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Glutathionylation at Cys-111 Induces Dissociation of Wild Type and FALS Mutant SOD1 Dimers
Redler, Rachel L.
Wilcox, Kyle C.
Proctor, Elizabeth A.
Fee, Lanette
Caplow, Michael
Dokholyan, Nikolay V.
Mutation of the ubiquitous cytosolic enzyme Cu/Zn superoxide dismutase (SOD1) is hypothesized to cause familial amyotrophic lateral sclerosis (FALS) through structural destabilization leading to misfolding and aggregation. Considering the late onset of symptoms as well as the phenotypic variability among patients with identical SOD1 mutations, it is clear that nongenetic factor(s) impact ALS etiology and disease progression. Here we examine the effect of Cys-111 glutathionylation, a physiologically prevalent post-translational oxidative modification, on the stabilities of wild type SOD1 and two phenotypically diverse FALS mutants, A4V and I112T. Glutathionylation results in profound destabilization of SOD1WT dimers, increasing the equilibrium dissociation constant Kd to ~10−20 μM, comparable to that of the aggressive A4V mutant. SOD1A4V is further destabilized by glutathionylation, experiencing an ~30-fold increase in Kd. Dissociation kinetics of glutathionylated SOD1WT and SOD1A4V are unchanged, as measured by surface plasmon resonance, indicating that glutathionylation destabilizes these variants by decreasing association rate. In contrast, SOD1I112T has a modestly increased dissociation rate but no change in Kd when glutathionylated. Using computational structural modeling, we show that the distinct effects of glutathionylation on different SOD1 variants correspond to changes in composition of the dimer interface. Our experimental and computational results show that Cys-111 glutathionylation induces structural rearrangements that modulate stability of both wild type and FALS mutant SOD1. The distinct sensitivities of SOD1 variants to glutathionylation, a modification that acts in part as a coping mechanism for oxidative stress, suggest a novel mode by which redox regulation and aggregation propensity interact in ALS.
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SOD1 oxidation and formation of soluble aggregates in yeast: Relevance to sporadic ALS development
Martins, Dorival
English, Ann M.
Redox Biology
Misfolding and aggregation of copper–zinc superoxide dismutase (Sod1) are observed in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Mutations in Sod1 lead to familial ALS (FALS), which is a late-onset disease. Since oxidative damage to proteins increases with age, it had been proposed that oxidation of Sod1 mutants may trigger their misfolding and aggregation in FALS. However, over 90% of ALS cases are sporadic (SALS) with no obvious genetic component. We hypothesized that oxidation could also trigger the misfolding and aggregation of wild-type Sod1 and sought to confirm this in a cellular environment. Using quiescent, stationary-phase yeast cells as a model for non-dividing motor neurons, we probed for post-translational modification (PTM) and aggregation of wild-type Sod1 extracted from these cells. By size-exclusion chromatography (SEC), we isolated two populations of Sod1 from yeast: a low-molecular weight (LMW) fraction that is catalytically active and a catalytically inactive, high-molecular weight (HMW) fraction. High-resolution mass spectrometric analysis revealed that LMW Sod1 displays no PTMs but HMW Sod1 is oxidized at Cys146 and His71, two critical residues for the stability and folding of the enzyme. HMW Sod1 is also oxidized at His120, a copper ligand, which will promote loss of this catalytic metal cofactor essential for SOD activity. Monitoring the fluorescence of a Sod1-green-fluorescent-protein fusion (Sod1-GFP) extracted from yeast chromosomally expressing this fusion, we find that HMW Sod1-GFP levels increase up to 40-fold in old cells. Thus, we speculate that increased misfolding and inclusion into soluble aggregates is a consequence of elevated oxidative modifications of wild-type Sod1 as cells age. Our observations argue that oxidative damage to wild-type Sod1 initiates the protein misfolding mechanisms that give rise to SALS.
•Key Sod1 catalytic and structure-stabilizing residues (Cys146, His120, His71) are oxidized in stationary-phase yeast.•Oxidized Sod1 is isolated in an inactive, high-molecular-weight, soluble aggregate.•Sod1 with native mass isolated from the same samples is not oxidized and is catalytically active.•Our results argue that oxidation triggers the formation of soluble Sod1-containing aggregates that may contribute to sporadic ALS development.
Graphical abstract
Wild-type Sod1; Oxidative PTMs; Soluble aggregates; Sporadic ALS; Yeast
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An emerging role for misfolded wild-type SOD1 in sporadic ALS pathogenesis
Rotunno, Melissa S.
Bosco, Daryl A.
Frontiers in Cellular Neuroscience
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that targets motor neurons, leading to paralysis and death within a few years of disease onset. While several genes have been linked to the inheritable, or familial, form of ALS, much less is known about the cause(s) of sporadic ALS, which accounts for ~90% of ALS cases. Due to the clinical similarities between familial and sporadic ALS, it is plausible that both forms of the disease converge on a common pathway and, therefore, involve common factors. Recent evidence suggests the Cu,Zn-superoxide dismutase (SOD1) protein to be one such factor that is common to both sporadic and familial ALS. In 1993, mutations were uncovered in SOD1 that represent the first known genetic cause of familial ALS. While the exact mechanism of mutant-SOD1 toxicity is still not known today, most evidence points to a gain of toxic function that stems, at least in part, from the propensity of this protein to misfold. In the wild-type SOD1 protein, non-genetic perturbations such as metal depletion, disruption of the quaternary structure, and oxidation, can also induce SOD1 to misfold. In fact, these aforementioned post-translational modifications cause wild-type SOD1 to adopt a "toxic conformation" that is similar to familial ALS-linked SOD1 variants. These observations, together with the detection of misfolded wild-type SOD1 within human post-mortem sporadic ALS samples, have been used to support the controversial hypothesis that misfolded forms of wild-type SOD1 contribute to sporadic ALS pathogenesis. In this review, we present data from the literature that both support and contradict this hypothesis. We also discuss SOD1 as a potential therapeutic target for both familial and sporadic ALS.
amyotrophic lateral sclerosis (ALS); sporadic amyotrophic lateral sclerosis; SOD1; protein misfolding; immunotherapy
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The Effects of Glutaredoxin and Copper Activation Pathways on the Disulfide and Stability of Cu,Zn Superoxide Dismutase*…
Carroll, Mark C.
Outten, Caryn E.
Proescher, Jody B.
Rosenfeld, Leah
Watson, Walter H.
Whitson, Lisa J.
Hart, P. John
Jensen, Laran T.
Culotta, Valeria Cizewski
The Journal of biological chemistry
Mutations in Cu,Zn superoxide dismutase (SOD1) can cause amyotrophic lateral sclerosis (ALS) through mechanisms proposed to involve SOD1 misfolding, but the intracellular factors that modulate folding and stability of SOD1 are largely unknown. By using yeast and mammalian expression systems, we demonstrate here that SOD1 stability is governed by post-translational modification factors that target the SOD1 disulfide. Oxidation of the human SOD1 disulfide in vivo was found to involve both the copper chaperone for SOD1 (CCS) and the CCS-independent pathway for copper activation. When both copper pathways were blocked, wild type SOD1 stably accumulated in yeast cells with a reduced disulfide, whereas ALS SOD1 mutants A4V, G93A, and G37R were degraded. We describe here an unprecedented role for the thiol oxidoreductase glutaredoxin in reducing the SOD1 disulfide and destabilizing ALS mutants. Specifically, the major cytosolic glutaredoxin of yeast was seen to reduce the intramolecular disulfide of ALS SOD1 mutant A4V SOD1 in vivo and in vitro. By comparison, glutaredoxin was less reactive toward the disulfide of wild type SOD1. The apo-form of A4V SOD1 was highly reactive with glutaredoxin but not SOD1 containing both copper and zinc. Glutaredoxin therefore preferentially targets the immature form of ALS mutant SOD1 lacking metal co-factors. Overall, these studies implicate a critical balance between cellular reductants such as glutaredoxin and copper activation pathways in controlling the disulfide and stability of SOD1 in vivo.
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Zinc Binding Modulates the Entire Folding Free Energy Surface of Human Cu,Zn Superoxide Dismutase
Kayatekin, Can
Zitzewitz, Jill A.
Matthews, C. Robert
Journal of molecular biology
Over 100 amino acid replacements in human Cu, Zn superoxide dismutase (SOD) are known to cause amyotrophic lateral sclerosis, a gain-of-function neurodegenerative disease that destroys motor neurons. Supposing that aggregates of partially-folded states are primarily responsible for toxicity, the role of the structurally-important zinc ion in defining the folding free energy surface of dimeric SOD was determined by comparing the thermodynamic and kinetic folding properties of the zinc-free and zinc-bound forms of the protein. The presence of zinc was found to decrease the free energies of a peptide model of the unfolded monomer, a stable variant of the folded monomeric intermediate and the folded dimeric species. The unfolded state binds zinc weakly with a micromolar dissociation constant, and the folded monomeric intermediate and the native dimeric form both bind zinc tightly, with sub-nanomolar dissociation constants. Coupled with the strong driving force for the subunit association reaction, the shift in the populations towards more well-folded states in the presence of zinc decreases the steady-state populations of higher-energy states in SOD under expected in vivo zinc concentrations (∼nanomolar). The significant decrease in the population of partially-folded states is expected to diminish their potential for aggregation and account for the known protective effect of zinc. The ∼100-fold increase in the rate of folding of SOD in the presence of micromolar concentrations of zinc demonstrates a significant role for a pre-organized zinc-binding loop in the transition state ensemble for the rate-limiting monomer folding reaction in this β-barrel protein.
ALS; beta-barrel dimer; metal binding; protein folding; thermodynamics and kinetics
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Glutathionylation potentiates benign superoxide dismutase 1 variants to the toxic forms associated with amyotrophic lateral sclerosis
McAlary, Luke
Yerbury, Justin J.
Aquilina, J. Andrew
Scientific Reports
Dissociation of superoxide dismutase 1 dimers is enhanced by glutathionylation, although the dissociation constants reported to date are imprecise. We have quantified the discreet dissociation constants for wild-type superoxide dismutase 1 and six naturally occurring sequence variants, in their unmodified and glutathionylated forms, at the ratios expressed. Unmodified superoxide dismutase 1 variants that shared similar dissociation constants with SOD1WT had disproportionately increased dissociation constants when glutathionylated. This defines a key role for glutathionylation in superoxide dismutase 1 associated familial amyotrophic lateral sclerosis.
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Ligand binding and aggregation of pathogenic SOD1
Wright, Gareth S.A.
Antonyuk, Svetlana V.
Kershaw, Neil M.
Strange, Richard W.
Samar Hasnain, S
Nature Communications
Mutations in the gene encoding Cu/Zn superoxide dismutase-1 cause amyotrophic lateral sclerosis. Superoxide dismutase-1 mutations decrease protein stability and promote aggregation. The mutant monomer is thought to be an intermediate in the pathway from the superoxide dismutase-1 dimer to aggregate. Here we find that the monomeric copper-apo, zinc-holo protein is structurally perturbed and the apo-protein aggregates without reattainment of the monomer–dimer equilibrium. Intervention to stabilize the superoxide dismutase-1 dimer and inhibit aggregation is regarded as a potential therapeutic strategy. We describe protein–ligand interactions for two compounds, Isoproterenol and 5-fluorouridine, highlighted as superoxide dismutase-1 stabilizers. We find both compounds interact with superoxide dismutase-1 at a key region identified at the core of the superoxide dismutase-1 fibrillar aggregates, β-barrel loop II–strand 3, rather than the proposed dimer interface site. This illustrates the need for direct structural observations when developing compounds for protein-targeted therapeutics.
Mutations of the SOD1 gene are implicated in neurodegenerative diseases such as amyotrophic lateral sclerosis. Wright and colleagues find that SOD1 aggregation in cells is arrested by compounds that bind at the core of SOD1 aggregates, rather than at the dimer interface site.
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Prognostic role of "prion-like propagation" in SOD1-linked familial ALS: an alternative view
Sugaya, Keizo
Nakano, Imaharu
Frontiers in Cellular Neuroscience
"Prion-like propagation" has recently been proposed for disease spread in Cu/Zn superoxide dismutase 1 (SOD1)-linked familial amyotrophic lateral sclerosis (ALS). Pathological SOD1 conformers are presumed to propagate via cell-to-cell transmission. In this model, the risk-based kinetics of neuronal cell loss over time appears to be represented by a sigmoidal function that reflects the kinetics of intercellular transmission. Here, we describe an alternative view of prion-like propagation in SOD1-linked ALS – its relation to disease prognosis under the protective-aggregation hypothesis. Nucleation-dependent polymerization has been widely accepted as the molecular mechanism of prion propagation. If toxic species of misfolded SOD1, as soluble oligomers, are formed as on-pathway intermediates of nucleation-dependent polymerization, further fibril extension via sequential addition of monomeric mutant SOD1 would be protective against neurodegeneration. This is because the concentration of unfolded mutant SOD1 monomers, which serve as precursor of nucleation and toxic species of mutant SOD1, would decline in proportion to the extent of aggregation. The nucleation process requires that native conformers exist in an unfolded state that may result from escaping the cellular protein quality control machinery. However, prion-like propagation-SOD1 aggregated form self-propagates by imposing its altered conformation on normal SOD1-appears to antagonize the protective role of aggregate growth. The cross-seeding reaction with normal SOD1 would lead to a failure to reduce the concentration of unfolded mutant SOD1 monomers, resulting in continuous nucleation and subsequent generation of toxic species, and influence disease prognosis. In this alternative view, the kinetics of neuronal loss appears to be represented by an exponential function, with decreasing risk reflecting the protective role of aggregate and the potential for cross-seeding reactions between mutant SOD1 and normal SOD1.
aggregate; amyotrophic lateral sclerosis; mutation; nucleation; prion; SOD1; kinetic model
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Post-translational modification of Cu/Zn superoxide dismutase under anaerobic conditions†
Leitch, Jeffry M.
Li, Cissy X.
Baron, J. Allen
Matthews, Lauren M.
Cao, Xiaohang
Hart, P. John
Culotta, Valeria C.
In eukaryotic organisms, the largely cytosolic copper and zinc containing superoxide dismutase enzyme (Cu/Zn SOD) represents a key defense against reactive oxygen toxicity. Although much is known about the biology of this enzyme under aerobic conditions, less is understood regarding the effects of low oxygen on Cu/Zn SOD from diverse organisms. We show here that like bakers' yeast (Saccharomyces cerevisiae), adaptation of the multicellular Caenorhabditis elegans to growth in low oxygen involves strong down-regulation of its Cu/Zn SOD. Much of this regulation occurs at the post-translational level where CCS-independent activation of Cu/Zn SOD is inhibited. Hypoxia inactivates the endogenous Cu/Zn SOD of C. elegans Cu/Zn SOD as well as a P144 mutant of S. cerevisiae Cu/Zn SOD (herein denoted as Sod1p) that is independent of CCS. In our studies of S. cerevisiae Sod1p we noted a post-translational modification to the inactive enzyme during hypoxia. Analysis of this modification by mass spectrometry revealed phosphorylation on serine 38. Serine 38 represents a putative proline-directed kinase target site located on a solvent exposed loop that is positioned at one end of the Sod1p beta-barrel, a region immediately adjacent to residues previously shown to influence CCS-dependent activation. Although phosphorylation of serine 38 is minimal when the Sod1p is abundantly active (e.g., high oxygen), up to 50% of Sod1p can be phosphorylated when CCS-activation of the enzyme is blocked, e.g., by hypoxia or low copper conditions. Serine 38 phosphorylation can be a marker for inactive pools of Sod1p.
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Pathological Roles of Wild-Type Cu, Zn-Superoxide Dismutase in Amyotrophic Lateral Sclerosis
Furukawa, Yoshiaki
Neurology Research International
Dominant mutations in a Cu, Zn-superoxide dismutase (SOD1) gene cause a familial form of amyotrophic lateral sclerosis (ALS). While it remains controversial how SOD1 mutations lead to onset and progression of the disease, many in vitro and in vivo studies have supported a gain-of-toxicity mechanism where pathogenic mutations contribute to destabilizing a native structure of SOD1 and thus facilitate misfolding and aggregation. Indeed, abnormal accumulation of SOD1-positive inclusions in spinal motor neurons is a pathological hallmark in SOD1-related familial ALS. Furthermore, similarities in clinical phenotypes and neuropathology of ALS cases with and without mutations in sod1 gene have implied a disease mechanism involving SOD1 common to all ALS cases. Although pathogenic roles of wild-type SOD1 in sporadic ALS remain controversial, recent developments of novel SOD1 antibodies have made it possible to characterize wild-type SOD1 under pathological conditions of ALS. Here, I have briefly reviewed recent progress on biochemical and immunohistochemical characterization of wild-type SOD1 in sporadic ALS cases and discussed possible involvement of wild-type SOD1 in a pathomechanism of ALS.
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Colocalization of 14-3-3 Proteins with SOD1 in Lewy Body-Like Hyaline Inclusions in Familial Amyotrophic Lateral Sclerosis Cases and the Animal Model
Okamoto, Yoko
Shirakashi, Yoshitomo
Ihara, Masafumi
Urushitani, Makoto
Oono, Miki
Kawamoto, Yasuhiro
Yamashita, Hirofumi
Shimohama, Shun
Kato, Shinsuke
Hirano, Asao
Tomimoto, Hidekazu
Ito, Hidefumi
Takahashi, Ryosuke
PLoS ONE
Background and Purpose
Cu/Zn superoxide dismutase (SOD1) is a major component of Lewy body-like hyaline inclusion (LBHI) found in the postmortem tissue of SOD1-linked familial amyotrophic lateral sclerosis (FALS) patients. In our recent studies, 14-3-3 proteins have been found in the ubiquitinated inclusions inside the anterior horn cells of spinal cords with sporadic amyotrophic lateral sclerosis (ALS). To further investigate the role of 14-3-3 proteins in ALS, we performed immunohistochemical analysis of 14-3-3 proteins and compared their distributions with those of SOD1 in FALS patients and SOD1-overexpressing mice.
We examined the postmortem brains and the spinal cords of three FALS cases (A4V SOD1 mutant). Transgenic mice expressing the G93A mutant human SOD1 (mutant SOD1-Tg mice), transgenic mice expressing the wild-type human SOD1 (wild-type SOD1-Tg mice), and non-Tg wild-type mice were also subjected to the immunohistochemical analysis.
In all the FALS patients, LBHIs were observed in the cytoplasm of the anterior horn cells, and these inclusions were immunopositive intensely for pan 14-3-3, 14-3-3β, and 14-3-3γ. In the mutant SOD1-Tg mice, a high degree of immunoreactivity for misfolded SOD1 (C4F6) was observed in the cytoplasm, with an even greater degree of immunoreactivity present in the cytoplasmic aggregates of the anterior horn cells in the lumbar spinal cord. Furthermore, we have found increased 14-3-3β and 14-3-3γ immunoreactivities in the mutant SOD1-Tg mice. Double immunofluorescent staining showed that C4F6 and 14-3-3 proteins were partially co-localized in the spinal cord with FALS and the mutant SOD1-Tg mice. In comparison, the wild-type SOD1-Tg and non-Tg wild-type mice showed no or faint immunoreactivity for C4F6 and 14-3-3 proteins (pan 14-3-3, 14-3-3β, and 14-3-3γ) in any neuronal compartments.
These results suggest that 14-3-3 proteins may be associated with the formation of SOD1-containing inclusions, in FALS patients and the mutant SOD1-Tg mice.
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Redox Properties of the Disulfide Bond of Human Cu,Zn Superoxide Dismutase and the Effects of Human Glutaredoxin 1
Bouldin, Samantha D.
Darch, Maxwell A.
Hart, P. John
Outten, Caryn E.
The Biochemical journal
The intramolecular disulfide bond in human Cu,Zn superoxide dismutase 1 (hSOD1) plays a key role in maintaining the protein's stability and quaternary structure. In mutant forms of SOD1 that cause familial amyotrophic lateral sclerosis (ALS), this disulfide bond is more susceptible to chemical reduction, which may lead to destabilization of the dimer and aggregation. During hSOD1 maturation, disulfide formation is catalyzed by the copper chaperone CCS1. Previous studies in yeast demonstrate that the yeast glutathione (GSH)/glutaredoxin redox system promotes reduction of the hSOD1 disulfide in the absence of CCS1. Herein, we further probe the interaction between hSOD1, GSH, and glutaredoxins to provide mechanistic insight into the redox kinetics and thermodynamics of the hSOD1 disulfide. We demonstrate that human glutaredoxin 1 (hGrx1) uses a monothiol mechanism to reduce the hSOD1 disulfide, and the GSH/hGrx1 system reduces ALS mutant SOD1 at a faster rate than WT hSOD1. However, redox potential measurements demonstrate that the thermodynamic stability of the disulfide is not consistently lower in ALS mutants compared to WT hSOD1. Furthermore, the presence of the metal cofactors does not influence the disulfide redox potential. Overall, these studies suggest that differences in the GSH/hGrx1 reaction rate with WT vs. ALS mutant hSOD1 and not the inherent thermodynamic stability of the hSOD1 disulfide bond may contribute to the greater pathogenicity of ALS mutant hSOD1.
Disulfide; redox potential; glutaredoxins; yeast; Cu,Zn superoxide dismutase; monothiol
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Protein Misdirection Inside and Outside Motor Neurons in Amyotrophic Lateral Sclerosis (ALS): A Possible Clue for Therapeutic Strategies
Ido, Akemi
Fukuyama, Hidenao
Urushitani, Makoto
International Journal of Molecular Sciences
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive muscle wasting and weakness with no effective cure. Emerging evidence supports the notion that the abnormal conformations of ALS-linked proteins play a central role in triggering the motor neuron degeneration. In particular, mutant types of superoxide dismutase 1 (SOD1) and TAR DNA binding protein 43kDa (TDP-43) are key molecules involved in the pathogenesis of familial and sporadic ALS, respectively. The commonalities of the two proteins include a propensity to aggregate and acquire detrimental conformations through oligomerization, fragmentation, or post-translational modification that may drive abnormal subcellular localizations. Although SOD1 is a major cytosolic protein, mutated SOD1 has been localized to mitochondria, endoplasmic reticulum, and even the extracellular space. The nuclear exclusion of TDP-43 is a pathological hallmark for ALS, although the pathogenic priority remains elusive. Nevertheless, these abnormal behaviors based on the protein misfolding are believed to induce diverse intracellular and extracellular events that may be tightly linked to non-cell-autonomous motor neuron death. The generation of mutant- or misfolded protein-specific antibodies would help to uncover the distribution and propagation of the ALS-linked proteins, and to design a therapeutic strategy to clear such species. Herein we review the literature regarding the mislocalization of ALS-linked proteins, especially mutant SOD1 and TDP-43 species, and discuss the rationale of molecular targeting strategies including immunotherapy.
seeding; subcellular localization; SOD1; TDP-43; non-cell-autonomous motor neuron death; antibody
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Early steps in thermal unfolding of superoxide dismutase 1 are similar to the conformational changes associated with the ALS-associated A4V mutation
Schmidlin, Tom
Ploeger, Ken
Jonsson, Amanda L.
Daggett, Valerie
Protein Engineering, Design and Selection
There are over 100 mutations in Cu/Zn superoxide dismutase (SOD1) that result in a subset of familial amyotrophic lateral sclerosis (fALS) cases. The hypothesis that dissociation of the dimer, misfolding of the monomer and subsequent aggregation of mutant SOD1 leads to fALS has been gaining support as an explanation for how these disparate missense mutations cause the same disease. These forms are only responsible for a fraction of the ALS cases; however, the rest are sporadic. Starting with a folded apo monomer, the species considered most likely to be involved in misfolding, we used high-temperature all-atom molecular dynamics simulations to explore the events of the wild-type protein unfolding through the denatured state. All simulations showed early loss of structure along the β5–β6 edge of the β-sandwich, supporting earlier findings of instability in this region. Transition state structures identified from the simulations are in good agreement with experiment, providing detailed, validated molecular models for this elusive state. Furthermore, we compare the process of thermal unfolding investigated here to that of the lethal A4V mutant-induced unfolding at physiological temperature and find that the pathways are very similar.
ALS; misfolding; molecular dynamics; SOD1; unfolding
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Prudencio, Mercedes
Durazo, Armando
Whitelegge, Julian P.
Borchelt, David R.
Journal of neurochemistry
Mutations in superoxide dismutase 1 (SOD1, EC 126.96.36.199) cause familial amyotrophic lateral sclerosis (fALS); with aggregated forms of mutant protein accumulating in spinal cord tissues of transgenic mouse models and human patients. Mice over-expressing wild-type human SOD1 (WT hSOD1) do not develop ALS-like disease, but co-expression of WT enzyme at high levels with mutant SOD1 accelerates the onset of motor neuron disease compared to mice expressing mutant hSOD1 alone. Spinal cords of mice expressing both proteins contain aggregated forms of mutant protein and, in some cases, evidence of co-aggregation of WT hSOD1 enzyme. In the present study, we used a cell culture model of mutant SOD1 aggregation to examine how the presence of WT SOD1 affects mutant protein aggregation, finding that co-expression of WT SOD1, human (hSOD1) or mouse (mSOD1), delayed the formation of mutant hSOD1 aggregates; in essence appearing to slow the aggregation rate. In some combinations of WT and mutant hSOD1 co-expression, the aggregates that did eventually form appeared to contain WT hSOD1 protein. However, WT mSOD1 did not co-aggregate with mutant hSOD1 despite displaying a similar ability to slow mutant hSOD1 aggregation. Together, these studies indicate that WT SOD1 (human or mouse), when expressed at levels equivalent to the mutant protein, modulates aggregation of FALS-mutant hSOD1.
superoxide; dismutase; aggregation; amyotrophic lateral sclerosis
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Different regulation of wild-type and mutant Cu,Zn superoxide dismutase localization in mammalian mitochondria
Kawamata, Hibiki
Manfredi, Giovanni
Human Molecular Genetics
The antioxidant enzyme Cu,Zn superoxide dismutase (SOD1) is predominantly localized in the cytosol, but it is also found in mitochondria. Studies in yeast suggest that apoSOD1 is imported into mitochondria and trapped inside by folding and maturation, which is facilitated by its copper chaperone for SOD1 (CCS). Here, we show that in mammalian cells, SOD1 mitochondrial localization is dictated by its folding state, which is modulated by several interconnected factors. First, the intracellular distribution of CCS determines SOD1 partitioning in cytosol and mitochondria: CCS localization in the cytosol prevents SOD1 mitochondrial import, whereas CCS in mitochondria increases it. Second, the Mia40/Erv1 pathway for import of small intermembrane space proteins participates in CCS mitochondrial import in a respiratory chain-dependent manner. Third, CCS mitochondrial import is regulated by oxygen concentration: high (20%) oxygen prevents import, whereas physiological (6%) oxygen promotes it. Therefore, SOD1 localization responds to changes in environmental conditions following redistribution of CCS, which operates as an oxygen sensor. Fourth, all of the cysteine residues in human SOD1 are critical for its retention in mitochondria due to their involvement in intramolecular disulfide bonds and in the interaction with CCS. Mutations in SOD1 are associated with autosomal dominant familial amyotrophic lateral sclerosis. Like the wild-type protein, mutant SOD1 localizes to mitochondria, where it induces bioenergetic defects. We find that the physiological regulation of mitochondrial localization is either inefficient or absent in SOD1 pathogenic mutants. We propose misfolding and aggregation of these mutants that trap them inside mitochondria.
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Metal-deficient aggregates and diminished copper found in cells expressing SOD1 mutations that cause ALS
Bourassa, Megan W.
Brown, Hilda H.
Borchelt, David R.
Vogt, Stefan
Miller, Lisa M.
Frontiers in Aging Neuroscience
Disruptions in metal ion homeostasis have been described in association with amyotrophic lateral sclerosis (ALS) for a number of years but the precise mechanism of involvement is poorly understood. Metal ions are especially important to familial ALS cases caused by mutations in the metalloenzyme copper-zinc superoxide dismutase (SOD1). To investigate the role of metals in aggregation of mutant SOD1, we have examined the localization of metal ions in a cell culture model of overexpression. Chinese hamster ovary cells (CHO-K1) were transfected to overexpress SOD1 fused to yellow fluorescent protein (YFP) to readily identify the transfected cells and the intracellular aggregates that develop in the cells expressing mutant or wild-type (WT) SOD1. The concentration and distribution of iron, copper, and zinc were determined for four SOD1 mutants (A4V, G37R, H80R, and D125H) as well as a WT SOD1 using X-ray fluorescence microscopy (XFM). Results demonstrated that the SOD1 aggregates were metal-deficient within the cells, which is consistent with recent in vitro studies. In addition, all SOD1 mutants showed significantly decreased copper content compared to the WT SOD1 cells, regardless of the mutant's ability to bind copper. These results suggest that SOD1 overexpression creates an unmet demand on the cell for copper. This is particularly true for the SOD1 mutants where copper delivery may also be impaired. Hence, the SOD1 mutants are less stable than WT SOD1 and if copper is limited, aggregate formation of the metal-deficient, mutant SOD1 protein occurs.
amyotrophic lateral sclerosis; superoxide dismutase; X-ray fluorescence microscopy; synchrotron
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Posttranslational Modifications in Cu,Zn-Superoxide Dismutase and Mutations Associated with Amyotrophic Lateral Sclerosis
Antioxidants & redox signaling
Activation of the enzyme Cu,Zn-superoxide dismutase (SOD1) involves several posttranslational modifications including copper and zinc binding, as well as formation of the intramolecular disulfide bond. The copper chaperone for SOD1, CCS, is responsible for intracellular copper loading in SOD1 under most physiological conditions. Recent in vitro and in vivo assays reveal that CCS not only delivers copper to SOD1 under stringent copper limitation, but it also facilitates the stepwise conversion of the disulfide-reduced immature SOD1 to the active disulfide-containing enzyme. The two new functions attributed to CCS, (i.e., O2-dependent sulfhydryl oxidase- and disulfide isomerase-like activities) indicate that this protein has attributes of the larger class of molecular chaperones. The CCS-dependent activation of SOD1 is dependent upon oxygen availability, suggesting that the cell only loads copper and activates this enzyme when O2-based oxidative stress is present. Thiol/disulfide status as well as metallation state of SOD1 significantly affects its structure and protein aggregation, which are relevant in pathologies of a neurodegenerative disease, amyotrophic lateral sclerosis (ALS). The authors review here a mechanism for posttranslational activation of SOD1 and discuss models for ALS in which the most immature forms of the SOD1 polypeptide exhibits propensity to form toxic aggregates.
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Monoaminergic control of spinal locomotor networks in SOD1G93A newborn mice
Milan, Léa
Barrière, Grégory
De Deurwaerdère, Philippe
Cazalets, Jean-René
Bertrand, Sandrine S.
Frontiers in Neural Circuits
Mutations in the gene that encodes Cu/Zn-superoxide dismutase (SOD1) are the cause of approximately 20% of familial forms of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. While ALS symptoms appear in adulthood, spinal motoneurons exhibit functional alterations as early as the embryonic and postnatal stages in the murine model of ALS, the SOD1 mice. Monoaminergic – i.e., dopaminergic (DA), serotoninergic (5-HT), and noradrenergic (NA) – pathways powerfully control spinal networks and contribute significantly to their embryonic and postnatal maturation. Alterations in monoaminergic neuromodulation during development could therefore lead to impairments in the motoneuronal physiology. In this study, we sought to determine whether the monoaminergic spinal systems are modified in the early stages of development in SOD1 mice. Using a post-mortem analysis by high performance liquid chromatography (HPLC), monoaminergic neuromodulators and their metabolites were quantified in the lumbar spinal cord of SOD1 and wild-type (WT) mice aged one postnatal day (P1) and P10. This analysis underscores an increased content of DA in the SOD1 lumbar spinal cord compared to that of WT mice but failed to reveal any modification of the other monoaminergic contents. In a next step, we compared the efficiency of the monoaminergic compounds in triggering and modulating fictive locomotion in WT and SOD1 mice. This study was performed in P1–P3 SOD1 mice and age-matched control littermates using extracellular recordings from the lumbar ventral roots in the in vitro isolated spinal cord preparation. This analysis revealed that the spinal networks of SOD1G93A mice could generate normal locomotor activity in the presence of NMA-5-HT. Interestingly, we also observed that SOD1 spinal networks have an increased sensitivity to NA compared to WT spinal circuits but exhibited similar DA responses.
serotonin; dopamine; noradrenaline; spinal cord; ALS; fictive locomotion; HPLC; extracellular recordings
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Destabilizing Protein Polymorphisms in the Genetic Background Direct Phenotypic Expression of Mutant SOD1 Toxicity
Gidalevitz, Tali
Krupinski, Thomas
Garcia, Susana
Morimoto, Richard I.
PLoS Genetics
Genetic background exerts a strong modulatory effect on the toxicity of aggregation-prone proteins in conformational diseases. In addition to influencing the misfolding and aggregation behavior of the mutant proteins, polymorphisms in putative modifier genes may affect the molecular processes leading to the disease phenotype. Mutations in SOD1 in a subset of familial amyotrophic lateral sclerosis (ALS) cases confer dominant but clinically variable toxicity, thought to be mediated by misfolding and aggregation of mutant SOD1 protein. While the mechanism of toxicity remains unknown, both the nature of the SOD1 mutation and the genetic background in which it is expressed appear important. To address this, we established a Caenorhabditis elegans model to systematically examine the aggregation behavior and genetic interactions of mutant forms of SOD1. Expression of three structurally distinct SOD1 mutants in C. elegans muscle cells resulted in the appearance of heterogeneous populations of aggregates and was associated with only mild cellular dysfunction. However, introduction of destabilizing temperature-sensitive mutations into the genetic background strongly enhanced the toxicity of SOD1 mutants, resulting in exposure of several deleterious phenotypes at permissive conditions in a manner dependent on the specific SOD1 mutation. The nature of the observed phenotype was dependent on the temperature-sensitive mutation present, while its penetrance reflected the specific combination of temperature-sensitive and SOD1 mutations. Thus, the specific toxic phenotypes of conformational disease may not be simply due to misfolding/aggregation toxicity of the causative mutant proteins, but may be defined by their genetic interactions with cellular pathways harboring mildly destabilizing missense alleles.
Author Summary
Correct folding and stability are essential for protein function. In cells, a network of molecular chaperones and degradative enzymes facilitate folding, prevent aggregation and ensure degradation of the misfolded proteins, thus maintaining protein homeostasis. In many diseases, including Amyotrophic Lateral Sclerosis (ALS), expression of a single mutant protein that misfolds and aggregates causes cellular toxicity that is strongly dependent on the genetic background. To address the influence of genetic background on the toxicity of aggregation-prone proteins, we established a C. elegans model of misfolding and aggregation of several distinct ALS-related mutants of superoxide dismutase 1 (SOD1). In one wild type genetic background (N2), these proteins exhibited only mild cellular toxicity despite strong, mutant-specific aggregation phenotypes. However, when SOD1 mutants were expressed in the background of mildly destabilized protein polymorphisms, their toxicity was enhanced and a number of distinct phenotypes were exposed. These synthetic phenotypes reflected the loss-of-function of the destabilized polymorphic proteins. Furthermore, the degree to which each of these phenotypes was exposed depended on the nature of the SOD1 mutation. These data suggest that the presence of mildly destabilizing polymorphisms in the genetic background may modulate and direct the specific toxic phenotypes in protein aggregation diseases.
Related Articles
Molecular Mechanisms and Clinical Implications of Reversible Protein S-Glutathionylation
Mieyal, John J.
Gallogly, Molly M.
Qanungo, Suparna
Sabens, Elizabeth A.
Shelton, Melissa D.
Antioxidants & Redox Signaling
Sulfhydryl chemistry plays a vital role in normal biology and in defense of cells against oxidants, free radicals, and electrophiles. Modification of critical cysteine residues is an important mechanism of signal transduction, and perturbation of thiol–disulfide homeostasis is an important consequence of many diseases. A prevalent form of cysteine modification is reversible formation of protein mixed disulfides (protein–SSG) with glutathione (GSH). The abundance of GSH in cells and the ready conversion of sulfenic acids and S-nitroso derivatives to S-glutathione mixed disulfides suggests that reversible S-glutathionylation may be a common feature of redox signal transduction and regulation of the activities of redox sensitive thiol-proteins. The glutaredoxin enzyme has served as a focal point and important tool for evolution of this regulatory mechanism, because it is a specific and efficient catalyst of protein–SSG deglutathionylation. However, mechanisms of control of intracellular Grx activity in response to various stimuli are not well understood, and delineation of specific mechanisms and enzyme(s) involved in formation of protein–SSG intermediates requires further attention. A large number of proteins have been identified as potentially regulated by reversible S-glutathionylation, but only a few studies have documented glutathionylation-dependent changes in activity of specific proteins in a physiological context. Oxidative stress is a hallmark of many diseases which may interrupt or divert normal redox signaling and perturb protein–thiol homeostasis. Examples involving changes in S-glutathionylation of specific proteins are discussed in the context of diabetes, cardiovascular and lung diseases, cancer, and neurodegenerative diseases. Antioxid. Redox Signal, 10, 1941–1988.
Potential Mechanisms of Protein–SSG Formation
Thiol-disulfide exchange
Sulfenic acid intermediates
Sulfenylamide intermediates
Thiyl radical intermediates
Thiosulfinate intermediates
S-Nitrosylated intermediates
Potential Catalysis of Protein Glutathionylation
Flavoprotein sulfhydryl oxidease (QSOX)
Other potential mechanisms of catalysis/control of protein S-glutathionylation
Proteomics of Discovery of Potential Protein–SSG Intermediates
Deglutathionylation (Reversal) of Protein–SSG: Properties of the Glutaredoxin Enzymes
Glutaredoxin Mechanism of Action
Modualtion of Grx Expression
Diabetes and Implications of Changes in S-Glutathionylation Status
Mechanism of hyperglycemic damage and ROS
Insulin-glucose dynamics and diabetes complications
Glucose metabolism: aldose reductase–SSG (Fig. 3, step 1a)
K+ channels: Grx regulated (Fig. 3, step 2a)
ATP-sensitive potassium channels
Voltage-gated potassium channels
Ca2+ channels: SERCA-SSG and Grx-reversible RyR-SSG (Fig. 3, step 3a)
Insulin exocytosis: Grx regulated (Fig. 3 step 6a)
Insulin receptor: Grx-reversible PTP1B-SSG (Fig. 3, step 6b)
Signal transduction [Fig. 3, Ras-SSG (step 7b), MEKK-SSG (step 8b), c-Jun-SSG (step 9b), Akt-SSG (step 10b), IKK-SSG (step 11b), NF-κB(p50)-SSG (steps 5a and 12b), and PKC-SSG (step 4a)]
Summary and discussion: Grx as a therapeutic target in diabetic complications
Cardiovascular Diseases and Alterations in Protein-S-Glutathionylation Status
Myocardial infarction
Protein kinase C (PKC)
Protein kinase A (PKA)
Nuclear factor κB (NF-κB)
Nonspecific oxidative injury
Cardiac hypertrophy
Implications of Protein S-Glutathionylation in Lung Disease
Tobacco exposure
Hyperoxic injury
Fibrotic and granulomatous diseases
Chronic obstructuve pulmonary disease (COPD)
Implications of Reversible Protein S-Glutathionylation in Cancer
Thiol oxidation and cancer
S-Glutathionylation and signal transduction in cancer
S-Glutathionylation and modulation of kinase/phosphatase signaling pathways
Protein kinase C (PKC)
I3 kinase and Akt
Protein tryosine phosphatase
c-Jun N-terminal kinase (JKN)
S-Glutathionylation and modulation of the proteasome pathway
S-Glutathionylation and modulation of transcription factors (c-Jun, NF-κB, p53, AP-1)
AP-1, c-Jun
Modulation of S-glutathionylation as a chemotherapeutic strategy for cancer
Implications of Protein S-Glutathionylation in Neurodegenerative Diseases
Oxidative stress and neurodegeneration
Sources of reactive oxygen and nitrogen species in brain
Alzheimer's disease
Parkinson's disease
Huntington's disease
Amyotrophic lateral sclerosis
Freidreich's ataxia
Glutaredoxin and neurodegeneration
Proteins associated with neurodegeneration that are redox regulated through S-glutathionylation
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH)
Mitochondrial NADP+-dependent isocitrate dehydrogenase (IDPm)
Tyrosine hydroxylase
Cytosolic calcium regulators
Proteasome degradation pathway
α-Ketoglutarate dehydrogenase
Summary and Conclusions
Frontier Areas of Investigation
Related Articles
Disulfide-Reduced ALS Variants of Cu, Zn Superoxide Dismutase Exhibit Increased Populations of Unfolded Species
Kayatekin, Can
Zitzewitz, Jill A.
Matthews, C. Robert
Journal of molecular biology
Cu, Zn superoxide dismutase (SOD1) is a dimeric metal binding enzyme responsible for the dismutation of toxic superoxide to hydrogen peroxide and oxygen in cells. Mutations at dozens of sites in SOD1 induce amyotrophic lateral sclerosis (ALS), a fatal gain-of-function neurodegenerative disease whose molecular basis is unknown. To obtain insights into effects of the mutations on the folded and unfolded populations of immature monomeric forms whose aggregation or self-association may be responsible for ALS, the thermodynamic and kinetic folding properties of a set of disulfide-reduced and disulfide-oxidized Zn-free and Zn-bound stable monomeric SOD1 variants were compared to the wild-type (WT) protein. The most striking effect of the mutations on the monomer stability was observed for the disulfide-reduced metal-free variants. Whereas the WT and S134N monomers are >95% folded at neutral pH and 37 °C, A4V, L38V, G93A, and L106V ranged from 50% to ∼90% unfolded. The reduction of the disulfide-bond was also found to reduce the apparent Zn affinity of the WT monomer by 750-fold, into the nanomolar range where it may be unable to compete for free Zn in the cell. With the exception of the S134N metal-binding variant, the Zn affinity of disulfide-oxidized SOD1 monomers showed little sensitivity to amino acid replacements. These results suggest a model for SOD1 aggregation where the constant synthesis of ALS-variants of SOD1 on ribosomes provides a pool of species in which the increased population of the unfolded state may favor aggregation over productive folding to the stable native dimeric state.
Disulfide bond; Zn binding; protein folding; aggregation
Related Articles
Structural Characterization of Zinc-deficient Human Superoxide Dismutase and Implications for ALS
Roberts, Blaine R.
Tainer, John A.
Getzoff, Elizabeth D.
Malencik, Dean A.
Anderson, Sonia R.
Bomben, Valerie C.
Meyers, Kathrin R.
Karplus, P. Andrew
Beckman, Joseph S.
Journal of molecular biology
Over 130 mutations to copper, zinc superoxide dismutase (SOD) are implicated in the selective death of motor neurons found in 25% of familial amyotrophic lateral sclerosis (ALS) patients. Despite their widespread distribution, ALS mutations appear positioned to cause structural and misfolding defects. Such defects decrease SOD's affinity for zinc, and loss of zinc from SOD is sufficient to induce apoptosis in motor neurons in vitro. To examine the importance of the zinc site in the structure and pathogenesis of human SOD, we determined the 2.0 Å resolution crystal structure of a designed zinc-deficient human SOD, in which two zinc-binding ligands have been mutated to hydrogen-bonding serine residues. This structure revealed a 9° twist of the subunits, which opens the SOD dimer interface and represents the largest inter-subunit rotational shift observed for a human SOD variant. Furthermore, the electrostatic loop and zinc-binding sub-loop were partly disordered, the catalytically important Arg143 was rotated away from the active site, and the normally rigid intramolecular Cys57-Cys146 disulfide bridge assumed two conformations. Together, these changes allow small molecules greater access to the catalytic copper, consistent with the observed increased redox activity of zinc-deficient SOD. Moreover, the dimer interface is weakened and the Cys57-Cys146 disulfide is more labile, as demonstrated by the increased aggregation of zinc-deficient SOD in the presence of a thiol reductant. However, equimolar Cu,Zn SOD rapidly forms heterodimers with zinc-deficient SOD (t1/2 ≈ 15 min) and prevents aggregation. The stabilization of zinc-deficient SOD as a heterodimer with Cu,Zn SOD may thus be a contributing factor to the dominant inheritance of ALS mutations. These results have general implications for the importance of framework stability on normal metalloenzyme function and specific implications for the role of zinc ion in the fatal neuropathology associated with SOD mutations.
Amyotrophic lateral sclerosis; Cu; Zn superoxide dismutase; Lou Gehrig's disease; zinc-deficient superoxide dismutase; crystal structure
Related Articles
Muscle cells and motoneurons differentially remove mutant SOD1 causing familial amyotrophic lateral sclerosis
Onesto, Elisa
Rusmini, Paola
Crippa, Valeria
Ferri, Nicola
Zito, Arianna
Galbiati, Mariarita
Poletti, Angelo
Journal of Neurochemistry
Amyotrophic lateral sclerosis (ALS) is a fatal motoneuronal disease which occurs in sporadic or familial forms, clinically indistinguishable. About 15% of familial ALS cases are linked to mutations of the superoxide dismutase 1 (SOD1) gene that may induce misfolding in the coded protein, exerting neurotoxicity to motoneurons. However, other cell types might be target of SOD1 toxicity, because muscle-restricted expression of mutant SOD1 correlates with muscle atrophy and motoneurons death. We analysed the molecular behaviour of mutant SOD1 in motoneuronal NSC34 and muscle C2C12 cells. We found that misfolded mutant SOD1 clearance is much more efficient in muscle C2C12 than in motoneuronal NSC34 cells. Mutant SOD1 forms aggregates and impairs the proteasome only in motoneuronal NSC34 cells. Interestingly, NSC34 cells expressing mutant SOD1 are more sensitive to a superoxide-induced oxidative stress. Moreover, in muscle C2C12 cells mutant SOD1 remains soluble even when proteasome is inhibited with MG132. The higher mutant SOD1 clearance in muscle cells correlates with a more efficient proteasome activity, combined with a robust autophagy activation. Therefore, muscle cells seem to better manage misfolded SOD1 species, not because of an intrinsic property of the mutant protein, but in function of the cell environment, indicating also that the SOD1 toxicity at muscle level may not directly depend on its aggregation rate.
amyotrophic lateral sclerosis; autophagy; motoneuron diseases; muscle cells; proteasome; SOD1
Related Articles
Single chain variable fragment antibodies block aggregation and toxicity induced by familial ALS-linked mutant forms of SOD1
Ghadge, Ghanashyam D.
Pavlovic, John
Koduvayur, Sujatha P.
Kay, Brian K.
Roos, Raymond P.
Neurobiology of disease
Approximately 10% of amyotrophic lateral sclerosis (ALS) cases are familial (known as FALS) with an autosomal dominant inheritance pattern, and ~25% of FALS cases are caused by mutations in Cu/Zn superoxide dismutase (SOD1). There is convincing evidence that mutant SOD1 (mtSOD1) kills motor neurons (MNs) because of a gain-of-function toxicity, most likely related to aggregation of mtSOD1. A number of recent reports have suggested that antibodies can be used to treat mtSOD1-induced FALS. To follow up on the use of antibodies as potential therapeutics, we generated single chain fragments of variable region antibodies (scFvs) against SOD1, and then expressed them as 'intrabodies' within a motor neuron cell line. In the present study, we describe isolation of human scFvs that interfere with mtSOD1 in vitro aggregation and toxicity. These scFvs may have therapeutic potential in sporadic ALS, as well as FALS, given that sporadic ALS may also involve abnormalities in the SOD1 protein or activity.
familial amyotrophic lateral sclerosis; mutant superoxide dismutase type 1; amyotrophic lateral sclerosis; ALS; single chain fragments of variable region antibodies; scFvs; motor neuron disease
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The Secret to Creating a Cozy and Charming Outdoor Space
The front yard is the area where people first 'meet' you ~ I
I'm a wife and mom to three boys who likes to mix old school homemaking with modern technology. I consider myself a wanna-be jack of all trades.
I love gardening, cleaning, crafting and DIYing ~ just about anything.

subset: commoncrawl


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Unless otherwise indicated, the material below has not been prepared by Van Eck Associates Corporation or HardAssetsInvestor.com.
Neither assumes any liability for any content on a third-party website or material prepared by a third party.
- Alternative Energy
Morning Call: Gold Dips On Greece Deal Hopes; Oil Edges Up; NatGas Down On Cooler Temps
Morning Call: Gold Holds Weekly Gains Ahead Of Greece Emergency Meeting; Oil & NatGas Sag
Week In Review: Gold Sags Ahead Of Greece Deadline; Grains Skyrocket; Palladium Slammed
Morning Call: Gold Surges To $1,200 As Dollar Hits 1 Month Low; NatGas Down; Oil Up
Morning Call: Gold Down For 5th Straight Session As US Personal Spending Jumps; NatGas Outperforms
***Top stories from the last 15 days
- Written by Julian Murdoch |
- March 23, 2010
How To Play Rising Uranium Demand
- Details
Uranium Vs. Nuclear Energy Companies
Just as with oil and gas companies, uranium's performance can vary quite a bit from the performance of the companies involved in its production, although there remains a high correlation between fuel and producer:
Over the past year, the two widely tracked indexes of nuclear stocks, the S&P Global Nuclear Energy Index and the WNA Nuclear Energy Index, have consistently beaten the implied price of uranium (from MF Global).
It's really no surprise that the price of uranium is up only 8.4 percent year-over-year, as few new reactors came online during the economic downturn. But what's interesting is that the companies involved in the nuclear industry survived the slowdown so well: The WNA Nuclear Energy Index is up 45.8 percent, while the S&P Global Nuclear Energy Index is up 35.8 percent.
Playing Nuclear Power
So how can investors approach the nuclear power space?
For starters, you could always go with narrowly focused fuel providers such as Uranium One Inc. (TSE: UUU) to gain your nuclear exposure (pardon the pun). But with their volatility and high leverage in the space, pure-play miners aren't for everyone.
Another method is to avoid miners themselves and focus instead on companies involved in fuel processing. GBI Research recently predicted that the market for nuclear fuel processing would double in worth from $20.8 billion in 2009 to $42 billion by 2020, driven mainly by growth in the Asia-Pacific region.
But perhaps the easiest method is to forgo the stock picking and check out one of the three ETFs tracking the market: the iShares S&P Global Nuclear Energy Index Fund (NYSE Arca: NUCL), the PowerShares Global Nuclear Energy Portfolio ETF (NYSE Arca: PKN) and the Market Vectors Nuclear Energy ETF (NYSE Arca: NLR):
Of the three funds, PKN is the clear winner, rising 37.0 percent over the past year (not too surprising, considering its benchmark is the aforementioned outperformer, the WNA Nuclear Energy Index). NUCL, which tracks the S&P Global Nuclear Energy Index, and PKN, which follows the DAXglobal Nuclear Energy Index, follow each other more closely; the two funds have risen a more modest 26.6 percent and 24.5 percent, respectively.
NLR, however, is far and away the largest of the three funds, at $177 million in assets; despite its success, PKN has only managed to attract $30 million since its 2008 launch. NUCL is the smallest, at just $16.8 million assets.
Of course, it's important to point out that the S&P 500 has beaten all of the nuclear indexes over the past year (up 51 percent). So if you're looking for something to beat the broader stock market, keep looking.
FYI: On Thursday, the International Energy Agency (IEA) and the OECD Nuclear Energy Agency (NEA) will hold a press conference for their latest joint report called "Projected Costs of Generating electricity - 2010 Edition." This report will present data on the cost of generating electricity using a wide range of input fuels, from traditional coal and gas to nuclear, as well as alternative green technologies such as wind, solar and biomass. The last paper on this subject by IEA was published in 2005, so it should hold some interesting updated info on the viability of nuclear.
If you liked this article, then check out:
- Thorium: Next-Gen Nuclear Fuel
- Constantine Karayannopoulos: The Road Ahead For Rare Earths
- Uranium's Tough Outlook
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- Morning Call: Gold Losing Streak At 6 Days Ahead Of Last Minute Greece Talks; NatGas Backtracks; Grains Surge
- Market Wrap: Gold Falls On Econ Data; NatGas & Grains Outperform


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And too few insights gleaned from them
2012 Multimedia Roundup
December 14, 2012|
The science images and videos that captured our attention in 2012
December 14, 2012|
The science images and videos that captured our attention in 2012
December 12, 2012|
Fat cells behave differently in obese individuals, causing inflammation and insulin resitance.
December 12, 2012|
Fungi in 100 million year-old seafloor sediments could possess novel antibiotics.
December 10, 2012|
The healing powers of maggots may lie in their secreted proteins, which restrain the human immune response.
December 6, 2012|
Insulin, long recognized as a primary regulator of blood glucose, is now also understood to play key roles in neuroplasticity, neuromodulation, and neurotrophism.
December 6, 2012|
Adipose tissue plays an immune role in individuals of normal wieght.
December 5, 2012|
Two species of songbirds pack their nests with scavenged cigarette butts that repel irksome parasites.
December 4, 2012|
Elderly people are worse at spotting untrustworthy faces, possibly due to decreased activity in the brain region associated with such perceptions.
December 1, 2012|
Meet some of the people featured in the December 2012 issue of The Scientist.
December 1, 2012|
Certain immune cells keep adipose tissue in check by helping to define normal and abnormal physiological states.


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Its when you do a girl on her back. When shes about to squirt, you stand up and squat over her and let her squirt you in the butt.
"She just bideted me in the butt"
by Ed M Rod January 31, 2008
After tagging a girl in the ass you piss on her arsehole to clean it up.
So I'm balls deep in the hookers ass and I gave her quick bidet to clean it up.
by Fuk Yoo December 13, 2003
<hygene> The process of washing one's ass in a public bathroom. May require an accomplice to hold the door closed and better if documented on video.
"grab the door, I gotta go bidet"
by D@nny April 19, 2007


text:
301 results for beauty+products
Design / Architecture
Design/Architecture Briefing
Culture / Film
K + D: Videos
Business / Manufacturing
The jellyfish problem – a beautiful solution
Monday 15 March
The words "jellyfish" and "lipstick" may not often feature in the same sentence.
The words "jellyfish" and "lipstick" may not often feature in the same sentence. But Japan's entrepreneurial scientists are in a race to produce the first range of jellyfish-related cosmetics, make-up and anti-ageing food…
Design / Interior design
The Salone series: Back to business at the Fiera
Thursday 14 April
For all the fun of the galleries, warehouse exhibitions and street parties elsewhere in Milan, the vast Rho fairground on the city's outskirts is where the real business of Salone takes place.
For all the fun of the galleries, warehouse exhibitions and street parties elsewhere in Milan, the vast Rho fairground on the city's outskirts is where the real business of Salone takes place. Across 24 halls, each one the…
Culture / Technology
Show time
Thursday 11 September
Launching new technology is about putting on an impressive and dazzling show. But don't get too blinded by the lights, says Monocle's Tom Hall.
Those shamanic soothsayers of technology – in an array of co-ordinated pastel-coloured shirts – have spoken again. This time they've made a watch. And on Tuesday, time stood still as they told us all about it.
Business / Society
A lot of bottle
Tuesday 3 February
A recent study suggests that enjoying a good drop of wine is soon set to be more popular in the UK than in its famed wine-loving neighbour, France. Monocle's Tom Edwards says cheers to that.
Recent data from leading wine exhibition and forum Vinexpo forecasts that the UK will overtake France to become the second-largest wine market in the world by value in 2018. The UK spend, according to the figures, will be…
Affairs / Publishing
Physical media isn't going away
Monday 10 September
We recently welcomed the young British author Niven Govinden into our studios at Midori House.
We recently welcomed the young British author Niven Govinden into our studios at Midori House. He talked to us about some of the benefits of digital publishing but he also discussed his love of the book as a physical object…
Affairs / Travel
Trading places
Thursday 16 April
Istanbul's vibrant and chaotic culture, retail and street-life will be hard to say goodbye to but will have left a lasting definition of 'quality of life' says Monocle's outgoing bureau chief Sophie Grove.
I am folding my tents here in Istanbul. Tomorrow morning after nearly two years as Monocle's bureau chief I'll return home to London via Monocle's Quality of Life Conference in Lisbon.
Design / Architecture
Design/Architecture Briefing
Design / Interior design
The Salone series: Seven year itch at Established & Sons
Monday 11 April
There's a great deal of expectation riding on this year's Salone del Mobile in Milan. As well as being the 50th anniversary of the fair, it's also the 150th anniversary of Italian unification.
Salone 2011 is being heralded by many as the first post-recession edition. There's also a feeling running through the industry that now is the chance to move on from the follies and failings of recent fairs – the over-sized…
Business / Luxury
Technically gifted
Friday 5 December
The talk of the recent New York Times International Luxury Conference in Miami was all about how to combine trinkets with technology. But Monocle's Nelly Gocheva isn't so sure the two industries belong together.
Luxury and craftsmanship have always gone together like champagne and canapés. But recently, a less likely third course – technology – has been making its way into the big product launches found at events such as The New…
Edits / Industry
The crème de la crème
Culture / Film
Moving pictures
Wednesday 4 February
Japanese masters of animation Studio Ghibli are undergoing a subtle transformation as co-founder Hayao Miyazaki hands over the reins. But Monocle's Robert Bound says its treasured characters are in safe hands.
At Studio Ghibli, that most wonderfully imaginative of animation production houses, there has been a changing of the guard. Hayao Miyazaki, at the helm of so many of the Japanese studio's classics – Spirited Away, Howl's…
Affairs / Health
Sino-Indian rapprochement… through the medium of yoga
Monday 27 June
If further proof were needed of China's boom, it was on display last week in a Guangzhou hall, sporting garish shades of locally branded lycra.
If further proof were needed of China's boom, it was on display last week in a Guangzhou hall, sporting garish shades of locally branded lycra.
Edits / Entertainment
Weekend Agenda
Saturday 15 December
This weekend check out David LaChapelle's retrospective in Stockholm, visit architect Thom Mayne's Perot Museum of Nature and Science in Dallas, enjoy Walter Salles favourite road films in New York and celebrate a great…
This weekend check out David LaChapelle's retrospective at the Fotografiska museum in Stockholm, visit Dallas's newest museum, and celebrate a great year in music for the XX.
Affairs / Soft Power
Why everyone loves a Brazilian
Wednesday 10 April
Monocle 24's resident Brazilian goes travelling in Europe and finds out what people really think of his country.
I am an inveterate optimist about my home country but I tend to be slightly offended if someone criticises it. Throughout my travels I've come to learn that I'm not alone in this complex feeling about Brazil. Many Brazil…
Design / Industry
Thinking outside the box
Monday 3 June
Rather than selling a product and enticing users in, a lot of packaging today is overcomplicated, user-unfriendly and plain unnecessary.
It's a story that's been repeated so many times it's become a cliché. Parents buy child expensive and/or exciting present for Christmas. Child then proceeds to spend more time playing with the large cardboard box that the…
Design / Architecture
Beauty from the inside out
Thursday 3 July
The Design Museum has handed an undeniably striking building its design of the year award – but, says Tom Morris, it should be what's underneath that counts.
Earlier this week, Zaha Hadid's Heydar Aliyev Center in Baku, Azerbaijan, won the design of the year award, given out each year by the Design Museum in London. It was chosen from a shortlist of over 70 nominees, which…
Edits / Entertainment
Weekend Agenda
Saturday 21 April
This weekend's highlights include dance in Hong Kong, a new collaborative exhibition in LA's Culver City and the release of Santigold's new album.
This weekend's highlights include dance in Hong Kong, a new collaborative exhibition in LA's Culver City and the release of Santigold's new album.


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Stock Vector Illustration:
Arabic Islamic calligraphy of Eid Mubarak on grungy abstract background. EPS 10. Vector illustration.
- Image ID: 101063122
- Copyright: Allies Interactive
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Talladega College, located in Talladega, Alabama, is a private, liberal arts college. It holds the distinction as Alabama's oldest private historically black college. As of 2009 the school received full SACS accreditation.…
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5 Things You Learn About Yourself By Working From Home
Most employees would do anything and everything to be granted the opportunity to work from home, even occasionally. The idea of working in pajamas, no...>
Obama Will Expand Overtime to 40 Percent of Salaried American Workers
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Drew Barrymore spent a majority of her teens battling drug and alcohol addiction. And while she's far from being rehab material, she says still a drinker--but does it in moderation.
Drew claims to have found "balance" in her life so she doesn't feel the need to cut booze out of her life entirely.
In a new Parade magazine interview, Drew says, "I'm not (sober) and I don't claim to be - quite the opposite. I've tried to find the balance. I hope it's balanced."
Drew, who grew up in the spotlight, had her first alcoholic drink at the age of nine, began smoking marijuana at 10 and tried cocaine for the first time at 12. She entered rehab for the first time at 13.
Luckily she got her life back on track when she was in her 20's and has become one of the most successful actresses in the biz.
She may not be sober, but clearly, she's learned that life is all about moderation.


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Description: Cady street in Watertown, Wisconsin.
Date: 1950-05-14
Description: Portrait of Francis Garrity, Jefferson County district attorney and president of the Wisconsin District Attorneys Association. He is being urged to run for...
Date: 1902
Description: Portrait of Mrs. Henry Scholz draped in a black cloth, surrounded by floral arrangements for her funeral. The portrait and arrangements are propped up agai...
Date: 1915 ca.
Description: A railroad bridge on the Chicago, Milwaukee, & St. Paul Railway.
Date: 1950-08-22
Description: View of Main Street showing stores, people and vehicles.
Description: Eight floral arrangements for the funeral of Mrs. Henry Scholz arranged on a small staircase covered in a black backdrop. A small portrait of her is place...
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Description: Palmyra Spring, called variously "Blue Spring" and "Aurelian Spring."
Date: 1868 ca.
Description: Studio portrait of the Kravig/Kravik sons, one seated and one standing.
Date: 1953-07-18
Description: Unidentified golfer at Koshkonong Mounds Country Club in Fort Atkinson, site of the 31st annual East-Central Wisconsin Golf Association tournament.
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Date: 1903 ca.
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By Andrea Hangst, On Sunday night, in front of a national television audience, the Pittsburgh Steelers play their second preseason game of the year, hosting the Indianapolis Colts and their rookie quarterback, Andrew Luck. Though...Read More
I don't know about you but I'm always pulling for the underdog. I had a guy named Ramon Foster on... Read More ↔
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Search results
Prestigious Pete
Mod note (Andy): throwback Thursday, this originally went up on 9/22/12. I would like to extend a warm welcome to myself, Prestigious Pete. I am a jealousy amalgam, created from combining all the conceited, self-assured finance super douches into one man ...
Prestigious Pete - Feb 19 2015 - 11:00am - 234 comments
Do I have a chance at Top 10 B-School's?
Stats: 3.5 GPA from Top Public School (Think Berkeley) JP Morgan Private Banking Analyst GMAT 730 Do I have a chance at top 10 business schools? Thanks! Chance Me HBS ...
Lovely-bird1 - May 22 2015 - 12:38am - 20 comments
Thoughts on HBS (Starting Out)
Mod Note (Andy): Each day we'll be posting the top WSO forum posts of 2014. This one was originally posted on 10/1/2014 and ranks #23 for the year by total silver banana count. You can see all our top ranked content here. I'm just about a month ...
baburator - Jun 30 2015 - 12:26pm - 89 comments
"Why Stanford Is Beating HBS Among Dual Admits"
This is consistent with what I've been hearing from inside sources for a number of years. That dual admits long used to split about 50/50 but that recently (for a few years now) it is heavily in Stanford's favor to the tune of 3:1. Quote: " ...
ibleedexcel - Feb 3 2015 - 10:05pm - 33 comments
Cross-Admit Battles
Quote: Who in their right mind would get accepted to Harvard Business School and turn it down? Turns out the answer is: someone who also got into Stanford. Interesting article about those fortunate enough to get accepted into multiple top MBA programs, ...
Wreak Peace - Feb 1 2015 - 4:00am - 35 comments
2nd Thoughts About HBS
I was fortunate to be accepted into HBS round 1, and am now weighing my options. I was also accepted to Booth(w/ 70K), Kellogg(w/ 90K), Tuck (full tuition), Yale SOM (full tuition), and McCombs (full tuition). Although HBS was my top choice, I am having a ...
HTownOrBust - Jan 3 2015 - 11:00am - 108 comments
HBS and GSB decisions- R1 Class of 2017
Anyone with good news today? Harvard Stanford HBS Stanford GSB ...
petergibbons - Dec 12 2014 - 1:41am - 33 comments
You won't believe who HBS dinged this year
Straight from poets&quants. I mean we've always known that HBS is selective, but the profiles of the people who got dinged this year is just insane. HBS admissions used to be kind of straightforward, but as the best students from the top schools ...
mbavsmfin - Feb 20 2015 - 4:13pm - 31 comments
What are the 'unicorn jobs' that M7 MBA students sometimes hold out for?
I read recently that HBS and GSB sometimes have lower placement rates upon graduation because the students hold out for 'unicorn jobs'. What would be some specific examples of jobs like this? Is it referring to positions such as C-suite at start ...
bashfulpanda - Mar 25 2015 - 2:30pm - 10 comments
Student complains about the HBS party scene
A HBS student indulges in self-righteous whining about the "excessive" partying scene at HBS and the lack of an intellectual culture. Is this guy freaking kidding? First, he doesn't have the courage to reveal his name since he knows his ...
mbavsmfin - Nov 26 2014 - 11:37pm - 43 comments


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Residents and business owners seeking federal disaster aid stemming from damage caused by Hurricane Sandy have an extra month to apply for assistance.
The Federal Emergency Management Agency extended its filing deadline for assistance to Jan. 28 from the previous deadline of Dec. 31.
Residents and business owners with private insurance are encouraged to apply, FEMA officials said, as benefits may cover costs not picked up by insurance.
Before applying for FEMA aid, applicants must register with the agency by calling 1 (800) 621-FEMA or visiting the disaster assistance website.
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Kid Impresses Girls With Smooth Foul Ball Switcheroo at Texas Rangers Game [VIDEO]
Not since Squints risked his life just to get one magic moment with Wendy Peffercorn has a kid pulled off such a smooth move with a lady.
Not since Squints risked his life just to get one magic moment with Wendy Peffercorn has a kid pulled off such a smooth move with a lady.
Most people won't ever be lucky enough to catch a foul ball at a baseball game, but one sure-handed fan put the rest of us souvenir-seekers to shame.
The photos are insane!
If you weren't already excited for opening day of the 2014 Major League Baseball Season, watch this and you will be!
Whether you agree or disagree with our rankings, count along with us some of the most memorable moments in World Series history.
Try to watch it just once because you won't believe what you just saw.
After the Bearcats win a game they like to have some fun during the post game press conference.
I think she honestly was not watching the game she just saw a ball and was like "Oh I am supposed to get that."
It is getting down to the last month of baseball for the playoff push. Teams want full crowds for home field advantage. Unfortunately some teams have afternoon games on Thursdays and it is hard to have a full crowd now that school has started.
I found myself getting a little choked up last night watching Cal Ripken's speech for his statue unveiling at Camden Yards. Cal Ripken is my favorite sports player of all time (Emmitt Smith is my second in case anyone is wondering)
About a year ago, an umpire named Jim Joyce managed to ruin a perfect game for the Detroit Tigers.
On the final out of the game, called a runner safe when he was clearly out. Jim has not been living down this blown call and he came out after the game that night with tears in his eyes feeling like he ruined a game of a lifetime for the pitcher Armando Gallaraga that night.
I know I don't live in Baltimore anymore but the Orioles are my team. I also know I am in Rangers territory right now but I don't care.


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FURNITURE: Antique Hammond organ; great piece of furniture in working condition with music books. Extras.More info Email a friend
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Giorgi Khimshiashvili
From Wikipedia, the free encyclopedia
Colonel Giorgi Khimshiashvili was a member of Khimshiashvili Dynasty and nephew of Sherip Khimshiashvili.
The Committee for the Independence of Georgia (Georgian: საქართველოს დამოუკიდებლობის კომიტეტი, Sak'art'velos damoukideblobis komiteti) or the Parity Committee (პარიტეტული კომიტეტი, Paritetuli komiteti) was an underground anti-Soviet organization active in the Georgian Soviet Socialist Republic in the early 1920s. It is commonly known as "Damkom" (short for "damoukideblobis komiteti," the Committee for Independence). The Committee was responsible for the preparation and guidance of the abortive August Uprising of 1924.
Military Center[edit]
|This article provides insufficient context for those unfamiliar with the subject. (January 2011)
- Head of Committee: Kote Abkhazi
- Colonel (Prince) Giorgi Khimshiashvili
- Alexander Andronikashvili
- Varden Tsulukidze
- Rostom Muskhelishvili
- Mikheil Zandukeli
- Simon Bagrationi-Mukhraneli
- Parnaoz Karalashvili
- Iason Kereselidze
- Ivane Kutateladze
- Simon Chiabrishvili
- Alexandre Machavariani
- Elizbar Gulisashvili
- Levan Klimiashvili
- Dimitri Chrdileli
External links[edit]
See also[edit]
- Committee for Independence of Georgia
- Batumi Mosque
- List of Georgian princely families
- History of Batumi
- Kote Abkhazi


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Western Digital Intro My Book World Edition II NAS
Western Digital Announces My Book World Edition II NAS
Western Digital, the world's leader in external storage solutions, today introduced its newly redesigned My Book World Edition II dual-drive network storage system in capacities of up to 4 TB. With the double protection of two Mirrored (RAID 1) drives and continuous backup software, the My Book World Edition II network storage system provides an extra-safe place for users to back up and store the data and digital media from all the computers on their network in one central location. Available now at select retailers and the WD online store, the new dual-drive systems join the recently introduced (Feb. 2009) My Book World Edition and are compatible with PC and Mac computers.
According to a July 2008 report by research firm Parks Associates, the number of households worldwide with data networks will grow from around 170 million in 2008 to 240 million by year-end 2012. The firm also reports that the average broadband household will see its digital media storage needs grow to nearly 900 GB by year-end 2012. In addition, consumers indicate that the most important feature for a network-attached storage (NAS) device is the amount of available storage. With its massive 4 TB capacity, the My Book World Edition II network storage system will serve this rapidly growing need for home data storage.
The My Book World Edition II network storage system uses RAID 1 (Mirrored) technology to automatically and continuously maintain a second copy of user's data. If one drive in the two-drive system ever fails, the system continues to run and the data is safe. In addition, the new My Book World Edition II network hard drive includes software that simplifies the task of setting up automatic and continuous data backup for all the PCs in the home. The My Book World Edition II storage systems ship in Mirrored mode and use half the capacity for file redundancy.
With its media server capabilities and fast transfer speeds, this high-capacity system makes it simple to build a centralized digital media library that everyone can easily share. Music, photos and videos can be streamed directly from the My Book World Edition II storage system to any PC, Mac or connected DLNA media player (such as TVs, Microsoft Xbox 360 and Sony PlayStation 3 game consoles or wireless digital pictures frames) using the integrated UPnP (Universal Plug and Play) media server and iTunes Music server software. Users can also securely access their files from anywhere in the world through the Internet using the free MioNet remote access service included with every My Book World Edition II storage system.
"Families have more and more digital media like movies, photos and music to store, share and protect. Having two drives inside the My Book World Edition II network storage system, instantaneously and automatically duplicating data, offers consumers the peace of mind of double safe, real-time protection of their valuable content," said Dale Pistilli, vice president of marketing for WD's branded products group. "Families can relax knowing their valuable media is backed up while enjoying the ability to stream their content to a plethora of different devices from PCs and Macs to PS3s, Xbox 360s and the latest connected TVs."
Price and Availability
The new My Book World Edition II network storage systems are available now in 2 TB and 4 TB capacities at select retailers and WD's online store (shopwd.com). MSRP for the My Book World Edition II dual-drive storage system with 4 TB is $699.99 USD and 2 TB is $399.99 USD.
The new My Book World Edition II network drive features:
- Automatic, continuous backup for all the computers on your network;
- Dual-drive system that mirrors valuable data for extra safe data protection;
- Centralized storage and sharing for all of your family's digital content;
- Streaming to any connected PC, Mac or DLNA certified game console or media player;
- Easy remote access to all your data from anywhere, anytime;
- Works seamlessly on networks with both Windows and Mac computers;
- Ability to centralize and stream music collection to a Mac or Windows PC using iTunes software;
- USB 2.0 port to turn any USB drive into an instant network drive or extra capacity for the My Book World Edition II;
- Cooler, quieter, eco-friendly design with drives using WD GreenPower Technology which run cooler, quieter and consume up to 33 percent less power;
- User serviceable;
- Capacity gauge to see at a glance how much space is available on your drive;
- High-speed data transfer with Gigabit Ethernet; and,
- 3-year limited warranty.
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Oxygen Premieres New Docu-Series MY SHOPPING ADDICTION Tonight, 10/15
Oxygen Media will premiere its authentic and thought-provoking new docu-series, MY SHOPPING ADDICTION, tonight, October 15 at 11pm ET/PT. The series captures an intimate look into the lives of young people facing a crisis brought on by a dangerous addiction to spending. Each hour-long episode follows two different shopping addicts who will be forced to face their problem head on with the help of a clinical psychologist who will guide them on the road to recovery.
The premiere episode follows Heather, whose shopping addiction began 10 years ago after she inherited a large sum of money from her grandmother. Heather has spent hundreds of thousands of dollars shopping and if she's not careful, she could run out of money in five years. The episode also captures Roshanda, who borrows money from friends and family in order to pack her home full of products from the 99 cent store. With the help of psychologists, Dr. Ramani and Dr. David Tolin, these women will be forced to face their issues and get to the bottom of their addiction once and for all.
"My Shopping Addiction" is produced by Screaming Flea Productions with Matt Chan, Jodi Flynn and Jeff Kuntz serving as Executive Producers.
Oxygen Media is a multiplatform entertainment brand that delivers relevant and engaging content to young women who like to "live out loud." Oxygen is rewriting the rulebook for women's media by changing how the world sees entertainment from a young woman's point of view. Through a vast array of unconventional and original content, including "The Glee Project," "Best Ink," and "Bad Girls Club," the growing cable network is the premier destination to find unique and groundbreaking unscripted programming. "The Glee Project" is a winner of a 2012 Gracie Award which honors programming created for women, by women and about women for "Outstanding Reality Show." A social media trendsetter, Oxygen is a leading force in engaging modern young women, wherever they are, with popular, award winning features online including www.OxygenLive.com, the real time social viewing party that is also available as an app for the iPhone and iPad. Oxygen is available in 80 million homes, and can be found online and on mobile devices at www.oxygen.com. Follow us on Twitter at www.twitter.com/OxygenPR. Oxygen Media is a service of NBCUniversal.
About Author
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God of War Collection - God of War Gameplay Movie
Kratos earns the trophy, "it's a huge one."
by Aaron Sampson on
Did you enjoy this video?Sign In to Upvote
Oh man I remember this. I thought it was pretty weird to go into a Hydra's mouth just to take a key from the Captain.
The Hydra impalement. Probably the most shocking scene I've ever experienced in video games.
"I didn't come back for you!" "NOOOO~!" Hah, brings back memories. :-)
lol i keep remembering this guy that Kratos didn't save. He will be back in the sequel. I really hope he is a mini-boss in a GOW III having is revenge from Kratos for killing him twice...lolol
I never played these games on the PS2 and now that I have a PS3 seems like the perfect time to get both :) Woo hoo!
Poor Hydra T_T LOL I want it already! >_


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Southaven, MS Extraordinary Women Conference 2015
- Religion & Spirituality
- 4560 Venture Dr Southaven, MS 38671, US
That's The Spirit: A Wine-Tasting Benefit for the Hospitality Hub
The Hospitality HUB
Thursday, April 25, 2013 from 5:30 PM to 7:30 PM (CDT)
Join The Hospitality HUB and friends Thursday, April 25, 5:30-7:30 p.m., at the Jack Robinson Gallery downtown (44 Huling) for food, music, and a wine-tasting presented by the experts from Kimbrough Wines.
Learn more about the HUB's mission and how we are connecting with individuals in need to help make positive changes in their lives. The Hospitality HUB, a 501(c)(3) non-profit organization, is a resource center for homeless persons in Downtown Memphis. Our mission is to connect individuals with the resources they need to begin their journey out of homelessness.
Contact the organizers (firstname.lastname@example.com) with any questions about the event.
Find the event on Facebook too -- https://www.facebook.com/#!/events/366257423490584/
In order to purchase these tickets in installments, you'll need an Eventbrite account. Log in or sign up for a free account to continue.


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_5L20353 copy
The Olympus E-PL5 review.
I have to say, you have a real knack for street photography. It helps that you're in Malaysia, I think. There people actually interact on the street. Calgary Canada would be considered unnaturally quiet for someone used to South East Asia. These days those who are out and about on foot seem to be occupied with their phones and uninterested by the people around them. As a society we are connected mostly though electronic means, it seems.
I've spent some time in Indonesia, and I imagine Malaysia is very similar. Jakarta is constantly moving, browsing, buying, selling, eating, cooking, talking, shouting, laughing and a million other things in a chaotic fashion everyday. Parts of Hong Kong were similar, but Jakarta was more chaotic. I actually felt like Hong Kong was peaceful after a month in Indonesia. At the time I was still too self concious to try street photography. I really wanted to, but I held back.
The next time I'm in Asia, I will try to overcome my anxiety. You are on to something with group street shooting workshops. With a group of fellow photographers, the whole experience becomes less daunting. Maybe I'll see if some of my local photography buddies want to try a bit of street photography. It could be fun!
I like this photo. Everyone around your subject is engaged in something, and she is lost to her private thoughts. She is lovely in her modest and attractive attire. This is a memorable photo.
Thanks Dillan. Reporting on life is my personal work - I love photojournalism, but I simply can't make a living from it.
Actually, if the group is too big, you become too obvious and intimidating. (Also, a target for thieves and pickpockets.) I do no more than 6 per workshop. Perhaps you could join one of my sessions if the timing works!
You never know. I will be back in the area again one day.
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