No description available.

Nicotine has multiple behavioral effects as a result of its action in the central nervous system. Nicotine strengthens the behaviors that lead to nicotine administration (primary reinforcement), and this effect of nicotine depends on mesotelencephalic systems of the brain that are critical to goal directed behavior, reward, and reinforcement. Nicotine also serves as a ‘reinforcement enhancer’ – drug administration enhances behaviors that lead to other drug and nondrug reinforcers. Although the reinforcement enhancing effects of nicotine may promote tobacco use in the face of associated negative health outcomes, the neuroanatomical systems that mediate this effect of nicotine have never been described. The ventral tegmental area (VTA) is a nucleus that serves as a convergence point in the mesotelencephalic system, plays a substantial role in reinforcement by both drug and nondrug rewards and is rich in both presynaptic and postsynaptic nicotinic acetylcholine receptors (nAChRs). Therefore, these experiments were designed to determine the role of the VTA and nAChR subtypes in the reinforcement enhancing effect of nicotine. Transiently inhibiting the VTA with a gamma amino butyric acid (GABA) agonist cocktail (baclofen and muscimol) reduced both primary reinforcement by a visual stimulus and the reinforcement enhancing effect of nicotine, without producing nonspecific suppression of activity. Intra-VTA infusions of a high concentration of mecamylamine a nonselective nAChR antagonist, or methylycaconitine, an α7 nAChR antagonist, did not reduce the reinforcement enhancing effect of nicotine. Intra-VTA infusions of a low concentration of mecamylamine and dihydro-beta-erythroidine (DHβE), a selective antagonist of nAChRs containing the *β2 subunit, attenuated, but did not abolish, the reinforcement enhancing effect of nicotine. In follow-up tests replacing systemic nicotine injections with intra-VTA infusions (70mM, 105mM) resulted in complete substitution of the reinforcement enhancing effects – increases in operant responding were comparable to giving injections of systemic nicotine. These results suggest that *β2-subunit containing nAChRs in the VTA play a role in the reinforcement enhancing effect of nicotine. However, when nicotine is administered systemically these reinforcement enhancing effects may depend on the action of nicotine at nAChRs in multiple brain nuclei.

Vascular Endothelial Growth Factor (VEGF) is a highly conserved ligand that is involved in the regulation of angiogenesis and vasculogenesis, however, alternative roles of the ligand have been emerging. Organisms such as jellyfish and Drosophila contain VEGF homologs, yet they do not possess endothelial cells or a vascular system indicating that VEGF might have other primitive roles. In this current study we investigated how VEGF affects the post-natal development of the intestinal epithelial by either overexpressing VEGF or by reducing the bioavailability of VEGF with the overexpression of soluble VEGF receptor (sFLT-1) within the gastrointestinal tract. After three weeks of VEGF overexpression, mutant mice displayed an increase in villus height and proliferation in the transit-amplifying zone with the decrease of crypts per measured length and Lgr5 expression. On the other hand, sFLT-1 overexpressing mice had an increase in crypt depth with a decrease in villus height, proliferation in the transit-amplifying zone, crypts per measured length and reduced expression of Dll1 and Bmp4. Overall the availability of VEGF has the ability to alter the proliferation of progenitor cells in the crypt by either a direct or indirect signals. These studies reveal that by some means VEGF is altering the developing post-natal intestinal epithelium and proliferation. Largely, elucidating the interaction between VEGF and intestinal stem cells in intestinal development and differentiation may help to advance intestinal stem cell therapies in intestinal dysfunction or disease

No description available.

No description available.

This thesis work provides an insight into the design of Force-amplifying Compliant Mechanisms (FaCMs) that are integrated with micromachined resonant accelerometers to increase their sensitivity. An FaCM, by mechanically amplifying the inertial force, enhances the shift in the resonance frequency of the beams used for sensing the acceleration whose effect causes an axial force on the beams. An extensive study on different configurations of resonators namely, single beam resonator, single-ended tuning fork (SETF), and double-ended tuning fork (DETF), is carried out to gain insights about their resonant behavior. The influence of the boundary conditions on the sensor’s sensitivity emerged from the study. We found that not only the force-amplification factor but also the multi-axial stiffness of the FaCM and proof-mass influence the resonance frequency of the resonator as well as the bandwidth of the modified sensor for certain configurations but not all. Thus, four lumped parameters were identified to quantify the effectiveness of an FaCM. These parameters determine the boundary condition of the sensing beams and also the forces and the moment transmitted to them. Also presented in this work is a computationally efficient model, called the Lumped Parameter Model (LPM) for evaluation of the sensitivity. An analytical expression for the frequency-shift of the sensing resonator beams is obtained by considering the FaCM stiffness parameters as well as the lumped stiffness of the suspension of the inertial mass. Various FaCMs are evaluated and compared to understand how the four lumped parameters influence the sensor’s sensitivity. The FaCMs are synthesized using topology optimization to maximize the net amplification factor with the volume constraint. One of the FaCMs outperforms the lever by a factor of six. Microfabrication of resonant accelerometer coupled with FaCM and comb-drive actuator is carried out using a silicon-on-insulator process. Finally, the selection map technique, a compliant mechanism redesign methodology is used for enhancing the amplification of FaCMs. This technique provides scope for further design improvement in FaCMs for given sensor specifications.

Simultaneously achieving high-sensitivity and a large resonance frequency of micromachined accelerometers is difficult because of the inherent trade-off between the two. In this thesis, we present a mechanical displacement-amplifying technique that is amenable to micromachining to enhance sensitivity without compromising on the resonance frequency and cross-axis sensitivity. Depending on the requirements of sensitivity alone or sensitivity and resonance frequency, Displacement-amplifying Compliant Mechanisms (DaCMs) are designed using the selection map-based technique, which indicates the limits of what is possible for given specifications on size and microfabrication. In order to prove the benefits of a DaCM, we modified the designs of two very sensitive capacitive micromachined accelerometers from the literature by incorporating DaCMs and showed that, within the same footprint on the chip, the displacement sensitivity could be enhanced by more than 60% while the resonance frequency was also improved by more than 30%. As the focus of the thesis is to explore the integration of DaCMs into accelerometers, the analytical, computational, and practical aspects are discussed in detail. Both single and dual axis in-plane accelerometers are considered. The fabrication processes used are Silicon-on-Insulator Multi-user MEMS Processes (SOIMUMPs) and a customized Silicon-on-Insulator (SOI) based process. The fabricated accelerometers are packaged and brought to the product form. They were tested at the die level as well as in the packaged form. Under dynamic conditions, the measured amplification factor of the fabricated single-axis in-plane accelerometer was observed to be 11. The overall dimension of the accelerometer was 4.25 mm × 1.25 mm. The first in-plane natural frequency of the fabricated accelerometer was found to be 6.25 kHz. The voltage sensitivity of the packaged accelerometer with the DaCM measured 26.7 mV/g at 40 Hz with differential capacitance sensitivity of 3926 ppm/g around the base capacitance of 0.75 pF. The fabricated dual-axis accelerometer has a special configuration of twelve folded-beam suspension blocks that de-couple any displacements along the two in-plane orthogonal axes. The decoupling feature is retained even after adding the DaCMs along both the axes. The total device size was 8.6 mm × 8.6 mm. The device was also fabricated and packaged inside a ceramic flat-pin package using hybrid die-to-die wire-bonding. Die-level dynamic characterization showed that the average geometric advantage achieved using the DaCMs is 6.2 along both the in-plane axes. The measured axial voltage sensitivity of about 580 mV/g for both the axes was achieved with a cross-axial sensitivity of less than 2% and a natural frequency of 920 Hz. The static capacitance sensitivity was found to be 0.296 × 106 ppm/g with a base capacitance of 0.977 pF. Also presented in this work is a wide-band dual-axis accelerometer without an amplifying mechanism. Its first two in-plane modal frequencies measured 14.2 kHz. The measured sensitivity of the packaged accelerometer along both the axes of the device was found to be 62 mV/g at 200 Hz. Aiming at towards cost-effective accelerometers for small-volume markets, we also developed a single-axis and two dual-axis meso-scale spring-steel in-plane accelerometers equipped with Allegro A1395 linear Hall-effect sensors for sensing the displacement of the proof-mass. The single-axis in-plane meso-scale accelerometer also contains a DaCM. It is observed through simulation that the single-axis design with a DaCM is 39% more sensitive and has 41% more bandwidth compared to a single-axis design without a DaCM. The measured sensitivity of the fabricated single-axis spring-steel accelerometer with a DaCM was found to be 71.4 mV/g with a minimum resolvable acceleration of 14 milli-g. The unique features of the first generation of dual-axis accelerometers are that a rechargeable Li-ion battery adds to the proof-mass. It also contains a de-coupling mechanism that can decompose any planar acceleration into its axial components. The second generation of dual-axis accelerometers is more compact in size. All the mechanical elements of the accelerometers are made of EN J42/AISI 1080 spring steel foil machined using Wire-cut Electro-Discharge- Machining. The measured sensitivity of the first generation of dual-axis meso-scale accelerometers is 78 and 108 mV/g along the X and Y axes whereas the second generation device exhibits a sensitivity of 40 mV/g for both the axes. The thesis concludes that the sensitivity of a displacement-based sensor can be improved using a suitably designed DaCM without compromising the resonance frequency and hence the bandwidth. Furthermore, the work describing the development of meso-scale accelerometers also establishes spring steel as a viable material for meso-scale applications.

This thesis deals with the design of two-axis displacement-amplifying compliant mechanisms (DaCMs) using topology optimization. The two-axis compliant mechanisms considered here are XY positioners and two-axis inertial sensors. A building block approach, with several single-axis DaCMs as building blocks, is used to conceive designs of compliant platforms that provide two orthogonal and independent movement of a common platform. Spring-mass-lever (SML) models of these designs are developed to simplify the analysis and design of the complicated arrangements of building blocks. The XY positioners designed in this work have perfectly de-coupled motion without compromising on the frequency; the best design of the stage has a displacement amplification of five resulting in the enhanced range of 4.2 % of the mechanism size–a significant improvement from the 1.67 %, the maximum range of the designs reported so far. Nearly 100% improvement is observed in the sensitivity of the two-axis accelerometer as compared with an existing design that occupied the same area. Multiple prototypes of XY positioners were fabricated on polypropylene sheets using CNC machining; and on spring steel and aluminium using wire-cut electro discharge machining. Mask layouts for two-layer two-axis accelerometers are designed for micro-fabrication using reactive ion etching and wafer bonding.

Epidermal wound healing requires the coordinated involvement of complex cellular and biochemical processes. In the case of epidermal wounds associated with burns, the healing process may be less than optimal and may take a significant amount of time, possibly resulting in infection and scarring. An innovative method to assist in the repair of the epidermis (the outer layer of skin) is to use an aerosolised apparatus. This method involves taking skin cells from an area of the patient's undamaged skin, culturing the cells in a laboratory, encouraging them to rapidly proliferate, then harvesting and separating the cells from each other. The cells are then sprayed onto the wound surface. We investigate this novel treatment strategy for the healing of epidermal wounds, such as burns. In particular, we model the application of viable cell colonies to the exposed surface of the wound with the intent of identifying key factors that govern the healing process. Details of the evolution of the colony structure are explored in this two-dimensional model of the wound site, including the effect of varying the initial population cluster size and the initial distribution of cell types with different proliferative capacities. During injury, holoclones (which are thought to be stem cells) have a large proliferative capacity while paraclones (which are thought to be transient amplifying cells) have a more limited proliferative capacity. The model predicts the coverage over time for cells that are initially sprayed onto a wound. A detailed analysis of the underlying mathematical models yields novel mathematical results as well as insight into phenomena of healing processes under investigation. Two one-dimensional systems that are simplifications of the full model are investigated. These models are significant extensions of Fisher's equation and incorporate the mixed clonal population of quiescent and active cells. In the first model, an active cell type migrates and proliferates into the wound and undergoes a transition to a quiescent cell type that neither migrates nor proliferates. The analysis yields the identification of the key parameter constraints on the speed of the healing front of the cells on this model and hence the rate of healing of epidermal wounds. Approximations for the maximum cell densities are also obtained, including conditions for a less than optimal final state. The second model involves two active cell types with different proliferative capacity and a quiescent cell type. This model exhibits two distinct behaviours: either both cell types coexist or one of them dies out as the wound healing progresses leaving the other cell type to fill the wound space. Conditions for coexistence are explored.