Browsing by Subject "Mn"
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Item Astrocyte-derived nitric oxide in manganese neurotoxicity: from cellular and molecular mechanisms underlying selective neuronal vulnerability in the basal ganglia to potential therapeutic modalities(Texas A&M University, 2007-04-25) Liu, XuhongChronic exposure to manganese (Mn) causes the neurodegenerative movement disorder, manganism. A mouse model was developed to elucidate mechanisms involved in the etiology and progression of injury. Twelve-week old female C57Bl/6J mice were exposed to MnCl2 (100 mg/kg/day) by oral gavage daily for 8 weeks. After the experiment striatal dopamine (DA) content was decreased with the manifestation of hypoactivity. A distinct population of neurons was vulnerable to the effects of Mn, including enkephalin (ENK)-positive projection neurons, interneurons expressing neuronal nitric oxide synthetase (nNOS/NOS1), and choline acetyltransferase (ChAT)-expressing interneurons. Activation of surrounding astrocytes occurred with expression of inducible nitric oxide synthase (iNOS/NOS2) and production of nitric oxide (NO)/peroxynitrite (ONOO-). Activated astrocytes were detected primarily near the microvasculature in both the striatum and globus pallidus (GP). It is suggested that Mn exposure may damage the blood-brain barrier (BBB) and induce astrocytosis and NOS2 expression, subsequent NO production may cause the death of adjacent neurons. This hypothesis was also tested in an in vitro co-culture model. Differentiated pheochromocytoma cells (PC12 cells) were co-cultured with primary astrocytes and exposed to Mn and inflammatory cytokines. Mn and cytokines induced NOS2 expression and NO production in astrocytes, which correlated with apoptosis of PC12 cells. Apoptosis of PC12 cells was prevented by overexpression of a phosphorylation-deficient mutant of I????B???? that inhibited NOS2 expression in astrocytes. It is concluded that Mn-and cytokine-dependent apoptosis in PC12 cells requires astrocyte-derived NO and nuclear factor ????B (NF-????B)-dependent expression of NOS2. To explore possible means of interdicting this inflammatory process in astrocytes, a noval pharmacologic ligands of the peroxisome proliferator-activated receptor gamma (PPAR????) agonist, 1,1-Bis(3'-indolyl)-1-(p-trifluoromethylphenyl) methane (DIM-C-pPhCF3) were used in the same co-culture system. DIM-C-pPhCF3 protected PC12 cells from apoptosis through inhibition of NOS2 expression in astrocytes after Mn and cytokines exposure. By contrast, the PPAR???? antagonist, 2-chloro-5-nitrobenzanilide (GW9622), had the opposite effect, increasing both NO production in astrocytes and neuronal injury. It is concluded that PPAR???? is involved in the regulation of NOS2 expression in astrocytes and that agonists of PPAR???? may represent a potential treatment method for Mn neurotoxicity.Item Shape memory response of ni2mnga and nimncoin magnetic shape memory alloys under compression(2009-05-15) Brewer, Andrew LeeIn this study, the shape memory response of Ni2MnGa and NiMnCoIn magnetic shape memory alloys was observed under compressive stresses. Ni2MnGa is a magnetic shape memory alloy (MSMA) that has been shown to exhibit fully reversible, stressassisted magnetic field induced phase transformation (MFIPT) in the I X-phase transformation because of a large magnetostress of 7 MPa and small stress hysteresis. The X-phase is a recently discovered phase that is mechanically induced, however, the crystal structure is unknown. To better understand the transformation behavior of Ni2MnGa single crystal with [100] orientation, thermal cycling and pseudoelasticity tests were conducted with the goal of determining the Clausius-Clapeyron relationships for the various phase transformations. This information was then used to construct a stresstemperature phase diagram that illustrates the stress and temperature ranges where MFIPT is possible, as well as where the X-phase may be found. NiMnCoIn is a recently discovered meta-magnetic shape memory alloy (MMSMA) that exhibits unique magnetic properties. The ferromagnetic parent phase and the paramagnetic martensite phase allow the exploitation of the Zeeman energy. To gain a better understanding of the transformation behavior of NiMnCoIn, thermal cycling and pseudoelasticity tests were conducted on single crystals from two different batches with crystallographic orientations along the [100](011), [087], and [25 7 15] directions. A stress-temperature phase diagram was created that illustrates the Clausius- Clapeyron relationships for each orientation and batch. SQUID tests revealed the magnetic response of the alloy as well as the suppression of the martensite start temperature with increasing magnetic field. Pseudoelasticity experiments with and without magnetic field were conducted to experimentally quantify the magnetostress as a function of magnetic field. For the first time, it has been shown that NiMnCoIn is capable of exhibiting magnetostress levels of 18-36 MPa depending upon orientation, as well as nearly 6.5% transformation strain in the [100] direction. The results of this study reveal increased actuation stress levels in NiMnCoIn, which is the main limitation in most MSMAs. With this increased blocking stress, NiMnCoIn is a strong candidate for MFIPT.Item Spectroscopic investigation of metal-RNA interactions(Texas A&M University, 2005-02-17) Vogt, Matthew JohnMetal-RNA interactions are important to neutralize the negative charge and aid in correctly folding the RNA. Spectroscopically active metal ions, especially Mn2+, have been used to probe the type of interaction the metal has with RNA. In previous studies, the hammerhead ribozyme, an RNA motif that catalyzes a site-specific phosphodiester bond cleavage reaction, was determined by room temperature EPR (electron paramagnetic resonance) studies to have a set of tightly and weakly bound metal ions. Under high salt concentrations, the hammerhead was found to bind a single Mn2+ ion with high affinity and with a characteristic low temperature EPR signal. Using site specific 15N labeling of a guanine residue in conjunction with ESEEM (electron spin echo envelope modulation) spectroscopy, the high affinity Mn2+ ion was conclusively determined coordinated to G10.1 of the proposed A9/G10.1 site with four water molecules coordinated to the Mn2+ ion. EPR power saturation studies determined that under low salt conditions the hammerhead coordinates up to four Mn2+ ions in relatively close proximity compared to an RNA duplex. EXAFS (extended X-ray absorption fine structure) spectroscopy was used to determine that a Cd2+ ion coordinates to both the Rp and Sp sulfur atoms of a phosphorothioate modification at the A9 phosphate of the hammerhead. Previous EXAFS results for the Mn2+ substituted A9 phosphorothioate suggested that the Mn2+ ion coordinates to the oxygen atom for both isomers. Molecular modeling suggested that the A9/G10.1 metal site will twist the phosphate group in order to accommodate this coordination. A Mn-GMP and Mn-phosphate model complexes were prepared and characterized by EXAFS to assign the origin of the features observed for the hammerhead sample. A series of RNA sequences with internal loops containing the sheared G-A metal ion binding motif showed greater thermal stabilization of the RNA structure in the presence of Mn2+ ions compared to sequences without the motif. The EPR binding isotherms also showed a set of moderately tight metal ion interaction while circular dichroism spectroscopy was used to investigate structural differences between the sequences. These results suggest a mostly electrostatic, not structural role, for the Mn2+ ion interactions with these sequences.