This dissertation comprises an introduction, background and current research progress in the area of classical antifolates as the targeted anticancer therapies.<br>In this study, twelve series of classical 5-, 6- and 7-substituted pyrrolo[2,3-d]pyrimidines were designed and synthesized. Extensive structure modifications of the pyrrolo[2,3-d] pyrimidine scaffold were investigated to determine selective transport via FR or/and PCFT and tumor targeted antifolates with GARFTase or multiple folate metabolizing enzyme inhibition.<br>The design strategies employed include: variation of the side chain substitution position (5-,6- and 7-substituted); variation of the side chain length (n=1-6); isosteric replacement of the 1,4-disubstituted phenyl ring with 1,2- and 1,3- disubstituted phenyl ring and 2,5- disubstituted thiophenyl ring; replacement the L-glutamate with variation at the á and ã carboxylic acids.<br>As a part of this study, a total of one hundred and fifty six new compounds (including new intermediates) were synthesized and separated. Of these, twelve series consisting of forty two classical antifolate final compounds were submitted for biological evaluation. In addition, bulk synthesis of some potent final compounds (2, 2.0 g; 161, 500 mg; 175, 1.0 g; 166, 500 mg; 194, 500 mg) was carried out to facilitate in vivo evaluation.<br>More importantly, a new Heck coupling of the thiophene iodide 301 and allyl alcohols to synthesize aldehydes in one step was discovered. Due to its potential use in analog synthesis of clinically used antifolates such as RTX and PMX, this mild conditioned and easy to handle Heck coupling reaction is highly attractive.<br>During this study, the SAR of folate transporters (RFC, FR and PCFT) and GARFTase inhibitors were extensively explored. The 6-substituted straight chain compound 166 (n=7) was extremely potent against KB tumor cells (IC50=1.3 nM, about 80-fold more potent than clinically used PMX) without any RFC activity. The 5- substituted phenyl compound 175 (n=4) showed AICARFTase as the primary target with potent KB tumor cell inhibition (IC50=7.9 nM, about 8-fold more potent than PMX) and also indirectly inhibited the mTOR pathway leading to tumor cell apoptosis. Due to their potent antitumor activities, these two compounds serve as leads for future structural optimization. / Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences; / Medicinal Chemistry / PhD; / Dissertation;

<p>This research presents the detailed investigation of coupled-mode flutter and non-synchronous vibration in turbomachinery. Coupled-mode flutter and non-synchronous vibration are two aeromechanical challenges in designing turbomachinery that, when present, can cause engine blade failure. Regarding flutter, current industry design practices calculate the aerodynamic loads on a blade due to a single mode. In response to these design standards, a quasi three-dimensional, reduced-order modeling tool was developed for identifying the aeroelastic conditions that cause multi-mode flutter. This tool predicts the onset of coupled-mode flutter reasonable well for four different configurations, though certain parameters were tuned to agree with experimentation. Additionally, the results of this research indicate that mass ratio, frequency separation, and solidity have an effect on critical rotor speed for flutter. Higher mass-ratio blades require larger rotational velocities before they experience coupled-mode flutter. Similarly, increasing the frequency separation between modes and raising the solidity increases the critical rotor speed. Finally, and most importantly, design guidelines were generated for defining when a multi-mode flutter analysis is required in practical turbomachinery design. </p><p>Previous work has shown that industry computational fluid dynamics can approximately predict non-synchronous vibration (NSV), but no real understanding of frequency lock-in and blade limit-cycle amplitude exists. Therefore, to understand the causes of NSV, two different reduced-order modeling approaches were used. The first approach uses a van der Pol oscillator to model a non-linear fluid instability. The van der Pol model is then coupled to a structural degree of freedom. This coupled system exhibits the two chief properties seen in experimental and computational non-synchronous vibration. Under various conditions, the fluid instability and the natural structural frequency will lock-in, causing structural limit-cycle oscillations. This research shows that with proper model-coefficient choices, the frequency range of lock-in can be predicted and the conditions for the worst-case, limit-cycle-oscillation amplitude can be determined. This high-amplitude limit-cycle oscillation is found at an off-resonant condition, i.e., the ratio of the fluid-shedding frequency and the natural-structural frequency is not unity. In practice, low amplitude limit-cycle oscillations are acceptable; this research gives insight into when high-amplitude oscillations may occur and suggests that altering a blade's natural frequency to avoid this resonance can potentially make the response worse.</p><p>The second reduced-order model uses proper orthogonal decomposition (POD) methods to first reconstruct, and ultimately predict, computational fluid dynamics (CFD) simulations of non-synchronous vibration. Overall, this method was successfully developed and implemented, requiring between two and six POD modes to accurately predict CFD solutions that are experiencing non-synchronous vibration. This POD method was first developed and demonstrated for a transversely-moving, two-dimensional cylinder in cross-flow. Later, the method was used for the prediction of CFD solutions for a two-dimensional compressor blade, and the reconstruction of solutions for a three-dimensional first-stage compressor blade. </p><p>This research is the first to offer a van der Pol or proper orthogonal decomposition approach to the reduced-order modeling of non-synchronous vibration in turbomachinery. Modeling non-synchronous vibration is especially challenging because NSV is caused by complicated, unsteady flow dynamics; this initial study helps researchers understand the causes of NSV, and aids in the future development of predictive tools for aeromechanical design engineers.</p> / Dissertation

The primary objective of the presented research is to develop a class of integrated compact silicon diffractive sensors (CSDS) based on in-plane diffraction gratings. This class of sensors uses a silicon-on-insulator (SOI) substrate to limit costs, exploit established fabrication processes, enable integration of supporting electronics, and use the well-understood telecommunications wavelength of 1.55µm. Sensing is achieved by combining constant-diffraction-efficiency and highly-angularly-selective in-plane resonance-domain diffraction gratings. Detection is based on the diffraction efficiency of the highly angularly selective grating. In this research, the design processes for the constant-diffraction-efficiency and the highly angularly selective gratings are detailed. Grating designs are optimized with rigorous coupled-wave analysis (RCWA) and simulated with finite-difference time-domain (FDTD) analysis. Fabrication results are presented for the CSDS gratings. An inductively coupled plasma (ICP) Bosch etch process enables grating fabrication to within one percent of designed values with nearly vertical sidewalls. Experimental results are presented for individual CSDS gratings, the prototype sensor, and a prototype linear sensor array. The results agree well with simulation. The linear sensor array prototype demonstrates the intrinsic splitting mechanism and forms the basis of a 2-D sensor array. Finally, a toluene sensor was functionally demonstrated. The proof-of-concept device includes a polymer immobilization layer and microfluidic delivery of toluene. Toluene concentrations as low as 100ppm are measured, corresponding to a refractive index change of 3x10⁻⁴ RIU.

The main concept of Body-Coupled Communication (BCC) is to transmit the electrical information through the human body as a communication medium by means of capacitive coupling. Nowadays the current research of wireless body area network are expanding more with the new ideas and topologies for better result in respect to the low power and area, security, reliability and sensitivity since it is first introduced by the Zimmerman in 1995. In contrast with the other existing wireless communication technology such as WiFi, Bluetooth and Zigbee, the BCC is going to increase the number of applications as well as solves the problem with the cell based communication system depending upon the frequency allocation. In addition, this promising technology has been standardized by a task group named IEEE 802.15.6 addressing a reliable and feasible system for low power in-body and on-body nodes that serves a variety of medical and non medical applications. The entire BAN project is divided into three major parts consisting of application layer, digital baseband and analog front end (AFE) transceiver. In the thesis work a strong driver circuit for BCC is implemented as an analog front end transmitter (Tx). The primary purpose of the study is to transmit a strong signal as the signal is attenuated by the body around 60 dB. The Driver circuit is cascaded of two single-stage inverter and an identical inverter with drain resistor. The entire driver circuit is designed with ST65 nm CMOS technology with 1.2 V supply operated at 10 MHz frequency, has a driving capability of 6 mA which is the basic requirement. The performance of the transmitter is compared with the other architecture by integrating different analysis such as corner analysis, noise analysis and eye diagram. The cycle to cycle jitter is 0.87% which is well below to the maximum point and the power supply rejection ratio (PSRR) is 65 dB indicates the good emission of supply noise. In addition, the transmitter does not require a filter to emit the noise because the body acts like a low pass filter. In conclusion the findings of the thesis work is quite healthy compared to the previous work. Finally, there is some point to improve for the driver circuit in respect to the power consumption, propagation delay and leakage power in the future.

Membrane proteins constitute approximately 30% of all genes in the human genome and two large families of membrane proteins are G protein-coupled receptors (GPCRs) and Solute Carriers (SLCs) with about 800 and 380 human genes, respectively. In Papers I, II and IV, we report 16 novel human Adhesion GPCRs found by searches in NCBI and Celera databases. In Paper I, we report eight novel human GPCRs, and six in Paper II. We identified two new human Adhesion GPCRs and 17 mouse orthologs in Paper IV. Phylogenetic analysis demonstrates that the 16 novel human genes are additional members of the Adhesion GPCR family and can be divided into eight phylogenetic groups. EST expression charts for the entire repertoire of Adhesions in human and mouse were established, showing widespread distribution in both central and peripheral tissues. Different domains were found in their N-terminus, some, such as pentraxin in GPR112, indicates that they take part in immunological processes. In Paper III, we discovered seven new human Rhodopsin GPCRs. In Paper V, we present the identification of two new human genes, termed SLC6A17 and SLC6A18 from the Solute Carriers family 6 (SLC6). We also identified the corresponding orthologs and additional genes from the mouse and rat genomes. We analysed, in total, 430 unique SLC6 proteins from 10 animal, one plant, two fungi and 196 bacterial genomes. In Paper VI, we provide the first systematic analysis of the evolutionary history of the different SLC families in Eukaryotes. In all, we analysed 2403 sequences in eight species and we delineate the evolutionary history of each of the 46 SLC families.

G protein-coupled receptors (GPCR) are integral membrane proteins with seven α-helices that translate a remarkable diversity of signals into cellular responses. The superfamily of GPCRs is among the largest and most diverse protein families in vertebrates. We have searched the human genome for GPCRs and show that the family includes approximately 800 proteins, which can divided into five main families; Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2 and Secretin. This study represents one of the first overall road maps of the GPCR family in a mammalian genome. Moreover, we identified eight novel members of the human Adhesion family which are characterized by long N-termini with various domains. We also investigated the GPCR repertoire of the chicken genome, where we manually verified a total of 557 chicken GPCRs. We detected several specific expansions and deletions that may reflect some of the functional differences between human and chicken. Substantial effort has been made over the years to find compounds that can bind and activate the melanocortin 4 receptor (MC4R). This receptor is involved in food intake and is thus an important target for antiobesity drugs. We used site-directed mutagenesis to insert micromolar affinity binding sites for zinc between transmembrane (TM) regions 2 and 3. We generated a molecular model of the human MC4R which suggests that a rotation of TM3 is important for activation of the MC4R. Furthermore, we present seven new vertebrate prolactin releasing hormone receptors (PRLHRs) and show that they form two separate subtypes, PRLHR1 and PRLHR2. We performed a pharmacological characterization of the human PRLHR which showed that the receptor can bind neuropeptide Y (NPY) related ligands. We propose that an ancestral PRLH peptide has coevolved with a redundant NPY binding receptor, which then became PRLHR. This suggests how gene duplication events can lead to novel peptide ligand/receptor interactions and hence spur the evolution of new physiological functions.

Landfills are considered to be one of the major sources of anthropogenic methane (CH4) emissions in the environment. A landfill biocover system optimizes environmental conditions for biotic CH4 consumption that controls the fugitive and residual emissions from landfills. A compost material has more oxidation potential in comparison to any other material due to its high porosity, organic content, free flux for gases and water holding capacity. Thermal, hydraulic, bio – chemical and mechanical (THMCB) properties are important factors that can significantly affect the performance of biocover material with regards to CH4 oxidation potential as well as structural stability. Technical data on the thermal, hydraulic and mechanical (THM) properties of compost based biocover materials are quite limited. Hence, a detailed experimental program has been carried out at the University of Ottawa to study the THM properties and behaviour of compost biocover material by conducting experimental tests on small compost samples as well as by performing column experiments. The test results indicate that lower water content (dry of optimum for compaction curve) shows more free air space (FAS) in comparison to higher water content. The compost has almost the same shear strength for various initial water contents and dry unit weights; however, it settles and swells more at higher water content than lower water content per mechanical test results. The thermal and hydraulic properties of compost are a function of the compaction degree in addition to various other parameters. It is also found that the THM properties of compost are strongly coupled and the degree of saturation greatly affects the FAS.

Urea is an important nitrogen fertilizer for plant nutrition, but is very susceptible to moisture sorption and caking even at low moisture contents, e.g. 0.25% w/w. When urea particles adsorb moisture followed by drying, crystal bridges form between urea particles. For particles in a bed, this process is called caking. Cakes in stored urea cause a degradation of its quality and value. Investigations of the moisture absorption in beds of manufactured urea particles and adsorption on the external and internal surfaces of urea particles are a necessary step if engineers are to recommend procedures to reduce caking and control inventories. Research on moisture adsorption and cake strength of urea fertilizer has not been sufficiently explored. Only recently have researchers started to devise tests to investigate the crystal bonding between two urea particles. Prior to this research, investigations of the moisture interactions in beds of urea were nearly non-existent. This thesis presents experimental, theoretical and numerical methods to investigate the coupled heat and moisture transfer processes in a bed of urea particles while the bed is exposed to ambient air with changing temperature and humidity.<p> Urea particles are nearly spherical with uniform particle size distribution. The particle size, its internal pore structure and rough crystalline external surface depend on the manufacturing process. In this thesis, two types of urea products are investigated, i.e. prill Georgia urea and granular Terico urea. The rough external surface and internal pore structure of each particle makes the total surface area exposed to water much larger than similar smooth and solid spherical particles. Although Georgia urea has higher external surface area than Terico urea, the latter type has larger total surface area and internal pore volume. For both Terico urea and Georgia, the internal surface area dominates the water sorption process but the external moisture sorption of Georgia urea is more important than that of Terico urea.<p> All the water vapor interaction experiments were carried out with air flow through a test bed because it shortens the duration of each experiment to a few hours in most cases. A series of experiments with step changes in inlet air temperature and humidity for air flow through a urea bed indicated that the measured outlet air temperature and humidity responses, each at a specific air flow rate, reveals a typical exponential or transient time change that can be characterized by a time constant. After formulating the theoretical problem for step changes in the inlet properties, the analytical solutions showed that the time constants of outlet response to whether a temperature step change or a humidity step change are functions of the convection coefficient and air velocity. The predicted outlet air temperature is determined by only one time constant for a temperature step change while it is determined by these two time constants for a humidity step change.<p> A new test cell with sampling test ports was developed to measure the transient moisture uptake of a urea particle bed and its distribution at any time without any interruption of the experiment. A novel particle sampling device, modified from a syringe and pistons, was designed to minimize the particle exposure to ambient air during the moisture content determination using a Karl Fischer titrator. Data from two continuous cyclic step changes in the inlet flow with relative humidities between 4% and 70% at room temperature showed a hysteresis in the isothermal moisture content for only the first cycle. After the second sorption- desorption cycle, the hysteresis disappeared. This implies that the internal pore and particle surface geometry changes are very slow after the first cycle.<p> A new theoretical porous media model was developed for a coupled heat and moisture transport process when humid air flowed uniformly through a large test bed in two coupled computational domains: internal domain (i.e., the particle phase) and the external domain (i.e., the interstitial air space). The moisture migration in two computational domains included: water vapor diffusion inside each particle, and water vapor convection and diffusion in the interstitial air space in the urea particle bed. For energy transport, the temperature was assumed to be uniform inside each particle, but heat convection and conduction between the urea particles and the interstitial air outside particles occurred throughout the bed. Both heat transfer and mass transfer in internal domain and external domain were coupled by the heat and mass convection at the gas-particle interface. The numerical simulation was compared with the data of moisture uptake and showed good agreement implying that the internal moisture diffusion that dominates the moisture uptake process is a very slow process.<p> These above experimental, theoretical and numerical research studies provide a set of information on how urea particles adsorb or desorb moisture from or to ambient air on the external and internal pore surface, which offers a useful suggestion for urea caking prevention and is also a first and necessary step to the study of further caking formation and strength.

Constantly changing environments force animals to adapt by cycling through multiple physiological states. Plasticity in sensory, motor, and modulatory neural circuits is an essential part of these adaptive processes. Invertebrates with their accessible, identifiable neurons are excellent models for investigating the molecular and cellular mechanisms underlying state-dependent neural plasticity, and provide insight into similar processes in more complex systems. These properties have allowed highly detailed characterization of several crustacean circuits with respect to their connectivities, cellular properties, responses to various inputs, and outputs. Serotonin (5-HT) is an important neuromodulator in virtually every animal species. 5-HT signals are mediated primarily by a large family of metabotropic receptors on target cells that activate diverse intracellular signaling cascades. Although 5-HT’s effects on crustacean circuits have been studied in detail, the mediating receptors have been inaccessible until recently. Crustacean receptors had not been cloned and specific drugs for use in physiological experiments could therefore not be identified. Coupling properties of 5-HT receptor families are strongly conserved between phyla, but pharmacological profiles are not. The extent of pharmacological divergence among invertebrates is unclear, however, as no systematic functional profile of 5-HT receptors from related species has been determined. This work shows that orthologs of two 5-HT receptors, 5-HT2b and 5-HT1a, are highly conserved at the molecular, functional and pharmacological level between two distantly related decapod crustaceans, Panulirus interruptus and Procambarus clarkii. A suite of drugs was functionally characterized at Panulirus and Procambarus 5-HT2b and 5-HT1a receptors in cell culture, which were then used to investigate the roles of the receptors in pyloric cycle frequency modulation in the stomatogastric ganglion, a model central pattern generator. The two receptor subtypes were found to serve different roles in the circuit and their function depends on the initial state of the circuit. Finally, an antibody recognizing 5-HT1a was used to map the localization of this receptor within the crayfish nervous system. 5-HT1a is localized to somata and neuropil throughout the nerve cord, suggesting it may respond to synaptic, paracrine or neurohormonal 5-HT signals. The protein and mRNA expression levels are variable between individual animals, perhaps reflecting distinct physiological states.

There are a significant number of microwave applications, including active antenna arrays, wireless communication systems, navigational applications, etc., where improvement of such qualities as manufacturing costs, size, weight, power consumption, etc. is still on the agenda of todays RF design. In order to meet these requirements, new technologies must be actively involved in fabrication of RF components with improved characteristics. One of such fabrication technologies is called LIGA, used before primarily in fluidics, photonics, bioengineering, and micromechanics, and only recently receiving growing attention in RF component fabrication. One of the RF components suffering limitations in performance due to limitations in fabrication capabilities is the compact single metal layer (SML) coupled-line 3-dB coupler, also called hybrid, required in some applications thanks to its ability to divide power equally and electrically isolate the output from the input. In todays practical edge-coupled SML coupler designs, the level of coupling is limited by the capabilities of the photolithographic process to print the coupled lines close enough for tight coupling and it is usually no tighter that 8 dB. A promising way to overcome this limitation is increasing the area of metallic interface of the coupled lines, thus increasing the mutual capacitance of the lines, and inherently the coupling between them. This should be preferably done with keeping the coupler compact with respect to the footprint area, which is attained by making taller conductors, i.e. employing the third dimension. In contrast with previously used RF component fabrication processes, LIGA is the technology that allows the designer to explore the third dimension and build tall conductors while being also able to use small features. When the two-dimensional edge-coupled SML couplers are extended into the three-dimensional structures, they rather become the side-coupled SML couplers. Tall-conductor coupled lines have been characterized in this work to reveal their dependence on their geometry and a 3-dB SML coupler with tall conductors has been developed and fabricated using LIGA at the Institute for Microstructure Technology (IMT), Karlsruhe, Germany. The simulation and measurement results demonstrate the potentially superior performance of LIGA couplers, and the promising capabilities of LIGA for fabrication of RF microstructures.