The rates of opioid prescription and use have continued to increase over the last few decades. In turn, a greater number of patients suffer from opioid tolerance. Treatment of acute pain is a clinical challenge for these patients. Acute pain can arise from common occurrences like surgical pain and pain resulting from the injury. P-glycoprotein (p-gp) is a transporter at the blood-brain barrier (BBB) associated with a decrease in the analgesic efficacy of morphine. Peripheral inflammatory pain (PIP) is a pain state known to cause a change in p-gp trafficking at the BBB. P-gp traffics from the nucleus to the luminal surface of endothelial cells making up the BBB. This surface where circulating blood interfaces with the endothelial cell is where p-gp will efflux morphine back into circulation. Osmotic minipumps were used as a long-term delivery method in this model of opioid tolerance in female rats. PIP induced p-gp trafficking away from nuclear stores showed a 2-fold increase when animals were exposed to opioids for 6 days. This observation presents a possible relationship between p-gp trafficking and the challenges of treating post-surgical pain in opioid tolerant patients. This could reveal potential strategies for improving pain management in these patients.

Glioblastoma multiforme is the most aggressive form of malignant brain tumor with poor prognosis. The efficacy of brain cancer treatment by chemotherapeutics is limited by the blood-brain barrier (BBB) which allows less than 2% of the small molecules and blocks almost all the macromolecules to transport into the brain. Delivery of the large molecules such as proteins and nucleic acids across the BBB is a great challenge for brain-targeted drug delivery. To overcome this obstacle, cell-penetrating peptides (CPPs) were used as vectors for delivery of nucleic acids across the BBB targeting glioblastomas. The CPPs have shown such promising carriers to deliver various cargoes ranging from small molecules to large molecules into the cells. This thesis is focused on the development of glioblastoma-targeting vectors based on modifications of the CPPs and the targeting peptides. The peptide-based vectors were developed to improve the transport of the nucleic acids across the BBB and specifically target glioblastomas. In this thesis, a series of peptide-based vectors targeting glioblastomas were synthesized and modified with targeting peptides by either covalent conjugation or non-covalent complex formation. The delivery of plasmid DNA (pDNA) in the complex with the peptide-based vectors was studied in the in vitro model of the BBB. The role of receptors expressed on the BBB was investigated. Scavenger receptors class A and B were found to be expressed on the BBB, and they were involved in the delivery of the pDNA across the BBB model. Moreover, various targeting peptides were modified with hexaglutamate to form non-covalent complexes with the CPPs for small interfering RNA (siRNA) delivery to glioblastoma cells. The non-covalent complex of the CPP and the targeting peptide showed greater gene-silencing efficiency than the consecutively covalent conjugation of the CPP and the targeting peptide for siRNA delivery to glioblastoma cells. Lastly, a number of novel, amphipathic peptides were developed based on the model amphipathic peptide. The prediction of the biological effect of the designed peptides using quantitative structure-activity relationship model showed a correlation with the experimental data. Finally, the CPP-based nucleic acid delivery vectors with homing peptide strategy have a potential for the BBB shuttle and the future use as a glioblastoma-targeted drug carrier in the in vivo studies and the clinical applications. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.</p>

This study investigates the mechanical and geometrical attributes of egg–box energy absorbing structures as crash safety barriers in the automotive industry. The research herein was originated from the earlier work of Prof. Shirvani, patented and further investigated by Cellbond Composites Ltd. who has invested in further research, for developing an analytical tool for geometric optimisation as an enhanced resolution to various shapes and materials. Energy absorption in egg-box occurs through plastic deformation of cell walls, examined through non–linear finite element simulations using ANSYS® and ANSYS/LS–DYNA® FE packages. Experimental dynamic crash tests have been designed to verify the validity of the FE simulations. Geometrical models are defined as 3D graphical representations, outlined in detail. Further, the impact behaviour of commercially pure aluminium egg-box energy absorbers is studied to identify the optimum design parameters describing the geometry of the structure. A simulation-based multi-objective optimisation strategy is employed to find a set of Pareto-optimal solutions where each solution represents a trade-off point with respect to the two conflicting objectives: the maximum impact force and the energy absorption capacity of the structure. The aim is to simultaneously minimise the former and maximise the latter, in the attempt to find purpose–specific optimal egg–box geometries. In light of the associated outcomes, it is shown that egg–box geometries with < ω ), thin walls (t < 1mm), short inter–peak distances and small peak diameters. M – < ω ), thin walls (t < 1mm), lengthy inter–peak distances and smaller peak diameters. It is concluded that, egg–box structures combined in the form of sandwich panels can be designed per application to act as optimised energy absorbers. Results of the proposed optimised sandwich structure are verified using analytical techniques.

The shift to the Cu/low-k interconnect scheme requires the development of diffusion barrier/adhesion promoter materials that provide excellent performance in preventing the diffusion and intermixing of Cu into the adjacent dielectrics. The integration of Cu with low-k materials may decrease RC delays in signal propagation but pose additional problems because such materials are often porous and contain significant amounts of carbon. Therefore barrier metal diffusion into the dielectric and the formation of interfacial carbides and oxides are of significant concern. The objective of the present research is to investigate the fundamental surface interactions between diffusion barriers and various low-k dielectric materials. Two major diffusion barriers¾ tatalum (Ta) and titanium nitride (TiN) are prepared by DC magnetron sputtering and metal-organic chemical vapor deposition (MOCVD), respectively. Surface analytical techniques, such as X-ray photoelectronic spectroscopy (XPS), transmission electron microscopy (TEM), and atomic force microscopy (AFM) are employed. Ta sputter-deposited onto a Si-O-C low dielectric constant substrate forms a reaction layer composed of Ta oxide and TaC. The composition of the reaction layer varies with deposition rate (1 Å-min-1 vs. 2 Å-sec-1), but in both cases, the thickness of the TaC layer is found to be at least 30 Å on the basis of XPS spectra, which is corroborated with cross-sectional TEM data. Sputter-deposited Cu will not wet the TaC layer and displays facile agglomeration, even at 400 K. Deposition for longer time at 2 Å-sec-1 results in formation of a metallic Ta layer. Sputter deposited Cu wets (grows conformally) on the metallic Ta surface at 300 K, and resists significant agglomeration at up to ~ 600 K. Cu diffusion into the substrate is not observed up to 800 K in the UHV environment. Tetrakis(diethylamido) titanium (TDEAT) interactions with SiO2, Cu and a variety of low-k samples in the presence (~ 10-7 Torr or co-adsorbed) and absence of NH3 result in different products. TDEAT interactions with SiO2 are dominated by Ti interactions with substrate oxygen sites, and that Ti oxide/sub-oxide bond formation can proceed with relatively low activation energy. No Ti carbide or Si carbide formation is observed. Co-adsorption of TDEAT and NH3 on SiO2 at 120K followed by annealing to higher temperature results in enhanced Ti-N bond formation, which is stable against oxidation up to 900K in UHV. Similarly, continuous exposures of TDEAT on SiO2 at 500K in the presence of NH3 exhibit a relatively enhanced Ti-N spectral component. Co-adsorption of NH3 and TDEAT on Cu (poly) surface at 120K, followed by annealing to 500K, results in complete desorption of Ti, N or C-containing species from the Cu substrate. Reaction of TDEAT with a Cu surface at 500K yields a Ti-alkyl species via a b-hydride elimination pathway. TDEAT/Cu interactions are not observably affected by overpressures of NH3 of 10-7 Torr. TDEAT interaction with a porous carbon doped oxide low-k substrate at 700K demonstrates undissociated or partly dissociated Ti-NR species trapped in the dielectrics matrix due to its high porosity. In addition, carbide formation is observed from C(1s) XPS spectra. For a hydrocarbon low-k film, the majority sites (carbon) are highly unreactive towards TDEAT even at higher temperature due to a lack of functional groups to initiate the TDEAT/low-k surface chemistry.

An extremely facile and novel method called spontaneous deposition, to deposit noble metal nanoparticles on a most stable form of carbon (C) i.e. diamond is presented. Nanometer sized particles of such metals as platinum (Pt), palladium (Pd), gold (Au), copper (Cu) and silver (Ag) could be deposited on boron-doped (B-doped) polycrystalline diamond films grown on silicon (Si) substrates, by simply immersing the diamond/Si sample in hydrofluoric acid (HF) solution containing ions of the corresponding metal. The electrons for the reduction of metal ions came from the Si back substrate. The diamond/Si interfacial ohmic contact was of paramount importance to the observation of the spontaneous deposition process. The metal/diamond (M/C) surfaces were investigated using Raman spectroscopy, scanning electron microscopy (SEM), x-ray photoelectron spectroscopy (XPS) and x-ray diffractometry (XRD). The morphology (i.e. size and distribution) of metal nanoparticles deposits could be controlled by adjusting the metal ion concentration, HF concentration and deposition time. XRD data indicate the presence of textured and strained crystal lattices of Pd for different Pd/C morphologies, which seem to influence the electrocatalytic oxidation of formaldehyde (HCHO). The sensitivity of electrocatalytic reactions to surface crystal structure implies that M/C could be fabricated for specific electrocatalytic applications. The research also presents electroplating of Cu on ruthenium (Ru), which a priori is a promising barrier material for Cu interconnects in the sub 0.13 μm generation integrated circuits (ICs). Cu plates on Ru with over 90% efficiency. The electrochemical nucleation and growth studies using the potentiostatic current transient method showed a predominantly progressive nucleation of Cu on Ru. This was also supported by SEM imaging, which showed that continuous thin films of Cu (ca. 400 Å) with excellent conformity could be plated over Ru without dendrite formation. Scotch tape peel tests and SEM on Cu/Ru samples both at room temperature (RT) and after annealing at 800 oC, showed no sign of delamination of the Cu film from Ru indicating strong adhesion. XRD patterns from Cu/Ru samples at RT through 800 oC indicated Cu in its characteristic face centered cubic (fcc) form with (111) phase dominating. Most importantly no new XRD peak emerged, even after annealing to 800 oC showing Cu and Ru did not interact much. The excellent adhesion and lack of metallurgical interactions between Cu and Ru underscored the potential application of Ru as a new Cu diffusion barrier in the next generation ICs.

This study asks the question: If we take a small neighborhood and introduce a barrier, how will the neighborhood change? Will it be better protected and flourish, or will it decay and die or perhaps will there be no change at all? What determines the outcome? This work tries to answer these questions by creating an Agent-Based Model (ABM) to test different scenarios and observe the results. Urban environments, both natural and built, are complex systems, containing a multitude of people, landscapes and buildings. Simple changes in street-lighting and sidewalks, the addition of trees and green scapes or the enforcement of “broken-window” policies impact local neighborhoods [1]. Measuring behavior changes on a neighborhood level are difficult to quantify, but by using ABM methods we can build our neighborhood, populate it with a variety of actors and watch their interaction with each other, and with introduced stimuli. Our simulation introduces a barrier (highway) with varying permeability into a mixed use neighborhood loosely based on Richmond’s Jackson Ward. Several metrics (such as property value, crime rates, etc.) were used to determine if the neighborhood was under duress, or thriving. In real-world terms we built a roadway though the neighborhood and observed the “severance effect” as our actors’ adapted to reduced mobility and remained within their accessible range.

Examined within this study were the relations between two processes within sexual identity development, sexual identity exploration and sexual identity commitment, and risky sexual behaviors. The moderating effects of sexual identity commitment, sexual self-efficacy, and positive condom use attitudes on relations between sexual identity exploration and risky sexual behaviors were also examined. Risky sexual behaviors included the frequency of substance prior to and barrier protection use during sex, multiple sex partners, and the initiation of sex prior to age sixteen. Study participants included 322 college students attending an urban university in the Southeastern United States. All were heterosexual and reported engaging in vaginal, anal or oral sex in the past 30 days. A high percentage of study participants reported at least one risky sexual behavior in the past 30 days, and most reported not using barrier protection during anal and oral sex. No direct effects were found between sexual identity exploration and any risky sexual behavior. Only one direct effect was found between higher levels of sexual identity commitment and lower frequencies of barrier protection use for oral sex. No moderating effects were found for sexual identity commitment, sexual self-efficacy, or positive condom use attitudes on relations between sexual identity exploration and any risky sexual behavior. The findings highlight the importance of examining how to get emerging adults to consistently use barrier protection during any type of sexual behavior. The results also underscore the complexity of sexual risk-taking during emerging adulthood, and the need for continued examination of the ways in which processes associated with sexual identity development may impact sexual risk-taking during emerging adulthood.

Patterns of the expansion of woody cover into grasslands on barrier islands of the Virginia coast were investigated. Seed dispersal of the dominant shrub Morella spp., was sampled deploying seed traps (n = 82) throughout a landscape under shrub encroachment pressure on Hog Island, VA. Traps were placed underneath: fruiting Morella, non-fruiting Morella, co-occurring species (Iva frutescens and Baccharis halimifolia) and in grass land, (no shrub cover). Environmental filters that act upon dispersed seeds and subsequently determine establishment patterns were also investigated. Dispersal distribution throughout the encroachment zone was leptokurtic and dispersal among cover types suggest co-occurring shrub species facilitate dispersal by functioning as bird perches. Interaction of biotic and abiotic factors mediate a complex process of establishment by influencing dispersal, germination and seedling survival to ultimately determine distribution patterns of woody plants in coastal environments.

The pediatric primary care setting has been discussed as playing a central role for the identification and treatment of behavioral and mental health disorders in youth. Although this setting is in a unique position to provide these services, there are many barriers to the integration of mental health care and pediatric primary care. The aim of this study is to examine perspectives of multiple stakeholders (i.e., patient, parent, nurse, resident, faculty, clinic director) in a pediatric primary care setting to explore barriers, behavioral and mental health needs, and facilitators to the integration and provision of mental health care for children and families in pediatric primary care. The study involved both focus group and individual interviews with a total of 36 stakeholders (patient n = 2; parent n = 7; nurse n = 4; resident n = 16; faculty n = 5; clinic director n = 2). A grounded theory approach was used to analyze the focus group and interview data. Barriers to integration and consequences of these barriers are presented, as well as facilitators identified by stakeholders to overcome these obstacles. Identified behavioral and mental health needs will also be presented. Limitations of the study and future directions are discussed.

Targeted drug delivery to the brain is difficult to achieve using conventional techniques, largely due to the blood-brain barrier’s (BBB) impediment to drug diffusion into the brain parenchyma. In response, development of convection-enhanced delivery (CED) offers the ability to circumvent the BBB and target specific areas of the brain. Predictability of infusate movement in pathological brain states during CED will maximize the effectiveness of this treatment, and therefore modeling of infusate movement must be characterized. Previous work from our lab effectively modeled CED in rats using the middle carotid artery occlusion model of cytotoxic edema. However, previous models examined for vasogenic edema study did not show pure vasogenic edema. The purpose of this study was to develop a model of pure vasogenic edema in the rat brain. In this study, we show that stereotactic 9 µL infusion of 1.0 mM DCA over 45 minutes into the rat corpus callosum reproducibly creates pure vasogenic edema, as observed in the peritumoral white matter surrounding gliomas.