Schedule of Events

Studying transmembrane receptors in mammalian cells is vital to understanding the complex downstream intracellular pathways and regulation controlling cell behavior. The presence or absence of external ligands to these receptors, including growth factors and extracellular matrix elements, have known effects on proliferation, migration, and survival in cells. Genetic mutations which result in deviation from normal regulation of these behaviors may result in cancer. Therefore, these receptors have become a popular target in treating several types of cancer. A class of receptor tyrosine kinase (RTK) known as epidermal growth factor receptor (EGFR) plays several important roles in conferring cell survival, and has become an area of great interest in treating cancers with epithelial morphology. Another class of cell surface receptors known as integrins adhere to certain extracellular matrix elements and also play a similar role in controlling cellular behavior. The extent to which these two types of cell surface receptors work together in cancer has been documented, but is not well characterized. This study uses the U87 glioblastoma cell line to study the possible overlap and co-dependence in the downstream pathways of EGFR and β1 integrins. The inhibitor gefitinib was used to inhibit EGFR, and an anti-CD29 antibody was used to inhibit β1 integrins. The effects of these inhibitions alone, and in tandem, were then analyzed through proliferation and clonogenic assays. Preliminary results indicate that the two inhibitors are more effective when used together, suggesting a possible co-dependence between EGFR and β1 integrin downstream pathways in mediating cell proliferation. 

A lack of critical iron in bacteria leads to the secretion of siderophores (small molecule metal chelators) to acquire iron from the external environment. Siderophores have high affinity for ferric iron (Fe3+) outcompeting host chelators, and making them virulence factors in infection. Some siderophores are assembled via a NRPS-independent siderophore (NIS) pathway. In this pathway, enzymes are small and independent, and create siderophores with hydroxamate and carboxylate functional groups. Understanding the structure of NIS synthetases may lead to the design of specific inhibitors (antibiotics) to fight pathogenic bacteria. The Hoffmann lab has used x-ray crystallography to determine the protein structure of NIS synthetase DesD from Streptomyces coelicolor bound to several substrates, as well as apo (empty of substrates), for comparison. DesD makes the siderophore desferrioxamine, requiring three iterative bonds and a macrocyclization event. DesD is one of the best biochemically characterized NIS synthetases so far, and this structure is solved as a model for the rest. We have mutated the binding site of DesD (Arg306Gln) to inactivate the enzyme while retaining the overall binding and fold. We collected data and solved the structures of apo Arg306Gln DesD, as well as bound to ATP and substrates. We observed several small positional changes in the active site residues. A C-terminal helix-to-coil transition, however, is a larger conformational change that may communicate structurally with the allosteric dimer. This structural information may allow for the design of an inhibitor that will prevent the binding of substrate in future work. 

Azepines are unsaturated heterocycles composed of six carbons and one nitrogen atom. In the past two decades, medications containing azepine ring as a major feature of the overall structure have proven to be excellent therapeutic agents, treating patients who suffer from severe pain, chronic schizophrenia, and growth hormone abnormalities. The practical usefulness of azepine derivatives is by no means limited to medical applications; 1,2,5-triazepines have been found in agricultural fields as plant protectants. Various synthetic methods have been developed for the construction of azepine rings. However, very limited focus has been directed toward stereochemical control during the formation of medium ring azacycles. Working under the mentorship of Dr. Jason Kingsbury, my research has been aimed toward the development of optically active phenyl-substituted N-acyl vinylaziridines as substrates for building stereochemically rich azepine rings. If successful, our efforts could revolutionize and expand the opportunities for everyday manufacture of pharmaceuticals and other biological probes.

Previous research has found that falls on stairs account for about 10% of fatal fall accidents (Startzell et al., 2000). The purpose of this study was to determine if there is a link between knee joint muscle strength and transition step preference in stair descent in elderly subjects.  Additionally, kinematic and kinetic values were compared between preferred and non-preferred lead legs.  Individuals 65 years and older were recruited for the study (17 females, 15 males). After completing a university IRB-approved consent form, each subject filled out a health questionnaire to ensure eligibility.  Stair descent was performed on a set of three standard sized stairs, with the right and left leg leading (order randomized). Motion capture data was recorded using 6 Vantage V5 cameras collecting at 120 Hz and two Kistler Force Plates collecting at 1200 Hz. Data was then analyzed using Vicon Nexus 2.0.  Knee extensor and knee flexor strength was determined by a Biodex System 3 isokinetic dynamometer set at 180º/s and at 60 º/s.  After data collection, subjects identified which was their preferred lead leg for decent. 57% of subjects preferred to lead with their stronger leg. Dependent t-test were used to determine differences in joint angles, joint torques and ground reaction forces between the preferred and non-preferred legs. Peak knee extensor torque was significantly different for the stronger leg when compared to the weaker leg, but there was no significant difference when preferred leg and non-preferred leg were compared (p < 0.05).

With the recent detection of gravitational waves by the Laser Interferometer Gravitational Wave Observatory (LIGO) a new era of gravitational wave astronomy is beginning. Finding an approximation for the background noise experienced by a gravitational wave detector would lead to more accurate readings and provide more information for the design of such instruments. This project has produced an estimate of the background noise in gravitational wave signals for that purpose. Gravitational radiation background noise is emitted by massive compact objects (such as black holes, white dwarfs and neutron stars) in orbit around supermassive black holes (SMBH) at the centers of galaxies. To calculate the background noise we approximate the energy released per compact object-SMBH interaction, the rate at which these interactions occur, the number of events per supermassive black hole, the number density of galaxies per volume of space, and lastly incorporate the cosmological evolution of these parameters. A calculation incorporating only the black hole-SMBH interactions has been made. The background noise emitted by other compact objects will be included in the future work. Fortunately, the black hole-SMBH interactions emit most of the gravitational radiation experienced. In the future, we will look to improve the approximations for the energy per event, redshift value and number of events per supermassive black hole. The final resultant from this project will be useful in the design of future gravitational wave detectors such as the Laser Interferometer Space Antenna (LISA) set to start soon.