MPTP-induced degeneration: interference with glutamatergic toxicity

Parkinson's disease (PD) is characterised by the progressive degeneration of nigrostriatal dopamine (DA) neurons resulting in the major symptoms of akinesia and rigidity. Although the primary cause of PD is still not known some features make this disorder a model for neurodegenerative diseases in general. It has been known for some time that symptomatic PD can be attributed to insults with symptoms occurring many years later such as post-encephalitic PD or PD following manganese poisoning. More recently, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) has been identified as a neurotoxin selective for melanin-containing dopaminergic neurons in humans and non-human primates. The specificity of this neurotoxin and the striking clinical similarities to idiopathic PD, seen in primates, make MPTP-induced parkinsonism the most useful animal model of a neurological disease. There are numerous theoretical possibilities to interfere with both MPTP-induced neurotoxicity and the symptomatology of PD. In recent years excitatory amino acids have gained considerable interest since they can cause excitotoxic lesion of neurons under a number of pathological conditions (Olney et al., 1989; Choi, 1988). Here we summarise the present data and provide new experimental evidence indicating that MPTP-induced degeneration of dopaminergic neurons does involve glutamate-mediated toxicity. It is concluded that glutamate-mediated excitotoxicity results in the destruction of DAergic somata in the substantia nigra. Non-competitive or competitive NMDA antagonists protect nigral neurons from MPTP-induced degeneration whereas their striatal terminals still seem to degenerate

Electrons in a ferromagnetic metal with a domain wall

We present theoretical description of conduction electrons interacting with a domain wall in ferromagnetic metals. The description takes into account interaction between electrons. Within the semiclassical approximation we calculate the spin and charge distributions, particularly their modification by the domain wall. In the same approximation we calculate local transport characteristics, including relaxation times and charge and spin conductivities. It is shown that these parameters are significantly modified near the wall and this modification depends on electron-electron interaction.Comment: 10 pages with 4 figure

Nucleation of Quark--Gluon Plasma from Hadronic Matter

The energy densities achieved during central collisions of large nuclei at Brookhaven's AGS may be high enough to allow the formation of quark--gluon plasma. Calculations based on relativistic nucleation theory suggest that rare events, perhaps one in every 10$^2$ or 10$^3$, undergo the phase transition. Experimental ramifications may include an enhancement in the ratio of pions to baryons, a reduction in the ratio of deuterons to protons, and a larger source size as seen by hadron interferometry.Comment: 22 pages, 7 figures available upon request, NUC--MINN--94/5--

Dynamical Viscosity of Nucleating Bubbles

We study the viscosity corrections to the growth rate of nucleating bubbles in a first order phase transition in scalar field theory. We obtain the non-equilibrium equation of motion of the coordinate that describes small departures from the critical bubble and extract the growth rate consistently in weak coupling and in the thin wall limit. Viscosity effects arise from the interaction of this coordinate with the stable quantum and thermal fluctuations around a critical bubble. In the case of 1+1 dimensions we provide an estimate for the growth rate that depends on the details of the free energy functional. In 3+1 dimensions we recognize robust features that are a direct consequence of the thin wall approximation and give the leading viscosity corrections.These are long-wavelength hydrodynamic fluctuations that describe surface waves, quasi-Goldstone modes which are related to ripples on interfaces in phase ordered Ising-like systems. We discuss the applicability of our results to describe the growth rate of hadron bubbles in a quark-hadron first order transition.Comment: 40 pages, 4 figures, revtex, minor changes, to be published in Phys. Rev.

Syntaxin 5 Is Required for Copper Homeostasis in Drosophila and Mammals

Copper is essential for aerobic life, but many aspects of its cellular uptake and distribution remain to be fully elucidated. A genome-wide screen for copper homeostasis genes in Drosophila melanogaster identified the SNARE gene Syntaxin 5 (Syx5) as playing an important role in copper regulation; flies heterozygous for a null mutation in Syx5 display increased tolerance to high dietary copper. The phenotype is shown here to be due to a decrease in copper accumulation, a mechanism also observed in both Drosophila and human cell lines. Studies in adult Drosophila tissue suggest that very low levels of Syx5 result in neuronal defects and lethality, and increased levels also generate neuronal defects. In contrast, mild suppression generates a phenotype typical of copper-deficiency in viable, fertile flies and is exacerbated by co-suppression of the copper uptake gene Ctr1A. Reduced copper uptake appears to be due to reduced levels at the plasma membrane of the copper uptake transporter, Ctr1. Thus Syx5 plays an essential role in copper homeostasis and is a candidate gene for copper-related disease in humans

A CDC20-APC/SOX2 Signaling Axis Regulates Human Glioblastoma Stem-like Cells

SummaryGlioblastoma harbors a dynamic subpopulation of glioblastoma stem-like cells (GSCs) that can propagate tumors in vivo and is resistant to standard chemoradiation. Identification of the cell-intrinsic mechanisms governing this clinically important cell state may lead to the discovery of therapeutic strategies for this challenging malignancy. Here, we demonstrate that the mitotic E3 ubiquitin ligase CDC20-anaphase-promoting complex (CDC20-APC) drives invasiveness and self-renewal in patient tumor-derived GSCs. Moreover, CDC20 knockdown inhibited and CDC20 overexpression increased the ability of human GSCs to generate brain tumors in an orthotopic xenograft model in vivo. CDC20-APC control of GSC invasion and self-renewal operates through pluripotency-related transcription factor SOX2. Our results identify a CDC20-APC/SOX2 signaling axis that controls key biological properties of GSCs, with implications for CDC20-APC-targeted strategies in the treatment of glioblastoma

Detection of Genetically Altered Copper Levels in Drosophila Tissues by Synchrotron X-Ray Fluorescence Microscopy

Tissue-specific manipulation of known copper transport genes in Drosophila tissues results in phenotypes that are presumably due to an alteration in copper levels in the targeted cells. However direct confirmation of this has to date been technically challenging. Measures of cellular copper content such as expression levels of copper-responsive genes or cuproenzyme activity levels, while useful, are indirect. First-generation copper-sensitive fluorophores show promise but currently lack the sensitivity required to detect subtle changes in copper levels. Moreover such techniques do not provide information regarding other relevant biometals such as zinc or iron. Traditional techniques for measuring elemental composition such as inductively coupled plasma mass spectroscopy are not sensitive enough for use with the small tissue amounts available in Drosophila research. Here we present synchrotron x-ray fluorescence microscopy analysis of two different Drosophila tissues, the larval wing imaginal disc, and sectioned adult fly heads and show that this technique can be used to detect changes in tissue copper levels caused by targeted manipulation of known copper homeostasis genes

Does Pilocarpine-Induced Epilepsy in Adult Rats Require Status epilepticus?

Pilocarpine-induced seizures in rats provide a widely animal model of temporal lobe epilepsy. Some evidences reported in the literature suggest that at least 1 h of status epilepticus (SE) is required to produce subsequent chronic phase, due to the SE-related acute neuronal damage. However, recent data seems to indicate that neuro-inflammation plays a crucial role in epileptogenesis, modulating secondarily a neuronal insult. For this reason, we decided to test the following hypotheses: a) whether pilocarpine-injected rats that did not develop SE can exhibit long-term chronic spontaneous recurrent seizures (SRS) and b) whether acute neurodegeneration is mandatory to obtain chronic epilepsy. Therefore, we compared animals injected with the same dose of pilocarpine that developed or did not SE, and saline treated rats. We used telemetric acquisition of EEG as long-term monitoring system to evaluate the occurrence of seizures in non-SE pilocarpineinjected animals. Furthermore, histology and MRI analysis were applied in order to detect neuronal injury and neuropathological signs. Our observations indicate that non-SE rats exhibit SRS almost 8 (+/22) months after pilocarpine-injection, independently to the absence of initial acute neuronal injury. This is the first time reported that pilocarpine injected rats without developing SE, can experience SRS after a long latency period resembling human pathology. Thus, we strongly emphasize the important meaning of including these animals to model human epileptogenesis in pilocarpine induced epilepsy