Parkinson’s disease patients present with the highest risk of dementia development. The thalamus, integral to several functions and behaviours is involved in the pathophysiology of Parkinson’s disease. The aim of this thesis was to determine if anatomical abnormalities in the thalamus are associated with the development of dementia in Parkinson’s disease. We examined the thalamus using macro and microstructural techniques and the white matter pathways that connect the thalamus with areas of the surrounding cortex using diffusion tensor imaging (DTI) based tractography. T1-weighted magnetic resonance and DT images were collected in 56 Parkinson’s disease patients with no cognitive impairment, 19 patients with mild cognitive impairment, 17 patients with dementia and 25 healthy individuals who acted as control subjects. An established automated segmentation procedure (FIRST FSL) was used to delineate the thalamus and a modified k-means clustering algorithm applied to segment the thalamus into clusters assumed to represent thalamic nuclei. Fibre tracts were determined using DTI probabilistic tracking methods available in FIRST. Microstructural integrity was quantified by fractional anisotropy and mean diffusivity (MD) DTI measures. Results show that microstructural measures of thalamic integrity are more sensitive to cognitive dysfunction in PD than macrostructural measures. For the first time we showed a progressive worsening of cellular integrity (MD) in the groups who had greater levels of cognitive dysfunction. Thalamic degeneration was regionally specific and most advanced in the limbic thalamic nuclei which influenced executive function and attention, areas of cognition that are known to be affected in the earliest stages of PD. The integrity of the fibre tracts corresponding to these thalamic regions was also compromised. Degeneration of fibre tracts was most evident in the dementia group, indicating that they may be more protected against Lewy pathology than the nuclei of the thalamus. Our findings confirm previous histological, animal and lesion studies and provide a reliable estimate of cortical degeneration in PD that can be applied non-invasively and in vivo. A longitudinal study is needed to monitor the progression of cognitive decline in PD but we have provided the basis for further investigation into the predictive validity of thalamic degeneration for cognitive dysfunction. In the future, the microstructural changes of the thalamus could be used as biomarkers for the identification of individuals with a higher risk for dementia development and for the longitudinal monitoring of any interventions into cognitive decline.

Remarkably, the central regions of galaxies are very important in shaping and influencing galaxies as a whole. As such, galaxy cores can be used for classification, to determine which processes may be important in galaxy formation and evolution. Past studies, for example, have found a dichotomy in the inner slopes of early-type galaxy surface brightness profiles. Using deprojections of the galaxies from the ACS Virgo and Fornax Cluster Surveys (ACSVCS/FCS), we show that, in fact, this dichotomy does not exist. Instead, we demonstrate that the brightest early-type galaxies tend to have central light deficits, a trend which gradually transitions to central light excesses – also known as compact stellar nuclei – as we go to fainter galaxies. This effect is quantified, and can be used to determine what evolutionary factors are important as we move along the galaxy luminosity function. The number of stellar nuclei that we observe is, in fact, an unexpected result emerging from the ACSVCS/FCS. Being three times more common than previously thought, they are present in the vast majority of intermediate and low-luminosity galaxies. Conversely, it has been known for over a decade that there is likely a supermassive black hole weighing millions to billions of solar masses at the center of virtually every galaxy of sufficient size. These black holes are known to follow scaling relations with their host galaxies. Using the ACSVCS, along with new kinematical data from long-slit spectroscopy, we measure the dynamical masses of 83 galaxies, and show that supermassive black holes and nuclei appear to fall along the same scaling relation with host mass. Both represent approximately 0.2% of their host’s mass, implying an important link between the two types of central massive objects. Finally, we extract elliptical isophotes and fit parameterized models to the surface brightness profiles of new Hubble Space Telescope imaging of the ACSVCS galaxies, observed in infrared and ultraviolet bandpasses. Taken together, the two surveys represent an unprecedented collection of isophotal and structural parameters of early-type galaxies, and will allow us to learn a great deal about the stellar populations and formation histories of galaxy cores. / Graduate

This dissertation attempts to extend the classes of halogen-containing systems which may be studied using solid-state nuclear magnetic resonance (SSNMR). As line shape broadening due to the quadrupolar interaction (QI) scales inversely with the applied field, high-field magnet technology is indispensable for this research. Combining advanced radiofrequency pulse sequences with high-field wideline data acquisition allowed for the collection of very broad SSNMR signals of all quadrupolar halogen nuclei (i.e., 35/37Cl, 79/81Br and 127I) within a reasonable amount of experimental time. The initial systems for study were of the MX2 variety (M = Mg, Ca, Sr, Ba; X = Cl, Br, I). In total, 9 anhydrous compounds were tested. The effects of hydrate formation were tested on 7 additional compounds. Systematic trends in the observed δiso values (and to a lesser extent, Ω and CQ) were found to be diagnostic of the extent of hydration in these materials. Resolving power was successfully tested using SrBr2, which possesses 4 magnetically unique sites. The composition of CaBr2•xH2O was convincingly determined using SSNMR data and the hydration trends noted above. The sensitivity of the QI to the local bonding environment (e.g., bond distance changes of less than 0.05 Å) was used to refine (when coupled with gauge-including projector augmented-wave density functional theory (GIPAW DFT) quantum chemical computations) the structure of MgBr2, and was used to correct prior NMR data for CaCl2 (earlier accounts had been performed upon a CaCl2 hydrate). During NMR data analysis of certain iodine-containing materials, it was found that standard fitting software (which uses perturbation theory) could not reproduce the observations. Proper analysis required the use of exact simulation software and allowed for the observation of high-order quadrupole-induced effects (HOQIE). This motivated further studies using rhenium-185/187 nuclei, where it was expected that HOQIE would be more dramatic. The observed rhenium SSNMR spectra possessed additional fine structure that had never been observed before experimentally, nor would be expected from currently-available perturbation theory analysis software. Lastly, preliminary results are shown where 127I SSNMR is used to study important supramolecular systems, and the composition of the popular synthetic reagent ‘GaI’ is elucidated.

Estrogens greatly affect the activity and connectivity of serotonergic neural cell populations, which extend from clusters of nuclei in the brainstem, termed the raphe nuclei, where estrogen receptor β is the most abundantly expressed estrogen receptor subtype. Estrogenic effects on the raphe nuclei are primarily important for influencing various neuropsychological behaviors, including depression, mood swings and anxiety behaviors. Because of this connection, phases of intense hormone fluctuations for instance during menopause are often associated with several mood disturbances that often reduce the quality of life of menopausal women. Accordingly, long-term use of hormone replacement therapy appeared to be the method of choice for many menopausal women to help alleviate vasomotor symptoms, which may include neuropsychological changes such as depression. However, given the limitations and number of serious health risks attributed to hormone replacement therapy, natural compounds such as phytoestrogens are receiving widespread awareness due to their occurrence in medicinal plant extracts and a wide variety of food items including dietary supplements with respective health claims. Flavonoids, particularly the isoflavones and the naringenin-type flavanones, belong to a group of polyphenolic plant-derived secondary metabolites known to possess estrogen-like bioactivities. Nevertheless, little is known about their transactivational activity and their potential to regulate endogenous gene expression of estrogen responsive genes in the raphe nuclei due to the lack of suitable cellular models expressing sufficient amounts of functional estrogen receptor β. Hence, a raphe nuclei-derived cell line that expresses a functional estrogen receptor β was sought as a model to investigate effects of flavonoids in vitro. In this regard, RN46A-B14 cells derived from embryonic day 13 rat medullary raphe nuclei were primarily used in this study as the main cellular model. Nonetheless, expression of endogenous estrogen receptor β in these cells was not sufficient to pursue downstream investigations of estrogen-dependent activities. To overcome this deficit, a rat raphe nuclei-derived in vitro model that overexpresses a functional estrogen receptor β was initially established (herein termed RNDA cells) by stably transducing its parent cell line, RN46A-B14 cells, with a suitable lentiviral expression vector encoding a human estrogen receptor β gene. The stable expression and the functional characterization of the transgenic receptor was confirmed by Western blot analysis and luciferase reporter gene assays, respectively. The same reporter gene assay was used to scrutinize the transactivational activity of the flavonoids in RNDA cells. Key results revealed that Genistein, Daidzein, Equol, Naringenin and 8-Prenylnaringenin demonstrated high transactivational activity in a concentration-dependent manner by stimulating luciferase expression from an estrogen responsive element-regulated reporter gene construct transiently transfected in RNDA cells. Low transactivational activity was observed in RNDA cells in response to increasing concentrations of 7-(O-prenyl)naringenin-4'-acetate. However, no transactivational activity was noticed in response to 6-(1,1-Dimethylallyl)naringenin in the studied cell model. All effects elicited by the flavonoids were antagonized by the pure estrogen receptor antagonist, Fulvestrant, indicating that all substances act by binding to and activating the transgenic ERβ. Additional effects were observed in RNDA cells in response to a co-treatment of 1 µM of either Genistein or Daidzein, but not Equol, with 10 nM 17β-Estradiol. Slight antagonistic effects were observed in the same studied cell line when either 8-Prenylnaringenin or 7-(O-prenyl)naringenin-4'-acetate, but not Naringenin or 6-(1,1-Dimethylallyl)naringenin, were co-added with 17β-Estradiol. Results from the reporter gene assays were validated on the basis of regulation of mRNA expression of estrogen responsive genes following the global assessment of 17β-Estradiol-induced gene expression in this cell line using a DNA microarray technique. Out of 212 estrogen-regulated genes with at least two-fold change of expression, six were selected according to specific features of estrogenic regulation of expression. The expression of the six selected 17β-Estradiol-regulated genes was validated using quantitative real-time PCR analysis. The regulation of mRNA expression of the selected genes in response to the tested flavonoids was then investigated in RNDA cells. Additionally, because RNDA cells encode a temperature-sensitive mutant of the Simian Virus 40 large T-antigen, their neuronal differentiation is constitutive upon shifting them from conditions promoting proliferation (permissive temperature) to differentiation (non permissive temperature). Hence, the regulation of mRNA expression of the selected genes in response to the tested flavonoids was additionally investigated as RNDA cells differentiate. In RNDA cells grown under proliferative conditions, 17β-Estradiol up-regulated mRNA expression of camello-like 5, sex determining region Y-box 18 and keratin type I cytoskeletal 19. Similar effects were observed in response to 8-Prenylnaringenin, Genistein, Daidzein and Equol. In addition, 17β-Estradiol down-regulated mRNA expression of neurofilament medium polypeptide and zinc finger DHHC-type containing 2. Similar effects were observed in response to 8-Prenylnaringenin, Naringenin, Genistein, Daidzein and Equol. Yet, no effect was observed on the regulation of mRNA expression of solute carrier family 6 member 4 in response to 17β-Estradiol or the flavonoids in RNDA cells grown under proliferative conditions. When RNDA cells were shifted to conditions promoting differentiation, changes in cell morphology, in mRNA expression levels and in responsiveness towards 17β-Estradiol or the flavonoids were observed. These expression studies additionally highlighted some of the genes as indicator genes for RNDA cellular differentiation. The newly established RNDA cell line should prove useful to elucidate basic physiological properties of estrogen receptor β in the raphe nuclei. The present study should serve as the basis to help shed light on molecular and cellular mechanisms following the action of phytoestrogens, endocrine disruptors or other exogenous estrogen receptor ligands in neural cell populations, particularly the raphe nuclei, for further applications within the brain.

Thesis (M.S.); Submitted to the Univ. of South Carolina, Columbia, SC (US); 1 Apr 2003. / Published through the Information Bridge: DOE Scientific and Technical Information. "JLAB-PHY-03-37" "DOE/ER/40150-2740" Clarisse Tur. 04/01/2003. Report is also available in paper and microfiche from NTIS.

Thesis; Thesis information not provided; 1 Feb 2003. / Published through the Information Bridge: DOE Scientific and Technical Information. "JLAB-PHY-03-38" "DOE/ER/40150-2762" Bin Zhang. 02/01/2003. Report is also available in paper and microfiche from NTIS.

Thesis (Ph. D.)--University of Missouri--Columbia, 1998. / Typescript. Vita. Includes bibliographical references (leaves : 325-355). Also available on the Internet.

Made available in DSpace on 2014-10-09T12:45:29Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T13:56:01Z (GMT). No. of bitstreams: 1 07295.pdf: 6617875 bytes, checksum: 02bc676c5e25a80397e40d7d6eecf61d (MD5) / Tese (Doutoramento) / IPEN/T / Instituto de Pesquisas Energeticas e Nucleares - IPEN/CNEN-SP

In this thesis I describe the development of a compact camera for ground-based multi TeV gamma-ray astronomy, using the Imaging Atmospheric Cherenkov Telescope (IACT) technique. The camera is based on multi-anode photomultipliers (MAPM) and is designed for use on the Gamma Cherenkov Telescope (GCT), which is proposed to be part of the Small Size Telescope (SST) array of the Cherenkov Telescope Array (CTA). GCT achieves high performance with a compact and cost efficient design via a Schwarzschild-Couder (SC) dual-mirror optical system. The GCT optical design allows the use of a compact camera of diameter roughly 0.5 m. The curved focal plane is equipped with 32 tiles of 64-pixels MAPM for a total of 2048 pixels of ~0.2° angular size, resulting in a field of view of ~9°. The GCT camera is designed to record the flashes of Cherenkov light from electromagnetic cascades, which last only a few tens of nanoseconds. I give a detailed description of the design, the challenges encountered during testing in the lab, and the performance of the most critical components. I give details on the custom front-end electronics modules that provide the required fast electronics, facilitating sampling and digitization, as well as first level of triggering. The camera-level triggering system is a custom backplane, developed to reject spurious triggers on the night sky background, which typically is of the order of few tens of millions of photons per pixel per second. This is to be compared with the rate of the astrophysical signal, which is of the order of few hundreds of events per second at the relevant energies. Additionally I provide a detailed description of all the software needed for the data acquisition and control of the camera, from the very low level drivers to high level and user friendly processes. I follow the commissioning of the camera, from the individual core components to the integration of the system. I then describe the integration of the camera on the GCT prototype telescope structure, and the achievement of "first light", validating for the first time the full proof-of-concept of an IACT with SC optics. I also report a study I performed on expectations for an extragalactic survey for blazars with CTA. The cumulative source count distribution of blazars is presented, including implications from two different phenomena: axion-like particle (ALP) to gamma-ray oscillations in the intergalactic magnetic field, and secondary gamma rays from hadronic origins. I conclude that a shallow and wide survey will provide the best science return for CTA, that the impact of ALP is modest and that the secondary mechanism of gamma-ray production would allow detection of blazars up to redshift of 1 in the multi-TeV energy band.

Des trous noirs supermassifs de plusieurs centaines de millions de masses solaires résident au centre de la plupart des galaxies massives. Dans 90% des cas, ces trous noirs sont dans état quiescent, très peu lumineux. Cependant, dans les 10% restant, des processus extrêmement violents sont observés, avec la libération d'énorme quantités d'énergie no- tamment en UV, X et gamma. On observe aussi parfois des jets puissants de matière pouvant s'étendre sur plusieurs centaines de kpc. Le coeur de ces galaxies sont appelés Noyaux Actifs de Galaxie (NAG). Ce sont parmis les objets les plus lumineux de l'univers. L'accrétion de la matière environnante sur le trou noir supermassif central est unanimement reconnue comme la source d'énergie la plus plausible pour expliquer la puissance phénoménale observée. L'énergie gravitationelle serait ainsi en partie libérée dans un disque d'accrétion, sous forme de rayonnement thermique piquant dans l'optique/UV, et en partie rayonnée en X/gamma par une couronne de plasma chaud présente dans l'environnement proche du trou noir.De nombreux phénomènes sont néanmoins encore très mal connus et beaucoup de ques- tions n'ont toujours pas de réponses satisfaisantes: quelles sont la dynamique et la structure des flots d'accrétion et d'éjection dans les NAG? Quels sont les processus radiatifs produisant le rayonnement UV/X? Quelle est l'origine des différentes composantes spectrales présentes dans ces domaines d'énergie? Cette thèse a pour objectif d'apporter de nouvelles contraintes observationnelles pour meux répondre à ces questions. Son originalité réside dans le développement et l'utilisation de modèles réalistes de Comptonisation thermique permettant d'une part de mieux contraindre les propriétés physiques et géométriques des régions d'émission UV/X et d'autre part de mieux comprendre l'origine des différentes composantes spectrales observées. Nous nous sommes notamment intéressés, au cours de cette thèse, à l'excès d'émission X-mou (<2 keV), présent dans un grand nombre de NAG, et dont l'origine est toujours inconnue.Ces travaux s'articulent autour de deux axes principaux. Le premier est l'étude spectrale détaillée de longues campagnes d'observation multi-longueur d'ondes de trois galaxies de Seyfert (NGC 5548, NGC 7213 et NGC 4593). La qualité des données ont ainsi permis de révéler les paramètres physiques (notamment la température et la profondeur optique) et géométriques de la couronne thermique à l'origine du continuum X. Le second axe porte sur l'analyse de données d'archives (en provenance du satellite XMM-Newton) d'un échantillon important de galaxies de Seyfert. Cela a permis d'apporter, cette fois ci, des contraintes plus générales sur les processus d'émission haute énergie observés dans ces objets. Ces deux approches ont notamment montré que l'exces d'émission X-mou pouvait provenir des couches supérieures chaudes du disque d'accrétion, suggérant un chauffage plus efficace en surface plutôt que dans les régions internes. / Supermassive black holes of several hundred million solar masses lie at the centre of most massive galaxies. In 90% of cases, these black holes are in quiescent, very low luminous states. Nevertheless, in the remaining 10%, extremely violent processes are seen, with the liberation of huge amounts of energy especially in the UV, X-ray and gamma-ray bands. We also sometimes observe powerful jets, extending up to several hundred kpc scales. The cores of these galaxies are called Active Galactic Nuclei (AGNs). These are among the most luminous objects in the Universe. The accretion of surrounding matter onto the central supermassive black hole is generally considered as the most likely energy source to explain the extraordinary observed luminosity. The gravitational energy would be partly liberated into an accretion disc as thermal radiation peaking in the optical/UV band, and partly radiated in the X-ray/gamma-ray band by a corona of hot plasma lying in the environment close to the black hole.However, several phenomena are still poorly understood and a number of questions lacks satisfactory answers: what are the dynamics and the structure of the accretion and ejection flows in AGNs? What are the radiative processes producing the UV/X-ray radiation? What is the origin of the different spectral components present in those energy bands? The goal of this thesis is to derive new observational constraints to better answer to these questions. Its originality resides in the development and application of realistic models of thermal Comptonization, allowing on the one hand to better constrain the physical and geometrical properties of the UV and X-ray-emitting regions, and on the other hand to better understand the origin of the different observed spectral components. In particular, we studied the excess of the soft (<2 keV) X-ray emission, seen in a great number of AGNs, and whose origin is still unknown.This work is structured along two main branches. One is the detailed spectral analysis of long, multiwavelength observational campaigns on three Seyfert galaxies (NGC 5548, NGC 7213 and NGC 4593). The quality of the data permitted to reveal the geometrical and physical parameters (in particular the temperature and optical depth) of the thermal corona producing the X-ray continuum. The second branch is based on the analysis of archival data (from the XMM-newton satellite) of a large sample of Seyfert galaxies. This allowed us to derive more general constraints on the high-energy emission processes observed in these objects. These two approaches have shown, in particular, that the soft X-ray emission excess may arise in the warm upper layers of the accretion disc, suggesting a more effective heating of the surface rather than the inner regions.