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This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
After the onset of brain ischemia, a series of events leads ultimately to the death of neurons. Many molecules can be pharmacologically targeted to protect neurons during these events, which include glutamate release, glutamate receptor activation, excitotoxicity, Ca2+ influx into cells, mitochondrial dysfunction, activation of intracellular enzymes, free radical production, nitric oxide production, and inflammation. There have been a number of attempts to develop neuroprotectants for brain ischemia, but many of these attempts have failed. It was reported that cyclosporin A (CsA) dramatically ameliorates neuronal cell damage during ischemia. Some researchers consider ischemic cell death as a unique process that is distinct from both apoptosis and necrosis, and suggested that mitochondrial dysfunction and Δψ collapse are key steps for ischemic cell death. It was also suggested that CsA has a unique neuroprotective effect that is related to mitochondrial dysfunction. Here, I will exhibit examples of neuroprotectants that are now being developed or in clinical trials, and will discuss previous researches about the mechanism underlying the unique CsA action. I will then introduce the results of our cDNA subtraction experiment with or without CsA administration in the rat brain, along with our hypothesis about the mechanism underlying CsA's effect on transcriptional regulation.
Brain ischemic stroke is a common neurological disease and a leading cause of severe disability and death in Western countries. It is proposed that the extent of tissue injury observed after ischemia largely reflects the damage incurred during reperfusion [
After the onset of brain ischemia, a series of events leads ultimately to the death of neurons [
In this review, I discuss the current problematic situation in the development of an effective neuroprotectant for ischemia and focus on CsA as an example of a promising candidate neuroprotectant. Then, I review our own work on CsA.
Currently, there are very few successful neuroprotectants. Edaravone (MCI-186) is one of a few effective neuroprotective agents that have already reached clinical application, although it is used only in a limited number of countries [
The following are examples of agents that were tested or are under clinical trial (
A 2005 phase III clinical trial [
Neuroprotective drug candidates and details of their clinical trials.
|Current status/Result of clinical trial
|NXY-059 (Cerovive)
|Trial in a larger number of cases indicated no significant activity. The program was terminated.
|The drug increased the combined endpoint of "death or disability" by about one-fifth.
|The drug did not demonstrate enough therapeutic efficacy in the treatment of acute ischemic stroke.
|A phase III trial exploring the efficacy in patients with cortical infarct is under way.
|A phase I trial is under way in the United States.
|Calcium Antagonists
|A clinical trial once suggested a beneficial effect, but none of the subsequent trials confirmed this result.
|Monosialoganglioside GM1
|There is not enough evidence to conclude that gangliosides are beneficial in acute stroke.
|Nootropil (Piracetam)
|There is not enough evidence to assess the effect of piracetam in acute ischemic stroke.
|A phase I clinical trial is under way in Europe.
|N-methyl-D-aspartate (NMDA) Receptor Antagonists
|The drug was not effective and might have a neurotoxic effect in brain ischemia.
|There is no evidence of benefit. Further development has been discontinued.
|No beneficial effects on the functional outcome of stroke in patients were accrued except in cases of lacunar syndromes.
|GABA Agonists
|The drug did not improve outcome in patients with major ischemic stroke.
|Sodium Channel Blockers
|The drug failed to show the efficacy in the treatment of acute stroke.
|Opioid Antagonists
|A phase III study was completed, but the results were not published.
|Membrane Stabilizers
|The drug was not efficacious in the treatment of moderate-to-severe acute ischemic stroke.
|The Phase III trial is under way.
|Poly ADP-ribose Polymerase (PARP) Inhibitors
|A Phase I clinical trial is under way in the UK.
|AX200 (Granulocyte Colony-Stimulating Factor (G-CSF))
|The drug failed to show the efficacy in the treatment of acute stroke.
|FK506 (Tacrolimus)
|A human stroke trial was stopped in phase II.
|Cyclosporin A
|A Phase II clinical trial, Neuroprotection Impact of Cyclosporin A in Cerebral Infarction (CsAStroke), is under way.
|PTP inhibitors
|No information about clinical trial for an inhibitor of PTP.
|No information about clinical trial for an inhibitor of PTP.
|A Phase III randomized multicenter clinical trial of high-dose human albumin therapy for neuroprotection in acute ischemic stroke.
|ONO-2506 (Proglia)
|A Phase III crinical trial in acute stroke patients was completed and failed to show the efficacy of the drug in the treatment of acute stroke.
|SUN-N4057 (Piclozotan)
|Phase II clinical trials are under way in the USA and Europe.
|Phase I clinical trials of TS-011 are under way.
When administered to patients with acute ischemic stroke, Tirilazad mesylate increased the combined endpoint of "death or disability" by about one-fifth but did not alter case fatality [
Nicaraven did not demonstrate enough therapeutic efficacy in the treatment of acute ischemic stroke, and its clinical trial application was declined [
Patients diagnosed as having acute ischemic stroke and who could receive drug treatment within 48 h of stroke onset were enrolled in one study. The improvement was significant in patients who started ebselen within 24 h of stroke onset but not in those who started treatment after 24 h. A phase III trial exploring the efficacy of ebselen in patients with cortical infarct is under way [
SUN-N8075 is a radical scavenger with neuroprotective properties. It also exerts blockade effects against T-type calcium channels as well as sodium channels. A phase I trial is under way in the United States [
Its efficacy in reducing infarct volume and improving outcome was demonstrated in animal models of focal ischemia, but subsequent clinical trials in stroke patients gave conflicting results. A clinical trial once suggested a beneficial effect [
There is not enough evidence to conclude that gangliosides are beneficial in acute stroke [
There is not enough evidence to assess the effect of piracetam in acute ischemic stroke [
In rat cortical slices and synaptosomes, E-2051 inhibited increases in glutamate and intracellular Ca2+, respectively, elicited by high K+, in a concentration-dependent manner. A phase I clinical trial is under way in Europe [
Selfotel was not an effective treatment for acute ischemic stroke. Furthermore, a trend toward increased mortality, particularly within the first 30 days and in patients with severe stroke, suggested that the drug might have a neurotoxic effect in brain ischemia [
There is no evidence of benefit from excitatory amino acid antagonists for acute stroke [
Magnesium inhibited NMDA receptors as well as voltage-dependent calcium channels (VDCCs). Magnesium is neuroprotective in animal models of stroke, and findings of small clinical pilot trials suggest a potential benefit to people. However, the present study [
In clinical trials, Clomethiazole did not improve outcome in patients with major ischemic stroke [
Studies failed to show the efficacy of lubeluzole in the treatment of acute stroke. Further development of this product has been stopped [
Although nalmefene appears to be safe and well tolerated, a study failed to find any treatment benefit in stroke patients treated within 6 h after onset. A phase III study was completed, but the results were not published. There is currently no active development of this drug for neuroprotection [
Citicoline (cytidine-5-diphosphocholine; CDP-choline) is a naturally occurring nucleotide derivative that may reduce central nervous system (CNS) ischemic injury by stabilizing cell membranes and reducing free radical generation [
DP-b99 is a lipophilic moderate-affinity chelator of zinc and calcium ions that acts selectively within cell membranes and has neuroprotective properties in animal models of stroke [
ONO-2231, a PARP inhibitor, is under development for the treatment of acute phase cerebral ischemic stroke. As PARP is an enzyme involved in cellular death, ONO-2231 is expected to be effective for diseases such as acute stroke. A Phase I clinical trial of ONO-2231 is under way in the UK [
G-CSF stimulates the Signal Transducers and Activators of Transcription 3 (STAT3) signaling pathway and inhibits PARP. The drug, AX200, is a manufactured form of G-CSF. AX200 stops neuronal cell death in the acute phase of stroke and stimulates the regeneration of the already damaged nervous tissue through the stimulation of neurogenesis as well as arteriogenesis and the reorganization of neuronal networks. It demonstrated safety and efficacy in patients with acute stroke in phase IIa clinical trials in Europe which have been completed. Further development is planned [
According to the recent report, they were not able to show efficacy for AX200 as a treatment for acute ischemic stroke. These results are disappointing and were unexpected to them because AX200 showed signs of efficacy in a previous clinical trial with a limited number of patients, as well as in numerous animal studies [
Exogenous human serum albumin administration has been found to be neuroprotective via reducing brain swelling, prevention of post-ischemic thrombosis, anti-oxidant activity, hemodilution and increasing the perfusion to the ischemic tissue [
Arundic acid (AA; ONO-2506), a novel modulator of astrocyte activation, significantly increased the mRNA expression of glutamate transporters (GLT-1 and GLAST) and GABA receptors (GABAA-R β1, GABAA-R β2, and GABAA-R β3). At a similar concentration range, the agent significantly decreased the mRNA expression of S-100β and NGF-β, as well as the lipopolysaccharide-stimulated mRNA expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) [
SUN-N4057 (Piclozotan) is a novel benzoxazepine derivative that has selective affinities to the 5-HT1A receptors. SUN-N4057 displayed pronounced neuroprotective activity compared with conventional neuroprotective agents, such as glutamate antagonists and antioxidants, in a rat model of middle cerebral artery occlusion (MCAO) [
Cytochrome P450s metabolize arachidonic acid to hydroxyeicosatetraenoic acids (HETEs) and epoxyeicosatrienoic acids (EETs). Among these, 20-hydroxyeicosatetraenoic acid (20-HETE) plays an important role in the regulation of vascular tone in the brain [
In T-cells, activation of the T-cell receptor normally increases intracellular calcium, which acts via calmodulin (CaM) to activate calcineurin. Calcineurin is a serine/threonine phosphatase that is regulated by Ca2+/CaM and that dephosphorylates the transcription factor nuclear factor of activated T-cells (NF-AT), which moves to the nucleus of the T-cell and activates the transcription of gene coding for interleukin-2 (IL-2) and related cytokines. FK506 prevents the dephosphorylation of NF-AT [
In 1994, Sharkey reported for the first time that FK506 was neuroprotective following cerebral ischemia [
Cyclosporin A (CsA) is a cyclic nonribosomal peptide of 11 amino acids produced by the fungus
It was reported that CsA dramatically ameliorates neuronal cell damage in the CA1 sector of the hippocampus during forebrain ischemia [
At least in animal models, CsA was reported to be effective in the treatment of TBI. For example, post-injury treatment with CsA significantly reduced mitochondrial dysfunction marker alpha-spectrin degradation in a mouse model [ Acute: TBI, SCI, stroke, and cerebral vasospasm following subarachnoid hemorrhage (SAH). Chronic: neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Parkinson's disease (PD), and Alzheimer's disease (AD). Selective neuronal brain protection from radiotherapy for brain cancer.
Acute: TBI, SCI, stroke, and cerebral vasospasm following subarachnoid hemorrhage (SAH).
Chronic: neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Parkinson's disease (PD), and Alzheimer's disease (AD).
Selective neuronal brain protection from radiotherapy for brain cancer.
Based on these good outcomes of animal experiments, a prospective, randomized, placebo-controlled Phase I/II trial was performed and published in 2009 with the aim to evaluate the safety, tolerability, and pharmacokinetics of a single intravenous infusion of CsA in patients with severe TBI [
On the other hand, a clinical study of 50 adults with severe TBI demonstrated the beneficial effect of 24 h of CsA treatment on brain extracellular metabolites using
A Phase II clinical trial, Neuroprotection Impact of Cyclosporin A in Cerebral Infarction (CsAStroke), is under way. The main objective of the study is to determine whether or not a single injection of CsA after intravenous thrombolysis can significantly decrease the volume of cerebral infarction [
Some researchers consider ischemic cell death as a unique molecular process that is distinct from both apoptosis and necrosis, and the accumulated evidence suggests that mitochondrial dysfunction and Δψ collapse are key steps in ischemic cell death [
As described above, CsA has a unique neuroprotective effect that is considered to be closely related to the molecular mechanisms of ischemic cell death in neurons
The well-known calcineurin function is a target for the widely used immunosuppressive molecules CsA and FK506 [
CypD, on the other hand, is an important modulator of the MPT pore, as described above. MPT is a Ca2+-dependent increase of mitochondrial membrane permeability that leads to the loss of Δψ, mitochondrial swelling, and rupture of the outer mitochondrial membrane. CypD is essential for MPT to occur, and CypD-dependent MPT regulates some forms of necrotic, but not apoptotic, cell death. The anti-apoptotic proteins Bcl-2 and Bcl-xL can block MPT and can therefore block MPT-dependent necrosis in addition to their well-established ability to inhibit apoptosis [
Calcineurin and CypD are distinct and separate key pharmacological targets of neuroprotective agents. Many previous reports have attributed the neuroprotective effects of CsA to pathways related to either or both of those target molecules. Calcineurin alone may not explain CsA's neuroprotective effect, because it was suggested that FK506's neuroprotective effect is much weaker than that of CsA in ischemia, despite the fact that the inhibitory effect of FK506 on calcineurin is 10 times stronger than that of CsA [ CypD deficiency resulted in a significant reduction of hypoxic-ischemic brain injury in adult mice but worsened injury in neonates. CypD-deficient cells also responded to various apoptotic stimuli in a manner similar to that of the WT, suggesting that CypD is not a central component of the apoptotic death pathway.
CypD deficiency resulted in a significant reduction of hypoxic-ischemic brain injury in adult mice but worsened injury in neonates.
CypD-deficient cells also responded to various apoptotic stimuli in a manner similar to that of the WT, suggesting that CypD is not a central component of the apoptotic death pathway.
Taken together, these data suggested that unidentified events underlie the CsA-mediated protective effect.
Pramipexole, an aminobenzothiazole compound, is a dopamine agonist with high spcificity for the D2 dopamine receptor family. Activation of the postsynaptic D2 receptor subtype provides the most robust symptomatic improvement in PD. Given its pharmacological profile, it is not surprising that pramipexole was found to be effective in ameliorating parkinsonian signs in animal models [
Several reports suggested that the PTP is a possible target of this drug [
Although Pramipexole (Mirapex) has been widely used as a dopamine agonist, there is no information about its clinical application as a PTP inhibitor.
Apart from a partial fatty acid oxidation inhibition, S-15176 was reported to prevent PTP opening. This effect was closely related with an increase in the Ca2+ loading capacity of mitochondria. Although S-15176 was a strong inhibitor of lipid peroxidation, experiments with another trimetazidine derivative lacking antioxidant activity demonstrated that this activity was not essential to the inhibitory effect. Binding studies elucidated mitochondrial binding sites of S-15176, especially those localized in the inner membrane, which were shared by several well-known inhibitors of PTP opening. These results strongly suggest that the mechanism by which S-15176 protects mitochondria against the deleterious effects of ischemia-reperfusion involves inhibition of PTP opening and provide evidence that the drug exerts its effect through low structural specificity binding sites located in the inner mitochondrial membrane [
As described above, CsA's effect on T-cell activation is based on effect on the transcription of gene coding for IL-2. Also, it was reported that CsA affects the transcription of brain-derived neurotrophic factor (BDNF) in neurons [
The rat brain ischemia model has been widely used as a standard by which to estimate a drug's effect. We used Wistar rats as model animals. For the cDNA subtraction method, we used the suppression-subtractive hybridization (SSH) method. SSH is an advanced PCR-based cDNA subtraction method with high sensitivity [ easy and cost-effective applicable when levels of starting material are minimal does not require prior knowledge of the transcriptomes can detect not only mRNA but also a variety of other RNA species (e.g., miRNA, siRNA) can obtain candidate cDNA clones during the analysis.
easy and cost-effective
applicable when levels of starting material are minimal
does not require prior knowledge of the transcriptomes
can detect not only mRNA but also a variety of other RNA species (e.g., miRNA, siRNA)
can obtain candidate cDNA clones during the analysis.
However, it also has disadvantages compared to Gene-chip:
Gene-chip is fast, simple, and shows more coverage Gene-chip does not need cloning or sequence steps.
Gene-chip is fast, simple, and shows more coverage
Gene-chip does not need cloning or sequence steps.
CsA was injected into the rat brains as previously described [
The animals were sacrificed under anaesthesia and the brains were removed and dissected. The hippocampal CA1 region was isolated and quick-frozen in liquid nitrogen. Total RNA was extracted from frozen tissues obtained from multiple animals, and Poly-A+ RNA was isolated from the total RNA.
This method is described in detail by Diatchenko
We detected many genes that were upregulated or downregulated by CsA administration. Among those, nine significantly upregulated genes and seven significantly downregulated genes were detected following CsA administration [
Elongation factor-1 gamma (EF-1-gamma): EF-1-gamma is one sub-unit of a multi sub-unit protein complex EF-1. EF-1 is a cellular protein complex that plays a role in protein synthesis by mediating the transfer of aminoacyl-tRNA to 80 S ribosomes [
Stearoyl-CoA desaturase 2 (SCD2): SCD2 catalyses a key step in the biosynthesis of oleic acid, a major fatty acid in myelin [
Beta sub-unit of chaperonin-containing TCP1: Chaperonin-containing TCP1 (CCT) is a heterooligomeric molecular chaperone that mediates folding of cytosolic proteins such as tubulin or actin in eukaryotes [
Fasciculation and elongation protein zeta1 (FEZ1): FEZ1 is a mammalian homologue of nematode gene unc-76. UNC-76 was shown to be necessary for normal axonal bundling and elongation within axon bundles in the nematode
14-3-3 eta: 14-3-3 family member proteins are known to regulate PKC activity, exocytosis and the cell cycle [
Syndecan-3: Syndecan-3 is known to be a direct binding partner of the peptide Y-P30, which crosses the blood-placenta barrier and accumulates in foetal cerebral neurons. There, it enhances survival of thalamic neurons and displays neuritogenic activities [
Ataxin-7-like protein 3: Ataxin-7-like protein 3 is reported to be a component of the TATA binding protein (TBP)-free-TBP-associated factor (TAF) complex/suppressor of yeast transposable elements (SPT) 3-TAF9-general control non-derepressible (GCN) 5 acetyltransferase (TFTC/STAGA) complex [
G-protein-coupled receptor 37 (Gpr37): Northern blot analysis revealed that Gpr37 is expressed in the central nervous system (CNS) [
ZW10 interactor (ZWINT): ZWINT is thought to be a component of the kinetochore [
Significantly downregulated genes were classified into two groups with respect to their functions. The first group encodes proteins that are reported to be detrimental to neuronal cells.
Complement protein C1q beta: C1q is the first component of the classical complement pathway (CCP).
Rab6b: Accumulation of aggregation-prone proteins activates protein quality control mechanisms, in order to prevent toxic activity. An important site for protein quality control is the endoplasmic reticulum (ER). RAB6 is a small GTPase that is involved in vesicular transport and mediates a coat protein 1 (COP1)-independent, retrograde trafficking route from the Golgi to the ER [
Visinin-like Ca2+ binding protein-1 (VILIP-1): VILIP-1 is a member of a superfamily of neuronal calcium sensor proteins [
These genes were reported to be important for oxidative metabolism.
Cytosolic malate dehydrogenase (cytMDH): Malate dehydrogenase (MDH) catalyses the NAD/NADH-dependent inter-conversion of malate and oxaloacetate in the cytoplasm (cytMDH) and mitochondria (MitMDH). cytMDH is a part of the malate-aspartate shuttle, controlling the brain mitochondrial NADH/NAD+ balance. Impairments in this shuttle may enforce anaerobic metabolism [
Oxidation resistance 1 homologue: The oxidation resistance 1 (Oxr1) gene was discovered in a search for human genes that function to protect against oxidative damage [
Adenylate kinase 3 (AK3): AK3 is present in the mitochondrial matrix and functions in transferring the high-energy phosphate to AMP from GTP synthesized by the TCA cycle. The ADP thus generated can then be phosphorylated to ATP by oxidative phosphorylation. Therefore, AK3 function may be a cellular coping mechanism for energy demand in the brain. It is reported that AK3 protein increases ~10-fold during neural differentiation [
X-linked phosphoglycerate kinase 1: Phosphoglycerate kinase 1 (PGK-1) is the enzyme required in the sixth step of the mammalian glycolytic pathway. It is reported that PGK-1 is upregulated by low oxygen tension. It is reported that the lack of functional HIF-1 complex completely abrogates the response of PGK-1 to hypoxia. Increasing evidence shows that this enzyme is a multifunctional molecule. PGK-1 can affect DNA replication and repair in the mammalian nucleus [
Our study demonstrates the following points:
CsA appears to affect the expression of many genes related to neuronal cell survival and regeneration. Many of the significantly upregulated genes identified in the present study are reported to be neurotrophic or have roles in the regeneration of damaged neurons. CsA reduces the expression of some genes that were reported to be detrimental to neuronal cells. CsA reduces the expression of certain genes that appear to be important for oxidative metabolism.
CsA appears to affect the expression of many genes related to neuronal cell survival and regeneration.
Many of the significantly upregulated genes identified in the present study are reported to be neurotrophic or have roles in the regeneration of damaged neurons.
CsA reduces the expression of some genes that were reported to be detrimental to neuronal cells.
CsA reduces the expression of certain genes that appear to be important for oxidative metabolism.
All of the significantly upregulated genes identified in our study are reported to be neurotrophic or to have roles in the regeneration of damaged neurons. EF-1-gamma, Syndecan-3, and Ataxin-7-like protein 3 are reported to have trophic effects on cells. SCD2 helps to generate the myelin sheath. CCT is a molecular chaperone and is reported to be involved in vesicular trafficking and neurite development. FEZ1 is known to stimulate neural differentiation of PC12 cells. The 14-3-3 family of proteins has an anti-apoptotic effect. GPR37 plays significant roles in brain development and human disease. Also, ZWINT is involved in faithful chromosomal segregation and pre-synaptic events in hippocampal neurons. In contrast, although three significantly downregulated genes (complement protein C1q beta, RAB6B, and VILIP-1) are known to facilitate the cell death pathway, expression of the other four genes is not reported to be detrimental to neuronal cells. cytMDH, OXR1, AK3, and PGK-1 are all related to oxidative metabolism.
Oxidative metabolism regulation is very important to neuronal survival, especially in ischemic conditions or during the process of ischemia-reperfusion injury. At least under normal conditions, cytMDH, AK3, and PGK-1 are thought to be important for energy production in the brain. In addition, the transcription of two genes (AK3 and PGK-1) is reported to be positively regulated by hypoxia-inducible factor-1 (HIF-1). However, it is possible that the expression of these genes increases ischemia-reperfusion injury by producing oxidative stress. On the other hand, OXR1 is known not only to be induced by hypoxia but also to have an important function in protecting against oxidative damage [
There is a report that immunosuppressive drugs are neurotrophic [
One possible mechanism that could solve this inconsistency is that an unknown factor resides in mitochondria and detects the MPT pore opening regulated by CypD, and then this factor translocates from the mitochondria to the nucleus and affects transcriptional regulation. A knockout study found that CypD deficiency worsened hypoxic-ischemic brain injury in neonates [
PHB1 is a 32 kDa protein that belongs to a family of proteins that share an evolutionarily conserved stomatin/prohibitin/flotillin/HflK/C (SPFH) domain. It is closely related to PHB2, also called B-cell receptor-associated protein 37 (BAP 37) and repressor of estrogen receptor activity (REA). The prohibitin amino acid sequence is highly conserved across species [
A model of signaling pathways includes hypothetic transcriptional factor (red ellipse) downstream from CypD (green hexagon). Mitochondria have a special protein pore that is formed in the membranes under certain pathological conditions, such as traumatic brain injury and stroke. This pore is the mitochondrial membrane permeability transition pore, or MPT pore. CypD is a modulator of this pore. VDAC (voltage-dependent anion channel) (blue cylinder) and ANT (adenosine nucleotide translocase) (yellow cylinder) are main components that constitute the MPT pore. An unknown factor resides in mitochondria and detects the MPT pore opening regulated by CypD. This factor then translocates from mitochondria to the nucleus and affects transcriptional regulation.
Brain protection therapy is urgently required. In pre-clinical studies, over 1000 potential neuroprotective therapies have been trialed targeting some of the molecular events described above, with many of these treatments providing protection [
The causes of the failure must be diverse. The effects of drugs may differ between animals and patients as a consequence of the differences in body sizes, circulatory systems, or brain physiologies. Or there may be a difference between the artificial animal ischemia model and human ischemia due to natural causes. Also, it is quite possible that pharmacological target molecules or events are inappropriately chosen in the failure cases. In this case, we have to seek out new drug targets that are different from those that were not successful.
CsA has a unique feature in that it targets mitochondrial dysfunction. Its action on MPT is gaining attention from many researchers. Given such circumstances, a new phase II clinical trial, "CsAStroke", has begun, with the aim of evaluating CsA's effect on the volume of cerebral infarction after intravenous thrombolysis [
Our findings revealed that, in rat brain, CsA appears to regulate the expression of many genes related to cell survival and regeneration. If we specify the transcriptional factor(s) responsible for this regulation, we should be able to mimic this transcriptional regulation without using CsA. Also, the characterization of this "survival pathway" may lead us to identify a novel system similar to neurotrophic factor signaling or an anti-apoptotic pathway. Consequently, CsA effects on transcriptional regulation and characterization of the genes discussed in our study will facilitate the development of new conceptual and pharmacological tools that target the activation of a novel neuroprotective mechanism based on the function of (still unidentified) transcriptional factor(s), such as PHB1 or similar molecules. On the other hand, we still do not know which transcriptional factor or factors is or are responsible for this CsA effect, nor have we tested known factors, such as calcineurin. We have not yet performed cDNA subtraction using FK506 to test the effect of calcineurin inhibition. Further investigations are required to figure out the mechanism underlying CsA's effect on transcriptional regulation.
Alzheimer's disease
amyotrophic lateral sclerosis
adenosine nucleotide translocase
brain-derived neurotrophic factor
classical complement pathway
Cyclosporin A
granulocyte-colony stimulating factor
Huntington's disease
hydroxyeicosatetraenoic acid
hypoxia Inducible factor-1
middle cerebral artery occlusion
malate dehydrogenase
mitochondrial membrane permeability transition
multiple sclerosis
nuclear factor of activated T-cells
poly ADP-ribose polymerase
Parkinson's disease
phosphoglycerate kinase 1
subarachnoid hemorrhage
spinal cord injury
signal transducers and activator of transcription 3
traumatic brain injury
voltage dependent anion channel
voltage-dependent calcium channel
I wish to thank Ken-ichi Yamamura for giving support to this study. I am grateful to Bo K. Siesjo and Tetsuyuki Yoshimoto for their special contributions to our project. I also thank Yuriko Kawakami for her technical assistance.
The author declares no conflict of interest.


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subset: commoncrawl


text:
Best Of :: People & Places
Who needs Tim and Willy? (Well, neither of the Valley's big country radio stations, apparently.) KNIX 102.5 FM's morning guys, Ben Campbell and Matt McAllister, have been holding down the fort for several years now, while KMLE 108 FM continues to shift through hosts for its morning show. In a time-slot that's been the basis of competition between the two stations for quite some time, Ben and Matt are now kings, especially since they're no longer in competition with their predecessors. For the kicker, KNIX still has Barrel Boy, who may just be the most iconic figure in Valley country radio right now. Sure, his most useful role is being the hefty dude who wears a barrel in public, but he's been a staple at big-time country concerts and other events in the Valley for some time now. The difference in programming between the two big country stations may not be huge, but personality still matters.
We'll admit to being influenced by repeated viewings of Wes Anderson's The Fantastic Mr. Fox on Blu-Ray, but still, we swear we've seen the mythic "Tempe Fox" prancing around the Broadmor neighborhood. He's usually spotted just out of the corner of our eye, always leading to the distinct possibility that we're imagining him completely. But forget reason — of all Arizona's fabled creatures (chupacabra, hoof-man, the Bigfoot in the Apache/Sitgreaves Forest), the fox seems the friendliest (not to mention most plausible). His bushy tail catches the eye, but he's quickly gone before you can whip out your camera phone. It sounds crazy, but we've even heard of one intrepid photographer who snapped off a couple shots, only to have the mysterious fox not show up in the pictures at all. A spirit vision, perhaps? The best part of this "legend," of course, is that it's absolutely true. The old neighborhoods near the ASU Tempe campus really have become home in recent years to several foxes. Residents theorize that they feed on roof rats and hang out near the George Ditch off College Avenue and 14th Street. Tempe officials confirm they're there, and no one knows how it happened. We're glad to know the Tempe Fox is real. (And that we're not crazy!)
Know any good jokes about Arizona State University? The folks in Hollywood certainly do, as Tinsel Town has dispensed a few zingers at ASU's expense over the years, all of which have been dead-on and absolutely hilarious. After all, there's plenty about the school to poke fun at, including its oft-ridiculed status as one of America's top party schools and its student body's reputation for preferring slamming beers to hitting the books. For instance, 30 Rock's resident blowhard Jack Donaghy (played by Alec Baldwin) stated in a 2010 episode that "a parent is the one person who thinks their [kids are] smart, even when they go to Arizona State." Zing. Such a diss was child's play to the sort of lampooning that took place last fall when Daniel Tosh filmed an entire episode of his popular Comedy Central show at ASU.It was part of his Tosh.0 College Campus Invasion and featured segments in which the acerbic comedian satirized frat boys and their tendency to hit on drunk girls (at Casey Moore's, no less), encouraged Sun Devil hotties to consume peppers and other spicy substances, and got naked in front of a biology class. Probably the most hilarious (or embarrassing) bit for ASU students was a highlight reel of a "Tweet and Greet," in which an endless stream of student traded insults with the Tosh, who got a choice quip about how "There's a lot of chlamydia here, apparently." At least he didn't refer to the university as "the Harvard of date rape," like those rascals over at The Daily Show.
In 2012, Frank Ocean made waves by coming out on his Tumblr page, gently shattering the glass ceiling in the notoriously homophobic circles of hip-hop and R&B. But he did more than that with the song "Thinking Bout You." He finally let the rest of the country know that it doesn't rain much here. "It usually doesn't rain in Southern California / Much like Arizona / My eyes don't shed tears/ But, boy, they bawl when I'm thinking 'bout you," Ocean sings with achingly gorgeous tone. In all seriousness, Channel Orange, Ocean's full-length, major label debut is one of the year's finest, and "Thinking Bout You," which effortlessly recalls the perfection of Prince and D'Angelo, is one of the record's most affecting moments. With a cracked falsetto, Ocean croons, "Do you think about me still? Or do you not think so far ahead? 'Cause I've been thinking about forever." It's crushing, a moment of pure soul-rending, and even if Arizona feels like a default rhyme, it's nice to be a part of such an astonishing pop song.
Coming up with a decent band name has never required particular brilliance. Just ask the "greats" — The Beatles, Led Zeppelin, The Smashing Pumpkins. But in the Internet age, there seems to be some sort of "WTF band name" arms race, with bands like fun., oOoOO, Snake! Snake! Snakes!, and Friends all competing to cram in enough punctuation and inscrutable capitalization to make it impossible to find the band in any given search engine. North Dakota — the Tempe-based trio of Michelle Blades, Mo Neuharth, and Emily Hobeheidar — don't have a hard moniker to spell, but it's still tough to find their web presence without a little Facebooking first. The geographical connections to the Midwest aren't made explicit on the trio's debut (there's a song called "Fargo," but also one called "China/Japan") but like their namesake state — so close to Canada that it's almost there — they blur the lines between borders and sounds, toeing the line between righteous indie rock and riot grrl screeds.
The Compound Grill — the music hall/eatery/bar launched by the people behind the annual The McDowell Mountain Music Festival (and the site of the festival since 2010) — may have closed, but there's good news: Its owners plan to continue the festival, which unites indie rockers, local bands, and some of the granola-crunchiest jam bands this side of Bonnaroo for three days of sun and noodling guitar solos. Bully for them — beyond the fact that the festival has hosted bands like Ozomatli, The Flaming Lips, Edward Sharpe and the Magnetic Fields, and The Carolina Chocolate Drops, it's maintained a spirit of community activism, donating to charities like Ear Candy and institutions like Phoenix Children's Hospital.


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Alternatively you can use a cloud hosting provider such as Amazon or Rackspace. If you choose to use a cloud hosting provider please consider the following:
- Email service provider: Your exchange server will need to have the cloud server whitelisted to allow email notifications to be relayed. This may require that the Cloud hosting provider and the Exchange service provider work together to set this up.
- AD Sync: In working with a current customer who recently migrated to a cloud hosting solution, they moved their Active Directory domain controller to a cloud hosted solution. It may be required that you setup a VPN tunnel between your cloud intranet server and your local network. The intranet server will need to be joined to your domain.
- SSL: As you are hosted through the cloud, it may be best to set up SSL on your cloud server to encrypt communication, particularly if you externalize your intranet server.
- Web services: our software communicates with our Web Services which are sent out constantly with updates for any product updates (patches/upgrades) as well as to keep you updated on your maintenance status. This will require the web server to allow traffic using port 443 to the web services URL.
We recommend reading our blog: Who Should Own Your Intranet? For advice and best practices on delegating intranet responsibility internally.
In short, no. Our Intranet Software contains both business features, which assist in improving and streamlining business processes and decreasing internal costs, as well as social features, which assist in improving employee engagement, enhancing intranet adoption and encouraging collaboration. However, you can turn off our social features at any time and still reap the rewards of implementing a business intranet. For more information on whether social is right for your business visit our Blogs section.
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I believe this is the right time to adopt student mobile devices and social media in the classroom. Recently I listened to W. Scott Lewis JD, an authority in managing classroom learning environment and student behaviour. He shared that cell phones do not have a place in his classroom because they often create distraction and compete for student attention. In my classroom I encourage students to use Twitter for note taking on both computers and cell phones. This serves as a memory aid as well as helps in creating Personal Learning Networks.
Students sharing subject matter findings on Twitter and following specialists in their field not only increase engagement and time on task ( mobile devices allow them to check updates on many occasions ), but they also build their professional reputation. In technology fields this is very important and may play a role in the hiring process. Seeding such Personal Learning Networks while still in school is of lasting benefit.
Social media, as any other tool, can be misused. Being an example to students on professional, responsible and effective use of Social Media is in my opinion a responsibility of faculty. Under the guidance of teachers, with tools like Twitter, students can participate in ongoing technical conferences and virtually listen to hallway conversations of industry leaders. They can read magazine articles or internet blogs through many eyes and spend time looking closely only at the crowd sourced articles. Twitter helps in resolving the basic question: "I don't know, what I should know". It provides suggestions on what subject matter authorities find important.


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Medals - Thursday 14 August
24 Aug 2008 7:13 BST
There are 15 gold medals to be won today. All times BST.
Archery (1)
Women's individual:
Juan Juan Zhang (Chn) Gold
Sung-Hyun Park (Kor) Silver
Ok-Hee Yun (Kor) Bronze
Equestrian (1)
Team dressage:
Germany Gold
Netherlands Silver
Denmark Bronze
Fencing (1)
Women's team sabre:
Ukraine Gold
China Silver
United States Bronze
Gymnastics (1)
Men's individual all-around:
Yang Wei (Chn) Gold
Kohei Uchimura (Jpn) Silver
Benoit Caranobe (Fra) Bronze
Judo (2)
Men's 100kg:
Tuvshinbayar Naidan (Mgl) Gold
Askhat Zhitkeyev (Kaz) Silver
Movlud Miraliyev (Aze) Bronze
Henk Grol (Ned) Bronze
Women's 78kg:
Yang Xiuli (Chn) Gold
Yalennis Castillo (Cub) Silver
Jeong Gyeongmi (Kor) Bronze
Stephanie Possamai (Fra) Bronze
Shooting (2)
Women's 50m rifle three positions:
Du Li (Chn) Gold
Katerina Emmons (Cze) Silver
Eglys Yaima Cruz (Cub) Bronze
Women's skeet:
Chiara Cainero (Ita) Gold
Kimberly Rhode (US) Silver
Christine Brinker (Ger) Bronze
Swimming (4)
Men's 200m breaststroke:
Kosuke Kitajima (Jpn) Gold
Brenton Rickard (Aus) Silver
Hugues Duboscq (Fra) Bronze
Women's 200m butterfly:
Liu Zige (Chn) Gold
Jiao Liuyang (Chn) Silver
Jessicah Schipper (Aus) Bronze
Men's 100m freestyle:
Alain Bernard (Fra) Gold
Eamon Sullivan (Aus) Silver
Jason Lezak (US) Bronze
Cesar Cielo Filho (Brz) Bronze
Women's 4x200m freestyle relay:
Australia Gold
China Silver
United States Bronze
Wrestling (3)
Men's Greco-Roman 84kg:
Andrea Minguzzi (Ita) Gold
Zoltan Fodor (Hun) Silver
Nazmi Avluca (Tur) Bronze
Ara Abrahamian (Swe) Bronze
Men's Greco-Roman 96kg:
Aslanbek Khushtov (Rus) Gold
Mirko Englich (Ger) Silver
Adam Wheeler (US) Bronze
Asset Mambetov (Kaz) Bronze
Men's Greco-Roman 120kg:
Mijain Lopez (Cub) Gold
Khasan Baroev (Rus) Silver
Mindaugas Mizgaitis (Lit) Bronze
Yuri Patrikeev (Arm) Bronze


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No. 7 Fort Cherry routs Serra Catholic, 86-19
The No. 7-ranked Fort Cherry Rangers cruised to their most lopsided victory of the year, 86-19, over Serra Catholic on Friday in a Class A Black Hills game.
Fort Cherry (6-1, 6-1) poured it on early, scoring 67 points in the first half and 46 in the first quarter. The 67 first-half points were more than the Rangers had scored in any game so far this year.
The win brings Fort Cherry one step closer to a conference title.
"We want to win this conference. That's our No. 1 goal," Fort Cherry coach Jim Shiel said. "We're taking it one game at a time."
With the game securely out of reach, the two teams agreed to play a 10-minute third quarter and five-minute fourth quarter with a running clock.
Four of the game's first nine plays went for touchdowns, with 27 points being scored within the first three minutes.
Fort Cherry senior running back Koltan Kobrys returned the opening kickoff 88 yards for a touchdown. After Serra Catholic (1-7, 1-6) went three-and-out on the following possession, the Rangers returned the Eagles' punt to the 4-yard line, setting up a Matthew Heslin touchdown pass to Kobrys on first down.
Junior Hamden Wyatt answered with an 85-yard kickoff return touchdown of his own, cutting the lead to 13-7.
Not to be outdone, Heslin threw a 50-yard touchdown pass to Alex Babirad on the Rangers' next play from scrimmage. The Eagles fumbled the ensuing kickoff and it was recovered by Fort Cherry, leading to another Heslin touchdown pass, 26 yards to Zachary Dysert.
Fort Cherry dominated the Eagles on the ground, totaling 443 yards on 27 carries. Kobrys led the way for the Rangers in the first half with 145 yards and three touchdowns on six carries.
After he was pulled midway through the second quarter, juniors Daniel Barley and Garrett Whalen picked up the slack. Barley rushed for 119 yards and two touchdowns on his five carries and Whalen added another 103 and a touchdown on his seven carries.
"We never want to embarrass another team," Shiel said, "but at the same time we get the young guys in and they're playing hard."
The second half started in similar fashion, with the Rangers scoring a touchdown on the first play from scrimmage. However, the touchdown came on the Eagles possession, with Jake Schulz returning a Zac Quattrone fumble 13 yards for a score.
Heslin's first four completions went for touchdowns, the fourth being a 3-yard catch by Whalen.
The Eagles' first offensive touchdown came in the first quarter when Quattrone connected with junior receiver Joe Satira on a 47-yard TD pass. Their other score was on a 45-yard Wyatt run in the fourth quarter.
Gary Horvath is a staff writer for Trib Total Media. Reach him at firstname.lastname@example.com.


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Google Books has the entire text of The Adventures of Tom Sawyer available for download in PDF format. The text is also searchable by word or phrase.
Mark Twain: A Film Directed by Ken Burns. The website that accompanies the PBS film Mark Twain, a documentary directed by Ken Burns, includes classroom activities, selected writings, a chronology of Twain's life, and links to related websites.
The Mark Twain House & Museum. The mission of The Mark Twain House & Museum is to foster an appreciation of the legacy of Mark Twain as one of our nation's defining cultural figures and to demonstrate the continuing relevance of his work, life, and times.
The Mark Twain Project. A collaboration between the Mark Twain Papers & Project of The Bancroft Library, the California Digital Library, and the University of California Press, this website contains reliable texts, accurate and exhaustive notes, and the most recently discovered letters and documents. Its ultimate purpose is to produce fully annotated, digital editions of everything Mark Twain wrote.
Doctorow, E.L. Creationists: Selected Essays 1993–2006. New York: Random House, 2006.
Emerson, Everett. Mark Twain: A Literary Life. Philadelphia: University of Pennsylvania Press, 2000.
Fishkin, Shelley Fisher. Lighting Out for the Territory: Reflections on Mark Twain and American Culture. New York: Oxford University Press, 1996.
Powers, Ron. Mark Twain: A Life. New York: Free Press, 2005.
Twain, Mark. The Adventures of Tom Sawyer. New York: Penguin Books, 1986.
—. Autobiography of Mark Twain. Vol. 1 2010, Vol. 2 2013 (stipulated by Mark Twain not to be published for at least 100 years after his death)
—. Collected Tales, Sketches, Speeches, and Essays 1852–1890. New York: Library of America, 1992.
—. Collected Tales, Sketches, Speeches, and Essays 1891–1910. New York: Library of America, 1992.
—. Mississippi Writings: The Adventures of Tom Sawyer, Life on the Mississippi, Adventures of Huckleberry Finn, Pudd'nhead Wilson. New York: Library of America, 1982.
Ward, Geoffrey C., Dayton Duncan, and Ken Burns. Mark Twain: An Illustrated Biography. New York: Alfred A. Knopf, 2001.


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Let Love Call The Shots
Soap operas love drama with a cheesy soundtrack, but unfortunately, there's a small chorus of haters for As The World Turns. This season the show has broken ground with their two new characters, Luke and Noah, a committed gay couple. Okay, so they've kissed three times on screen and they're already moving in together, but they're so cute…and so controversial. The American Family Association wants people to protest all Proctor & Gamble products (Tide, Crest, and Pampers are among them) because they say the company, which produces ATWT, "promotes the homosexual agenda". To see where America really stands, P&G, who included the gay love story on the show in an effort to show diversity, has set up a hotline. If you want to see more of these two hunks kissing, you can call the number to support Luke & Noah. You don't have to give your name or any information, just a push of a button so they can keep pushing each other's.


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My Lords,
Ladies and Gentlemen,
Dear Friends,
It is a great pleasure for me to address your prestigious assembly
today. It is a huge honour and I must confess : it is a huge surprise. To
what do I owe this distinction? To the fact that I am a Frenchman? Or is it
because I wrote a book on Napoleon? Maybe simply because, like you, I strive
to be an advocate for freedom.
You embody the British legal tradition serving
justice and the common good. You are the guarantors of the Rule of Law and,
therefore, of respect for democracy.
Even though the French are renowned for
their Cartesian approach, I would like to begin with a paradox: never have
democratic values been so widespread
and never have they been so threatened by doubt.
Today, the number of democratic
States is indeed continually increasing:
But democracy seems confronted
by a crisis of confidence within the very countries where it originated.
* * *
1. Let us be guided by two principles : firmness and rigour. Firmness in the
face of threats, and rigour in our commitment to uphold the very principles
of democracy: freedom, respect and justice.
From the outset, both our democracies have faced this fundamental tension;
how can we guarantee the freedom of individuals while imposing upon them the
necessary constraints of society?
As soon as they stray from either of these imperatives of
safety and freedom, democracies are fragile.
There as well as here,
democracy is never secured for good. It requires the constant struggle of
women and men who believe in it.
* * *
2. Today, this difficult balance between freedom and security is being put
to the test.
The 9/11 attacks have ushered in an era of fear in our countries. And everybody
knows that fear is democracy's worst enemy.
threats we are all confronted by cannot but fuel this feeling of fear. Indeed,
they follow radically new rules.
Overall, we knew of specific, local and temporary threats.
We now feel a general, global and continuous threat. Faced with this new reality,
our fellow citizens'
expectations are high. They require from governments a keen sense of their
responsibilities and the ability to strengthen security measures without undermining
individual freedoms.
3. The first priority is to reaffirm the authority of governments.
Let our
two countries be in the forefront of the battle against all forms of crime
and threats. My friend David BLUNKETT and I have already shared our
views on this key issue and agreed for the most part. Let us adapt to the
world as it evolves.
Against terrorism first:
Second, we must tackle Organized Crime:
Third, we must
also join forces against cybercrime
Fourth, I want to mobilize new tools
against illegal immigration networks,
which supply illegal workers and women for procuring networks:
battle against crime is important.
Yet, and this is the main point I want
to make tonight, this necessity for an efficient fight against crime must
not lead us to forget the fundamental
rules of democratic life.
More than ever, we must respect our values.
When confronted with barbarism, dictatorship or violence, democracy is strong
because it refuses to use
the same tools as the opponent. It is strong because it has in-built checks
ensure its decisions are regularly reviewed. It is strong because it respects
self-imposed rules:
Let me stress this again, efficiency ensures the necessary respect of our
core values : we will not tolerate databases created to address protective
and security issues being used for other purposes. I will see to it that
this principle is strictly respected.
At the heart of this new system,
we must therefore rely on the Courts to exercise the necessary control on
government decisions and acts, and
make sure that
these respect basic human rights.
This is an essential part of the right
balance which we strive to find.
Let's look our world straight in the face:
We are confronted by many of these issues not only at the
national level but at the European level. Therefore, the drafting of common
strategies must be
part of our response. That requires some degree of approximation, for example
to ensure interoperability or greater dialogue between Courts of different
countries. It also requires the strenghtening of common instruments, such
as Europol and Eurojust. Let's be pragmatic, but pragmatism must not
be an excuse for minimalist action into this key area. What is at stake, here,
is not ideological battles but the security and basic freedoms of our citizens.
original aspect of building Europe is, precisely, to start from the needs
of citizens and devise common, concrete, methods of cooperating. That means
cooperating in Europe when the relevant problem affects the whole of Europe.
This is why it constitutes a true testing ground for modernity, a model
for the future organisation of the world.
The main task, now, is to promote the widest
possible use of those operating rules. Europe, when united, has enough authority
to make itself heard and
to press for the universal respect of the principles and methods it is committed
Ladies and Gentlemen,
In France, probably as well as in Britain, we are aware that we're living
in difficult times. Politics are in need of a new compass.
But we often forget
that this hardship is also a new opportunity: an opportunity for governments
to prove their sense of responsibility, an opportunity for
citizens to reaffirm how committed they are to democratic principles.
has to seize this opportunity to set an example, to make heard the voice
of responsibility, the united voice of peoples all over the world, the
voice of faithfulness to the human condition itself. A hundred years after
the Entente Cordiale, France and Britain can once again, through their exemplary
cooperation, show the way and together plough the furrow of freedom.
In saying
this, I am thinking of the "Lettres sur la Nation anglaise",
that Voltaire published in 1733, in your language, after his two and a half
years of exile in England. He discovered here the virtue of tolerance and
praised your political mores, celebrating in your country "the temple
of liberty ".
Today, between our two nations – I feel it after
my few hours of exile – the
fascination is still intact. Coming to France when you're British, like
coming to Britain when you're French, means being prepared to face new
surprises. There is indeed between us this mirror of strangeness, this inexhaustible
well of mystery which is the source of all true passion. Between you and us,
there will be many more centuries of Entente Cordiale.
Thank you.
Faculty of Laws - University College London - Bentham House
- Endsleigh Gardens - London WC1H 0EG - +44 (0)20 7679 2000 - Copyright © 1999-2005


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Posted on May 14, 2013 by: acid stag
It's finally here! Stream the most hyped album of this decade: Daft Punk's Random Access Memories.
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In snow and cold conditions, the home side were dominant in the set piece and with a strong driving maul that Hill conceded his team had failed to contain.
And with Exeter Chiefs next up at Sixways on Saturday he admitted his Warriors would have o work hard to get that part of their game right.
"On a day like today neither side were going to score tries from open play. It was too wet and the hands were so cold. Teams were going to score by kicking well and having a good scrum and driving maul," said Hill.
"I thought the half backs for London Irish kicked very accurately and put us under a lot of pressure, unfortunately our half backs didn't have the same accuracy.
"The driving maul was very efficient for them. We had worked hard at that, but today we came off second best. They were able to drive us at will and they scored two tries from a drive and the third from a scrum came after another.
"We had numerous opportunities five or ten metres out from their line, far more than they did, and failed to do the same.
"I am disappointed and we are all very disappointed because we have worked hard on our mauling strategy, but today when we needed it in wet conditions it didn't happen.
"We targeted this to try and break that away run, but the first 20 minutes we have conceded two tries to driving mauls," he added.
"On a day like today, when it was a big day for them, we fuelled the crowd and fuelled the Irish players. You've got to keep the crowd quiet and play well and start well - but it didn't happen.
"On wet days it is a battle of the forwards, if you win that and your half backs kick well it is not rocket science - you win the game. But we didn't have a strong enough platform and didn't kick well enough.
"We have got ourselves in a better frame of mind and work harder. The pitch at Sixways next week will be heavy, we've had rain and snow, and we have got to be ready for that sort of game."


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Baseball notes: West players able to enjoy the thrill of victory
As the West Pioneers closed in on a victory over South in a doubleheader opener Tuesdayat Westubran, Devin Daignault experienced the calling of senior leadership.
"We were pretty excited," said Daignault, a utility player whose primary duties are at first base and pitcher. "We had to calm them down a little bit, get them in the right mindset and get through it."
History hasn't been kind to the Pioneers' baseball program. But West flipped the script on a 122-game City League losing streak, defeating South 10-2 for its first victory in league play since April 2006.
South salvaged a split with a 16-7 victory in the nightcap, but the Pioneers (1-7) still welcomed the relief from a league victory drought that began when Daignault was in the fourth grade.
"I'm glad they got to experience what it's like to win," said West's first-year coach, Jeff Hoover, who played for the Pioneers in the early 1980s. "Man, do these kids need that. If you go out and bust it every day and don't see results, imagine what that's like."
West was 2-19 last season, sweeping a non-league doubleheader against Sunrise Academy for the program's first victories since 2007. City League victories have their own significance for the Pioneers, though. After Tuesday's split, West has won just eight of 255 league games since 1998, according to league archives.
In the Pioneers' victory over South, Daignault fueled a big inning with a three-run triple, and sophomore Devan Extine pitched a complete game.
"Coach has provided a motto to the team that when we're hitting, pass the torch," said Daignault, part of a senior trio that includes outfielder Irving Henriquez and transfer infielder Bobby Tager. "I believe that we got that implemented in that inning."
For Hoover, who played collegiately at Barton Community College and Emporia State, the seeds of victory are sown in practice. His regimented workouts and high demands have produced some attrition of players since the start of the season, but Hoover sees signs of improvement.
"It's no different than dealing with your own kids," Hoover said. "If expectations are high, then kids will raise their level. We try to hold the kids accountable when they're doing things good or bad."
Daignault, whose father, Phil, is West's athletic director, started the second game on the mound and was staked to an early lead. South used a nine-run inning to turn momentum in its favor.
Still, one victory represents evidence of an ongoing effort to alter the athletic fortunes at West. Daignault was the kicker for the Pioneers' playoff qualifying football team last fall, and qualified for the state swim meet during the winter.
"I just want to get us what we can and have a great senior year," Daignault said.
Change at the top – A strong reliance on youth and a team batting average under .200 have contributed to a 1-5 start for McPherson.
The Bullpups have also dealt with a sudden coaching change.
Longtime assistant Grant Myers was appointed as McPherson's interim coach Mondayafter Steve Williams resigned following complaints about his treatment of players. Williams, who coached Hutchinson to 277 victories from 1989-2010, was in his first season with the Bullpups.
Williams, who had served as an assistant at McPherson College prior to his hiring at MHS, was suspended March 31 after the Bullpups split a season-opening doubleheader with Rose Hill. McPherson, which plays its home opener Thursday against Circle, has since lost doubleheaders at Andale and Winfield.
"Coach Williams is a friend of mine still," Myers said. "We have closure now and we're moving on. There are a few things that you tinker with as a coach, but for the most part, it stays pretty much the same."
McPherson has three seniors and two juniors on its roster.
"By the end of the season, I think we can be pretty good," said Myers, whose team is scheduled to play its next 10 games at home. "We knew with our youth it was going to be rough early. As far as the kids go, they're resilient and they'll get after it."


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Good Morning, Hilary Duff, And Other News
- We get to see Angelina Jolie's new boobs on Sunday. [Lainey Gossip]
- Ellen Page's publicist wants you to believe Alexander Skarsgard turned her straight. Sold. [Dlisted]
- There's a Towel Thursday now? [theCHIVE]
- James Lipton used to be a pimp. An actual pimp. [tooFab]
- Why The Return Of "Arrested Development" Brought Out The Worst In Everybody [BuzzFeed]
- I honestly thought this was Megan Draper in lingerie for a second. [Popoholic]
- UPDATE: Elizabeth Olsen is still the hotter Olsen spawn. [Hollywood Tuna]
- Kelly Brook is selling AXE now, so give me three cases of Extreme Douche Sunrise and two Bro Dawg Musks. [DrunkenStepfather: Site is NSFW]
- Tom Hardy will see Christian Bale and raise him a diamond necklace… [FilmDrunk]
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text:
of Attraction
Starring: Julianne
Moore, Pierce Brosnan, Parker Posey and Michael Sheen
Directed by: Peter Howitt
speaking? Laws of Attraction is nothing more
than Romantic Comedy 101 curriculum. However, in the cookie-cutter-esque
roles of he and she on the way to romance, via comedy, are four
very talented people, (Julianne Moore, Parker Posey, Pierce Brosnan
and Michael Sheen) that make the film actually enjoyable. And
once you've recognised the common variety of spotted Hollywood
Comediac Romantisaur before you, you can just let go, relax and
watch the fine specimens relate in their confined habitat.
Story goes... Audrey Woods (Julianne Moore) is a successful divorce
attorney. She's got it all...well accept a love life - natch.
Well that right there is going to change boys and girls!
a uneventful case brings her face to face with disheveled cutey
and super attorney, Daniel Rafferty (Pierce Brosnan) the sparks
fly, or should I say flies spare? The two have that immediate
gonna-be-in-love-in-a-week distaste for each other as the attempt
to re-create Hepburn and Tracy jousts in the court room...
a rock and roll mega-divorce involving a spoiled designer (Parker
Posey ) and a poser punker (Michael Sheen), divides Audrey and
Daniel professionally, they find themselves thrown together romantically.
two end up in Ireland, in a fairytale castle, and in the middle
of the world's most romantic Irish festival. Fast then you can
say, "Blarney to ye Flanigan," and after a few wee tinkles
of the tap, the two find themselves married! (Audio hint: insert
a Lucky Charms guy voice for affect/effect here please->)
Oh, my now howyda be tinkin' that there happen ya floogerts?
We all watch
the formula unroll and viola! the plot she arrives with a perfect
little pink bow.
Posey, who may be one of the most underrated talents working in
film, positively steals her scenes from the ever-glowing Julianne
Moore. Parker just takes over with her natural ability to be outrageously
funny - standing at the edge of over-the-top - yet be completely
conceivable and somehow physically stunning.
And Ms. Julianne,
a trumpeted talent, shows you there's no genre she can't tackle.
She's an acting chickbabe of rare talent. Her delivery of some
expected lines show you why some are stars and some work in Road
The men offered for our viewing pleasure come in two completely
different yet delectable categories ...you get the manly man matured
port in Pierce Brosnan....a fellow that makes you want to add
the "age" to Bond...if you know what I mean....and I
think that you do. And you get the bad boy rock and roll dreamscape
complete with naughty accent in Michael Sheen). Purr.
So, while the film makes no attempt to be remotely original it's
still a fun, downright enjoyable, evening at the motion picture
theater. It's most definitely a chick-flick and more for the over
25 crowd....enjoy.
Snack recommendation:
Irish soda bread and Brioski
The TEE NOW!
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Come and experience a casual dinning environment that provides an assortment of Asian inspired baked goods, sandwiches, and specialty drinks.
Vegetarian Menu
To accommodate those who prefer non-meat products (by request).
- Fresh-Squeezed Sugar Cane
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text:
Mandela calls for renewed fight against TB
Page Tools
Nelson Mandela smiles after delivering his speech at the 15th International AIDS Conference.
Nelson Mandela has called for the battle against tuberculosis to be stepped up, saying the fight against AIDS is incomplete without targeting the lung disease.
"TB is too often a death sentence for people with AIDS. It does not have to be this way," said Mr Mandela, who successfully battled tuberculosis while in prison during the apartheid era.
The Nobel laureate spoke to reporters at Bangkok's International AIDS Conference.
Tuberculosis is one of the most common diseases to attack AIDS patients after their immune systems have been destroyed by the virus. Many people with HIV die prematurely from TB because they are not treated in time.
"The world has made defeating AIDS a top priority. This is a blessing, but TB remains ignored," said Mr Mandela, who is 86 on Sunday.
He noted that mankind has known the cure for TB for more than 50 years, but said that what has been missing is the "will and the resources to quickly diagnose people with TB and get them the treatment they need".
"We can't fight AIDS unless we do much more to fight TB as well," Mr Mandela said to loud applause by scores of activists, admirers and staff, who joined the packed news conference - the most well-attended at the six-day conference.
Lights were turned down low and photographers were asked not to use flash to avoid discomforting the ailing former president of South Africa.
During his 27 years in prison under the apartheid regime, Mr Mandela had a brief bout of tuberculosis and a prostate operation. He also had an eye operation in 1994 that repaired tear duct damage caused from crushing limestone rocks while in prison.
He recounted that when he was diagnosed with TB "there were long faces" among his friends, who did not want him to disclose his illness to others.
He said he was cured in four months, and urged other TB patients not to be embarrassed about disclosing their illness.
Worldwide, one-third of people living with HIV are co-infected with TB, which causes up to 40 per cent of AIDS-related deaths.


text:
Jones Snowboards, an award-winning snowboard brand created by professional big mountain snowboarder Jeremy Jones is proud to introduce a line of women's boards for the 2012/2013 season. In the true spirit of Jones Snowboards the women's series is designed for freeride progression of the highest order.
"Since the first day Jones Snowboards hit shops I've been asked by the ladies, 'Where are the women's boards?'" says Jeremy Jones. "We built Jones' women's boards to combine the characteristics and offering's of the men's line with the dimensions demanded by our team of amazing female freeriders."
Jones women's diverse team includes: Holly Enderle winner of King of the Hill in 2011, who has been riding the Mothership extensively this year; Liz Daley, a splitboard mountaineer riding the Women's Solution; Bibi Pekarek, who will appear in Jeremy Jones' new film "Further" coming out this fall and Callan Chythlook-Sifsof an Alaska-native, who competes in X Games Boardercross and is a member of the US Snowboard team.
The debut women's line from Jones Snowboards focuses on big mountain freeriding, powder, all-mountain versatility and a splitboard model for going deeper into the backcountry with ease. The three models are a direct evolution of one of the men's models, but with customized sidecut, flex, length and waist widths.
The Mothership is an ash-wood topped beauty built for women who fiend for steep terrain and fast lines. Mellow Magne-Traction keeps the Mothership solid on ice, while the blunt nose, directional rocker and camber underfoot deliver the float and stability to bomb rowdy terrain.
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Find Jones Snowboards women's collection in specialty snowboard and outdoor stores worldwide starting in fall 2012. Learn more about Jones Snowboards new women's line at jonessnowboards.com.


text:
How would people answer the following question;
what does good customer service mean to you/
You are Here: Home > Forums >< Careers and Jobs >< Career sectors and graduate employment
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- 25-09-2007 21:00
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- 03-10-2007 09:22
I would answer it with something like:
"Establishing when there is a problem. When one arises, then dealing with it as swiftly and efficiently as possible, to the satisfaction of both the customer and the company. If possible, I would also find a way to exceed customer expectations by going a little bit further for them than they would expect."
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- 03-10-2007 11:44
Okay I have a job interview for this company called Ardington Fulfilment, which is a factory of some sort. I'd be working in a call centre. But I'm dreading the question 'What do you know about this company'? Cos I'm dreading it.... Would something like 'I know you have warehouse facilites that other companies use to store products. You also are responsible for shipping customers items from the wholesalers and you have call centre facilites which I assume are for dealing with feed back and complaints' Would that be ok???
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- 04-10-2007 09:28
Maybe slightly more depth if possible, such as who their main competitiors are, but that will probably be okay.
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- 04-10-2007 12:02
Ah good I had the interview and it was v.informal they didnt ask me thank God!
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- 14-11-2007 13:21
I just posted this in the other thread, but I found this video on interview technique given by that bird out of Brookside at the bottom of this page
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- 22-11-2007 10:47
Another one is:
Have you applied any where else?
I got asked that in my TopShop interview yesterday. Didn't know whether I should be honest or not
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- 23-11-2007 22:08
many thanx,very useful
La Trampa
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- CV Helper
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- 69
- 27-11-2007 22:08
great stuff in this thread
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(Original post by pinkpinkuk)
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- 28-11-2007 22:09
I tend to find a good questions to ask them is "What, for you, is the best thing about working here?"
I got a horrible 2 questions the other day:
"Describe yourself in 3 words"
Followed by:
"How would your family and closest friends describe you in 3 words?"
EEK! lol i got the second one
and i got ... How would you handle a customer if they lost their temper ?
i thought that ws a bad one.
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- 13-12-2007 02:31
I hate being asked what flaws you have and to list things you would inprove about yourself... always go in knowing the anwser to these ones!
Nad B
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- 10-01-2008 20:05
Tnx ur da best dis is really good. I had lots of interviews but they all say some one was better than me so don't end up getting it. This will really help in my next interview (if I get one).
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- 30-01-2008 16:34
How would you answer..
'Name a highstreet shop that you think has good customer service and why?'
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- 01-02-2008 10:50
Well the why bit is looking for you to give an example of a time when you were treated well I think. So for example, you could say 'HMV, because when I had a problem finding a CD I wanted, they spent a lot of time searching and then ordering it for me, and ringing me as soon as they had it' etc etc.
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- 04-02-2008 12:03
Any body know how a can impress an interviewer while going for a job for sales executive?
Anything in particular?? I have the interview today.
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- 07-02-2008 14:15
I am doing my dissertation on students going into careers. Here is something I wrote...
Many graduates see going for a job interview as a bit of an ordeal.
Does this describe you?
An interview can be a nerve-racking experience. You want the job you are going for and you are under pressure to perform.
For the better jobs there will often be first, second and in some cases third interviews.
First interviews will follow a brief telephone interview and is used as part of an employer's screening process. Essentially they are 'getting rid of the bad stuff' and trying to find the good stuff (which is hopefully you). Only 20% of candidates get this far.
Second interview tips: Second interviews will look further examine your technical or specialist skills. They will give the chance for the owner, director or senior partner to rake a look at you. You need to be able to anticipate questions you'll be asked, have convincing answers and deliver replies professionally.
An employer will be looking for the following things from you:
- Will this person be able to do the job?
- Will you fit into the team?
- Are you enthusiastic and motivated?
The ability to the job is perhaps the most important part. This can come down to the work experience you have.
You need to guarantee your success by…
• Having extensive knowledge about the organisation you are applying to.
• Having tip-top interview skills
• Making sure you fit well into the job.
• Sell yourself professionally and enthusiastically.
The Interview generally follows a simple structure:
1. There is a formal start, introduction etc.
2. A middle – a carefully timed sequence of questions
3. An opportunity for you to ask questions (you must ask some!)
4. An end.
The formal start – making the right impression
Lets get this right and keep it simple.
You need to have the right appearance and body language. The morning of the interview make sure you clean up good, put on your best suit, a light touch of perfume/aftershave, some brightening eye drops and a good smile.
Wake up with an air of assertiveness, self-confidence and ready for the challenge ahead. Don't mention anything negative about yourself and if your interviewer brings up anything negative, turn it into a positive.
Speak with great communication skills. See the recommended books on NLP if you want to learn some more about this. Body language is important with communication skills. Make sure you sit in an open body position at a slight angle so not to cause confrontation. Lean forward slightly to show interest, main eye contact and relax!
Make sure your handshake is firm but not knuckle breaking.
It's Question Time!
The most common areas to be questioned upon are…
- About you
- About your academic record
- Your work experience
- Your career objectives, dreams and motives
- Your knowledge of the company you are applying for
- Your personal achievements outside work
To break this down further think remember these things:
• When you talk about yourself remember to be positive. Highlight your strengths and remember they will always ask you about negatives. Always turn negatives into positives. For example, you could say you are always too hard on yourself and expect too much from yourself. This is a negative easily turned into a positive.
• When asked about you're A-levels or degree you may be asked why you chose certain subjects. Answer clearly and concisely.
• When is comes to work experience then you are going to be asked questions on your main responsibilities, lessons learnt, what you found difficult, how you got on with your boss etc.
• Make sure you know why you want the job you are interviewing for, what other jobs you have applied to and where you want to be in 5 to 10 years time.
• IMPORTANT! Your knowledge of the organisation. What do you like about the company? What key issues need addressing? Why will you fit in?
• Make sure you have some personal achievements to hand. Travelling the world, charity work, stand up comedian, sports…
Turn the table around! It's your turn to ask some questions!
Some good ones are…
• Is there anything you have heard from me today that worries you that I wouldn't fit into this job role? (You then tell them why they are wrong!)
• Do you like working here? Why do you like it so much?
• What do you think the strengths of the company are?
• What scope is there for personal growth?
• What kind of people would I be working with if I got the job?
MOST IMPORTANTLY your questions should be showing the interviewer that you are very INTERESTED in working at their company. If you act like you are interested and that you have got other job offers and that you are trying to pick the best job for you (rather than them pick you), then you will seem more sought after.
Thank the interviewer, say it was nice to meet them and do the obligatory handshake goodbye.
Make sure you send them a thank you email the next day re-iterating that you enjoyed meeting them and clarifying a couple of your positive points (subtly
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- 18-02-2008 12:26
I have got 'Where do you shop for clothes?' and 'Who are our competitors?' for a jib in Monsoon.
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- 20-03-2008 14:08
Hello, I have an assessment centre next week. I am new to this site. I don't know where to post about my assessment centre. By what means I prepare.
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- 10-05-2008 17:01
Just wanted to say thanks for this thread, due to various factors (mostly chronic illness and being an over-studious nerd) I'd managed to reach the age of 20 without ever having a job-so I was feeling pretty hopeless about finding one for summer. I will now be working full time at Internationale all summer-got offered the job on the spot after my interview.
As well as several questions from the OP, I also got:
Give an example of a time when you have experienced poor customer service
So yes thanks again OP
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- 30-05-2008 16:16
Montrose: excellent thread, can't compete on seriousness so...
Here are some questions I've heard personally been asked and made up just now. If i'm interviewing i just make questions up and see where it takes us... (i've also added some answers, they aren't very good, but i hope they are somewhat funny):
If you could be a fish, what fish would you be? - starfish ('cos
i'm the brightest (joke) - a good answer mind you!)
Why do banks charge a higher "overdraft rate" when they know that there is insufficient funds? - they really like your house
If you had a million dollars how would you spend it? - bail out a bank
What is your motivation in life? - to acquire myself a nice business card with fancy lettering and a nice title under my name. that and the opportunity to pilfer some quality stationery.
What was the funniest thing you have ever experienced? - this interview/ your face/ voice/ last job's pay package
Big Mac's or Whoppers? - whats the difference? they all come from the same pet store.
Questions to ask your interviewer (when you know you aren't gonna get the job. probably cos you gave answers similar to mine lol :
What is it about me that makes you so drawn to me?
Whats the deal with 'I before E'?
How many times have you been naked in public? Elaborate
remeber, no matter how badly the interview is going and how dreadful you are feeling you can always make yourself feel better by leaning across the table and punching the interviewer on the nose.Last edited by uthinkilltellu; 30-05-2008 at 16:20.
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text: 12/05/14 4/13/14 POPSUGAR Celebrity Grumpy Cat Grumpy Cat in Pharrell's Hat at the MTV Movie Awards 2014 Watch Out, Pharrell, Grumpy Cat Has Got Your Hat April 13, 2014 by Maria Mercedes Lara 559 Shares Chat with us on Facebook Messenger. Learn what's trending across POPSUGAR. View on One Page Photo 5 of 6 Start Slideshow ADVERTISEMENT () Share This Link Copy What's Your Reaction? Thanks for your reaction Don't forget to share this with your friends! ← Use Arrows Keys → 5 Previous Next Grumpy CatMTV Movie AwardsRed Carpet


text:
Kids Speak; 6th Graders at Sartell Middle School [Audio]
What are 6th graders thankful for and what is the meaning of Thanksgiving? Listen to 6th graders at Sartell-St. Stephen Middle School talk with Jay Caldwell of WJON.
Annette –
Connor –
Devante –
Dylan –
Greta –
Hannah –
Lauren –
Lexi –
Zach –


text:
Today, I had drunk sex with a girl that I barely know. I didn't have a condom and was nervous about getting her pregnant, but she assured me that I could pull out. Right when I was about to pull out, she wrapped her legs around me and yelled, "BE MY BABY'S DADDY!" I couldn't get out in time. FML
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text:
(2010/01/28 18:21), Takahiro Itagaki wrote: > > KaiGai Kohei<kaigai(at)ak(dot)jp(dot)nec(dot)com> wrote: > >> The attached patch uses one TOC entry for each blob objects. > > When I'm testing the new patch, I found "ALTER LARGE OBJECT" command > returns "ALTER LARGEOBJECT" tag. Should it be "ALTER LARGE(space)OBJECT" > instead? As I remember, we had decided not to use LARGEOBJECT > (without a space) in user-visible messages, right? Sorry, I left for fix this tag when I was pointed out LARGEOBJECT should be LARGE(space)OBJECT. Thanks, -- OSS Platform Development Division, NEC KaiGai Kohei <kaigai(at)ak(dot)jp(dot)nec(dot)com>
Next: From: Ivan Sergio Borgonovo Date: 2010-01-29 00:00:26 Subject: returning array in a field together with other types Previous: From: Peter Eisentraut Date: 2010-01-28 23:22:03 Subject: Re: Review: Typed Table


text:
The Australian cinema has built up a reputation for quirky, low-budget gems, but this comedy-romance succeeds only on the first two counts. Arquette tries hard, but is hopelessly miscast as a dowdy housewife (even with spectacles, you can't believe it) who is whisked off her feet by the man of her dreams (Spence). There's a bit of a twist at the end, and some good intentions, but you'd be better off staying home and reading Mills & Boon.
Release details
|90 mins
Cast and crew
|Michael Pattinson
|Suzanne Hawley
|Rosanna Arquette
Bruce Spence
Hugo Weaving
Kerry Walker


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A data transfer problem of the near future can soon become a thing of the past, according to Athena Wireless Communication, Inc. The company's new A060 Mini Radio, "the world's first all-digital, multi-gigabit capacity, 60 GHz millimeter-wave radio which transfers data at fiber-like rates" could be "the perfect, cost-effective solution" to telecommunication operators' needs for backhaul capacity, Athena Wireless said in a press release Tuesday.
The number of mobile internet users is expected to surpass the number of line-based internet users this year worldwide, and the demand for data on mobile phones is already on the cusp of historical highs. Wireless telecommunication operators will soon be in need of much more backhaul capacity of their cellular base stations and pico cells.
Athena's A060 Mini Radio has a multi-gigabit data capacity designed to eliminate the need to install or lease fiber cable while providing fiber-like speeds for cellular backhaul.
The all-digital radio, measuring 7" X 7" X 3" (including antenna), uses newly developed miniature antenna and RF semiconductor technologies to allow telecommunication providers and businesses to rapidly move to 1.25Gbps full duplex or higher Ethernet backhaul. The A060 Mini Radio is also an alternative to fiber-optic cabling.
"The A060 Mini Radio will fill the need for more backhaul capacity for the telecommunication providers and the enterprise market, and will require little capital investment and low ongoing operating expense," Eduardo Tinoco, CEO of Athena Wireless Communications, Inc. said. "Performing at fiber-like speeds for cellular backhaul, the A060 will enable its users to significantly increase their system capacities for point-to-point deployments and service quality while using both new and existing technology. It's today's answer to tomorrow's problem."