Indiana University-Purdue University Indianapolis (IUPUI) / Glioblastoma is a lethal cancer that arises from support cells in the nervous system and kills around 20,000 people in the United States each year. While much is known about the highly malignant primary glioblastoma, the natural history of lower grade glioma (LGG) is less understood. While the majority of LGGs are initiated by a mutation in isocitrate dehydrogenase, the events leading to their malignant progression into a grade IV tumor are not known. Analysis of primary tumor sample data has revealed that low transcript levels of Angiomotin-like-1 (AmotL1) strongly associate with poor outcomes of patients with these cancers. Follow-up RNA-sequencing of human embryonic astrocytes with AmotL1 silencing revealed the downregulation of many transcripts that encode proteins mediating gap junctions (GJ) between astrocytes, especially connexin-43 (Cx43). Cx43 protein oligomerizes to form functional channels comprising the astrocytic GJ. AmotL1 knockdown through RNA interference decreases Cx43 transcript and protein levels while increasing its distribution to GJs. This suggests increased GJ formation and intercellular communication, as similar localization patterns are observed in differentiated astrocytes. Astrocytes with AmotL1 knockdown also display a pronounced pancake-like morphology, suggesting that the actin cytoskeleton is affected. Imaging reveals that cells with reduced AmotL1 have characteristic losses in both stress fibers and focal actin under the cell body but notable increases in cortical F-actin. Consistent with previous studies, AmotL1 may promote increases in the number and thickness of F-actin fibers. Because actin binding to related angiomotins is inhibited by phosphorylation from the LATs kinases, I define the effects of expressing wildtype AmotL1 versus mutants that mimic or prevent phosphorylation by LATs1/2. Interestingly, expression of AmotL1 S262D in combination with NEDD4-1, a ubiquitin ligase, results in a profound loss of actin stress fibers. Dependence on NEDD4-1 suggests that this phenotype is due to the induced degradation of proteins that promote F-actin, e.g. RhoA. These results directly support a model in which phosphorylated AmotL1 specifically inhibits F-actin formation as opposed to unphosphorylated AmotL1 which is known to promote stress fiber formation. Thus, in addition to regulating polarity and YAP/TAZ transcriptional co-activators, AmotL1 plays major functions in dictating cellular F-actin dynamics. / 2021-01-01

Indiana University-Purdue University Indianapolis (IUPUI) / As the search for ever-higher-speed, greater-density, and lower-power technologies accelerates, so does the quest for devices and methodologies to fulfill the increasingly-difficult requirements for these technologies. A possible means by which this may be accomplished is to utilize superconducting devices and graphene nanoribbon nanotechnologies. This is because superconductors are ultra-low-power devices capable of generating extremely high frequency (EHF) signals, and graphene nanoribbons are nanoscale devices capable of extremely high-speed and low-power signal amplification due to their high-mobility/low-resistance channels and geometry-dependent bandgap structure. While such a hybrid co-integrated system seems possible, no process by which this may be accomplished has yet been proposed. In this thesis, the system limitations are explored in-depth, and several possible means by which superconducting and graphene nanotechnological systems may be united are proposed, with the focus being placed on the simplest method by which the technologies may be hybridized and integrated together, while maintaining control over the intended system behavior. This is accomplished in three parts. First, via circuit-level simulation, a semi-optimized, low-power (~0.21 mW/stage) graphene-based amplifier is developed using ideal and simplified transmission line properties. This system is theoretically capable of 159-269 GHz bandwidth with a Stern stability K >> 1 and low noise figure 2.97 <= F <= 4.33 dB for all appropriate frequencies at temperatures between 77 and 90 K. Second, an investigation of the behavior of several types of possible interconnect methodologies is performed, utilizing hybrid substrates and material interfaces/junctions, demonstrating that an Ohmic-contact superconducting-normal transmission line is optimal for a hybrid system with self-reflections at less than -25 dB over an operating range of 300 GHz. Finally, a unified layout and lithography construction process is proposed by which such a hybrid system could be developed in a monolithic physical system on a hybrid substrate while maintaining material and layout integrity under varying process temperatures.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18863号 / 医博第3974号 / 新制||医||1008(附属図書館) / 31814 / 京都大学大学院医学研究科医学専攻 / (主査)教授 渡邊 直樹, 教授 岩田 想, 教授 岩井 一宏 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

The incorporation of molecules as low-cost and stable structures in electronic circuits is a promising strategy to miniaturize electronic components. Although single-molecule electronics is still at an early phase, the investigation of charge transport through single molecules is fundamentally important to understand the relevant scientific concepts and technological applications. In this dissertation, we measured and modulated the charge transport perpendicular to the plane of small benzene derivatives. In contrast to the conventional strategy to link molecules to electrodes via anchoring groups, we used the electrode potential to control the geometry of molecules and to form the junctions through π-system-metal electrode interactions. Using a combination of electrochemical STM (EC-STM) imaging and STM-BJ methods, the measurement of charge transport through single, flat oriented tetrafluoroterephthalic acid (TFTPA) molecules on an electrified Au (111) electrode showed that, at potentials below the potential of zero-charge (pzc) of Au(111), the molecules lie flat on the electrode and form highly ordered structures. The conductance of TFTPA, along the axis perpendicular to the benzene plane, is 0.24 ± 0.04 G0, consistent with reports for other molecules oriented flat in the junction. The configuration dependent conductivity has been confirmed by first-principles non-equilibrium Green’s function computation performed by Professor John Perdew and Dr. Haowei Peng at Temple University. Hence, the electrochemical surface potential can be employed to control the orientation of molecules to access a new charge transport measurement axis. Building on our previous results (Chapter 3), we studied charge transport through two fundamentally important molecules, tetracyanoquinodimethane (TCNQ) and tetrafluorotetracyanoquinodimethane (F4TCNQ) to determine the effect of molecule-electrode binding while maintaining the same core molecular structure. The findings show that on the negatively charged Au(111), the flat-oriented TCNQ and F4TCNQ molecules exhibit similar but high conductance of ~ 0.22 ± 0.01 G0 and 0.24 ± 0.01 G0, respectively. In addition to the high conductance, two peaks at 0.02 G0, and 0.05 G0 were detected for both molecules, assigned to the bidentate-bidentate and monodentate-bidentate configurations. Density functional theory (DFT) and non-equilibrium Green’s function (NEGF) calculations were performed by Professor Manuel Smeu and Dr. Stuart Shepard at Binghamton University to determine the conductance of four distinct molecular configurations. The results show how the orientation of molecules in the junction and the molecule-electrode denticity influence the molecular orbital offsets relative to the Fermi level and the consequent charge transport. The electronic structure and charge transport through single molecules can be modulated using various functional groups. Interestingly, our previous findings (Chapters 3, and 4) showed that the conductance perpendicular to the plane of TFTPA and TCNQ/F4TCNQ was similar to the parent molecules (TPA and TCNQ). Thus, it appeared that fluorination did not significantly change charge transport properties perpendicular to the molecular plane. Building on our previous studies, we measured the conductance through mesitylene substituted with electron-withdrawing groups (e.g., NO2, Br) or with electron-donating groups (e.g., CH3) to determine if other groups might impact conductance. Our results showed that the conductance perpendicular to the molecular plane increases by introducing electron-withdrawing groups and decreases as electron-donating groups are introduced to the mesitylene molecule. Density functional theory (DFT) and non-equilibrium Green’s function (NEGF) calculations were performed to rationalize our experimental findings (By Professor Smeu and Dr. Stuart Shepard). We demonstrated that the changes in the conductance perpendicular to the molecular plane correlate well with the Hammett constant of the corresponding functional groups, indicating the importance of the nature and strength of chemical substituents on the degree of conductance modulations at least for mesitylene derivatives. Following up on the modulation of charge transport through the intrinsic properties of molecules, we investigated the effect of solvent polarity on conductance of single molecules. Particularly, we focused on charge transport through dimethylaminobenzonitrile (DMABN), a molecule that shows unique behavior, such as noticeable bulk electronic modulations in response to the physical properties of the solvents in which the molecule is immersed, e.g., dual fluorescence in polar environment, due to the stabilized intramolecular charge transfer (TICT) state. Our charge transport results show that the conductance of DMABN in a polar solvent (acidified water) is ~ten times higher than the value observed in toluene (nonpolar solvent). The conductance of a molecule with no TICT properties shows no solvent polarity-dependent conductance, indicating that the intrinsic properties of DMABN (i.e., the TICT effect) play a critical role in the enhanced conductivity in the polar solvent. Molecular dynamics calculations (performed by Professor Manuel Smeu, and Dr. Stuart Shepard) suggest that the DMABN molecule can undergo internal rotation in the junction in polar solvents, result in a higher conductance compare to the planar geometry. Our results demonstrate that molecules exhibiting TICT properties can be promising candidates to design molecular devices with sensing and switching functionalities. The findings of this dissertation, in combination with the calculations (via collaboration with computational experts), show that the intrinsic and extrinsic properties of junctions, e.g., the geometry of molecule within the junction, the charge transport axis, the molecule-electrode binding, the characteristics and electronic structure of the molecules investigated, and the physical properties of the environment, influence charge transport through single molecules. This fundamental understanding and the ability to control charge transport through single molecules may allow the design of practical devices, e.g., large-scale molecular architectures and circuits, molecular switches, and sensors. / Chemistry

No description available.

The thermal design constraint of power electronic converters under the specific power loss and heat sink is mainly determined by the maximum permissible junction temperature of the power devices. As the power density and switching frequency increase, transient electro-thermal models become more and more important for the thermal management system design of the power electronic converters. In traction inverters, the junction temperature has huge variation because the fundamental frequency and phase currents vary significantly during the load cycles. Thus, the junction temperature estimation becomes extremely important for the reliability of traction inverters. In this thesis, the transient electro-thermal analysis of a traction inverter considering the inter-dependency of the power losses and junction temperature in an iterative process is implemented. Considering the impact of circuit stray parameters on the switching loss, the temperature dependent power loss model is built based on the datasheet values and the measured switching losses. A state-of-the-art thermal model of the entire inverter including the power modules and the heat sink is developed considering the thermal coupling effects of multiple power devices. By using transient thermal simulation, the linearity of the heat transfer process of the entire traction inverter is verified. The impact of the material thermal properties on the thermal impedance is also presented. In addition, the accuracy of the combination of the thermal subsystem models is verified with simulation. The developed transient electro-thermal model is then used to simulate the junction temperature profiles of the inverter under different operating conditions. Finally, the developed model is experimentally verified. By considering the thermal impedance of the thermal grease layer, the simulation results match with the experimental results very well. The proposed electro-thermal model can provide important information for the thermal management system design, package optimization, long-term reliability analysis, and maximum rating characterization of the traction inverters. / Thesis / Master of Applied Science (MASc)

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24493号 / 医博第4935号 / 新制||医||1063(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 浅野 雅秀, 教授 万代 昌紀, 教授 上杉 志成 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Protocadherine spielen eine wichtige Rolle bei der Entwicklung des Nervensystems und sind an Prozessen der Zellmigration und -differenzierung, sowie der Hemmung von Zellwachstum beteiligt. Um die Funktion und Regulation von Protocadherin gamma C3 (PcdhγC3) an mikrovaskulären Endothelzellen des Großhirns (cEND) und des Kleinhirns (cerebEND) zu untersuchen, wurden die PcdhγC3-Knock-out (KO) Zelllinien mit der CRISPR/Cas9 Methode etabliert. Der KO führt zu verminderten Barriereeigenschaften der Blut-Hirn-Schranke (BHS), was sich in einer erhöhten Permeabilität für Fluoreszein und einem verringerten transendothelialen elektrischen Widerstand (TEER) widerspiegelt. Es konnte eine Veränderung der Wachstumsrate und dem Adhäsionsverhalten der KO-Zellen nachgewiesen werden. Auch die Expression der Tight-Junction-Proteine, sowie einiger Komponenten des Wnt und mTOR Signalwegs wurden durch den KO von PcdhgC3 beeinflusst. / Protocadherins (Pcdhs) play an important role in neuronal development, cell migration and differentiation, as well as inhibition of cell growth. To investigate the function and regulation of Protocadherin gamma C3 (PcdhgC3) on microvascular endothelial cells of the cerebrum (cEND) and cerebellum (cerebEND), PcdhgC3 knock-out (KO) cell lines were generated, using the CRIPS/Cas9 method. The Knock-out lowers the barrier function oft he blood-brain-barrier (BBB), which can be seen in lower transendothelial electrical resistance (TEER) and higher permeabilitiy for fluorescein. We detectet a change in the growth rate and the cellular adhesion of the KO-cells. Also the expression of tight-junction proteins, as well as parts oft the Wnt and mTOR signalling pathway are altered by the KO of PcdhgC3.

Historical archaeologists are turning more and more attention to the study of capitalism in post-Industrialist nations. Rhoda Halperin's concept of householding considers networks of families or other groups that operate outside of the mainstream capitalist economy. The concept is most often applied in anthropological contexts, but may be a useful tool in the study of homesteading in the American West. At Benmore, a small homesteading community in southern Rush Valley, Tooele County, Utah, 20 families sought to survive by dry farming in a marginal environment. The enthusiasm of such residents as Israel Bennion, whose journal provides deep insight into the town's short existence, may have united the community under the ideology of self-sufficiency and resulted in an example of householding in early twentieth century Utah. This thesis utilizes surface data from Benmore, compared to surface and excavation data from Tintic Junction—a railroading town approximately 20 miles away from Benmore—to consider whether Benmore fits Halperin's concept of householding and the extent to which the community operated outside of the mainstream economy. The data is considered both in order to better define the community of Benmore and to determine whether Halperin's concept may be applicable to future homesteading studies throughout the American West. I argue that the specific questions considered in identifying householding are useful but that a broader theoretical approach is necessary to fully consider the dynamics of homesteading towns in Utah and the West.

The purpose of this thesis project was to examine the function of connexin-36 (Cx36) gap junctions (GJs) in producing alcohol's intoxicating and rewarding effects. GABA neurons are thought to inhibit dopamine (DA) neurotransmission in the mesocorticolimbic system, which originates in the midbrain ventral tegmental area (VTA) and projects to limbic structures such as the nucleus accumbens (NAcc). The mesolimbic DA system is believed to be the neural substrate of alcohol intoxication and addiction (Tepper, Paladini, & Celada, 1998). Alcohol suppresses the firing rate of GABA neurons in the VTA (Gallegos, Criado, Lee, Henriksen, & Steffensen, 1999) and presumably disinhibits DA neurons thereby resulting in enhanced release of DA in the NAcc. Interestingly, VTA GABA neurons appear to form part of a larger syncytium of GABA neurons in the reticular formation that are linked by electrical synapses via Cx36 GJs (Allison, et al., 2006; Stobbs, et al., 2004; Lassen, et al., 2007). Gap junction blockers, including the Cx36-selective antagonist mefloquine, also suppress the excitability and electrical coupling of VTA GABA neurons (Stobbs, et al., 2004). Thus, I hypothesized that Cx36 GJs cause synchrony in VTA GABA neurons which alcohol blocks to cause intoxication and reward. To accomplish these studies I compared the effects of intoxicating doses of ethanol in Cx36 knockout (KO) mice and mefloquine-treated mice and their wild-type (WT) controls with two tests that index ataxia, an open field activity system and the fixed-speed rotarod apparatus, as well as with ethanol self-administration. I found that Cx36 KO and mefloquine-treated mice exhibit significantly more ethanol-induced loss of movement in the open field test, a paradigm which indexes gross motor activity and tremor, but less ataxia than their WT controls in the rotarod paradigm, a paradigm which indexes balance and coordination. Most importantly, both Cx36 KO and mefloquine-treated mice consumed less ethanol than their controls. These findings provide evidence in support of the hypothesis that Cx36 GJs are important targets for ethanol effects in the mesolimbic system.