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Superconductivity in magnesium diboride (MgB2) was first discovered in 2001. It is unique in that it has two superconducting gaps. The transition temperature of 39 K exceeded the maximum transition temperature thought to be possible through phonon mediated superconductivity. Through the study of MgB2, a general paradigm is being formulated to describe multi-gap superconductors. The paradigm includes inter-band and intra-band scattering between the gaps which can cause a smearing of the gap parameter over a distribution instead of a single value. Although each gap is individually thought to be well described by the BCS theory, the interaction between the two gaps causes complications in describing the overall superconducting properties of MgB2. The focus of this work was to lay the groundwork for an MgB2-based Josephson junction technology. This includes improving on a previously established baseline for all-MgB2 Josephson junctions, utilizing the Josephson Effect to experimentally verify a model pertaining to the two-gap nature of MgB2, specifically the magnetic penetration depth, and designing, fabricating, and testing multi-junction devices and circuits. The experiments in this work included fabrication of Josephson Junctions, DC superconducting quantum interference devices (SQUIDs), Josephson junction arrays, and a rapid single flux quantum (RSFQ) circuit. The junctions were all made utilizing the hybrid physical-chemical vapor deposition method, with an MgO sputtered barrier. The current process consists of three superconducting layers which are patterned using standard UV photolithography and etched with Ar ion milling. There were SQUIDS made with sensitivity to magnetic fields parallel to the film surface, which were used to measure the inductance of MgB2 microstrips. This inductance was used in design of more complicated devices as well as in calculating the magnetic penetration depth of MgB2, found to be about 40 nm at low temperature, in good agreement with a previously published theoretical model. Planar-type DC SQUIDs were also made to present the feasibility of the technology for application purposes. The large voltage modulation of over 500 μV at 15 K for these devices along with operation up to 37 K shows that MgB2 is a potential replacement for low temperature devices. The junction series arrays were fabricated with 100 junctions of equal size to present the ever-increasing robustness of the technology. The devices served well to measure the large property spread associated with these junctions and have been well established as a diagnostic tool for improving this spread. The culmination of this work was a basic RSFQ toggle flip flop circuit. A DC measurement of these circuits yielded digital operation up to 180 GHz at low temperature and about 63 GHz at 20 K. This is not yet near the potential limit of MgB2 established by the value of the superconducting gap parameters, but a huge success in showing that MgB2 is a viable option for pursuing superconducting digital electronics suitable for low power, cryogen-free operation. / Physics

abstract: In this research, our goal was to fabricate Josephson junctions that can be stably processed at 300°C or higher. With the purpose of integrating Josephson junction fabrication with the current semiconductor circuit fabrication process, back-end process temperatures (>350 °C) will be a key for producing large scale junction circuits reliably, which requires the junctions to be more thermally stable than current Nb/Al-AlOx/Nb junctions. Based on thermodynamics, Hf was chosen to produce thermally stable Nb/Hf-HfOx/Nb superconductor tunnel Josephson junctions that can be grown or processed at elevated temperatures. Also elevated synthesis temperatures improve the structural and electrical properties of Nb electrode layers that could potentially improve junction device performance. The refractory nature of Hf, HfO2 and Nb allow for the formation of flat, abrupt and thermally-stable interfaces. But the current Al-based barrier will have problems when using with high-temperature grown and high-quality Nb. So our work is aimed at using Nb grown at elevated temperatures to fabricate thermally stable Josephson tunnel junctions. As a junction barrier metal, Hf was studied and compared with the traditional Al-barrier material. We have proved that Hf-HfOx is a good barrier candidate for high-temperature synthesized Josephson junction. Hf deposited at 500 °C on Nb forms flat and chemically abrupt interfaces. Nb/Hf-HfOx/Nb Josephson junctions were synthesized, fabricated and characterized with different oxidizing conditions. The results of materials characterization and junction electrical measurements are reported and analyzed. We have improved the annealing stability of Nb junctions and also used high-quality Nb grown at 500 °C as the bottom electrode successfully. Adding a buffer layer or multiple oxidation steps improves the annealing stability of Josephson junctions. We also have attempted to use the Atomic Layer Deposition (ALD) method for the growth of Hf oxide as the junction barrier and got tunneling results. / Dissertation/Thesis / Ph.D. Materials Science and Engineering 2013

Gap Junctions als wichtigste Elemente der Zelle zur Ermöglichung einer interzellulären Kommunikation erlauben eine koordinierte Antwort auf externe und interne Stimuli und somit ein Zusammenspiel von Zellgruppen und Organen im Gesamtorganismus. In der vorliegenden Arbeit wurde der Einfluss einer mittelfristigen und chronischen Stimulation neonataler Rattenkardiomyozyten durch Insulin und den Wachstumsfaktoren Insulin-like Growth Factor-1 (IGF-1), Vascular Endothelial Growth Factor (VEGF), Transforming Growth Factor-β (TGF-β) und Fibroblast Growth Factor-2 (FGF-2) auf die Expression der Connexine 40, 43 und 45 untersucht. Dabei zeigte sich unter der Insulin-Stimulation eine konzentrationsabhängige Regulation der Connexin 43 (Cx43) Expression. Die Exposition gegenüber IGF-1 hatte einen signifikanten Anstieg der Cx43 Proteinmenge zur Folge. Unter 24stündiger VEGF- oder FGF-2-Stimulation fand sich dagegen diesbezüglich kein relevanter Unterschied. Die Analysen nach langfristiger Exposition gegebenüber TGF-β zeigten eine signifikante Abnahme der Cx43 Proteinmenge bei unveränderter Cx43 mRNA. Zur Erfassung mittelfristiger Veränderungen wurden die Kardiomyozyten jeweils 3 Stunden mit den Wachstumsfaktoren VEGF und TGF-β inkubiert. Dabei zeigte sich jeweils eine signifikante Zunahme der Cx43 Proteinmenge und –mRNA. Die Connexine 40 und 45 waren in den ventrikulären Kardiomyozyten nur spärlich nachweisbar und durch keinen der untersuchten Faktoren signifikant induzierbar.

The Cx43 CT mimetic peptide, αCT1, originally designed to bind to ZO1 and thereby inhibit Cx43/ZO1 interaction, was used as a tool to probe the role of Cx43/ZO1 association in regulation of epithelial/endothelial barrier function. Using both in vitro and ex vivo methods of barrier function measurement, including Electric Cell-Substrate Impedance Sensing(ECIS), a TRITC-dextran transwell permeability assay, and a FITC-dextran cardiovascular leakage protocol involving Langendorff-perfused mouse hearts, αCT1 was found to protect the endothelium from thrombin-induced breakdown in cell-cell contacts. Barrier protection was accompanied by significant remodeling of the F-actin cytoskeleton, characterized by a redistribution of F-actin away from the cytoplasmic and nuclear regions of the cell, towards the endothelial cell periphery, in association with alterations in cellular orientation distribution. In line with observations of increased cortical F-actin, αCT1 upregulated cell-cell border localization of endothelial VE-cadherin, the Tight Junction protein Zonula Occludens 1 (ZO1) , and the Gap Junction Protein (GJ) Connexin43 (Cx43). A ZO1-binding-incompetent variant of αCT1, αCT1-I, indicated that these effects on barrier function and barrier-associated proteins, were likely associated with Cx43 CT sequences retaining ability to interact with ZO1. These results implicate the Cx43 CT and its interaction with ZO1, in the regulation of endothelial barrier function, while revealing the therapeutic potential of αCT1 in the treatment of vascular edema. / Doctor of Philosophy / Endothelial cells make up blood vessels within the heart and regulate the exchange of fluids between the circulation and heart tissue. In many forms of heart disease, the cardiac endothelium is disrupted, resulting in a damaging leakage and buildup of fluids within the heart. This work explores how a small peptide, derived from a naturally occurring molecule, may help to prevent fluid-associated damage to the heart by stabilizing the blood endothelium.

Master of Science / Department of Diagnostic Medicine/Pathobiology / Thu Annelise Nguyen / Colorectal cancer is one of the most common cancers in the United States with an early detection rate of only 39%. Colorectal cancer cells along with other cancer cells exhibit many deficiencies in cell-to-cell communication, particularly gap junctional intercellular communication (GJIC). GJIC has been reported to diminish as cancer cells progress. Gap junctions are intercellular channels composed of connexin proteins, which mediate the direct passage of small molecules from one cell to the next. They are involved in the regulation of the cell cycle, cell differentiation, and cell signaling. Since the regulation of gap junctions is lost in colorectal cancer cells, the goal of this study is to determine the effect of GJIC restoration in colorectal cancer cells. Overexpression of connexin 43 (Cx43) in SW480 colorectal cancer cells causes a 6-fold increase of gap junction activity compared to control un-transfected cells. This suggests that overexpressing Cx43 can restore GJIC. Furthermore, small molecule directly targeting gap junction channel was used to increase GJIC. Gap junction enhancers, PQs, at 200 nM showed a 4-fold increase of gap junction activity in SW480 cells. Using Western blot analysis, Cx43 isoform expression was seen to shift from P0 to P1 and P2 isoforms after treatment with PQ1 200 nM for 1 hour. Overall, the results show that overexpression of connexin and small molecules such as gap junction enhancers, PQs, can directly increase gap junction activity. The findings provide an important implication in which restoration of gap junction activity can be targeted for drug development.

Bevölkerungswachstum, Klimawandel und steigende Umweltbelastung durch Emission von Schadstoffen zählen zu den größten Herausforderungen dieses Jahrhunderts. In dieser Arbeit sollen daher die CO2-Emissionen untersucht werden, welche durch und an unterschiedlichen Knotenpunkten entstehen. Für diese Untersuchungen sollen daher für drei verschiedene Knotenpunktarten, drei verschiedene Verkehrsstärken und vier verschiedene Fahrzeugtypen die CO2-Emissionen berechnet werden.

Doctor of Philosophy / Department of Diagnostic Medicine/Pathobiology / Thu Annelise Nguyen / Gap junctional intercellular channels allow the cells to communicate with each other. A breach in gap junctional intercellular communication (GJIC) affects cell growth and proliferation. In addition, many neoplastic cells exhibit a decrease in GJIC. Many factors that decrease GJIC have been shown to potentiate cancer formation. 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD), an environmental pollutant, is a carcinogen; however, its mechanism of carcinogenicity is unclear. Therefore, we examined the effect of TCDD on GJIC in MCF-7, a human breast cell line and normal mammary epithelial cells (HMEC). TCDD showed a decrease in GJIC in MCF-7 cells caused by increased phosphorylation of gap junctional protein, Cx43. PKCα-mediated phosphorylation of Cx43 was confirmed by inhibitor studies using calphostin C. Interestingly, TCDD affected GJIC in HMEC through a novel pathway involving redistribution of Cx43 to the perinuclear membrane. Our studies suggest that TCDD causes decrease in GJIC which could potentially lead to cancer. This also indicates that if GJIC is restored it could decrease cell growth and proliferation. Therefore, we investigated the role of substituted quinolines (PQ1), shown to bind with gap junctional proteins by computational docking. The results showed that indeed PQ1 significantly increases GJIC and exerts anti-tumor effect in human breast cancer cells compared to control without treatment or HMEC. We found an increase in GJIC, growth attenutation and increased apoptosis in T47D human breast cancer cell line. Our studies suggest that PQ1 is a novel gap junctional activator causing a decrease in tumor growth. Since PQ1 alone is effective in decreasing tumor growth in breast tumors, we proposed to test its efficacy with the current drug of choice for breast cancer, tamoxifen. The combinational treatment of tamoxifen and PQ1 showed a significant decrease in cell viability, increase in BAX (Bcl2-associated X), and, increase in caspase 3 activation compared to individual treatments. Hence, combinational treatment of PQ1 and tamoxifen can potentiate decrease in tumor growth. In conclusion, downregulation of gap junctions can potentiate tumor growth while restoration of GJIC can induce apoptosis and decrease tumor growth.

published_or_final_version / Zoology / Doctoral / Doctor of Philosophy