ in GPCR-Hippo pathway signaling in breast carcinoma invasion and metastasis. An understanding of the mechanisms by which the Hippo pathway is regulated by GPCRs may lead to new potential therapeutic targets for the treatment or prevention of metastatic breast cancer.

With increase in traffic volume and change in travel related characteristics, vehicular emissions and energy consumption have increased significantly since two decades in India. Current models are not capable of estimating vehicular emissions accurately due to inadequate representation of real-world driving. The focus of this paper is to understand the level of Indian Driving cycle (IDC) in representing the real-world driving and to assess the impact of real-world driving on vehicular emissions.

The study has revealed that IDC does not represent the real-world driving. Irrespective of road classes, about 30% of time is spent below 20 km/hr and the speed too exceeds IDC’s maximum limit of 42 km/hr. Emissions are estimated for different driving patterns using International Vehicle Emission (IVE) model. Emission rates vary significantly from one class of road to another and the largest effect is on local streets.