<p>Chemokine receptors are members of the seven transmembrane receptor (7TMR) superfamily and are regulated by the G-protein coupled Receptor Kinase (GRK)/ b-arrestin system. CCL19 and CCL21 are endogenous agonists for the chemokine receptor CCR7. They are known to be equipotent in promoting Gi/o mediated calcium mobilization, chemotaxis and inhibition of adenylyl cyclase activity. Here we test the hypothesis that these ligands are biased agonists that differentially activate the G-protein coupled Receptor Kinase (GRK)/ b-arrestin system.</p><p>In order to test whether these ligands have distinct activity, murine T lymphocytes were used to compare the effects of CCL19 and CCL21 activation of CCR7 at endogenous expression levels. While each ligand stimulates similar chemotactic responses, we also find that CCR7 ligands lead to differential signaling. For instance, CCL19 is markedly more efficacious than CCL21 for the activation of ERK and JNK, but not AKT in these cells. Furthermore, ERK activation and chemotaxis are maintained as separate pathways, also distinguishable by their dependency upon PKC and PI3 kinase, respectively. Thus, CCL19 and CCL21 stimulate equal activation of PI3 kinase, AKT, and chemotaxis, but are in fact biased agonists leading to differential activation of MAP kinase in murine T lymphocytes. </p><p>To determine the mechanism of CCR7 ligand bias, we used HEK-293 cells expressing CCR7 to compare the proximate signaling events following CCL19 and CCL21 activation. We found striking differences in the activation of the GRK/ b-arrestin system. CCL19 leads to robust CCR7 phosphorylation and b-arrestin2 recruitment catalyzed by both GRK3 and GRK6 while CCL21 activates GRK6 alone. This differential GRK activation leads to distinct functional consequences. Only CCL19 leads to the recruitment of b-arrestin2-GFP into endocytic vesicles and classical receptor desensitization. In contrast, each agonist is fully capable of signaling to MAP kinase through b-arrestin2 in a GRK6 dependent fashion. </p><p>Therefore, CCR7 and its ligands represent a natural example of ligand bias whose mechanism involves differential GRK isoform utilization by CCL19 and CCL21 despite similar G-protein signaling. This study suggests that the GRK signatures of 7TMRs can determine the function of discrete pools of b-arrestin and thus guide its cellular effects.</p> / Dissertation

<p>The Duke storage has been developed as a dedicated driver for the storage ring based free-electron lasers (FEL) and a high flux Compton gamma-ray source, the High Intensity Gamma-ray Source. The storage ring can be operated from about 250 MeV to 1.2 GeV, which can produces FEL lasers over a wide range of wavelengths and gamma-rays with a tunable energy from 1 MeV to 100 MeV. The Duke light source facility conducts world-class researches across a wide range of scientific disciplines and technological applications.</p><p> In a storage ring, beam instabilities can cause a signifcant degradation in machine performance. In the Duke storage ring, coupled-bunch instabilities (CBIs) are the main source which limit ultimately achievable beam current in multi-bunch operations. In order to to suppress CBIs in the Duke storage, we developed a bunch-bybunch longitudinal feedback (LFB) system which is based on a field programmable gate array (FPGA) embedded system. During the design and implementation of the LFB system, several novel methods and techniques are developed in numerical analysis of feedback control and kicker cavity design/fabrication. High current are realized at low energies by using the LFB system. In addition, after the successful commissioning of the LFB system, a analog transverse feedback (TFB) system has been upgraded to a digital one using the same technique as the LFB system. </p><p>The LFB system has been routinely operated for HIGS. Additional,the LFB and TFB feedback systems become an useful diagnostic tools in researches of electron beam dynamics, FEL lasing process, and background of HIGS. The control of CIBs in different operation modes are studied using the feedback system. Furthermore, based on the TFB system, a novel bunch cleaning method has been developed to reduce the background of gamma-ray.</p> / Dissertation

Lysophosphatidic acid (LPA) is a mitogenic lipid that enhances cell growth, proliferation and motility through binding and activation of at least four receptors, LPA1/Edg2, LPA2/Edg4, LPA3/Edg7, and PPAR and #947;. Here, we show that LPA stimulation inhibits the cell cycle regulator and tumor suppressor, p53. Ten M LPA reduced the cellular levels of total p53 and p53 phosphorylated at serine 15 by approximately 50% in A549 cells and this effect was sustained for at least 6 h. This resulted in a corresponding decrease in p53-mediated transcription. Transient-transfection of the Edg-family LPA receptors, LPA1-3 in HepG2 cells, which do not respond to LPA, also showed this inhibitory response. The response was specific to LPA receptors since neither Gi-coupled M2 muscarinic acetylcholine receptors, nor a mutant LPA1 receptor (LPA1 R124A), which is unable to bind LPA, inhibited p53 activity. Both transient-transfection of the LPA-degrading lipid phosphate phosphatase-1 (LPP-1), or exogenous addition of phospholipase B, which decreases exogenous lysophosphatidate, reversed the LPA receptor-induced decrease in p53-mediated transcription. Although pertussis toxin did not prevent the inhibition of p53, a mutant LPA1 receptor (LPA1 and #8710;361), which lacks the C-terminal PDZ-binding domain, failed to inhibit p53 function. This establishes LPA-mediated inhibition of p53 function requires an interaction with PDZ-containing proteins. These data establish a novel role for LPA-mediated receptor activation in diminishing p53 activity; which, in addition to LPAs well-characterized effects on growth-promoting signaling pathways, is likely to contribute to the survival and proliferation of cancer cells. Of the Edg-family LPA receptors, the LPA1 receptor is the most widely expressed. In the next study, we investigated the agonist-induced endocytosis of the human LPA1 receptor, bearing an N-terminal FLAG epitope tag, in stably transfected HeLa cells. LPA treatment induced the rapid endocytosis of approximately 40% of surface LPA1 within 15 minutes. Internalization was dose dependent and LPA specific since neither lysophophatidylcholine nor sphingosine-1-phosphate induced LPA1 endocytosis. Removing agonist following incubation resulted in LPA1 recycling back to the surface. LPA1 internalization was strongly inhibited by dominant-inhibitory mutants of both dynamin2 (K44A) and Rab5a (S34N). Finally, our results indicate that LPA1 exhibits basal, LPA-dependent internalization in the presence of serum-containing medium.

We consider a type of forced "Van Der Pol" oscillator where the forced function is periodic and oscillatory around the t-axis. This problem derived from an electrical model. The important issues here is that this circuits presents the spiking phenomena over a one time period and it has important applications in signal processing and digital communication. The three most important problems that we addressed here in this thesis are to compute the number of spikes a solution completes in one time period (it can be used to transform the analog signal into digital information), how the dynamics of the number of spikes change with respect to the parameters amplitude (k) and frequency (w), and when the coupled circuits synchronize (i.e., the driver and the respond are on synchronous). Sophisticated mathematical and numerical analysis has been developed that enable us to give a complete study of the problems above described.

The thesis is devoted to the study of spontaneous synchronization of coupled nonlinear oscillators. It consists of two major parts. The first describes synchronization of Josephson junctions embedded in a transmission line. I consider in detail a new phenomenon ??eation of inert oscillator pairs ??ich was observed in analytical studies. The second part of the thesis describes synchronization of an array of single mode fiber lasers, with special interest in the phenomenon of synchronization of subsets of fiber lasers in a two dimensional array through a specific arrangement of the under-pumped lasers.

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A safe electrical connection between the human body and the recording circuit is required for the acquisition of physiological signals such as the electrocardiogram (ECG), electroneurogram (ENG), or electromyogram (EMG). The recording chip is conventionally connected to the human body through a blocking capacitor. The capacitor avoids any DC current flowing from the recording system into the patient¡¦s body in the case of chip failure. However, the large capacitor area in an integrated chip and its effect on the signal transform function make the use of a coupling capacitor undesirable. In principle, a DC-coupled system can be used to overcome this limitation. The DC-coupled amplifier connects directly to the patient. However, a DC failure current caused, for example, by a gate-oxide short failure could harm the patient. To detect a dangerous condition, a safety monitoring system is proposed in this thesis. The safety monitoring system applies a test signal and physiological signals to the amplifier input. The disappearance of the test signal in the event of circuit failure is detected at the amplifier output. The recording system can then be switched into a safe state. The analysis of the monitoring system, its design procedure and simulation results are presented in this thesis. Moreover, the first measured results are reported for a system realized as an integrated circuit in TSMC 0.35 £gm 2P4M CMOS process technology.

This study is focus on the integration and miniaturess of the active circuit and antennas. Recently, the monolithic microwave integrated circuits have been mature in communication markets and the associated handsets are interesting in the quality and profile. The antenna plays a role as a radiator in wireless system. Therefore, the performance dominates the quality of communication. The aspect of the antenna usually occupies the majority communication hardware¡¦s area. Comparing many front end circuit elements, the challenges in the antennas will be more crucial. Therefore, it has well merits in designing high integration and bandwidth antennas. Based on the integration of the active circuits stage and antennas, this work presents the aperture coupled active antenna with harmonic suppression and broadband dual feeds circularly polarized patch antenna. Utilizing the bented aperture and insertion of narrow rectangular slots on excitation edge for shifting the high order harmonic components from the active stage, the harmonic suppression characterization is implemented by the above approach. The other active antenna, braodband dual feeds circularly polarized antenna, is achieved with spatial power combining. The subject aims the different excitated patch structures and replacing the periodic feeding lines as active circuits in the discussion. Relative to the conventional 50 Ohm feeds, the mechanics of the feeds are modified with stepped impedance resonators and stubs at the same physical wave length condition for achieving the integration of the antenna and the circuit. Besides, this antenna can exhibit excellent behavior and compact the size in the effective frequency range.

The purpose of our research is growing the coupled InGaAs quantum dots on the n-type substrate by molecular beam epitaxy in laboratory, and we choose 5,10 and 15 nanometers to be the thicknesses of GaAs spacer between the quantum dots layer. Due to the couple effect, we hope to realize the theorem of intermediate band proved by Luque and Marti. We measure the characteristic of samples by electroluminescence spectra, photoelectric current spectra, electrical absorption spectra and electro reflectance spectra in laboratory; moreover, we acquire the basic parameters of solar cell by AM1.5G for analyzing. From the basic parameters of solar cell, we know that the quantum dots can enhance the photocurrent by absorbing additional photons , however, the strain caused by quantum dots would decay the open voltage seriously, so that the efficiency always under the baseline. Each efficiency of 9-stack QDs are 4.3%(c494),5.1%(c519),5.3% (c520),and each efficiency of 9-stack Dwells are 3.9%(c524),4.2%(c525),4.7%(c526), and 10-stack QDs(5nm) is 2.9%(c514),and 12-stack QDs(10nm) is 4.48%(c538),and 12-stack QDs(15nm) is 5.89%. The break through of this paper is that the efficiency of c529¡]VOC=0.64V,JSC=11.97mA/cm2,FF=67%,£b=5.89%¡^is higher than GaAs¡]VOC =0.87 V, JSC =7.4 mA/cm2,FF=72.3%,£b=5.6%¡^,and we attribute this performance to its good quality of miniband, because the current can be enhanced a lot, and it will make up for the lose of open voltage and filling factor, so that the efficiency can be higher than GaAs baseline.

Vibration energy harvesters, or energy scavengers, recover mechanical energy from their surrounding environment and convert it into useable electricity as sustainable self-sufficient power sources to drive micro-to milli-Watt scale power electronics in small, autonomous, wireless devices and sensors. Using semiconducting, organic piezoelectric nanomaterials are attractive in low-cost, high resistance to fatigue, and environmentally friendly applications. Significantly, the deposition processes of sputtering ZnO (zinc oxide) thin films with high c-axis preferred orientation and electrospun PVDF (polyvinylidene fluoride) nanofibers with high piezoelectric £]-phase crystallisation are controlled at room temperature. Thus they don¡¦t have the necessity of post-annealed and electrical repoling process to obtain an excellent piezoelectricity, and are suitable for all flexible substrates such as PET (polyethylene terephthalate) and PI (polyimide). These works are divided into two parts. Part 1: Flexible piezoelectric harvesters based on ZnO thin films for self-powering and broad bandwidth applications. A new design of Al (aluminum)/PET-based flexible energy harvester was proposed. It consists of flexible Al/PET conductive substrate, piezoelectric ZnO thin film, selectively deposited UV (ultraviolet)-curable resin lump structures and Cu (copper) foil electrode. The design and simulation of a piezoelectric cantilever plate was described by using commercial software ANSYS FEA (finite element analysis) to determine the optimum thickness of PET substrate, internal stress distribution, operation frequency and electric potential. With the optimum thickness predicted by developed accurate analytical formula analysis, the one-way mechanical strain that is efficient to enhance the induced electric potential can be controlled within the piezoelectric ZnO layer. In addition, the relationship among the model solution of piezoelectric cantilever plate equation, vibration induced electric potential and electric power was realized. ZnO thin film of high (002) c-axis preferred orientation with an excellent piezoelectricity was deposited on the Al/PET by RF (radio-frequency) magnetron sputtering in room temperature. Al was sputtered on the PET substrate as the bottom electrode because of its low sheet resistance, superior adhesion with PET, and lattice constants matching with ZnO thin film. The selectively deposited UV-curable resin lump structures as proof mass were directly constructed on flexible piezoelectric plate using electrospinning with a stereolithography technique. One individual harvester achieves a maximum OCV (open-circuit voltage) up to 4V with power density of 1.247 £gW/cm2. This self-powered storage system can drive the warning signal of the LED (light emitting diode) module in both resonant and non-resonant conditions. We also succeeded in accomplishing a broad bandwidth harvesting system with operating frequency range within 100 Hz to 400 Hz to enhance powering efficiency. This system comprises four units of individual ZnO piezoelectric harvester in the form of a cantilever structure connected in parallel, and rectifying circuit with storage module. In addition, a modified design of a flexible piezoelectric energy-harvesting system with a serial bimorph of ZnO piezoelectric thin film was presented to enhance significantly higher power generation. This high-output system was examined at 15 Hz. The maximum DC (direct current) voltage output voltage with loading was 3.18 V, and the maximum DC power remained at 2.89 £gW/cm2. Furthermore, in order to examine the deformation between interfaces and the adhesion mechanism of multi-layer flexible electronics composites (e.g., ITO (indium tin oxide)/PET, Al/PET, ZnO/ITO/PET, and ZnO/Al/PET), nanoscratching and nano-indention testing (nanoindenter XP system) were conducted to analyze the adhesion before and after the vibration test. The plastic deformation between the ductile Al film and PET substrate is observed using SEM (scanning electron microscopy). Delamination between the ZnO and Al/PET substrate was not observed. This indicates that Al film provides excellent adhesion between the ZnO thin film and PET substrate. Part 2: Pre-strained piezoelectric PVDF nanofiber array fabricated by near-field electrospining on cylindrical process for flexible energy conversion. In various methodologies of energy harvesting from ambient sources, one-dimensional nanoharvesters have been gaining more attention recently. However, these nanofibers fabricated by micro-forming technologies may not easily control their structural diameter and length. This study originally presented the HCNFES (hollow cylindrical near-field electrospining) process to fabricate permanent piezoelectricity of PVDF piezoelectric nanofibers. Under high in-situ electric poling and strong mechanical stretching effect during HCNFES process, large PVDF nanofiber array with high piezoelectric £]-phase crystallisation was demonstrated. These pre-strained piezoelectric PVDF nanofibers fabricated by HCNFES with high process flexibility at low cost, availability in ultra-long lengths, various thicknesses and shapes can be applied at power scavenge, sensing and actuation. Firstly, PVDF nanofibers lay on a PET substrate, silver paste was applied at both ends of fibers to fix their two ends tightly on a Cu foil electrode pair. The entire structure was packaged inside a thin flexible polymer to maintain its physical stability. Repeatedly stretching and releasing the nanoharvester (NH 1) with a strain of 0.05% at 5 Hz vibration created a maximum peak voltage and current of -50 mV and -10 nA in forward connection, respectively. Secondly, a total of 44 parallel nanofibers have been fabricated and transferred onto an IDT (interdigital) electrode with 64 electrode pairs as a nanohavester (NH 2) to amplify current outputs under repeated mechanical vibration and impact tests. Under a repeated maximum strain of 0.14% at 6 Hz vibration, a peak current of 39 nA and peak voltage of 20.2 mV have been measured. Impact testing at 15 Hz, peak current of 130 nA has been collected with a voltage of 24.4 mV. Finally, the single PVDF fiber as nanoharvester (NH 3) with a strain of 0.05-0.1% at 5 Hz vibration created a maximum peak voltage and current of -45 mV and -3.9 nA, respectively. The maximum power remained at 18.45 pW/cm2 with a load resistor of 6.8 M£[. Based on the mechanism of converes piezoelectric effect, ANSYS software with coupled field analysis was used to realize piezoelectric actuation behavior of the PVDF fibers. From the observation of actuation property, a fixed-fixed single nanofiber was tested under different DC voltage supply. Comparing the polarized fiber with non-polarized fibers, the measurement of the center displacements as a function of electric field was conducted and characterized.