Neurotransmitter Receptor Plasticity and Its Functional Consequences in Relation to Alzheimer's Disease

Neurotransmitter receptor sites have been examined in both human postmortem tissue and a lesioned polysynaptic pathway in rat brain using quantitative ligand binding autoradiography. Human Postmortem Studies The putative involvement of glutamatergic mechanisms in the pathophysiology of Alzheimer's disease (A. D. ) was investigated by determining the distribution and density of Na+ -dependent glutamate uptake sites and glutamate receptor subtypes; kainate, quisqualate and N-methyl-D-aspartate (NMDA), in adjacent sections of frontal, temporal and cerebellar cortex from six patients with A. D. and six age-matched controls. The number of senile plaques in each region was determined in adjacent sections to those used for receptor autoradiography. Binding of [3H]-D-aspartate to Na+-dependent uptake sites was reduced by approximately 40% throughout A. D. frontal cortex relative to controls, indicating a general loss of glutamatergic presynaptic terminals. [3H]-Kainate binding was significantly increased by approximately 70% in deep layers of A. D. frontal cortex compared to controls, but unaltered in superficial laminae. Scatchard analysis of this response indicated an increase in kainate receptor numbers with no change in receptor affinity. [3H]-Kainate binding and senile plaque numbers were positively correlated (r=0.914) in deep layers of A. D. frontal cortex, but unrelated in superficial laminae (r=0.089). There was a small reduction (25%) in NMDA-sensitive [3H]-glutamate binding only in superficial layers of A. D. frontal cortex relative to controls, although [3H]-glutamate binding in A. D. subjects was unrelated to senile plaque numbers in these cortical layers (r=0.104). Quisqualate receptors, as assessed by [3H]-a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid ([3H]-AMPA) binding were unaltered in A. D. frontal cortex compared to controls. There was no significant alteration in any glutamate binding sites in A. D. temporal cortex relative to control brains, despite the presence of senile plaques in comparable numbers to those found in A. D. frontal cortex. However, in the molecular layer of cerebellar cortex from A. D. subjects, there was a significant reduction (40%) in the number of [3H]-AMPA binding sites indicating a loss of quisqualate receptors in this region. [3H]-D-aspartate, [3H]-kainate and NMDA-sensitive [3H]-glutamate binding were unaltered in either the molecular or granule cell layers of A. D. cerebellar cortex. Within the cerebellum, senile plaques were found in very small numbers in only two A. D. brains. These results indicate anatomically-selective alterations in glutamatergic sites within the A. D. brain. The association of the kainate response in frontal cortex with the level of local neuropathology and the loss of quisqualate receptors in the cerebellum in the absence of gross neuropathological change suggests that the mechanisms of glutamatergic dysfunction in A. D. are heterogeneous with respect to anatomical locus. Rat Visual System Studies The rat visual system was employed as a model polysynaptic pathway in which to examine neurotransmitter receptor alterations under conditions of functional deficit. Within the visual system, glutamate is the major excitatory transmitter, although serotonin, noradrenaline, acetylcholine and GABA (y-aminobutyric acid) are also involved in visual processing. Unilateral orbital enucleation experiments were undertaken to examine: (1) the response of glutamate receptor subtypes under conditions of reduced glutamatergic input; (2) receptor regulation in separate but functionally related systems, by simultaneously quantifying specific serotonergic, noradrenergic, GABAergic and cholinergic receptors post-lesion; and (3) the relevance of alterations in neurotransmitter receptors to changes in local cerebral function, by combining the [14C]-2-deoxyglucose technique for the measurement of cerebral glucose use with in vitro receptor autoradiography. The results presented in this thesis highlight the applicability of quantitative receptor autoradiography in studies of receptor dynamics in both rat polysynaptic systems and human neurodegenerative disease. The novel alterations in glutamatergic sites in the A. D. brain uncovered by the present investigations provide new insight into the role of glutamatergic dysfunction in the pathophysiology of the disease

The Intermediate Coupling Regime in the AdS/CFT Correspondence

The correspondence between the 't Hooft limit of N=4 super Yang-Mills theory and tree-level IIB superstring theory on AdS(5)xS(5) in a Ramond-Ramond background at values of lambda=g^2 N ranging from infinity to zero is examined in the context of unitarity. A squaring relation for the imaginary part of the holographic scattering of identical string fields in the two-particle channels is found, and a mismatch between weak and strong 't Hooft coupling is pointed out within the correspondence. Several interpretations and implications are proposed.Comment: 10 pages, LaTeX, reference adde

Dual expansions of N=4 super Yang-Mills theory via IIB superstring theory

We examine the dual correspondence between holographic IIB superstring theory and N=4 super Yang-Mills theory at finite values of the coupling constants. In particular we analyze a field theory strong-coupling expansion which is the S-dual of the planar expansion. This expansion arises naturally as the AdS/CFT dual of the IIB superstring scattering amplitudes given a genus truncation property due to modular invariance. The space-time structure of the contributions to the field theory four-point correlation functions obtained from the IIB scattering elements is investigated in the example of the product of four conserved stress tensors, and is expressed as an infinite sum of field theory triangle integrals. The OPE structure of these contributions to the stress tensor four-point function is analyzed and shown not to give rise to any poles. Quantization of the string in the background of a five-form field strength is performed through a covariantized background field approach, and relations to the N=4 topological string are found.Comment: LaTeX, 40 pages, 5 figure

Assessing cardiovascular links to depression and anxiety in Australian professional drivers.

Train and truck drivers experience a myriad of unique occupational factors, which have been postulated to contribute to a high incidence of health conditions such as depression anxiety and cardiovascular disease amongst this population. The present study aimed to identify associations between heart rate variability and negative mood states such as depression and anxiety in a cohort of Australian truck and train drivers. 120 professional drivers (60 truck drivers, 60 train drivers) were recruited from the local community. Participants complete a battery of psychometric questionnaires to assess levels of negative mood states such as depression and anxiety. Participants then completed a baseline (resting) and active (driving) task while concurrent electrocardiography data was collected to obtain heart rate variability parameters. Anxiety and depression were found to be associated with increases in low frequency heart rate variability and sympathovagal balance, and a reduction in total power. The present study identified associations between negative mood states and heart rate variability parameters that are unique to this cohort

Changes in the secretory profile of NSCLC-associated fibroblasts after ablative radiotherapy: potential impact on angiogenesis and tumor growth

In the context of radiotherapy, collateral effects of ablative ionizing radiation (AIR) on stromal components of tumors remains understudied. In this work, cancer-associated fibroblasts (CAFs) isolated from freshly resected human lung tumors were exposed to AIR (1x18Gy) and analyzed for their release of paracrine factors. Inflammatory mediators and regulators of angiogenesis and tumor growth were analyzed by multiplex protein assays in conditioned medium (CM) from irradiated and non-irradiated CAFs. Additionally, the profile of secreted proteins was examined by proteomics. In functional assays, effects of CAF-CM on proliferative and migratory capacity of lung tumor cells (H-520/H-522) and endothelial cells (HUVECs), and on the tube-forming capacity of endothelial cells was assessed. Our data show that exposure of CAFs to ablative doses of ionizing radiation results in a) down-regulated release of angiogenic factors SDF-1, angiopoietin and thrombospondin-2; b) up-regulated release of growth factor bFGF from most donors, and c) unaffected expression-levels of HGF and inflammatory mediators IL-6, IL-8, IL-1ƒÒ and TNF-£. Conditioned medium from irradiated and control CAFs did not affect differently the proliferative or migratory capacity of tumor cells (H-520/H-522), whereas migratory capacity of endothelial HUVEC cells was partially reduced in the presence of irradiated CAF conditioned medium. Overall we conclude that AIR mediates a transformation on the secretory profile of CAFs that could influence the behavior of other cells in the tumor tissue and hence guide to some extent therapeutic outcomes. The downstream consequences of the changes observed in this study merits further investigations

Dynamical density functional theory for the evaporation of droplets of nanoparticle suspension

We develop a lattice gas model for the drying of droplets of a nanoparticle suspension on a planar surface, using dynamical density functional theory (DDFT) to describe the time evolution of the solvent and nanoparticle density profiles. The DDFT assumes a diffusive dynamics but does not include the advective hydrodynamics of the solvent, so the model is relevant to highly viscous or near to equilibrium systems. Nonetheless, we see an equivalent of the coffee-ring stain effect, but in the present model it occurs for thermodynamic rather the fluid-mechanical reasons. The model incorporates the effect of phase separation and vertical density variations within the droplet and the consequence of these on the nanoparticle deposition pattern on the surface. We show how to include the effect of slip or no-slip at the surface and how this is related to the receding contact angle. We also determine how the equilibrium contact angle depends on the microscopic interaction parameters.Comment: 35 pages, 10 figure

Momumentum Analyticity and Finiteness of Compactified String Amplitudes, Part I: Tori

We generalize to the case of compactified superstrings a construction given previously for critical superstrings of finite one loop amplitudes that are well-defined for all external momenta. The novel issues that arise for compactified strings are the appearance of infrared divergences from the propagation of massless strings in four dimensions and, in the case of orbifold schemes, the contribution of tachyons in partial amplitudes with given spin structure and twist sectors. Methods are presented for the resolution of these problems and expressions for finite amplitudes are given in terms of double and single dispersion relations, with explicit spectral densities.Comment: 18 pages, te