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Parkinson's disease (PD) is a progressive, neurodegenerative condition that has increasingly been linked with mitochondrial dysfunction and inhibition of the electron transport chain. This inhibition leads to the generation of reactive oxygen species and depletion of cellular energy levels, which can consequently cause cellular damage and death mediated by oxidative stress and excitotoxicity. A number of genes that have been shown to have links with inherited forms of PD encode mitochondrial proteins or proteins implicated in mitochondrial dysfunction, supporting the central involvement of mitochondria in PD. This involvement is corroborated by reports that environmental toxins that inhibit the mitochondrial respiratory chain have been shown to be associated with PD. This paper aims to illustrate the considerable body of evidence linking mitochondrial dysfunction with neuronal cell death in the substantia nigra pars compacta (SNpc) of PD patients and to highlight the important need for further research in this area.
Parkinson's disease (PD) is a progressive, neurodegenerative condition characterised by deterioration of the dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc) [1, 2]. The exact mechanism by which SNpc cell death in PD occurs is poorly understood, but several lines of evidence implicate mitochondrial dysfunction as a possible primary cause due to the central role of mitochondria in energy production, along with oxidative stress, ubiquitin system impairment and excitotoxicity, all of which may be interlinked [3–5]. Mitochondrial dysfunction with complex I deficiency and impaired electron transfer in the substantia nigra in PD have been reported [3, 4]. Moreover, mutations in several mitochondrial proteins have been associated with familial forms of PD [5–7], as well as the presence of deletions in mitochondrial DNA identified in aging controls and PD substantia nigra [8]. This paper discusses the possible mechanisms relating mitochondrial impairment to cell death in PD.
Mitochondria are found in virtually all eukaryotic cells and function to generate cellular energy in the form of adenosine triphosphate (ATP) by oxidative phosphorylation and are thought to be derived evolutionarily from the fusion of prokaryotic and eukaryotic organisms [9, 10]. They are also involved in regulation of cell death via apoptosis, calcium homeostasis, haem biosynthesis, and the formation and export of iron-sulphur (Fe-S) clusters, that have been reviewed in detail elsewhere [11–13], and function in the control of cell division and growth.
Structurally, mitochondria are composed of a double lipid bilayer with a phospholipid outer membrane and an inner membrane which surrounds the intracompartmental matrix (Figure 1). The space between the two membranes is important in, and contains the major units of, oxidative phosphorylation [9]. Mitochondria are unique amongst cellular organelles in that they have their own, circular, double-stranded, DNA (mtDNA) which is inherited almost exclusively down the maternal line and codes for 37 mitochondrial genes, 13 of which translate to proteins involved in oxidative phosphorylation [10, 14]. The remaining genes encode transfer (22) and ribosomal (2) RNA allowing the mitochondria to generate their own proteins [10]. Although mitochondria have the ability to produce proteins, the vast majority of proteins that function within the mitochondria, including those involved in DNA transcription, translation, and repair, are encoded by nuclear DNA and are transported into the mitochondria from the cytosol [10]. As mtDNA is located in the mitochondria in close proximity to the electron transport chain it is more susceptible to damage from free radicals generated during oxidative phosphorylation [15]. This damage may lead to mutations that have been linked with PD [13, 16] and will be discussed later.
The electron transport chain is composed of five complexes including an ATP-synthase located in the inner mitochondrial membrane. The function of the chain is to generate cellular energy in the form of ATP. This is accomplished by the transport of electrons between complexes causing proton (H+ ions) movement from the matrix to the intermembrane space generating a proton concentration gradient used by ATP-synthase to produce ATP (Figure 2).
Whilst electron transport is a highly efficient process in mitochondria [17], during the process of oxidative phosphorylation, electrons can leak from the chain, specifically from CI [18] and CIII [19], and react with oxygen to form superoxide (·O2−). Under normal physiological conditions this ·O2− production occurs at relatively low levels, with approximately 1% of the mitochondrial electron flow forming ·O2− [20], and is removed by mitochondrial antioxidants such as manganese superoxide dismutase (MnSOD) which converts ·O2− to H2O2 which is then converted to H2O by glutathione (GSH). Given the high activity of the respiratory chain under even normal circumstances, the small leakage of electrons in mitochondria is still a major source of ·O2− within many eukaryotic cells [21]. It is thought that dysfunction in this process leading to an increase in ·O2− production could be one of the main drivers of cell death in the SNpc in PD [22, 23].
As neurons have a considerable energy need and are also highly equipped with mitochondria they are extremely sensitive to mitochondrial dysfunction. Several neurological disorders are associated with mitochondrial dysfunction and demonstrate enhanced production of free-radical species [16, 24]. The first line of evidence for a link between mitochondrial dysfunction and PD came from the description of Complex I (CI) deficiency in the postmortem SNpc of PD patients and has been suggested to be one of the fundamental causes of PD [4, 25]. This CI deficiency was also seen in the frontal cortex in PD [26], and in peripheral tissues such as platelets [27] and skeletal muscle [28] suggesting that there is a global reduction in mitochondrial CI activity in PD. This defect may be due to oxidative damage to CI and misassembly, since this is a feature of isolated PD brain mitochondria [3]. Incidental Lewy body disease (ILBD) which is considered by some to be a preclinical indicator of PD, has been shown to have an intermediate level of CI activity in the SNpc between healthy and PD patients [22] which further supports the theory of mitochondrial dysfunction. This inhibition of CI can lead to the degeneration of affected neurons by a number of mechanisms such as increased oxidative stress and excitotoxicity [23] which will be described below.
A decrease in the function of Complex III has also been reported in the lymphocytes and platelets of PD patients [27, 29]. A link between impairment of mitochondrial CIII assembly, an increase in free radical-production, and PD has also been identified [30]. This increase in free radical release may be due to the increased leakage of electrons from CIII (as explained below). Alternatively the inhibition of CIII assembly causes a severe reduction in the levels of functional CI in mitochondria [31] which could lead to an increase in free-radical production through CI deficiency. In addition, the CI and II electron acceptor ubiquinone has also shown to be reduced in the mitochondria of PD patients [32] and loss of DA neurons in aged mice treated with the Parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was attenuated by ubiquinone [33], providing more evidence for the involvement of mitochondrial dysfunction in PD.
Complex I or III inhibition causes an increase in the release of electrons from the transport chain into the mitochondrial matrix which then react with oxygen to form reactive oxygen species (ROS) such as ·O2−, hydroxyl radicals (·OH) and nitric oxide (NO·). This increase in the normal electron leakage occurs by blockage of electron movement along the chain to the next acceptor molecule. An example of this is the finding that blockade of the electron accepting capability of the ubiquinone binding site of Complex I leads to an increased production of electron radicals in rat skeletal muscle mitochondria [34]. The ROS formed can act as signalling molecules by causing lipid peroxidation or promote excitotoxicity, all leading to modification of proteins and eventual cell death. The main areas in which ROS cause damage in the cell include oxidative DNA damage, lipid peroxidation, and protein oxidation and nitration. The ·OH radical has been shown to react with the double bond of DNA bases leading to damaging DNA lesions [35] and an impairment of normal cellular function. There is evidence linking this mechanism of cell death to PD in the finding of increased levels of 8-hydroxyguanosine, produced by oxidative damage to DNA, in the SNpc of PD patients [36, 37]. Peroxynitrite (formation discussed below) also increases DNA single-strand breaks [38] which cause activation of poly (ADP-ribose) polymerase (PARP) which in turn disrupts the mitochondrial respiratory chain and ATP production via depletion of intracellular NAD+ stores, so exacerbating the original mitochondrial dysfunction [39].
Amongst the most common mechanisms of protein damage caused by ROS is oxidation to form carbonyl groups on proteins and nitration by peroxynitrite. Reactive ROS can readily oxidise amino acids on various cellular proteins to form carbonyl groups, which can disrupt the physiological function of the affected protein and lead to cytotoxic protein aggregates, activation of cell death pathways, and impairment of neuroprotective pathways [40]. An increase in these carbonyl groups has been reported in the SNpc and in the basal ganglia and prefrontal cortex of PD patients [41] suggesting a role in the disease which is widespread throughout the brain. Peroxynitrite formed by the reaction of ROS with nitric oxide and nitrates tyrosine residues on proteins [42], damaging them and leading to cell death. These nitrotyrosine residues are present in Lewy bodies in PD neurons signifying the possibility that protein nitration may contribute to the pathology of PD [43]. Peroxynitrite [44] and other ROS [45] can also oxidise sulphydryl groups on glutathione, leading to depletion of antioxidant defences, and other thiol containing cofactors disrupting various cellular processes and structures. The final link between PD and mitochondrially generated ROS through protein damage comes with the discovery of nitrated and oxidatively damaged misfolded proteins that have strong genetic links with the disease such as α-synuclein, DJ-1, Parkin and PINK1 [46–51] suggesting that these disease-associated proteins are major targets of free-radical damage in sporadic forms of PD.
Lipid peroxidation is another of the main types of cellular damage caused by ROS occurring when ROS react with hydrogen in the lipid leading to the formation of a lipid radical. This radical can then form a further lipid radical via an intermediary by reacting with a hydrogen atom leading to a chain reaction and breakdown of the lipid. In the cell membrane, phospholipids are particularly susceptible to this damage due to their polyunsaturated nature, leading to damage to cell and organelle membranes and severe cellular dysfunction. There have been strong links between increased lipid peroxidation and PD with increased levels shown to be present and cause cell death in the nigral cells of PD patients [36, 37], suggesting a role for it in the mechanisms of neuronal death.
All of these mechanisms of oxidative stress can feed back to the mitochondria via a series of signalling pathways and cause further exacerbation and mitochondrial dysfunction by damaging mtDNA. In this way, ROS-driven mitochondrial dysfunction acts to propagate itself via a feedback loop leading to accelerated cellular damage and death and contributing to PD.
This oxidative damage could be exacerbated in PD by the discovery of reduced antioxidant defences in patients with the disease. The main line of evidence regards reduced GSH, which has been found to be selectively decreased in the SNpc of patients with PD [52], leading to a decline in cellular capability to inactivate H2O2 and peroxynitrite. This is thought to be an early event in PD pathology since lower levels of reduced GSH in incidental LB disease are of the same magnitude as those found in PD [53]. There have not been consistent reports of changes in the levels of most of the other major antioxidant systems; however, cases of an increase in mitochondrially located MnSOD in PD patients have been described [54, 55]. This supports a link between mitochondrial dysfunction generated superoxide and PD since MnSOD is the main ·O2− scavenging system in mitochondria.
Since there are elevated markers of oxidative damage in the brains of PD patients, including lipid peroxidation [36] protein damage [41, 43], and oxidative DNA damage [36, 37], oxidative stress is an established event in PD. This evidence combined with the PD-like effects of known Complex I inhibitors such as MPTP [56] and rotenone [57] and an increase in the activity of neutralising superoxide dismutase (SOD), particularly the mitochondrially localised MnSOD, being found in neurodegenerative disease patients [58] points to a strong link between ROS, possibly caused by mitochondrial dysfunction and PD.
Iron may also be involved in the production and propagation of oxidative stress in the mitochondria of DA neurons in PD. Iron is intrinsically linked with mitochondrial function and particularly the brain, since iron is an integral component of all respiratory chain complexes and the uptake of iron by the brain is linked with mitochondrial energy demands [59]. Increased iron levels in the brain have long been associated with PD [60–63] although this increase may be an effect of the normal pathological clearance of iron that occurs during cell death that occurs in PD. More recently, a specific increase in intracellular iron has been observed in SNpc neurones in PD patients [46] suggesting an increase in the cellular accumulation of iron in the disease. Cellular iron normally enters into neurones via the transferrin receptor system and evidence suggests that there is a reduction of this system in PD [64, 65] although this may relate more to the loss of SNpc neurones in PD [47]. This iron may also be taken up into the mitochondria in the SNpc via the transferrin receptor 2 and increased levels of ferritin have been reported in the mitochondria of SNpc DA neurons of PD patients and rats treated with rotenone [48]. ROS with a low oxidative potential, like ·O2− generated via dysfunction of oxidative phosphorylation, can increase the release of reactive ferrous iron from this ferritin so leading to the creation of more ROS via the Fenton reaction [49] and increasing oxidative stress and cell damage. The evidence that abnormal iron homeostasis is present in PD is clear; however, the role of iron in PD as either an initiator or a consequence of pathology remains to be elucidated.
The cellular damage caused by electron transfer chain inhibition may contribute to neuronal excitotoxicity exacerbating neurotoxicity in PD. Several mechanisms for excitotoxicity in neurodegenerative conditions have been proposed [50, 51]. Excitotoxicity occurs when depolarisation of the neuronal cell membrane from −90mV to between −60 and −30mV leads to a decrease in the magnesium blockade of N-methyl-D-aspartate (NMDA) receptors. This, in turn, leads to NMDA receptor activation by latent levels of glutamate and causes an intracellular Ca2+ accumulation. This increase in Ca2+ is then thought to cause neurotoxicity by two main mechanisms. Firstly, Ca2+ causes an increase in intracellular NO via activation of nitric oxide synthase (NOS). The excess of NO in the cell can react with ·O2− to form peroxynitrite [66], which can cause cell death by mechanisms similar to those caused by ROS and mentioned above. Besides the peroxynitrite, NO itself can lead to cell damage via nitrosylation of various proteins.
A second mechanism driven by intracellular Ca2+ increase causes toxicity in DA neurons by acting on mitochondria themselves. The Ca2+ influx is extensively accumulated in the mitochondria and leads to effects on mitochondrial membrane potential and ATP synthesis as well as generation of ROS [67] contributing to the oxidative damage discussed above. This also all feeds back causing further malfunction of the cell's Ca2+ homeostasis and additional cellular damage.
Mitochondrial dysfunction can lead to excitotoxicity and cause a reduction in cellular ATP levels, an increase in cellular Ca2+, or a combination of both [23]. Inhibition of Complex I, and consequently ATP generation, lowers intracellular ATP, leading to partial neuronal depolarisation, due to a reduction in the activity of Na+/K+-ATPase. The Na+/K+-ATPase acts to maintain the resting membrane potential of the cell. A reduction in ATP levels will compromise this function leading to depolarisation and, therefore, excitotoxicity via over activation of NMDA receptors. Intracellular Ca2+ can be increased by two methods, that is, either directly by mitochondrial impairment or by over activity of NMDA receptors. Mitochondria can take up Ca2+ from the cytosol via an uniporter transporter or a transient "rapid mode", both of which rely on the mitochondrial membrane potential, reviewed by [68]. The ROS generated by mitochondrial respiratory chain dysfunction can damage the mitochondrial membranes and disrupt this mechanism of Ca2+ uptake and storage, thereby raising intracellular Ca2+ levels and exacerbating the excitotoxicity. Sherer et al. showed that this could be a viable mechanism for cell death in PD by inhibiting Complex I in SH-SY5Y cells and showing a disruption in the mitochondrial membrane potential leading to an increased susceptibility to calcium overload [69]. It has also been shown that there is an increase in glutamate activity linked to excitotoxicity in the SNpc of mice treated with the Parkinsonian toxin MPTP, which may be linked to apoptosis and autophagy [70]. This evidence suggests that mitochondrially derived or driven excitotoxicity could be a major contributory factor in PD.
Further to being integrally involved in mitochondrially generated excitotoxic cell death in PD, Ca2+ has been implicated in other mechanisms of cell death in the disease that may involve compromise of the role of mitochondria as one of the major intracellular Ca2+ stores. Sheehan et al. reported that mitochondria from PD patients showed lower sequestration of calcium than age-matched controls suggesting a role for Ca2+ homeostasis dysfunction in PD [71]. This would lead to higher intracellular Ca2+ levels, which has been shown to amplify free-radical production [72] and, therefore, an increase in ROS. An increase in cytosolic Ca2+ due to mitochondrial dysfunction has also been suggested to activate calpains and so raise levels of toxic α-synuclein proposing another link with PD [73], a discovery supported by the protective effect of calpain inhibition in an MPTP model of PD [74].
A role for Ca2+ and mitochondria has also been suggested in a mechanism of increased susceptibility to cell death specific to SNpc DA neurons and, therefore, relevant for PD. SNpc DA neurons are atypical in the brain in that they have self-generated pacemaker activity [75] mediated by Cav1.3, a rare L-type Ca2+ channel [60]. This activity means that that the Cav1.3 channels are open for a higher proportion of time than Ca2+ channels in other neurons leading to an increased ATP usage in the cells to pump Ca2+ across the membrane up steep concentration gradients [61]. This elevated need for ATP would lead to an increase in the activity of the electron transport chain, therefore increasing ROS production so exacerbating any mitochondrial dysfunction and making SNpc DA neurons more prone to cell death.
Dopamine metabolism generated oxidative stress has long been implicated in PD [40]. However, more recently, it has been suggested that ROS or reactive quinones produced by oxidation of dopamine, either spontaneously or by monoamine oxidase (MAO), may have a inhibitory effect on the proteins of the mitochondrial respiration chain [76–78]. Khan et al. showed that dopamine inhibits Complexes I and IV, most probably through the actions of the dopamine-generated quinones rather than through ROS [62]. MAO-A is bound to the outer mitochondrial membrane and can oxidise dopamine to form the metabolite 3,4 dihydroxyphenylacetic acid (DOPAC), which can itself, or through oxidation to quinones, locally inhibit Complexes I and IV [78, 79] although a contradictory report suggests dopamine but not DOPAC inhibits the electron transport chain [63]. A recent study has shown that dopamine itself, rather than any oxidation products can directly inhibit Complex I [80] however, more work would need to be carried out to confirm this as there is no corroborating evidence.
These links between mitochondrial dysfunction and dopamine are supported by reports that the PD neurotoxins and Complex I inhibitors MPTP and rotenone increase dopamine oxidation and turnover [64, 65] although whether this is indirectly due to the ROS generating effects of the toxins is not clear. This hypothesis could offer an explanation as to why DA are more susceptible than other neurons to toxin or mutation mediated mitochondrial dysfunction PD, as they are already under a higher level of oxidative stress due to dopamine metabolism generated electron transfer chain inhibition.
Studies of families who suffer from inherited forms of PD have identified a number of genes encoding mitochondrial proteins or proteins implicated in mitochondrial dysfunction [46–51, 81].
The α-synuclein gene encodes a small protein of the synuclein family that is localised to nerve terminals although the physiological function of α-synuclein is unclear. The first link between α-synuclein and PD came with the discovery of mutations in the α-synuclein gene in PD patients [48, 49, 51]. This evidence was supported by the discovery that aggregates of α-synuclein are the major components of LBs [82]. Although there are many theories on the mechanism by which mutant α-synuclein causes neuronal cell death in PD, it has recently been reported that there is an association between α-synuclein and mitochondrial dysfunction [83, 84]. Mutant α-synuclein is targeted to and accumulates in the inner mitochondrial membrane (IMM) and can cause Complex I impairment and an increase in ROS, possibly leading to cell death [85].
Parkin, PTEN-induced putative kinase 1 (PINK1), and DJ-1 are genes that code for proteins that are crucially involved in mitochondrial function and resistance to oxidative stress and have been linked with PD. The Parkin gene encodes an E3 ubiquitin ligase involved in the ubiquitin-proteasomal system, marking proteins for degradation by the proteasome. Mutations in Parkin have been linked to autosomal recessive juvenile parkinsonism [86]. Parkin has also been shown to interact with and promote degradation of α-synuclein [87]; therefore, a loss of function Parkin mutation could contribute to the α-synuclein driven cell death mentioned above. It has been suggested that Parkin may also be involved in mitochondrial function and protection from mitochondrially generated ROS. Recent work in Parkin null mice has shown a reduction in subunits of Complex I and IV and reduced function in the mitochondrial respiratory chain along with increased oxidative stress in brain tissue [88]. This is supported by reduced mitochondrial Complex I activity in Parkinsonian patients with Parkin mutations [89] and the increased age-dependent or rotenone (a Complex I inhibitory toxin) induced DA neuronal degeneration and mitochondrial abnormalities in Parkin mutant drosophila [90]. Moreover, a recently generated zebrafish model of Parkin deficiency showed increased sensitivity of Parkin mutants to proteotoxic stress with no manifestation of dopaminergic neuron loss or affected mitochondrial morphology or function [91].
PTEN-induced putative kinase 1 (PINK1) is a serine/threonine kinase located in the inner mitochondrial membrane [92] which functions to protect neurons against various types of cell stress. Mutations in PINK1 are found to be associated with a autosomal recessive form of PD [93]. This pathogenesis may be associated with the loss of kinase activity as PINK1 is known to protect against cell death only if the kinase function is intact [94]. Several independent groups reported a role of PINK1 in mitochondrial integrity by regulating the mitochondrial fission machinery [95], which might have an impact on dopaminergic synapses and contribute to DA neuron degeneration [96–98]. Knockdown of PINK1 has been shown to induce mitochondrial oxidative stress, mitochondrial fragmentation, and autophagy and dysregulate calcium homeostasis in SH-SY5Y cells [76, 98]. Moreover, there is evidence of interplay between PINK1 and Parkin, since Parkin can reduce mitochondrial dysfunction caused by down-regulation of PINK1 [77]. Furthermore, it has been shown recently that both PINK1 and Parkin are involved in removal of damaged mitochondria. The proposed model suggests that in response to mitochondrial depolarization PINK1 accumulates on the mitochondrial membrane and recruits Parkin to promote mitophagy [78, 79]. Therefore, the pathology of mutant PINK1 and/or Parkin in Parkinsonism may arise from the inability to remove dysfunctional mitochondria [99].
The DJ-1 gene encodes a widely expressed protein found in neurons and glia in all central nervous system (CNS) regions [100]. Bonifati first identified an association between DJ-1 and autosomal recessive early-onset PD [46, 101], with numerous further familial mutations in DJ-1 being identified [102]. Reports have shown that DJ-1 is present in mitochondria and protects against oxidative neuronal death [103], DJ-1 deficient mice are more susceptible to MPTP [81] and DJ-1 knockdown in a neuroblastoma cell line renders the cells vulnerable to oxidative stress [104]. Finally, a critical role for DJ-1 in mitochondrial function is shown by a rescue effect of DJ-1 on neuronal cell death caused by PINK1 but not Parkin deletion [83]. Moreover, loss of DJ-1 leads to mitochondrial fragmentation, impaired dynamics, induced oxidative stress, and autophagy [84, 105]. In conclusion, DJ-1 protein has been observed to have pleiotropic functions (see [106] for further review), with an antioxidative role to be the most consistent finding. This may provide a link to PD whereby a loss of function mutation of DJ-1 causes an increase in mitochondrial dysfunction and oxidative damage leading to nigral neuron cell death.
Omi/Htra2 is a mitochondrially located stress protective serine protease which has been linked to neurodegeneration [107, 108] with loss of function mutations being seen in some PD patients [109]. Although certain studies report no clear genetic association between the Omi/HtrA2 gene sequence variations and PD [110], there is evidence of mitochondrial pathology caused by loss of the Omi/HtrA2 protein function [111]. Omi/Htra2 has also been shown to have links with Pink1 in protecting against oxidative stress [112] and interacting in a prosurvival pathway [113, 114]. Therefore, mutations in this mitochondrially targeted gene may predispose cells to damage via oxidative stress generated from mitochondrial dysfunction.
Leucine-rich repeat kinase 2 (LRRK2) is a large (280kDa) protein with kinase activities. Mutations in LRRK2 were first linked with autosomal dominant PD by Zimprich et al. in 2004 [115] and represents the most significant cause of autosomal dominant PD. LRRK2 has been shown to be localised to the outer mitochondrial membrane [116, 117] providing an association between mutations in this protein in PD and mitochondrial function. LRRK2 has also been shown to be linked with mitochondria by the finding that Drosophila with LRRK2 mutations show increased susceptibility to the Complex I inhibitor and mitochondrial toxin rotenone and increased protection against DA neuron degeneration by the mitochondrially protective protein Parkin [118].
A loss of function mutation in the lysosomal type 5 P-type ATPase, ATP13A2, has been shown to have links with a hereditary form of autosomal recessive early onset PD with dementia [119]. Gitler et al. reported that functional ATP13A2 can protect against α-synuclein overexpression induced toxicity and that knockdown of ATP13A2, enhances α-synuclein misfolding in neuronal models of PD [120]. With α-synuclein shown to be toxic to Complex I [85], loss of function mutations in ATP13A2, and therefore impaired α-synuclein clearance, could be a link to mitochondrial dysfunction in PD.
PLA2G6 is a calcium-independent phospholipase A2 linked to infantile neuroaxonal dystrophy [121] and neurodegeneration with brain iron accumulation [101] that has recently been implicated in PD [122, 123]. PLA2G6 have been shown to locate to [124], and have a protective role against oxidative stress in [125], pancreatic β-cell mitochondria providing a possible link between loss of function mutations in this protein and mitochondrial dysfunction in PD. How, for example, PLA2G6 regulates iron, a major mitochondrial cofactor is not clear.
Besides nuclear DNA mutations, there have been links between mtDNA mutations and PD. Bender et al. [8] and Kraytsberg et al. [126] showed high levels of mtDNA deletions in neurons in the SNpc of PD sufferers. It has been hypothesised that these pathologic DNA rearrangements are not primary drivers of the disease but may be caused by oxidative stress generated during mitochondrial dysfunction, and this may further exacerbate cellular damage [127]. The mitochondrial transcriptional factor A (TFAM) regulates transcription of mtDNA and was linked to PD by the finding that TFAM knockout mice (MitoPark mice) had reduced mtDNA expression and respiratory chain deficiency in SNpc DA neurons, which lead to a Parkinsonian phenotype [128]. Although some studies showed that TFAM mutations do not significantly increase the risk of PD [129, 130], an investigation into the influence of TFAM variants on PD depending on mtDNA haplogroup found certain variants increased the chances of developing PD [131], suggesting a possible role for mtDNA, in some instances, and respiratory chain dysfunction in PD. Mitochondrial DNA polymerase γ 1 (POLG1) is an enzyme involved in the synthesis and regulation of mtDNA and has been shown to have links with PD, including reduced activity of mitochondrial respiratory chain complexes [132, 133]. The involvement of mutations of this protein in PD suggests a role for dysregulation of mtDNA in mitochondrial dysfunction in the disease. However, whether or not there is a common hereditary role for POLG1 in PD needs further study, since a large-scale study does not support this hypothesis [134] (Table 1).
The histological hallmark of PD is the presence of proteinaceous intraneuronal inclusions termed Lewy bodies (LBs) along with the presence of Lewy neurites (LNs) within neuronal dendrites and axons [135, 136]. Dysfunction of protein metabolism appears to be an important factor in LB formation and the associated neurodegeneration (see for further review [137]), but the significance of these aggregates is still a subject of debate. It is unclear if LBs are pathogenic and mechanistically cause neuronal death [138] or rather the actual function of LBs is neuroprotective by sequestering unwanted, potentially toxic proteins [139–141]. The latter hypothesis is supported clinically by evidence, particularly from autosomal recessive juvenile Parkinson's disease due to Parkin mutation demonstrating that neurodegeneration can occur without the presence of LBs in both apparently sporadic and familial forms of PD [142, 143]. LBs are also reported in cognitively intact individuals over 65 years [144] although this may indicate a prodromal phase of PD prior to clinical presentation.
LBs are typically found in brainstem nuclei and in limbic and neocortical regions in PD and Dementia with Lewy bodies patients (DLB), and additionally, they can be identified in autonomic ganglia in the periphery [145]. There are two morphological types of LBs: brainstem (classic) and cortical Lewy bodies. Classic Lewy bodies are intracytoplasmic eosinophylic inclusions that consist of a dense core surrounded by a pale halo [135]. They are spherical in shape however, a recent report of Kanazawa et al. showed also convoluted LBs and their continuity with LNs, which may suggest evolution from LNs to LBs [146]. Typically, classic LBs are seen in dopaminergic neurons of the substantia nigra and noradrenergic neurons of the locus coeruleus although they were originally described in neurons of the basal forebrain [147]. Cortical LBs are less well-defined structures compared to classic LBs and are without the halo and are predominantly located in limbic areas of the brain, such as the amygdala, entorhinal, insular, and cingulate cortices [145]. Ultrastructurally, both classic and cortical LBs are composed of filamentous, insoluble in SDS, material resembling neurofilament [148]. Electron microscope examination of Lewy bodies demonstrates that the core contains dense granular material, whereas the outer halo is composed of radiating filaments of 7–20nm in diameter [135]. Staging of severity of the pathology of PD and DLB based on the distribution of LBs in the brain have been put forward and are used in the classification of the neuropathology of PD and DLB [149].
Immunohistochemical staining and proteomic analyses have deciphered the complexities of the molecular composition of Lewy bodies and Lewy neurites. α-synuclein [135, 150], ubiquitin [151], and neurofilaments [152] appear to be the major components, with α-synuclein representing the most prominent and consistent marker of LB/LN. More recently triple immunolabeling for these epitopes has revealed a three-layered internal structure of LBs and LNs [146]. These primary molecular constituents are stratified into concentric layers with ubiquitin staining in the center, surrounded by α-synuclein and neurofilament on the periphery, which is consistent with previous observations [153].
A large number of mitochondria have been observed in early-stage LBs [132, 154]. Mitochondrial accumulation has also been found in nigral Lewy and pale bodies (possibly precursors of LBs [133]) and cortical LBs but not in classical LBs in PD and in a mouse 26S proteasomal knockout model [132]. This may suggest direct involvement of mitochondria in early stages of LB formation. According to the aggresome-related model of LB formation, mitochondria may be sequestered to the inclusion bodies in order to facilitate the removal of unwanted proteins (see [140] for extensive review). LBs also contain components of the ubiquitin-proteasome system although unlike functional aggresomes, they fail to degrade abnormal proteins but sequester them to delay neuronal death [153].
Proteomic analysis of mitochondrial protein composition of the substantia nigra of mice treated with MPTP compared to controls showed significant changes in numerous protein expression. Of these proteins, DJ-1 protein levels were significantly increased in the toxin-treated mice and also colocalised with α-synuclein in LB-like inclusions in the remaining nigral neurons. Moreover, DJ-1 was present in the halo of classical LBs in nigral tissue of PD patients [155]. Parkin, PINK1, and Omi/HtrA2 have also been localized to the LBs in cases with PD [156–159]. These proteins have been shown to interact and are also involved in proteasomal functions [160, 161]. Thus, there is a potential link between mitochondrial and proteasomal functions, which may influence α-synuclein biology. The interplay may involve oxidative stress and ATP production [161]; however, a wider impact of these cellular pathologies may be speculated. In addition, α-synuclein has been shown to affect both proteasome and mitochondria [162, 163] therefore, a vicious cycle of mitochondrial and proteasomal dysfunction and α-synuclein aggregation in LBs may exist (see for review [164]).
There is extensive evidence that PD can be caused by neurotoxins, specifically MPTP [165], rotenone [166], paraquat [167], diquat [168], and 1-Trichloromethyl-1,2,3,4-tetrahydro-β-carboline (TaClo) [169, 170]. These compounds are thought to act via various mechanisms, but all by causing mitochondrial dysfunction.
The first toxin that linked mitochondrial Complex I inhibition and PD was MPTP (Figure 3). MPTP is produced as a byproduct of the synthesis of a meperidine analogue with heroin-like properties [171]. Langston et al. described in 1983 that users of meperidine reported striking Parkinsonian symptoms and related this to the presence of MPTP [172]. It has also been shown to closely reproduce the DA degeneration and symptoms of PD in various animal experimental models [173, 174] and has been the most widely used toxin in animal models of PD [175]. MPTP readily crosses the blood brain barrier and is converted to the toxic 1-methyl-4-phenyl-2,3-dihydropyridium ion (MPP+) (Figure 3) by monoamine oxidase B in astrocytes [176] and is then taken up into DA neurons by DAT seen as a reduction in MPTP toxicity in DAT deficient mice [177]. MPP+ is taken up into mitochondria via passive transport due to the large mitochondrial transmembrane gradient [178], where MPP+ inhibits mitochondrial Complex I [179]. This inhibition of Complex I leads to cell death via energy deficits [180], free radical and ROS generation [181], and possibly excitotoxicity [182]. In an MPTP mouse model of PD, α-synuclein is nitrated [183], providing another link between MPTP and PD. However, despite all of the evidence of links between MPTP and PD, there are differences between MPTP models of PD and idiopathic PD with variations in disease progression, an acute onset, and the lack of typical LB formation [184].
Rotenone (Figure 3) is a widely used pesticide and naturally occurring neurotoxin that has been found to have links to PD [166]. Rotenone is highly lipophilic and able to easily cross the blood brain barrier and enter neuronal cells and intracellular organelles, such as mitochondria, without the aid of transporters. Rotenone specifically blocks the ubiquinone binding site of Complex I, preventing the transport of electrons from Complex I to ubiquinone leading to the release of free radicals into the mitochondrial matrix and ROS formation [34]. This evidence that rotenone is a specific inhibitor of Complex I, which in turn leads to ROS production and oxidative stress, can also cause PD-like behavioural symptoms such as akinesia and rigidity in rats [185]. Rotenone administration has been shown to oxidatively modify DJ-1 and cause α-synuclein aggregation, which are effects linked to PD and localised to the DA neurons of the SNpc [186]. Betarbet et al. reported LB-like ubiquitin and α-synuclein containing cytoplasmic inclusions in the brains of rotenone treated rats [57]. This evidence, taken together, presents a strong link between rotenone exposure, mitochondrial dysfunction and PD. However, there is also evidence to suggest rotenone causes damage to neurons in the striatum but not SNpc [187], suggesting that it may not be an entirely accurate model of PD.
Paraquat and diquat are widely used herbicides shown to have links with PD [167, 168]. They are hydrophilic compounds and, therefore, do not readily cross the blood brain barrier and the mechanism by which they enter the brain is unclear although uptake by a neutral amino acid [188] or polyamine [189] transporters has been suggested. Paraquat and diquat have very similar structures to MPTP and MPP+ (Figure 3), suggesting a similar toxic mechanism. However, unlike rotenone and MPP+, paraquat does not inhibit Complex I and is not taken up by DAT, suggesting an alternative mechanism of cell death [190]. A toxic mechanism is described where paraquat is reduced to the paraquat radical by Complex I causing accelerated lipid peroxidation [191, 192]. An alternative theory whereby paraquat is reduced to the paraquat radical by Complex II has also been reported [193]. A final hypothesis for the formation of the paraquat radical is that paraquat is reduced by NADPH-cytochrome p450 reductase [194] or NADPH-cytochrome c reductase [195] in the cell. Whichever complex or enzyme is involved, the paraquat radical can react with oxygen to form ·O2− and cause oxidative stress and mitochondrial dysfunction [192]. This mechanism of cell death may target the DA neurons specifically because of their constant state of oxidative stress leaving them more vulnerable than other cells. It has also been shown that paraquat can lead to an increase in both α-synuclein levels and aggregation [196]. Although the exact mechanism has yet to be elucidated, mitochondrially derived paraquat radical, combined with its effects on α-synuclein, indicate paraquat toxicity as a possible mitochondrially mediated form of PD. Diquat also generates oxygen radicals in rat brain microsomes [197]; a discovery that, when coupled with its similarity in structure and properties with paraquat, suggests a possible similar role for diquat in mitochondrial dysfunction in PD.
β-carbolines such as TaClo have structures similar to that of MPTP (Figure 3) and may be neurotoxic for DA neurons and lead to a PD-like syndrome [169, 170]. Trichloroethylene (TCE) is an industrial solvent used as a degreasing agent and in dry cleaning. TCE is a major environmental contaminant in the air, the water system and soil, and there is, therefore, exposure at low levels to various groups in the population. It has been discovered that TCE can be converted to the β-carboline TaClo in man [198]. TaClo can cross the blood brain barrier following intraperitoneal injection in the rat [199]. Rausch et al. found that micromolar concentrations of TaClo caused up to 50% cell death in primary C57/B16 mouse DA mesencephalon cultures [200]. This is supported by in vivo studies showing a reduction in DA metabolism [201], with a progressive reduction in locomotion and increase in apomorphine-induced rotations in behavioural tests [202–204] and the discovery of a strong inhibition of mitochondrial Complex I in vitro [205]. Taken together, these data present a strong case for the neurotoxic properties of TaClo against DA neurons. Interestingly, further work showed that N-methyl-TaClo is a more potent inhibitor of mitochondrial Complex I and more neurotoxic than TaClo itself [206]. This evidence suggests that TaClo or another related toxin could cause PD with mitochondrial dysfunction playing a central role. The mechanisms of environmental toxin induced neuronal cell death are summarised in Figure 4.
However, this evidence of mitochondrial Complex I inhibition leading to neuronal cell death in PD following toxin exposure requires further investigation following the findings of Choi et al. that midbrain neurons without Complex I activity were still susceptible to cell death following rotenone, MPTP, or paraquat treatment [207]. This suggests that mitochondrial dysfunction could either be occurring parallel to another nonmitochondrial cell death mechanism or as a secondary effect driven by some other cellular stress or damage such as toxic protein accumulation due to ubiquitin-proteasome system impairment [208], inflammation [209], or DNA damage [210].
This paper demonstrates a considerable body of evidence linking mitochondrial dysfunction, specifically respiratory chain inhibition, with neuronal cell death in the SNpc of PD patients. Many of the mutations related with PD have been shown to involve mitochondrial proteins or proteins linked to mitochondrial dysfunction. Furthermore, neurotoxins that can cause a PD-like syndrome are strong inhibitors of the mitochondrial electron transfer chain (see Figure 5). However, the exact mechanisms of cell death in sporadic PD are still unclear and it has not been conclusively proved whether mitochondrial dysfunction is a primary driver of cellular stress and damage in the disease or a secondary consequence of another insult.
Further investigation should be carried out into how genes implicated in PD, such as UCH-L1 [211], as well as those mentioned in this paper, may affect mitochondrial function and how mutations in these genes could lead to mitochondrial defects. Although slightly out of the scope of this paper, it would also be of interest to explore how reported crosstalk between mitochondria and endoplasmic reticulum [212] may be involved in cell death control, the processing of proteins and Ca2+ homeostasis, and how any deficits in these systems could impact on PD pathology.
The authors gratefully acknowledges support from the UK Health Protection Agency. M. Kurzawa is supported by a PhD studentship from the UK Lewy Body Society.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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The internet is a crazy place and if you aren't careful, you can definetly get lost in cyber space. It takes time to find websites that you can rely on to give you the best travel advice. However, when it comes to finding a great hostel/guesthouse online, I know I can rely on….
Choosing The Right Hostel/Guesthouse Part 2
Backpackers Guide to Central Europe
Budget backpacking isn't just about South East Asia or South America. Those looking a little closer to home can get their culture fix and pit their wits in some challenging environments, while also enjoying some of the most stunning scenery anywhere in the world. Central Europe has been a favourite amongst backpackers for a number of years due to good value accommodation, cheap cost of living and some very diverse cultures.
Yoga Lovers In North America Get Your Passport To Prana
While I was living in Rishikesh, India for a couple of months, I met a yoga teacher from Canada who spends half of the year teaching in Canada and the other half teaching in India and Thailand. She introduced me to both acro yoga and Passport to Prana. Now some of you may know what acro yoga is but what is this Passport to Prana?
Ibiza Outside The Clubbing Season
Ibiza may be the most well known party island in the world, but there is so much more to offer from the Golden Isle than hedonistic all night parties. Making a trip to the Balearic Island outside the clubbing season is an experience not to be missed. It'll be much cheaper too.
What's Happening With Society?
The other morning I took a bus to get to the subway station so that I could get to the gym. It was a fairly early rise for me as I tend to often sleep in. As I walked out my door, the bus literally pulled up right in front of me – I love it when that happens. I walked onto the very crowded bus to see almost every single person on their crackberries or iphones. Seriously, who are you texting in the early morning?

subset: commoncrawl


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The Mets face Alfredo Simon, Johnny Cueto and Mat Latos this weekend in Cincinnati.METS (66-74, fourth place/NL East) vs. CINCINNATI REDS (66-74, fourth place/NL Central)
Friday: RHP Bartolo Colon (12-11, 4.01) vs. RHP Alfredo Simon (13-9, 3.28), 7:10 p.m. ET
Saturday: RHP Dillon Gee (6-6, 3.61) vs. RHP Johnny Cueto (16-8, 2.26), 4:10 p.m. ET
Sunday: RHP Zack Wheeler (9-9, 3.45) vs. RHP Mat Latos (5-4, 3.46), 1:10 p.m. ET
Reds short hops
• Center fielder Billy Hamilton is expected to be the primary competition for Jacob deGrom in the NL Rookie of the Year competition. Hamilton, who turns 24 on Tuesday, is batting .267 with six homers and 46 RBIs and has a franchise-rookie-record 55 steals in 76 attempts. The previous franchise rookie steals record had been 54, by Bob Bescher in 1909. Hamilton has the most steals by a Reds player regardless of experience since Deion Sanders recorded 56 in 1997.
• Second baseman Brandon Phillips is 0-for-his-last-20. He missed 31 games through Aug. 17 while recovering from surgery to address a torn ligament in his left thumb.
• Shortstop Zack Cozart, who was poised to rejoin the Reds on Thursday in Baltimore after the birth of his son, instead remained in Cincinnati because of right-wrist soreness.
• Johnny Cueto's 205 strikeouts are the most by a Reds pitcher in a season since Edinson Volquez notched 206 in 2008. Assuming he produces two or more Saturday, it will become the most Ks since Aaron Harang had 218 in '07.
• Alfredo Simon represented Cincinnati in the All-Star Game as a replacement for Cueto, who pitched the Sunday before the event. Simon had opened the season as the fifth starter when Mat Latos was sidelined rehabbing elbow and knee injuries.
• Right-hander Homer Bailey, who signed a six-year, $105 million contract in February, was due to undergo season-ending surgery Friday to repair a torn flexor tendon in his pitching elbow. He is expected to be ready for spring training.
• First baseman Joey Votto has been on the disabled list since July 8 with a strain in his left knee. He was hitting only .255 with six homers in 220 at-bats before landing on the DL. Of late, Todd Frazier primarily has started at first base.
• The Reds were 51-44 and 1½ games out of first place at the All-Star break. They are 14-30 since resuming play.


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This content has been marked as final. Show 6 replies
1. Re: Xml Publisher Report Without RDFAlexAnd Oct 11, 2011 10:11 AM (in response to 889643)Oracle XML Publisher Report Designer's Guide1 person found this helpful
you can create report with
- data definition
- template (rtf, pdf ...)
see - Process Overview in docs
also http://oracle.anilpassi.com/xml-publisher-concurrent-program-xmlp.html
xml data can be selected using package or xml template
see what you have
2. Re: Xml Publisher Report Without RDF869773 Oct 11, 2011 12:02 PM (in response to 889643)Yes we can create RTF Template with out using RDF.1 person found this helpful
1. Create an XML file Where it consists of all SQL queries that are useful for the report and You need to upload the XML file in XML Publisher Responsbility --> Data Definition --> Data Template --> Upload . Upload the XML Template File in the given path.
To view any of the XML file for the sample sake, Every report in Subledger accounting in R12 is with out rdf. Please check it for further reference.
2. Register the Executable as JAVA CONCURRENT PROGRAM not ORACLE REPORTS. Concurrent Program Output as XML with specific parameters you need.
3. Then Register and upload the New RTF & XML Files in XML Publisher Responsibility.
4. Then Run the Conc Program with out RDF.
3. Re: Xml Publisher Report Without RDF889643 Oct 12, 2011 6:21 AM (in response to 889643)Thank u,
Here I need to customize the Sales Order XSL Template which is a seeded template in Order Management.
and it will execute when user select the actions button-> print and prview .so there is no concurrent program for this.they did the setups for this.
I didn't find any datetemplate for this in data defination window.here I need to change this one as
1. Update the Report Header to read "Dispatch Note" instead of "ORDERING DOCUMENT".
2. Inclusion of logo for each police authority (Open Issue).
3. Modification to include *"United Kingdom" instead of U.S.* in the free text portion of the PRODUCT section. "United Kingdom" value will be derived from the country specified for the selected organization and not hardcoded.
4. Footer to include shipment date instead of Sales Order Creation date and the document should be available to print only after Ship Confirm.
5. Updating the Layout template in the Transaction Type setup, so that it points to the modified layout template.
6. The modified Dispatch Note document will be included in the Ship Confirm document set and this document set will be included in the respective Ship Confirm rules. This Ship Confirm Rule will be attached in the Shipping parameters tabs for both the organisations. This step would enable the Dispatch Note to be printed automatically after successful completion Ship Confirm process.
I have *.XSD file and .XSL file * .. I don't find any data template in datadefination window to see the SQL query.
I thought now i have to change the *.XSD AND .XSL FILES* is it right? Is there any other solution for this ..
Edited by: 886640 on Oct 11, 2011 6:41 AM
Edited by: 886640 on Oct 11, 2011 10:00 PM
Edited by: 886640 on Oct 11, 2011 11:07 PM
4. Re: Xml Publisher Report Without RDFAlexAnd Oct 12, 2011 6:22 AM (in response to 889643)>1 person found this helpful
I have *.XSD file and .RTF file * .. I don't find any data template in datadefination window to see the SQL query.
I thought now i have to change the .XSD file is it right? if i change this file the changes will effect in the template or not? Is there any other solution for this ..
are you sure about *.XSD and *.RTF ?
RTF template is face of report.
also you need any data for report (xml data)
xml data can be selected using package or xml template
*.XSD may be schema for xml data or may be not
need to find how xml data are formed.
of course you can create your report, for example, based on rtf, xsl template and package and then create concurrent and add it to group
5. Re: Xml Publisher Report Without RDFUser389723 Mar 26, 2013 6:13 PM (in response to AlexAnd)The below link does not open, any alternatives please?
6. Re: Xml Publisher Report Without RDFuser4929345 Mar 27, 2013 7:08 PM (in response to 889643)Hi Ashok,
I am having similar requirement..?
I have rtf template, xsd file, xsl file but no rdf.. did you get any hands on it..?


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partner marriage .travel partner
every time you fly anywhere...be ready to meet me...yes..right there, in the sky)you will be surprised if I offer you to drink-tea or coffee?may be some wine?)))haha)))I will keep you warm with a blanket or bring you cold drinks)))and you will recognize me...and will say-oh Olya!!Holy God!we finally met))))haha)) I hope that our first meeting will be more romantic, though I don't mind it to be in the sky)))the land will do too))))
Looking for a nice man to create a family, caring,who knows how to respect a woman,how to love her, to make her happy, happy woman=happy you)


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Restaurant on fire in Dublin city centre
Units from Dublin Fire Brigade are tonight battling a blaze at the Kingfisher restaurant on Parnell Street.
A spokesman for Dublin Fire Brigade confirmed that there are two district officers and five pumps in use at the scene at the Kingfisher Townhouse opposite the Rotunda Hospital.
"At this stage we do not know what started the fire," the spokesman said.
Incident is upgrade to a command level 3 5 pump fire and TTL in use.BA teams still dealing with fire.— Dublin Fire Brigade (@DubFireBrigade) February 26, 2016
Incêndio na Parnell Street pic.twitter.com/UT41r0wpf2— Dr. Divago (@gabrielfforsi) February 26, 2016
Chipper on Parnell street on fire every body seems to be ok @rtenews #Dublin pic.twitter.com/noXxPqNOy4— jay (@Jaysca1) February 26, 2016


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Perky sundress in short (mid-knee) or long length. Empire waistline joins to flared skirt. Back zipper. Sash and straps can be made to contrast. Sash at empire line ties into bows at sides.
Links to reviews/blog posts Edit
Sources/Vendors Edit
Gallery Edit
[insert your photos of this pattern made up]
Wishlist Edit
[insert your username, and make sure your preferences allow for people to contact you via e-mail. Do not list your email address here!]


text:
The Courtyard Fort Lauderdale Weston, with redesigned guest rooms, is located off I-75 and is near the BB&T Center, Sawgrass Mills Mall and 72 holes of premier golf. Our hotel is also near Cleveland Clinic Florida and provides complimentary shuttle service for easy access. For your convenience, free Wi-Fi is also available property-wide. Stay energized with signature Starbucks beverages and choose from a variety of menu selections served at The Bistro Eat. Drink. Connect. , a unique dining experience among Weston hotels near Fort Lauderdale. Unwind in our newly remodeled accommodations boasting modern design elements and thoughtful amenities. Traveling for work or a special occasion? Host meetings and more in over 1,900 sq. ft. of flexible event space and take advantage of complimentary business services at our hotel near Sunrise. Whether here for business or leisure, the Courtyard Fort Lauderdale Weston is sure to meet any travel need.
Your restaurant destination near Fort Lauderdale for refreshing breakfast choices in the morning, and a variety of dinner and cocktail options in the evening. The Bistro also offers specialty Starbucks coffee beverages to help you get a jump on the day.Starbucks
We also offer a menu of beverages made with Starbucks coffee, designed to get you through the day.


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"Barnet accident and emergency"
About: Barnet General Hospital Barnet General Hospital EN5 3DJ
Posted by Anonymous
I went to barnet accident and emergency dept today. The third time me or my 14 year old have visited in three years. A fantastic place. The walk from the car park is maybe a touch tricky if you're poorly but the staff are fantastic. My son hurt his arm and they even had a specialist explaining to him: how he'd hurt it, what to do to help the arm to recover and then how to avoid the same strain again. We never wait longer than 20 minutes to see a nurse. There are facilities to buy tea, coffee, pop or snacks 24 hrs a day. The staff are all very kind and helpful, especially the a and e drs.
Response from Barnet General Hospital 2 years ago
Thanks so much for your lovely feedback, we're delighted you had a good experience with us! We will pass your feedback on to our team at Barnet Hospital.
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text:
Blonde Jokes (FREE)
By Ronald Bell
Open iTunes to buy and download apps.
How can you tell if a blonde has been using the computer? There's white-out on the screen!
Blonde Jokes is a collection of hilarious and fun blonde jokes.
With Blonde Jokes, you'll be the life of the party with your endless collection of blonde jokes.
What's New in Version 1.1
Fixed an orientation bug which occurred while the iPad was laying flat on a surface.
iPad Screenshots
- Free
- Category: Entertainment
- Updated: 23 February 2011
- Version: 1.1
- Size: 0.5 MB
- Language: English
- Developer: Ronald Bell
- © 2010 Bell Standard, Inc.
Compatibility: Requires iOS 3.2 or later. Compatible with iPad.


text:
- Description
The Turino 7 piece Dining Set includes a table and six chairs. The large spacious tabletop offers ample food and elbow room and seating space for many. Thick, sturdy legs in an X-design complete the piece. The side chairs feature traditional straight lines and simplistic chair backs. A luxurious tan fabric covers a plush seat. Finished in a grey oak stain, this piece is sure to complement any homes decorDimensions
Table: 72" x 40" x 30" tall; Chairs: 19" x 23" x 40" tall, Seat Height: 18"
More from this collection: 457-417
- Additional Information
Additional Information
SKU 16001110 MPN 457-417M2 GTIN UPC 081438237091 Brand Powell Collection 457-417 Assemble Length N/A Assemble Width N/A Assemble Height N/A Assembly Required Yes Material Wood Finish Oak Sizes N/A Styles Contemporary Shapes N/A Shipping Time 1-2 Weeks Free Shipping Yes
- Reviews
Disclaimer: Pictures displayed may include optional products not included in the price. Computer monitors often display color variations. Color swatches are shown if alternative colors are available. Please call us or email us if you have any questions!


text:
Home > Door Entry > Video Wired > Fermax > Video Panels
Catalogue No: 5471Brand: Fermax
Current Item:
Click for delivery info
Marine Directory Panel ST3. For display of house names/numbers alongside Marine Panels ST3. Built to the Marine panels same high grade, with display 'windows' made of 6 mm-thick polycarbonate, resistant to hits and high temperatures.
Education, Council, NHS, Police and Emergency ServicesClick Here
© 2017 OLSP Limited.
Order Helpline 0800 880 6123email: @ click here


text: President John Henry Eden claims, I believe, that the ZAX unit from which he developed was constructed by the United States government just before the war, as a way of continuing government presence following disaster. "Disaster" came in 2242 when Dick Richardson died. Eden gained self-awareness and assumed command of the Enclave. Before Richardson's death, Eden served as Presidential advisor and AI administrator of Raven Rock. Vault122 15:51, 11 April 2009 (UTC)


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Hey I arrive in Sydney in September and Im looking to do fruit picking in Griffith NSW to allow me to apply for my 2nd year visa.
I was wondering if I have to do 3 months work all at once? and can I use my 2nd year visa in a few years? or do I have to use it straight away.
Any advice will help thanks


text: On my Zio, whenever I call someone or get a call, my phone is in speakerphone. If I press menu, I can see it is toggled on but when I press it to toggle it off it shows it is getting pressed but it does not toggle off and just remains in speakerphone. I can not deactivate it and so now I am stuck making or recieving all calls in speakerphone. I have looked all through settings but see nothing related to this. This have been going one for a few days and I have restarted a lot and pulled the battery and all to no effect. Anyone know what caused this or how to fix it. Thanks, Joe


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Transocean Ltd. announced that Ihab Toma notified the company of his resignation as Executive Vice President, Chief of Staff effective December 31, 2013.
With Mr. Toma's departure, the position of Chief of Staff will be eliminated and responsibilities redistributed.
Effective immediately, the company's Board of Directors has designated the Chief Executive Officer, Steven L. Newman; the Executive Vice President and Chief Financial Officer, Esa Ikaheimonen; and the Executive Vice President and Chief Operating Officer, John Stobart; as the members of the company's executive management team pursuant to the company's organizational regulations.
Transocean Ltd.
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text:
With First Tutors: Music you can search for a Earlston double bass tutor. Double Bass tuition are a brilliant method to start a fun new hobby, pick up a new skill and gain confidence with double bass. Use our service to search for Earlston double bass tutors and choose which matches your requirements so you can begin your double bass tuition in Earlston straight away!
First Tutors: Music is the only place to find Earlston double bass tutors in the UK, helping you discover Earlston double bass tuition close to you and Earlston tutors to assist with any instrument, for example, piano, violin or guitar. We can help you find Earlston double bass lessons or a one-to-one Earlston double bass teacher to prepare for double bass grades and develop your double bass skills! We order Earlston double bass teachers near you according to their tuition prices and proximity to you.
If you are a double bass teacher and would like to offer your double bass tuition services in Earlston or anywhere else across the UK, please register with First Tutors: Music or learn about us here. Becoming a Earlston double bass teacher is a fantastic way to re-affirm your own knowledge through providing double bass lessons while helping others, all in the Earlston area!


text:
Best Protein Powder Blogs
Choosing the best whey powder is very important in getting all the health benefits of it. It is one.. of the best protein sources obtainable in the world. The amino acid which has to be in a protein.. powder is fully found in whey protein.
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What is best whey protein in the market? Find out the best protein powder through whey protein.. reviews and also uncover the truth about whey protein side effects and the relation between whey.. protein and weight loss.
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Reviews of the best protein powders
Owner: Tess01
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Other Tags: protein powder reviews, protein powder


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This exceptional modern style villa is situated in the sought-after area of Sol de Mallorca, offering a touch of Majorcan stone façade which makes this newly built property truly unique.
The impressive architecture and luminous rooms of this villa, comprising a total of 7 bedrooms and 6 bathrooms plus a large living area with sliding double glazed doors onto terraces of 250 m2 are what makes this property differential. This impressive object disposes of a state of the art intelligence system, double glazed windows throughout and under floor heating. Besides it is fully furnished to a modern and minimalist taste. The outside area with 3 cascading pools, large terraces and landscaped gardens offer an idyllic modern atmosphere. The light-flooded bedrooms are distributed on two floors, both double bedrooms on the upper level are en-suite with terraces and partial sea views. The open plan dining and kitchen area disposes of state of the art appliances and offers staff quarters and a laundry room. Additionally this property offers three parking spaces on the grounds.
Terrace/Outdoor Space, Staff Quarters, Security System, Privacy Fence, Pool - Outdoor, New Development
walking distance to beach, various terraces, utility room, top quality, swimming pool, storeroom, sea views, satellite tv, roof terrace, patio, living room with fireplace, laundry room, installed music system, ideal family home, garden, fitted kitchen, fireplace, excellent condition, electric gates, close to schools, children's pool, central heating, built to high standards, alarm system, air conditioning hot/cold, adsl
Property Condition: Ready to move in
|Rental start date
|Rental end date
|1 May 2017
|30 Jun 2017
|14,300 € /Week
|€ /Monthly
|1 Jun 2017
|31 Aug 2017
|19,500 € /Week
|€ /Monthly
|1 Sep 2017
|31 Oct 2017
|14,300 € /Week
|€ /Monthly
Luxury houses and villas for sale in Sol de Mallorca
Sol de Mallorca is an outstanding residential development situated on Mallorca in the municipality of Calvià. We offer the finest luxury houses and villas for sale in Sol de Mallorca, boasting a superb seafront location on Calle Joan Miró and Avenida Portals Vells. Indeed, Joan Miró, one of the finest streets in the area, is the site of the...
Sotheby's International Realty® is a registered trademark licensed to Sotheby's International Realty Affiliates LLC. Each Office is independently Owned and Operated.


text: Synta Pharmaceuticals Corp. (NASDAQ: SNTA) today announced presentation of results from the GALAXY-1 trial, a global, randomized, multi-center study designed to identify the patients with advanced non-small cell lung adenocarcinoma most likely to benefit from second-line treatment with the Company's lead drug candidate, the Hsp90 inhibitor ganetespib, in combination with docetaxel versus docetaxel alone. The results will be presented Monday, October 28 2013, at 10:30 AM local time during an oral session at the 15 th World Conference on Lung Cancer (WCLC) in Sydney, Australia. Ganetespib is a second-generation inhibitor of the chaperone protein Hsp90, which is critical for the activation and stability of numerous proteins that drive cancer growth and proliferation. Ganetespib has been studied in over 25 clinical trials and 800 patients to date. In these trials, ganetespib has shown durable objective responses, including CRs (complete responses) and near-CRs, when used alone, as monotherapy administration, in patients with several different types of late-stage cancer, as well as a favorable safety profile, with no evidence of the serious liver or common ocular toxicities seen with other Hsp90 inhibitors. "Our strategy with the GALAXY lung cancer program has been to use a large, global Phase 2b trial to increase the probability of a positive outcome in Phase 3," said Dr. Safi R. Bahcall, President and CEO, Synta. "We designed the GALAXY-1 trial, which enrolled close to 400 patients in total, to address two primary questions: (1) how to optimize patient selection for Phase 3 and (2) how to reduce the operational risks from heterogeneous populations and treatment patterns that often confound large, pivotal studies. The one-year follow-up results from GALAXY-1 address both these questions, confirming our choices for patient selection and increasing our confidence in a positive outcome for the ongoing GALAXY-2 trial." "'As the data become more mature, the improvements in progression-free survival and overall survival with ganetespib and docetaxel in the patient subpopulation selected for Phase 3 study are very encouraging," said Dr. Suresh Ramalingam, M.D., Professor, Hematology & Medical Oncology, and Director, Division of Medical Oncology, of the Winship Cancer Institute of Emory University, and a principal investigator of the GALAXY program. "These results bode well for the mirror image GALAXY-2 trial."


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Read your message in General and hopped right to it Shin.
It's time for a brand new thread - hopefully it turns out better than the ECW reboot.
Raw around May/June is where things got really weird. Like they were trying to placate Austin who was their biggest star, but they kept booking him angles he had already worked. First we got The Undertaker, which even caused the fans to say uncle. Then you had The Big Show, so it was Wrestlemania XV again, except they actually went through with it and Ric Flair was a poor man's Vince. It was all leading to an Eddie & Benoit v Austin feud which was actually pretty interesting and could have got Austin back into the swing of things. But then they decided to mess with things, book him in a gimmicky Brock Lesnar match and Austin was basically done for good.
I could be alone in this, but I didn't mind HBK joining the nWo. At least on the surface, it made a ton of sense and gave Nash somebody to bounce off of. Logistically it didn't make the most sense, since we didn't know that HBK could still go and the nWo essentially was dead in the water at that time. However, it was a small detail I didn't mind. Sort of like how I enjoyed the WCW Tag division circa 1999 even though the rest of the year was largely hot garbage.


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Reviews of Mundulea Reserve
They do not necessarily represent the views of Expert Africa.
Marvellous Mundulea
This was a very special place: a bush camp, not luxurious (it doesn't set out to be luxurious) but comfortable.
Bruno is an outstanding guide and what he is doing on the reserve is fascinating. It was lovely eating food cooked by Tommy over an open fire.
Mundulea is a private reserve where the owner, Bruno, is looking to restore the environment to its pre-cattle farming state. This is not a short-term project as over-grazing has caused significant bush-encroachment. But Bruno is very dedicated to the cause, which is well worth supporting - not least because this sort of private project may ultimately (and sadly) prove to be the best hope for Africa's megafauna in particular in the medium- to long-term.
Bruno himself is a true (latter-day) 'renaissance man'. Sculptor, film-maker, photographer, birding guide and bush expert, he has a wealth of knowledge on a wide range of topics and is genuinely curious about many others. Over the four nights we were there our conversaations ranged across, inter alia, the origins of multi-cell life (based on local fossiles), the eating habits of porcupines (more complex than you might think), the genetics of the zebra (and kite) family, undoing the damage of over-intensive farming, local politics, the Chinese in Africa, and human dietary issues.
Mundulea is a true bushcamp. But the accommodation is very comfortable - and we commend in particular the shower which is as good as any we have found on our numerous trips to Africa. Much of the fittings have been made by Bruno and his team from locally available materials (including scrap metal from the area's farming days). Bruno produces amazingly good meals on an open fire, which would do credit to many a modern kitchen.
The waterhole right outside the camp attracts a good range of mammals day and night and, although we were a few weeks early for the peak period, we also saw a wide range of birds.
Best of all, no trucks! Mundulea is all about walking and we enjoyed some excellent rambles through the bush morning and evening.
In short, highly recommended.
Mundulea Reserve review
Brilliant as ever. Our time with Bruno was amazing. We would like to find a way of helping Bruno with his work there and spoke to him about it.
We would like to talk to Chris about it sometime.
Mundulea Reserve
Bruno and Kai took excellent care of us.
The children really enjoyed the trip and was fully engaged in the things Bruno explained to them. The food was great, I think they were surprised how much we (including the kids) can eat.
A wild reservation in a remote area
A very authentic camp with the tents placed within a bomba. We were the only guests at the time and enjoyed our numerous walks and conversations with Bruno Hebe, the owner who is a most interesting guide.
The amenities were very basic - much like living in the bush - but a wonderful experience. Walking was the only activity.
Outstanding and Inspirational
Spent 3 nights here, and could have spent longer.
It was fascinating and learned so much from Bruno about the bio diversity on Mundulea and surrounding area. Bruno is an excellent host and a first class guide. A wonderful insight into Namibia.
Would love to go back and see how Bruno's vision develops.
long walks in the bush ;)
Not sure how much lea way Bruno gives to those who are less fit or used to the heat than he is! Just about managed to keep up, but certainly not for the faint-hearted.
Bruno is an extremely knowledgeable guide and we had a lovely 3 days here (even though the animals were all hiding!). Would defiinitely return, but maybe after some training or at the end of the trip when we had acclimatised to the heat
Managing Expectations
I could be critical but nature controls the viewing not the people. We had three quite difficult days and the experience fell short of our expectations. On the positive side you have the opportunity to spend time with one of the best guides in Africa and gain a detailed understanding of the bush and how it works.
On the downside this is a farm (well 4 actually) that has over 2,000 animals and i can confirm they are there as you see them as you drive in and there are dozens of tracks and more poo than you can shake a stick at, but on the walks the chances of seeing anything away from a waterhole seem to be very low.
Bruno is keen to keep the animals wild (good) but this means they are not comfortable with people on foot and very skittish near the waterholes. If you love to walk (we do) this is great but 6 hours at 30+ degrees is tough, if you want to photograph animals or at least see them (we do) this is probably not a great place to start.
Overall it is a wonderful experience but the advertising and the hype are not quite what you get - or were we just very unfortunate.
Expert Africa comments
We were really sorry to read that this experienced traveller did not enjoy Mundulea. Prior to arriving, he spent six nights game-viewing in Etosha National Park. This could normally be relied upon for lots of great wildlife sightings and large volumes of game, but extensive bush fires and ill-timed road works both detracted from this experience.
By contrast, Mundulea doesnt have dense game or animals that are particularly relaxed near people, and so we never expect great wildlife sightings here. Bruno is passionate about keeping the wildlife at Mundulea wild commenting that its distrust of humans has stood it in good stead through many centuries of hunting. So Munduleas experience is much more about learning about the finer workings of the bush on foot, whilst treating wildlife sightings as a bonus.
So whilst Mundulea usually complements Etosha very well in an itinerary. However, in this case it clearly didnt work at all well, as game viewing was very sparse both in Etosha and here.
Mundulea Reserve review
An excellent bush experience, but if you're looking for easy spotted game this is not the place.Read more about the whole safari
An unforgettable experience
Previous guests have expounded on the wonders of Mundulea, and we can only add our admiration for what Bruno is succeeding in doing on this vast reserve.
Yes, the tents are simple, but not basic, the beds are very comfortable, the night-sky view from the loo extraordinary, and the wake up calls of the francolins and the babblers something to be experienced. We even had a leopard calling metres from our tent in the night. Bruno's home cooking was the best food we had on the whole trip (and that is saying something). We were the only guests so we had two days of gentle trailing with Bruno and his son, during which we learnt so much about the animals, plants and the exceptional geology of the area, not to mention history and politics! Like many other guests, we have become "poo" experts and we now have to find a use for all our knowledge in rural Sussex!
This is a true bush-camp but with enough of the creature-comforts to make it a wonderful experience for all ages. We could not recommend it too highly.


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Please use this identifier to cite or link to this item:
|A Model for Astrometric Detection and Characterization of Multi-Exoplanet Systems
|Thompson, Margaret
|Spergel, David
|Astrophysical Sciences
|Class Year:
|In this thesis, we develop an approximate linear model of stellar motion in multiplanet systems as an aid to observers using the astrometric method to detect and characterize exoplanets. Recent and near-term advances in satellite and groundbased instruments are on the threshold of achieving sufficient (⇠10 micro-arcsecond) angular accuracies to allow astronomers to measure and analyze the transverse motion of stars about the common barycenter in single- and multi-planet systems due to the gravitational influence of companion planets. Given the emerging statistics of extrasolar planetary systems and the long observation periods required to assess exoplanet influences, astronomers should find an approximate technique for preliminary estimates of multiple planet numbers, masses and orbital parameters useful in determining the most likely stellar systems for follow-up studies. In this paper, we briefly review the history of astrometry and discuss its advantages and limitations in exoplanet research. In addition, we define the principal astrometric signature and describe the main variables affecting it, highlighting astrometry's complementary role to radial velocity and photometric transit exoplanet detection techniques. We develop and test a Python computer code using actual data and projections of the Sun's motion due to the influence of the four gas giants in the solar system. We then apply this model to over 50 hypothetical massive two- and three-exoplanet systems to discover useful general patterns by employing a heuristic examination of key aspects of the host star's motion over long observation intervals. Finally, we modify the code by incorporating an inverse least-squares fit program to assess its efficiency in identifying the main characteristics of multi-planet systems based on observational records over 5-, 10- and 20-year periods for a variety of actual and hypothetical exoplanetary systems. We also explore the method's sensitivity to measurement frequencies, intervals and errors.
|101 pages
|Type of Material:
|Princeton University Senior Theses
|Appears in Collections:
|Astrophysical Sciences, 1990-2017
Files in This Item:
|Adobe PDF
|Request a copy
Items in Dataspace are protected by copyright, with all rights reserved, unless otherwise indicated.


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So I saw some comments on FB this morning. I did not, repeat, did NOT watch the episode. I'll just watch it tonight but have you guys heard the rumors of who dies tonight? Pretty sad.
Most Helpful Guy
Yes I saw the leakage , the end was... well I cried 😢😢😢😢😢😢00|00|0
Noooooooo!!! Oh boy.
- Show AllShow Less
Yeah I treated myself to stuff for a nice dinner during the show and chocolate cake... but not so good if I cry into my treats lol
Well the epsoide it self isn't much it's just the ending and trust me east before it , I am still sad because of it 😔


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Stayhound is an application that helps users locate reliable, safe and trustworthy sitters for their beloved pets. Stayhound users connect via their Facebook account since this helps ensure honesty and it let's Stayhound tell only the people who users trust that they are in need of pet sitting services. Users can also setup a profile for their furry friend so others can learn about the particular pup that they may be hosting. Profiles consist of a user uploading a photo of their pet, including the pet's name and a description so people know what the dogs are like. Stayhound enables users to let their friends know that they need a pet sitter and provides a link to their pet's Stayhound profile so the Facebook friends can check out the pet and respond with their availability via email and Facebook through Stayhound. For users who do not have a Facebook account, but who want to still use Stayhound's services, they can email Stayhound and they say that they will see what they can do to help. Stayhound aims to support responsible pet ownership and to connect pets with loving families.Show more screenshots »
Stayhound was developed by a group of animal lovers who found that their pets' lives are better when there is a support network of other pet lovers who can watch over the pet when the owner is unable to. Stayhound is a Portland, Oregon based operation led by CEO Alexis Peterka. By logging in and posting through Facebook, users can reach out to a community of friends who they already trust. Stayhound has been featured in Fast Company, Oregon Live, Need to Know on PBS and now AppAppeal.com! As of March 2012, the site is in its Beta form and is looking to add more features and functionality soon.
Stayhound is different from other social networks in that its focus is solely on connecting pets to the best and most reliable pet sitters. They really intend to improve the quality of pets' lives by bringing them together with other families or people who will love them almost as much as the owner does and who can care for them when the owner is unable to. Stayhound only connects through Facebook, so this may make it tough for people who have small circles of online friends to connect to a pet sitter. However, the concept is good and creating a pet profile is a nice way to feature the pet more fully than a normal Facebook post.
Stayhound has an excellent design and a professional and put-together motif that fits well with their mission. The site is fast, responsive and there were no broken or dead links observed during the trial. It is easy to sign up for the service if the user already has an established Facebook account. The only downside might be for those who do not have Facebook since it really makes this app ineffective in that case.
Registering for Stayhound can be completed by visiting the website's homepage and clicking on the "Connect With Facebook" link in the upper-right corner. From there users are taken to the standard Facebook permissions tab and they can select if they want their Stayhound activity to be visible by everyone, by their friends or kept private. From there users can access their Stayhound dashboard and setup their pet's profile.
Stayhound is a free application to use. The site is supported through the Wieden + Kennedy's tech incubator Portland Incubator Experiment (PIE).
Stayhound is a solid application for those who use Facebook, who have a significant set of friends and who has a pet who may need to have a babysitter in the near future. It is a pretty specific target audience, however for those who meet these qualification, Stayhound could be a handy and helpful way to connect their pets to a perfect "other family."


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Mark Ruth
Mark Ruth is the Project Leader of the Strategic Energy Analysis Center.
Project Leader
On staff since 1993 (SEAC staff since 2014)
Phone number: 303-384-6874
Email: firstname.lastname@example.com
Areas of expertise
- Energy systems and their simulation
- Biomass processing to fuels and chemicals
- Hydrogen production and delivery
- Transportation issues
Primary research interests
- Tool development
- Energy systems integration (ESI)
- Energy distribution
- Retail market structures and consumers
- Technology integration
- Innovation options
Education and background training
- B.S. in chemical engineering, University of Colorado, Boulder, CO, 1993
Prior work experience
- Hydrogen Program Integrator, NREL – Systems Engineering and Program Integration Office (October 2008 - November 2013)
- Interim Biomass Program Integrator, NREL – Systems Engineering and Program Integration (March 2010 - October 2010)
- Senior Engineer II, NREL – Systems Integration (January 2008 - October 2008)
- Senior Engineer I – Macro-System Model, NREL – Systems Integration (January 2005 - January 2008)
- Process Engineer I, NREL – Biomass Center (June 1993 - January 2005)
Other affiliations
- American Institute of Chemical Engineering
Selected publications
Bragg-Sitton, S.M., R. Boardman, M. Ruth, O. Zinaman, and C. Forsberg. "Rethinking the Future Grid: Integrated Nuclear Renewable Energy Systems: Preprint." Paper presented at the 9th Nuclear Plants Current Issues Symposium: Moving Forward, Charlotte, NC, December 2014. NREL/CP-6A20-63207.
Ruth, M.F., O.R. Zinaman, M. Antkowiak, R.D. Boardman, R.S. Cherry, and M.D. Bazilian. "Nuclear-Renewable Hybrid Energy Systems: Opportunities, Interconnections, and Needs." Energy Conversion and Management 78 (February 2014): 684-94. NREL/JA-6A50-58087. doi:10.1016/j.enconman.2013.11.030
Timbario, T.A., T.J. Timbario, M.J. Laffen, and M.F. Ruth. 2011. "Methodology for Calculating Cost-Per-Mile for Current and Future Vehicle Powertrain Technologies, with Projections to 2024." Paper presented at Society of Automotive Engineers 2011 World Congress & Exhibition, Advanced Fuel Cell Vehicle Applications, Warrendale, PA, 2011. Paper No. 2011-01-1345. NREL/CP-6A10-52454. doi:10.4271/2011-01-1345.
Ruth, M., T. Mai, E. Newes, A. Aden, E. Warner, C. Uriarte, D. Inman, T. Simpkins, and A. Argo. 2013. Transportation Energy Futures Series: Projected Biomass Utilization for Fuels and Power in a Mature Market. Golden, CO: National Renewable Energy Laboratory. NREL/TP-6A20-53336; DOE/GO-102013-3707.
Ruth, M., M. Laffen, and T.A. Timbario. 2009. Hydrogen Pathways: Cost, Well-to-Wheels Energy Use, and Emissions for the Current Technology Status of Seven Hydrogen Production, Delivery, and Distribution Scenarios. Golden, CO: National Renewable Energy Laboratory. NREL/TP-6A1-46612.
Aden, A., M. Ruth, K. Ibsen, J. Jechura, K. Neeves, J. Sheehan, B. Wallace, L. Montague, A. Slayton, and J. Lukas. 2002. Lignocellulosic Biomass to Ethanol Process Design and Economics Utilizing Co-Current Dilute Acid Prehydrolysis and Enzymatic Hydrolysis for Corn Stover. Golden, CO: National Renewable Energy Laboratory. NREL/TP-510-32438.
Full list of Mark Ruth publications (NREL)


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Nowadays, all you see is either stick-thin women or curvy women with a small waist and big boobs and butt. But what about the women with regular, boring bodies? The "normal" bodies if you will. What is your opinion?
Most Helpful Guy
I prefer them over skeletons and girls with massive fat thighs.21|10|0
thanks for mh!
Most Helpful Girl
i think they're normal bodies!!! in a good way00|00|0


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Are you seeking investment capital?
150 companies that have come through Arcview have raised more than $125 million from Arcview's 600+ high net-worth Investor Members. This makes Arcview the #1 source of deal flow for investors in the cannabis industry.
Arcview hosts weekly pitch webinars and five in-person Arcview Investor Pitch Forums each year.
If you think your company has what it takes to be selected to participate, please tell us about your company to the level you are comfortable to the right. We will be in touch about possible next steps.
Note that to qualify to pitch Arcview you must be beyond the idea phase and have an actual business with financial projections, a pitch deck, etc. If you are a great entrepreneur but aren't quite far enough along for Arcview, you might be a good fit for Arcview's partner accelerator, Canopy.


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World of Haven at Wikia
Welcome to the World of Haven mini wiki at Scratchpad!
You can use the box below to create new pages for this mini-wiki. Make sure you type
[[Category:World of Haven]] on the page before you save it to make it part of the World of Haven wiki (preload can be enabled to automate this task, by clicking this link and saving that page. Afterwards, you may need to purge this page, if you still see this message).
This mini wiki is a description of the world of Haven.


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Erasmus QUAlity Hosting Framework
On September 30th, EUCA presented the main deliverables of its project E-QUA, Erasmus QUAlity Hosting Framework: 15 quality criteria for the international mobility of university students, a strong connection with the labour market for the development of soft skills and a pathway for the recognition of the competences acquired during the mobility period into the Diploma Supplement. The conference was hosted by Mrs. Krystyna Łybacka, Member of the European Parliament's CULT Committee. During the conference the main deliverables of the project were discussed in a round table with Ms Vanessa Debiais – Sainton, Erasmus Team Leader, DG EAC, European Commission, and Mr Nicola Filizola, Co-founder of the garagErasmus Foundation. To give your own feedback on the project's deliverables, described in the Handbook of the project, fill in the survey!


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We gave this video the title of "Idol Worship" because many times that is exactly what Catholics are accused of without really knowing what we believe. This video is an attempt to creatively give expression to what the Catholic Church teaches about the Communion of Saints and our relationship with Mary the Mother of Jesus our savior.
We are not idol worshipers. Catholics know very clearly who they worship and that is one God in three persons; the Father, the Son and the Holy Spirit. We do honor the saints including Mary and we believe that through Jesus Christ we are connected, we have a communion.


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WASHINGTON — The Commerce Department's National Telecommunications and Information Administration (NTIA) and the Department of Agriculture's Rural Utilities Service (RUS) announced that they received almost 2,200 applications requesting nearly $28 billion in funding for proposed broadband projects reaching all 50 U.S. states and territories and the District of Columbia.
This is the first round of American Recovery and Reinvestment Act funding aimed at expanding broadband access and adoption to help bridge the technological divide and create jobs building Internet infrastructure, with $4 billion available through loans, grants, and loan/grant combinations.
The Recovery Act provided a total of $7.2 billion to NTIA and RUS to expand access to and adoption of broadband services. Of that funding, NTIA will utilize $4.7 billion to deploy broadband infrastructure in unserved and underserved areas in the United States, expand public computer center capacity, and encourage sustainable adoption of broadband service. RUS will invest $2.5 billion to facilitate broadband deployment primarily in rural communities. Approximately $2.4 billion from RUS and up to $1.6 billion from NTIA is available in this first grant round.
In the coming weeks, NTIA and RUS will post online a searchable database containing summaries of all applications received. The dollar figures cited here represent applicants' self-reported totals from proposals submitted before the Aug. 20. These results are preliminary estimates, however, and may change as the applications are reviewed for errors, omissions and duplications.


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Mumbai: I know surgery is necessary and Ive accepted that reality... Im okay... Im relaxed, Sachin Tendulkar told The Telegraph on Wednesday, the day after the Board revealed his right shoulder would be operated upon in London.
Speaking on the way to his room at the Taj, he added: While the announcement was made yesterday, Id been (mentally) preparing myself for the last couple of days... As in the past, Im strictly being guided by medical opinion.
Sachin, it may be recalled, was on holiday in the UK last summer when he underwent surgery on the left elbow. I got it done because it had to be... The situation isnt any different this time, he pointed out.
That surgery kept Sachin off competitive cricket for four-and-half months. This time, he wont be taking guard for (as of now) eight weeks after coming out of the operation theatre.
Asked whether hed spoken to Dr Andrew Wallace, who will again be wielding the scalpel, Sachin replied: No... The physio (John Gloster) has been interacting with him... Ive only seen the scans...
Sachin and wife Anjali intend leaving for London quietly. If the world gets to know, then Im going to have a problem controlling things... Its just a surgery and I should be allowed to have that without any (Media) attention, he said.
According to the fitness report presented to the Board by Gloster, Sachin requires surgery for a posterior labrum tear of the right shoulder with an associated para-labral cyst. That the cyst is very close to a major nerve is cause for more concern.
Meanwhile, Sachin remarked he wasnt even aware that he was being booed (by a section of the Wankhede crowd) after falling cheaply in the first innings of the Test which ended in a huge win for England.
Honestly, I had no idea... One doesnt think of the crowd either while going out to bat or on getting out... Others told me about the booing... That didnt affect me and, in any case, Ive been around for a number of years, he signed off, peparing to clear his room and head home.
At the international level, the number of years is 16-plus.