• 1,4-Dioxane Remediation Using a Constructed Wetland

      Quanrud, David M.; Ward, William Jackson; Quanrud, David M.; Karpiscak, Martin; Marsh, Stuart; Hutchinson, Charles (The University of Arizona., 2008)
      This research addressed the question whether a constructed wetland system with phytoremediation could successfully uptake 1,4-Dioxane in groundwater and secondary effluent. It further addressed whether open pond storage could successfully treat wetland discharge. The project was located at the University of Arizona's Constructed Ecosystems Research Facility (CERF) in Tucson, Arizona. This two-year field study was motivated by previous laboratory studies which demonstrated the capability of plants to remediate the recalcitrant contaminant 1,4-Dioxane.The study was conducted in two open steel tanks configured to simulate constructed wetlands. The efficacy of 1,4-Dioxane uptake by cottonwood trees was tested in a side-by-side comparison utilizing planted and unplanted tanks. The sub-surface hydraulic conditions were fully characterized by bromide tracer studies. Six experiments were conducted, in which tapwater or secondary effluent was spiked with 5.2 mg/L 1,4-Dioxane and fed to the planted and unplanted (control) tank. The tank discharges were retained in separate open ponds to test if open pond storage would reduce 1,4-Dioxane content. Additional side experiments were conducted to examine the role of volatilization and UV degradation. Comparison of 1,4-Dioxane mass discharge from the planted and the control tank demonstrated an 18-48 percent uptake by the cottonwood trees. Mass balance assessments showed 1,4-Dioxane uptake efficiency was positively correlated to cottonwood transpiration rates in the planted tank. The open pond 1,4-Dioxane measurements demonstrated a 64-85 percent reduction in 1,4-Dioxane concentration due to volatilization during the initial 120 hours pond lapse time. Elimination of 1,4-Dioxane from the ponds followed first order kinetics. Field and laboratory side experiments demonstrated the potential for UV photo degradation of 1-4-Dioxane.
    • 1. Anionic additions to glycosyl iodides 2. Neutral addition of alcohols to glycosyl iodides 3. Glycosyl iodides in solid phase oligosaccharide synthesis

      Gervay, Jacquelyn; Hadd, Michael Joseph (The University of Arizona., 1998)
      The usefulness of glycosyl iodides in carbohydrate chemistry has been demonstrated. Both anionic and neutral nucleophiles have been shown to react readily with glycosyl iodides as the glycosyl donor. High yields and stereoselectivity were obtained along with short reaction times. Anionic nucleophiles gave β glycosides selectively, whereas neutral nucleophiles gave α glycosides in the presence of tetrabutylammonium iodide. Initial investigation of the applicability of these glycosidation conditions to solid phase oligosaccharide synthesis has been accomplished.
    • 1. Development of a novel ELISA for the testing of glycobioconjugates as anti-HIV agents 2. Synthesis of potential inhibitors of the HIV entry mechanism 3. Probing the secondary structural characteristics of oligosaccharides utilizing circular dichroism

      Gervay-Hague, Jacquelyn; McReynolds, Kathrine Dawn (The University of Arizona., 1999)
      AIDS, or acquired immunodeficiency syndrome, is caused by the human immunodeficiency virus (HIV). HIV is a retrovirus that is capable of rapid genetic mutation, which makes the virus and the disease difficult to treat. Several drug therapies are currently available, in the form of viral enzyme inhibitors. Other inhibitors of the viral entry and replication process are being investigated to enhance the drug therapy arsenal. Our research has focused on the development of HIV entry inhibitors. We are working towards the development of novel carbohydrate-based agents that are capable of binding the gp120 protein on the viral surface, such that viral entry into an uninfected host cell is prevented. In order for our research to progress, a qualitative method by which our synthetic compounds could be evaluated for gp120 binding was sought. We have developed a unique ELISA (enzyme-linked immunosorbent assay) that indicates whether or not a compound has binding affinity for the viral protein. A TIRF (total internal reflection fluorescence) microscopy method, has been developed as part of a collaborative effort with the laboratories of Professors Saavedra and O'Brien, to assess active compounds for quantitative equilibrium binding constants to gp120. We have synthesized several carbohydrate-based molecules targeted to one or more of the binding sites on the surface of gp120; the galactosylceramide site, the V3 loop, and the CD4 binding site. Utilizing both the ELISA and TIRF methods, we have succeeded in probing the binding profile of gp120. Circular dichroism studies have also been employed to evaluate the secondary structural characteristics of oligomeric carbohydrate materials. Molecules with helical properties have potential as CD4 binding site inhibitors. The long term goals of this project involve the synthesis and gp120 binding evaluation of novel carbohydrate-based materials to serve as entry inhibitors of the HIV replication process. A possible application of this project lies in the development of compounds capable of binding to more than one site on the protein. A variation of this goal involves the tethering of various compounds with specificities to different sites on gp120, for the purpose of inhibiting multiple binding sites on the protein.
    • 1. Synthesis of C-glycoside sulfones via oxirane-thirane exchange 2. Preparation of sialic acid derivatives amenable to solid-phase synthesis 3. Conformational analysis of complex polysaccharides

      Gervay, Jacquelyn; Flaherty, Terrence Michael (The University of Arizona., 1997)
      As part of a program directed toward the synthesis of novel glycosyl transferase inhibitors possessing a sugar-CH₂-SO₂-CH₂-SO₂-CH₂-nucleoside structure, β-C-glycoside sulfones have been prepared with high stereoselectivity. Both glucose and fucose derivatives were prepared. Sulfur incorporation was achieved by free radical addition of thiolacetic acid to exocyclic glycals. As part of a program directed toward the preparation of amide-linked sialic acid oligomers, a strategy was developed for the synthesis of sialic acid derivatives possessing either a free amine or a free acid functionality. Solution phase coupling of these monomers using standard peptide coupling techniques resulted in the synthesis of (1 → 5)-amide linked sialic acid dimers. As part of a program directed toward the identification of novel helical structures, the solution phase conformation of the polylactone of colominic acid was examined by NMR and molecular modeling. The two structures generated from molecular modeling that were consistent with the NOE data were both helical.
    • The 11/10th century B.C.E. transition in the Aijalon Valley Region: New evidence from Tel Miqne-Ekron Stratum IV

      Dever, William G.; Ortiz, Steven Michael (The University of Arizona., 2000)
      Recent deconstructionist trends within Syro-Palestinian archaeology and biblical studies have now converged on the Israelite Monarchy causing two major ceramic reappraisals of the Iron Age I and II Periods. The result is a proposal for a new low chronology in Syro-Palestinian archaeology. These trends are creating more problems than they are solving by naively assuming ceramic change was consistent throughout Syro-Palestine and manipulating the archaeological data to fit the new models. The dissertation addresses the radical archaeological and historical reconstructions of the current trend by focusing on the Iron Age I-II transition in the northern parts of the Philistine coast and Shephelah (foothills)--Aijalon Valley Region. Excavations at Tel Miqne-Ekron provide new evidence for an evaluation of recent chronological proposals and aide in the development of a ceramic corpus of the Aijalon Valley Region. As a border site between the coastal region and the hills, Tel Miqne is an important site to isolate and compare regional variations and the complex socioeconomic variables that pattern the archaeological record. The dissertation is divided into three parts. Part I includes a review of current work in Syro-Palestinian Iron Age research and an overview of ceramic theory development. Part II contains the core database: (1) development of the Tel Miqne Stratum IV typology, and (2) a comparanda, with other sites in the region and attempt to isolate the chronological and spatial patterns of the Iron Age transition (11/10th century B.C.E.). Part III contains the results and interpretations. This study concludes that: (1) ceramic change is not chronologically homogeneous and therefore regional variation must be incorporated in all ceramic analyses; (2) the proposed new Low Chronology for the Iron Age in the southern Levant cannot be supported by the archaeological evidence; and (3) the Aijalon Valley Region reflects the complexity of the Iron Age transition as many ethnic elements and political groups vied for control of the important crossroads and access to coastal ports.
    • 15-deoxy-delta-12, 14-prostaglandin J2 (15d-PGJ2) Mediated Signaling in Colon Cancer

      Mehta, Dipti J; Gerner, Eugene W.; Bowden, Tim G.; Martinez, Jesse D.; Nelson, Mark A. (The University of Arizona., 2006)
      Normal tissue structure and function are maintained by a dynamic interaction between epithelial cells and the stroma consisting of fibroblasts, adipose, vasculature and resident immune cells, and a multitude of cytokines and growth factors. Stroma was usually studied in the background of the malignant lesion, only in recent years researchers have started considering its role before carcinogenic lesions appear. Recent studies have shown that stromal cells and their products can cause the transformation of adjacent cells through transient signaling during phenomena like adipogenesis and inflammation by secreting various cytokines and chemokines into the matrix which can lead to apoptosis resistance, proliferation, mutations etc. Research in the last few years has demonstrated a functional role for stroma in the initiation and progression of breast, colon and prostate carcinomas. In this study effect of adipogenesis and/or inflammation on prostaglandin biosynthesis is investigated and the effects that these prostaglandins can have on epithelial cells is highlighted. This work demonstrates that normal colonic fibroblasts CCD18Co can produce anti-tumorigenic and pro-tumorigenic prostaglandins during adipogenesis and that this signaling is mediated via COX-2 activation. Although deoxycholic acid (DCA), a secondary bile acid that is responsible for inflammation in the gastro-intestinal tract, induces COX-2 signaling in the fibroblasts the downstream signaling of prostaglandin synthases is suppressed. Adipogenesis also leads to an increased polyamine catabolism. Effects of the prostaglandins were studied on various epithelial colon cancer cell lines. It was seen that 15d-PGJ2 causes growth inhibition and apoptosis in all cell lines tested and it was demonstrated that an activated K-RAS suppressed this phenomena. It was also seen that 15d-PGJ2 treatment could induce MAPK signaling and that an activated K-RAS suppressed JNK activation via AKT and MKK4. In conclusion this work reports that colonic fibroblasts can produce anti-tumorigenic factors like 15d-PGJ2 which may then induce apoptosis in epithelial cancer cells. This would be suppressed by an activated K-RAS and at the same time 15d-PGJ2 mediated MAPK signaling could confer a growth advantage for these cells and thus aid in tumor progression.
    • 1D and 2D Photonic Crystal Nanocavities for Semiconductor Cavity QED

      Gibbs, Hyatt M; Richards, Benjamin Colby; Peyghambarian, Nasser; Norwood, Robert (The University of Arizona., 2011)
      The topic of this dissertation is photonic crystal nanocavities for semiconductor cavity quantum electrodynamics. For the purposes of this study, these nanocavities may be one dimensional (1D) or two dimensional (2D) in design. The 2D devices are active and contain embedded InAs quantum dots (QDs), whereas the 1D devices are passive and contain no active emitters. The 2D photonic crystal nanocavities are fabricated in a slab of GaAs with a single layer of InAs QDs embedded in the slab. When a cavity mode substantially overlaps the QD ensemble, the dots affect the linewidths of the observed modes, leading to broadening of the linewidth at low excitation powers due to absorption and narrowing of the linewidths at high excitation powers due to gain when the QD ensemble absorption is saturated. We observe lasing from a few QDs in such a nanocavity. A technique is discussed with allows us to tune the resonance wavelength of a nanocavity by condensation of an inert gas onto the sample, which is held at cryogenic temperatures. The structural quality at the interfaces of epitaxially grown semiconductor heterostructures is investigated, and a growth instability is discovered which leads to roughness on the bottom of the GaAs slabs. Adjustment of MBE growth parameters leads to the elimination of this roughness, and the result is higher nanocavity quality factors. A number of methods for optimizing the fabrication of nanocavities is presented, which lead to higher quality factors. It is shown that some fundamental limiting factor, not yet fully understood, is preventing high quality factors at wavelengths shorter than 950 nm. Silicon 1D devices without active emitters are investigated by means of a tapered microfiber loop, and high quality factors are observed. This measurement technique is compared to a cross-polarized resonant scattering method. The quality factors observed in the silicon nanocavities are higher than those observed in GaAs, consistent with our observation that quality factors are in general higher at longer wavelengths.
    • 1α,25-DIHYDROXYVITAMIN D: REGULATION OF BIOSYNTHESIS AND INTERRELATIONSHIPS WITH THE PARATHYROID GLAND

      Haussler, Mark R.; Hughes, Mark, 1950- (The University of Arizona., 1977)
    • 1α,25-DIHYDROXYVITAMIN D₃ RECEPTORS IN INTESTINE: PROPERTIES AND UTILIZATION IN AN ASSAY FOR THIS STEROL HORMONE

      Haussler, Mark R.; Brumbaugh, Peter Flory, 1949- (The University of Arizona., 1975)
    • 2 μm Pulsed Fiber Laser Sources and Their Application in Terahertz Generation

      Peyghambarian, Nasser; Fang, Qiang; Fallahi, Mahmoud; Kieu, Khanh; Shi, Wei; Peyghambarian, Nasser (The University of Arizona., 2012)
      In this dissertation, an all-fiber-based single frequency nanosecond pulsed laser system at ~ 1918.4 nm in master-oscillator-power-amplifier (MOPA) configuration is present. The nanosecond pulse seed is achieved by directly modulating a continuous wave (CW) single frequency fiber laser using a fast electro-optical modulator (EOM) driven by an arbitrary waveform generator (AWG). One piece of single mode, large core, polarization-maintaining (PM) highly thulium-doped (Tm-doped) germanate glass fiber (LC-TGF) is used to boost the pulse power and pulse energy of these modulated pulses in the final power amplifier. This laser system can work in both high power and high energy regime: in high power regime, to the best of our knowledge, the highest average power 16 W and peak power 78.1 kW are achieved for single frequency transform-limited ~2.0 ns pulses at 500 kHz and 100 kHz repetition rate, respectively: In high energy regime, nearly 1 mJ and half mJ pulse energy is obtained for ~15 ns pulses at 1 kHz repetition rate and 5 kHz repetition rate, respectively. Theoretical modeling of the large-core highly Tm-doped germanate glass double-cladding fiber amplifier (LC-TG-DC-FA) is also present for 2&mum nanosecond pulse amplification. A good agreement between the theoretical and experimental results is achieved. The model can simulate the evolution of pump power, signal energy, pulse shape and the amplified stimulated emission (ASE) in the amplifier. It can also be utilized to investigate the dependence of the stored energy in the LC-TGF on the pump power, seed energy and repetition rate, which can be used to design and optimize the LC-TG-DC-FA to achieve higher pulse energy and average power. Two channel of high energy nanosecond pulses (at 1918.4 nm and 1938 nm) are utilized to generate THz wave in a quasi-phase-matched (QPM) gallium arsenide (GaAs) based on difference frequency generation. THz wave with ~ 5.4μW average power and ~18 mW peak power has been achieved. Besides, one model is built to simulate a singly resonated THz parametric oscillator. The threshold, the dependence of output THz energy on pump energy has been investigated through this model. One pump enhanced THz parametric oscillator has been proposed. The enhancement factor of the nanosecond pulses in a bow-tie ring cavity has been calculated for different pulse duration, cavity length and the transmission of the coupler. And the laser resonances in the ring cavity have been observed by using a piezo to periodically adjust the cavity length. We also build an all-fiber thulium-doped wavelength tunable mode-locked laser operating near 2&mum. Reliable self-starting mode locking over a large tuning range (>50 nm) using fiber taper based carbon nanotube (FTCNT) saturable absorber (SA) is observed. Spectral tuning is achieved by stretching another fiber taper. To the best of our knowledge, this is the first demonstration of an all-fiber wavelength tunable mode-locked laser near 2&mum.
    • 2016 Arizona Statewide Emergency Medical Services Needs Assessment (ASENA)

      Derksen, Daniel; George, Taylor A.; Derksen, Daniel; Butler, Matthew; Barraza, Leila (The University of Arizona., 2017)
      Emergency Medical Services (EMS) is an institution and product of public health, health care, and public safety that is chopped and scattered across multiple jurisdictional deployment methodologies throughout Arizona. To fully-asses the EMS needs of the state, those jurisdictions are considered as a whole; for it is the whole that makes a system, and a system is what truly impacts patient outcomes. Evaluating the ""whole"" is the genesis and driver of the 2016 Arizona Statewide EMS Needs Assessment (ASENA). The primary objective of ASENA is to establish a current ""snap-shot"" of EMS in the state while simultaneously identifying needs and/or areas that can be targeted for further analysis and/or improvement as part of Population Health Management and Emergency Medical Services Integration under the AZ Flex Grant funded by the U.S. Health Resources and Services Administration (HRSA). In addition, the secondary objective of ASENA is to compare and contrast this current ""snap-shot"" with data obtained in a more narrow needs assessment conducted in 2001, allowing comparison of changes in Arizona's critical access EMS system over 15 years. To accomplish this, a 105-question needs assessment survey tool was developed and distributed to EMS agencies throughout the state. The fully-vetted survey tool collected information pertaining to sixteen core functional sections. Eighty-six agencies fully-completed the needs assessment survey tool, with respondents evenly distributed across the state's four EMS coordinating regions and representative of the various service-delivery methodologies. The combined service areas of the respondents cover over 85% of the state's population. Arizona's statewide EMS system is well organized and positioned to deliver advanced levels of prehospital care for the vast majority of its citizens and visitors, with some variation between urban and rural regions. Key needs identified relate to: patient care reporting between EMS providers, emergency departments and receiving hospitals; quality assurance activities; education and skills training programs; dispatch system capabilities; mass casualty and public health preparedness; equipment and supplies; and more robust use of data and analyses to inform continuous EMS system improvement.
    • 3 Essays in Natural Disaster Adaptation

      Bakkensen, Laura; Blair, Logan; Baldwin, Elizabeth; Smith, Craig (The University of Arizona., 2023)
      Natural disasters present a considerable threat to the welfare of society. This is especially true for growing coastal populations facing stronger and more frequent hurricanes. In response, special building codes in the US are now available through the International Code Council (ICC) that mandate technology like reinforced roof-to-wall connections in new coastal homes ex-ante, and ex-post aid programs through the Federal Emergency Management Agency (FEMA) have grown tremendously. However, despite their critical roles, ICC codes have only been fully adopted by one state, Florida, while others debate their costs and market alternatives. There also remain salient concern over the equitable distribution of FEMA aid for which the literature struggles to untangle. This dissertation asks whether hazard-resistant building code institutions hold legitimizing public values outside of the market, in particular the ability to sidestep damage associated with behavioral bias, internalize physical externalities, and attenuate long run recovery for low-income households. In addition, I argue that our current understanding of equity in ex-post aid is limited by geographic and program aggregation, and ask whether FEMA’s Blue Roof Program, which installs temporary roofs following a hurricane, contribute to class and race-based disparities at the program-property level. Employing a novel property-level dataset on damages over time derived from remotely sensed images of Bay County Florida following Hurricane Michael, I find strong evidence that hazard-resistant codes reduced roof damage through improved preparedness, spill over beyond the individual to protect nearby homes from debris, and attenuated long recoveries---especially in low-income areas. This implies that places exposed to similar disaster risk, but resist modern code institutions, may miss welfare gains and a considerable opportunity to protect their most vulnerable populations. Second, I find that FEMA’s Blue Roof Program prioritizes homes with larger roofs, likely due to associated private contract incentives. However, market alternatives appear to perform worse along these dimensions, and neither arrangement discriminated along indicators of class or race such as home value and percent non-white.
    • The 3-phosphoinositide pathway as a potential target of anti-cancer therapy

      Powis, Garth; Lemke, Leslie Eileen, 1969- (The University of Arizona., 1998)
      The major mediator of the 3-phosphoinositide signal transduction pathway is phosphatidylinositol (PtdIns) 3-kinase (Kapellar and Cantley, 1994). The study of the 3-phosphoinositide pathway has been facilitated by the existence of potent irreversible inhibitors of p110 PtdIns 3-kinase, such as wortmannin (WM) (Powis et. al, 1994). Anti-metabolites of the 3-phosphoinositides generated in this pathway, such as 1D-3-Deoxyphosphatidylinositol (3'Deoxy-PtdIns), are also useful tools. 3'Deoxy-PtdIns is an analog of PtdIns which, although it can be phosphorylated at the 4 or 4 and 5 positions of its inositol ring, is an anti-metabolite of 3-phosphoinositide signaling molecules (Kozikowski et al., 1995). In this study WM and 3'Deoxy-PtdIns were used to determine whether the 3-phosphoinositide pathway was a useful target for the development of a anti-cancer therapy. We found that WM and 3'Deoxy-PtdIns both inhibited the growth of murine C3H and human MCF-7 mammary tumors in vivo, however WM did not inhibit the growth of human UACC2150 tumor. The ability of WM to inhibit C3H tumor growth was not related to inhibition of tumor total PtdIns 3-kinase activity. The existence of the WM-insensitive PtdIns 3-kinase activity observed in these tumors was confirmed in C3H and MCF-7 cell culture lysates, solid tumors and tissue homogenates. In addition to being resistant to inhibition by WM, MCF-7 cell lysate total PtdIns 3-kinase activity was also resistant to five known p110 PtdIns 3-kinase inhibitors. Human normal colon mucosa, colon tumors and placenta also contained WM-insensitive populations of PtdIns 3-kinase activity. Human placental homogenate was chosen as the source for the purification of WM-insensitive Ptdlns 3-kinase because it contained a profile of PtdIns 3-kinase activity which was similar to that of MCF-7 cells. Purification of WM-insensitive PtdIns 3-kinase from human placenta did not result in the identification of PtdIns 3-kinase related proteins. Although WM appeared to inhibit tumor growth by a non-PtdIns 3-kinase dependent mechanism, the results of this study confirmed that the 3-phosphoinositide signal transduction pathway was involved in the growth of mammary tumors. Because of its predominance in solid tumors and normal tissues, the WM-insensitive PtdIns 3-kinase, once identified, may be a suitable target for anti-cancer drug development.
    • A 450K arsenite-binding protein of the rabbit liver cytosol

      Bogdan, Gregory Michael; Aposhian, H. Vasken; Gandolfi, A. Jay; Liebler, Daniel C.; Brendel, Klaus; Lindell, Thomas (The University of Arizona., 1994)
      Inorganic arsenic administered to animals is primarily associated with liver cytosolic macromolecules. The specifics of this binding and its role in arsenic toxicity have never been fully examined. This dissertation concentrated on determining the species of inorganic arsenic which binds to liver cytosolic proteins, the specific proteins involved and the characteristics of their arsenic binding using an in vitro incubation system to [⁷³As]-label proteins. Arsenite was the species which bound cytosolic proteins and this was attributed to its affinity for protein sulfhydryls. Ammonium sulfate precipitation of cytosolic proteins revealed three arsenite-binding proteins (AsBPs) with molecular weights of 100K, 450K and >2000K as determined by size-exclusion chromatography. Similar-sized proteins were observed in liver cytosol prepared from a rabbit administered [⁷³As]-arsenite in vivo. The binding of arsenite to the 450K AsBP was most stable and further work focused on its purification and characterization. Trivalent arsenic affinity chromatography suggested a dithiol-like binding site. Amino acid composition indicated less than 0.5 mol% cysteine residues and implied that other thiol-containing functional groups may be used to complex arsenite. Arsenite inhibits enzymes which contain protein-bound lipoic acid, such as pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, by presumably binding to these dithiol functional groups. Thin-layer chromatography and mass spectrometry established that arsenite complexes with reduced lipoic acid and might be binding to similar dithiol groups on the 450K AsBP. Comparison of the arsenite-binding activities of pyruvate dehydrogenase, α-ketoglutarate dehydrogenase and cytosol showed increases for the enzymes but a decrease for cytosol after pre-treatment with NADH which reduces lipoic acid groups. However, the arsenite-binding activity of the 450K AsBP increased by 26-fold. Antibody affinity studies, though, showed that the 450K AsBP was not recognized by antibodies which cross-react with lipoic acid epitopes on proteins. Preparative SDS-PAGE was successful in purifying the 450K AsBP by over 2300-fold. Attempts at sequencing this protein indicated a blocked N-terminus. Chemical cleavage by cyanogen bromide produced two fragments of approximately 60K and 53K. Isolation of these fragments and their sequencing is continuing.
    • 5-HT1F Receptor Agonism for the Treatment of Spinal Cord Injury

      Schnellmann, Rick G.; Simmons, Epiphani Ciara; Bhattacharya, Martha; Largent Milnes, Tally; Doyle, Kristian; Madhavan, Lilitha (The University of Arizona., 2021)
      Spinal cord injury (SCI) is characterized by vascular disruption leading to ischemia, decreased oxygen delivery and loss of mitochondrial homeostasis. The dysregulation observed with SCI leads to defective respiratory chain function and reduced ATP production, exacerbating neuronal death and loss of locomotor capability. A growing body of research supports pharmacological induction of mitochondrial biogenesis (MB) as an effective approach to treat SCI. MB is a multifaceted process involving the integration of highly regulated transcriptional events, lipid membrane and protein synthesis/assembly and replication of mitochondrial DNA (mtDNA). We previously identified 5-hydroxytryptamine receptor 1F (5-HT1F) agonism as a potent inducer of MB in multiple organ systems. The series of studies presented herein explores the therapeutic potential of 5-HT1F receptor agonism on MB induction and recovery following SCI using a moderate force-controlled impactor-induced contusion mouse model. Post-SCI, mitochondrial dysfunction presents in the spinal cord, as indicated by decreased mtDNA and mitochondrial protein expression. Daily treatment with LY344864 and lasmiditan, two highly specific 5-HT1F receptor agonists, beginning after injury, not only attenuates these decreases, indicating MB, but also accelerates recovery, as denoted by decreased lesion volume and enhanced locomotor function. 5-HT1F receptor agonism increased locomotor capability, with both LY344864- and lasmiditan-treated mice reaching a Basso-Mouse Scale (BMS) score of ~3.4 by 21d, while vehicle-treated mice exhibited a score of 1.9. Importantly, knockout of the 5-HT1F receptor blocked these effects. Remarkably, a similar degree of locomotor restoration was observed when treatment was initiated 1 or 8h after injury, emphasizing the potential clinical applicability of this therapeutic approach. Furthermore, lasmiditan is FDA-approved for the treatment of migraines and could be repurposed for the treatment of SCI. In addition, injured mice treated with 5-HT1F receptor agonists display decreased Evan’s Blue dye accumulation and increased protein expression of tight junctions in the spinal cord compared to vehicle-treated mice, suggesting enhanced restoration of vascular integrity. These findings led us to investigate if lasmiditan induces MB and function specifically in endothelial cells. In vitro studies determine lasmiditan induces MB and enhances early-phase angiogenic pathways via Akt-eNOS activation in primary cultures of mouse cerebral endothelial cells. These data provide evidence that induction of MB via 5-HT1F receptor agonism may be a promising strategy for the treatment of SCI and related CNS injuries characterized by mitochondrial and vascular dysfunction.
    • 5-HYDROXYTRYPTAMINE AS AN INHIBITORY MODULATOR IN AUDIOGENIC SEIZURE

      Laird, Hugh E., 1939- (The University of Arizona., 1974)
    • "5-minute" solar oscillations observed in the continuum: Simultaneous three-wavelength photometric measurements with a ground-based instrument

      Hill, Henry A.; Womack, Gary Lynn (The University of Arizona., 2001)
      This dissertation reports on the first "5-minute" solar oscillation observations obtained with the Photometric Telescope, an instrument constructed in the Department of Physics at the University of Arizona. The instrument is designed to simultaneously acquire spatially resolved intensity images of the solar surface at three wavelengths in the solar continuum: 507 nm, 747 nm, and 1600 nm. Images were recorded at an approximate 30 second cadence, weather permitting, for an approximate 3 month duration during the Spring of 1999. A central rectangular region of the solar disk spanning ±0.53 R(⊙) in a direction parallel to the solar equator and ±0.636 R(⊙) in a direction parallel to the solar axis is used in obtaining the "5-minute" results. Differential spatial filters utilizing the natural logarithm are developed. Proper design of these filters allows great reductions in the sensitivity to terrestrial atmospheric fluctuations as well as instrumental noise sources such as image fitter. The processing techniques utilized allow the simultaneous observation of solar oscillations in the 2500 to 3600 μHz region at each of the three instrumental wavelengths. The spatial filters used have high sensitivity to modes in the ℓ = 4 to ℓ = 8 range. One-day power spectra from 40 long observing days are averaged. Concurrent data from the SOHO satellite's Luminosity Oscillation Imager is analyzed in a similar manner showing results in outstanding agreement with the Photometric Telescope spectra. Further comparison of measured power spectra peak locations with theoretically predicted peak locations verifies the Photometric Telescope as a capable helioseismology instrument. New "5-minute" oscillation results are also presented. The amplitudes of the individual "5-minute" oscillations are on the order of 10-100 ppm, in agreement with previous amplitude measurements. While these amplitudes vary greatly depending on the details of the stochastic excitation, the oscillation amplitude ratios and phase differences of solar oscillations for the 507 nm, 747 nm, and 1600 nm wavelengths can be measured with a high degree of accuracy. This dissertation reports the first such measurements. The amplitude ratios (I'/I)₇₄₇/(I'/I)₅₀₇ ∼ 0.6 and (I'/I)₁₆₀₀/(I'/I)₅₀₇) ∼ 0.25 are found to be independent of frequency over the frequency region studied and nearly independent of the angular degree of the mode. By contrast, the relative phase differences (φ₇₄₇ - φ₅₀₇) and (φ₁₆₀₀ - φ₅₀₇) are found to have a significant frequency dependence and to depend somewhat sensitively on the angular degree of the mode. The measured wavelength dependent amplitude and phase relationships provide an invaluable diagnostic tool which can be used in future work to help identify longer period and lower amplitude oscillatory modes.
    • A 50,000 year beryllium-10 record from Gulf of California sediments.

      McHargue, Lanny Ray.; Damon, Paul; Donahue, D.; Jull, Timothy; Hatheway, Arthur (The University of Arizona., 1994)
      The cosmogenic radionuclide ¹⁰Be from a marine sediment core was studied to help understand late Quaternary variations in the geomagnetic field and cosmic rays. The primary objective of this study was to see if the ¹⁰Be anomalies observed in polar ice cores could be observed in mid-latitude marine sediments. A partly-varved sediment core from the upper 50 meters of Leg 64 (DSDP) in the Gulf of California was determined to be ideal. A chronology of the core was determined by radiocarbon analysis, sedimentation rates, and oxygen-isotope stratigraphy. It was found that radiocarbon analysis of total carbon content was reliable only for the sediments younger than 16,000 B.P. Older sediments contain a modern ¹⁴C component added during diagenesis. Radiocarbon analysis of the Holocene sediments showed that the laminations in the sediments formed yearly. Thus, a reasonably reliable chronology for the lower sections of the core was determined from the relatively constant and high sedimentation rate. In addition, data from the authigenic fraction of the sediments were gathered for aluminum, iron, manganese, calcium, magnesium, and beryllium. From these data, the determination of the history of the waters of the Gulf of California was possible. Hydrothermal activity, glacial meltwater events, and the changing water masses in the Gulf of California possibly have left a record in the core studied. Analysis of the ¹⁰Be data along with the elemental data shows that the ¹⁰Be concentrations in the authigenic fraction of the sediments tracked the production rate of this isotope in the atmosphere. The ¹⁰Be concentrations at this site were little affected by diagenesis, hydrothermal activity, and terrigenous input. Most of the ¹⁰Be deposited at site 480 originated from the open sea. The changing geomagnetic dipole moment for the Holocene is seen in the ¹⁰Be data. The production rate for ¹⁰Be during the late Pleistocene tracked the changing dipole moment of the Earth as shown in other studies. Two ¹⁰Be anomalies correspond with the Mono Lake and Laschamp geomagnetic excursions. It was determined that the geomagnetic excursions could not have produced these anomalies. The data for the ¹⁰Be anomalies are consistent with a previous hypothesis for supernovae shock waves and the generation of cosmic rays. It is proposed that a series of such shock waves compress the heliosphere and affect the magnetosphere of the Earth. For such a mechanism to produce the observed geomagnetic excursions, either an enhanced interplanetary magnetic field must be externally imposed on the magnetosphere, or external forcing creates a corresponding non-linear response from the magnetodynamo of the Earth.