Human ITPase (encoded by the ITPA gene) is a protective enzyme which acts to exclude noncanonical (deoxy)nucleoside triphosphates ((d)NTPs) such as (deoxy)inosine 5′-triphosphate ((d)ITP), from (d)NTP pools. Until the last few years, the importance of ITPase in human health and disease has been enigmatic. In 2009, an article was published demonstrating that ITPase deficiency in mice is lethal. All homozygous null offspring died before weaning as a result of cardiomyopathy due to a defect in the maintenance of quality ATP pools. More recently, a whole exome sequencing project revealed that very rare, severe human ITPA mutation results in early infantile encephalopathy and death. It has been estimated that nearly one third of the human population has an ITPA status which is associated with decreased ITPase activity. ITPA status has been linked to altered outcomes for patients undergoing thiopurine or ribavirin therapy. Thiopurine therapy can be toxic for patients with ITPA polymorphism, however, ITPA polymorphism is associated with improved outcomes for patients undergoing ribavirin treatment. ITPA polymorphism has also been linked to early-onset tuberculosis susceptibility. These data suggest a spectrum of ITPA-related disease exists in human populations. Potentially, ITPA status may affect a large number of patient outcomes, suggesting that modulation of ITPase activity is an important emerging avenue for reducing the number of negative outcomes for ITPA-related disease. Recent biochemical studies have aimed to provide rationale for clinical observations, better understand substrate selectivity and provide a platform for modulation of ITPase activity.
Inosine triphosphate pyrophosphatase (ITPase) has a critical role in sanitizing nucleotide pools by removing (deoxy)nucleoside triphosphates ((d)NTPs) containing noncanonical purines [1–7]. ITPase is a pyrophosphohydrolase and converts noncanonical purine (d)NTPs, such as (deoxy)inosine 5′-triphosphate ((d)ITP), into their corresponding nucleoside monophosphate ((d)NMP); releasing pyrophosphate (PPi)  (Fig. 1). Noncanonical purine (d)NTPs spontaneously arise in cells. In the purine biosynthesis pathway, phosphorylation of inosine 5′-monophosphate (IMP), a precursor to adenosine 5′-monophosphate (AMP) and guanosine 5′-monophosphate (GMP), can produce both ITP and dITP [9, 10]. Additionally, oxidative deamination of adenine containing nucleosides/nucleotides or deamination of guanine containing nucleosides/nucleotides results in the formation of inosine containing nucleosides/nucleotides . In general, evidence supports that ITPase, and its orthologs, prevent the accumulation of noncanonical purine (d)NTPs and are conserved throughout the three domains of life and are even found in viruses [2–4, 12–16]. Research with bacterial, yeast and murine systems has demonstrated that ITPase deficiency and/or polymorphism can result in sensitivity to noncanonical purines, increased mutation rates, delayed cell cycle progression, DNA damage and chromosomal abnormalities such as double-strand breaks [17–21].
ITPase is expressed in all major adult human tissues . Results from Northern blot and cDNA microarray data indicate the highest expression is in the heart, liver, thyroid and thymus . Likewise, mouse Itpa is expressed in all major tissues, however the highest expression levels were found to be in the testis, brain and thymus . Mouse Itpa expression is driven by a TATA-less promoter which has characteristics that suggest it is a ubiquitously expressed housekeeping gene whose expression can be amplified under certain conditions .
Studies in a mouse model suggest that the role of ITPase is highly pronounced in cardiac tissues . Cardiomyopathy in ITPase knock-out mice appears to result from the accumulation of ITP in the nucleotide pools and subsequent utilization of the contaminated pool. Analysis of the nucleotide content of total heart RNA revealed high levels of IMP which were roughly equivalent to 1 % of the AMP level whereas IMP was undetectable in wild-type total RNA samples . Similarly, increased levels of dIMP were observed in DNA harvested from embryos deficient in ITPase . The structural similarities between adenine, guanine and hypoxanthine (hypoxanthine is the nucleobase of ITP) (see Fig. 2), make it plausible that ITP can act as an improper substrate and replace canonical nucleotides in some processes. One study has shown that actomyosin binding of ITP in place of ATP reduces the shortening velocity and rate of force recovery and results in disordered striation during activation . Therefore, an increase in ITP levels could affect actomyosin function, leading to disorganization of sarcomere structure in the developing heart. It is likely that the accumulation of (d)IMP in heart nucleic acids leads to the production of DNA lesions, defective proteins, nonfunctional RNAs and reduced cell proliferation [6, 18]. Because organ development among mammals is very similar , these observations should be highly relevant to humans. The critical role for ITPase in the heart is underscored by the observation that the heart is among the four tissues with the highest ITPA expression in humans .
For any cell in any organism one can imagine that genetic polymorphism could modulate purine metabolism and alter the amount of: hypoxanthine entering the purine salvage pathway, IMP produced from de novo purine biosynthesis, or phosphorylation/reduction of IMP to (d)ITP . In any of these cases, proper function of ITPase would be vital to insure that inosine is excluded from the nucleic acids and nucleotide pools. Concurrent polymorphism in ITPase may lead to pleiotropic outcomes such as DNA damage, interference with gene expression and RNA function, and altered activity for nucleotide binding proteins [6, 17]. Additionally, it is possible that conditions which exacerbate nitrosative stress, such as inflammation, would result in increased deamination of adenine and guanine containing nucleosides and nucleotides; resulting in increased concentrations of (d)ITP . Support for these ideas stem from data we published in 2012 showing that perturbation of purine metabolism in Escherichia coli leads to substantial incorporation of (deoxy)inosine in nucleic acids . Furthermore, an association between ITPA polymorphism and mitochondrial dysfunction has been reported, suggesting nucleotide imbalances may alter mitochondrial function . Altogether, ITPase is an essential protector of homeostasis in the cell, and most likely reduces the occurrence of genome instability, cancer, ageing, and disease in humans.
Below I will summarize several recent studies concerning ITPase biochemistry and clinical outcomes associated with ITPA polymorphism or mutation. The goal of this review is to: (1) strengthen the connection between basic science and clinical studies; (2) summarize the many disparate clinical outcomes that have recently been linked to ITPA polymorphism/mutation; (3) argue in favor of viewing ITPA variation as a disease spectrum; and (4) suggest rationale for modulation of ITPase activity in an effort to reduce the number of negative outcomes for ITPA-related disease.
ITPase is a pyrophosphohydrolase that excludes noncanonical purines from the (d)NTP pools by hydrolyzing the acidic anhydride bond between the alpha and beta phosphates of the incoming (d)NTP (Fig. 1) [8, 28, 29]. A key step in the enzyme mechanism appears to be substrate binding, and ITPase only has high affinity for NTPs containing noncanonical purines (ITP, dITP and xanthosine 5′-triphosphate) [2, 5, 8]. Tight binding of the noncanonical nucleobase in the nucleobase binding pocket of the enzyme allows proper alignment of distal catalytic residues to catalyze hydrolysis of the phosphoanhydride bonds, while interactions with NTPs containing canonical bases result in improper alignment of the proposed catalytic residues and the scissile phosphoanhydride bond, and a much lower rate of catalysis [2–4].
ITPase is an α/β homodimeric protein . Each monomer consists of 194 amino acid residues and the protein forms a 45 kDa dimer . The protein has a central elongated mixed β-sheet which forms a platform to support two globular lobes . ITP binds in a cleft, between the lobes, adjacent to the dimer interface. The specificity pocket is buried deep within the dimerization lobe of each monomer while the catalytic site is toward the periphery, close to the dimer interface in the N-terminal lobe . Catalysis requires Mg2+ [28, 30], and is thought to occur via acid-base chemistry [3, 4], although the specific mechanism has not been elucidated. Maximal activity has been observed with alkaline pH and in the presence of reducing agent such as dithiothreitol (DTT) [5, 28] (see reference  for a review of biochemical studies).
ITPase does not discriminate between the ribose and deoxyribose carbohydrate moiety, and hydrolyzes phosphoanhydride bonds in noncanonical NTPs and dNTPs with equal activity [2, 5]. One study has reported strong positive cooperativity for the E. coli ITPase ortholog, RdgB , however, cooperativity has not been reported elsewhere. Human ITPase is competitively inhibited by inosine 5′-diphosphate, but not NMPs or any nucleoside tested . Interestingly, strong substrate inhibition has been observed in multiple studies using purified ITPase in the presence of elevated levels of ITP or dITP [2, 5, 28]. The enzyme has also been shown to be inhibited by Cd2+, Co2+ and Ca2+ ions .
ITPase has been studied for over 40 years , however, the mechanism employed by ITPase to discriminate between canonical and noncanonical (d)NTPs is not fully understood. X-ray crystal structures of the protein-substrate complex have been solved [3, 4], and several evolutionarily conserved residues have been shown to govern substrate selectivity , but rigorous biochemical validation of the predictions have not been performed. The ITPase substrate specificity pocket is shown in Fig. 3.
An initial site-directed mutagenesis screen of the substrate specificity pocket supported several assertions based on the crystal structure [4, 31]. Experimental design of this screen allowed differences in specific activity to reflect differences in K M and provide surrogate measurements of substrate binding . Based on these measurements it seems that ITPase favors NTPs containing electronegative atoms at the 6-position, such as ITP and GTP over NTPs containing electropositive atoms such as the 6-position amine of ATP. Indeed, x-ray crystallography data suggest that three binding pocket residues have potential for making favorable hydrogen bonding interactions with the electronegative 6-postion carbonyl of ITP or GTP , however, biochemical data indicates Arg-178 as the most crucial residue for this discrimination . X-ray data places Arg-178 within 3 Å (hydrogen-bonding distance) of both the 6-positon carbonyl oxygen and 7-position ring nitrogen atoms of the nucleobase in ITP. In this position Arg-178 would form favorable hydrogen bond interactions with ITP or GTP, but not ATP, which may account for its essential role in ITP detoxification and substrate selectivity . Additionally, mutation of Arg-178 to alanine, or even the conservative arginine to lysine substitution (R178K), prohibits complementation of ITPase defects in E. coli in two in vivo tests. Hence, Arg-178 has been classified as essential for ITPase activity . A substitution to cysteine at this position was identified in a patient suffering from infantile encephalopathy  and will be discussed below.
The ITPase nucleobase binding pocket adopts a topography that is exquisitely complementary to the incoming hypoxanthine base of ITP [3, 4]. While the mechanism for discrimination against adenine containing nucleotides lies primarily in hydrogen bonding capacity, discrimination against guanine containing NTPs appears to be governed by steric hindrance [4, 31]. Phe-149 is the major determinant for excluding GTP from the binding pocket. Mutation to alanine results in a roughly 6-fold increase in hydrolysis of GTP, and a lower level of complementation for ITPase defects in E. coli. Phe-149 is positioned in close proximity to the 2-positon ring carbon of the nucleobase. In GTP, this position is bonded to an exocyclic amine, which is absent in ITP. Thus Phe-149 actively excludes GTP from entering the binding site, and prevents proper alignment of the catalytic residues with the scissile phosphoanhydride bond [4, 31]. Overall, site-directed mutation experiments indicate that modifications which cause slight enlargements of the nucleobase binding site, reduce the level of discrimination afforded by the enzyme.
To date, ITPase biochemistry remains understudied; however, some advances have been made concerning substrate selectivity  and a clinically relevant variant [33–35]. Knowledge gaps exist in the biochemical understanding of ITPase and its specific role in purine metabolism . For example, it is unknown if ITPase has protein-binding partners, if the enzyme is posttranslationally modified, or if it is allosterically regulated. Additionally, the role of substrate inhibition  in cellular function is vastly unknown and may serve to modulate the intracellular concentration of ITP, IMP or even inosine. Support for this idea lies in the discrepancy among data obtained from assays using either purified/recombinant ITPase or whole-cell extracts. For example, Bakker et al. found that ITPase is not subject to substrate inhibition when erythrocyte cell extracts are used as the protein source , whereas enzymology studies using purified/recombinant ITPase as the source of protein reported substrate inhibition [2, 5, 28]. Taken together, these results hint that the level of substrate inhibition for ITPase may be modulated in vivo. Overall, a better understanding of substrate inhibition may serve as a fruitful avenue for therapeutic modulation of ITPase activity (see below). Importantly, for one clinically significant variant, c.94C > A (p.Pro32Thr), a clear biochemical rationale for decreased enzyme activity is known (see below) [33–35].
Over the last decade the pharmacogenetic significance of ITPA variation has been established. In humans, at least thirty polymorphisms have been identified in the ITPA gene [32, 38–44]. To date, seven of the variants have been shown to be clinically relevant (see Table 1) [32, 40–42, 44]. Multiple reports have demonstrated that ITPA status affects outcomes of hepatitis C treatment [45, 46] and thiopurine therapy [36, 47]. Additionally, ITPA mutation has been shown to cause early infantile encephalopathy  and variation has been linked to young-onset tuberculosis susceptibility . Therefore, the spectrum of phenotypes related to ITPA status is full range and spans improved therapeutic outcomes to infantile death.
In 2004 it was estimated that about 5 % of the world population harbors the c.94C > A (p.Pro32Thr) ITPA variation with the highest penetrance, 14 to 19 %, in Asian populations . Since then several more polymorphisms have been identified [32, 40, 44] (see Table 1) and recent reports suggest that nearly a third of the population may harbor ITPA polymorphism that is associated with decreased ITPase activity [49–51]. In fact, even heterozygous variation which results in overall ITPase activity that is 60 % of the homozygous wild-type level can be clinically significant [49, 51–54], however, pathological mutations are very rare .
Genotype status can result in a varying degree of reduction in ITPase activity. Most studies have focused on ITPase activity in erythrocytes for the more common polymorphisms, c.94C > A (p.Pro32Thr) and c.124 + 21A > C, and the results between studies are in good agreement [38–40]. For example, in Caucasian populations, the c.94C > A (p.Pro32Thr) polymorphism results in severe reduction of ITPase activity and the mean activity for heterozygous individuals is about 25 % of the wild-type levels while homozygous individuals retain less than 1 % of the wild-type levels . The c.124 + 21A > C variant results in a more moderate reduction in ITPase activity, and heterozygotes retain about 60 % of the wild-type levels while homozygous individuals retain about 30 % of the wild-type levels. Consequently, c.94C > A (p.Pro32Thr) and c.124 + 21A > C compound heterozygosity results in severe reduction of ITPase activity and these individuals retain about 8 % of the wild-type levels . It is important to underscore that these data are obtained from erythrocytes, and that the level of activity observed may be different for different cell types within the same individual.
Clinically relevant ITPA variants are listed in Table 1. Of the seven variants, four are single nucleotide substitutions, one a nonsense mutation, along with a duplication and a deletion. The later three instances are very rare and can be considered mutations as opposed to variants. These three mutants were identified in a cohort of homozygous patients suffering from infantile encephalopathy . These mutants are predicted to have the greatest effect on protein structure/function by changing the length of the 194 residue protein and most likely result in a nonfunctional protein. The nonsense mutation (c.452G > A) introduces a premature stop codon at amino acid position 151, resulting in a C-terminal truncated protein, which would lack the highly conserved specificity pocket containing the SHR signature sequence at positions 176–178. For the duplication mutant (c.359_366dupTCAGCACC), an 8 bp duplication is introduced which results in a frameshift starting at amino acid positon 123. This mutation is predicted to produce a 225 amino acid polypeptide with altered amino acid sequence. Concerning the deletion mutation (c.264-607_295 + 1267del), a deletion of 1,874 base pairs was identified which completely spans exon 5 and is predicted to result in an out of frame transcript. ITPase activity in erythrocyte or fibroblast cells derived from patients homozygous for each of these three mutations was severely diminished, indicating significant loss of activity for the protein .
Of the four single nucleotide variants/mutants that are clinically relevant, two affect protein structure. Among these the c.94C > A (p.Pro32Thr) variant is the most studied. This common point mutation is thought to affect the protein in three different ways: decreased expression of the full length transcript, reduced catalytic activity and decreased stability [33–35, 55]. This variation has been shown to alter mRNA splicing events such that exon 2 and 3 are misspliced; an activity which presumably results in a nonfunctional protein. While this missplicing event happens in wild-type cells to some extent, the level of missplicing increases over three-fold for homozygous variants . Additional studies have shown that substitution of proline with threonine at position 32 results in a protein with nearly two-fold less catalytic activity and reduced stability [33–35]. This position in the polypeptide chain is located in an exterior loop that is adjacent to the protein-dimer interface and close to residues that are thought to be involved in enzyme catalysis [3, 4]. Proline at this position is thought to have a role in restricting flexibility of the external polypeptide chain, which reduces ability of solvent to infiltrate the protein interior and helps maintain proper positioning of catalytic residues [33, 34]. Hence, this single nucleotide polymorphism (SNP) results in poor expression of an unstable, catalytically compromised protein.
The c.532C > T (p.Arg178Cys) mutant is very rare and has been recently identified in a patient suffering from infantile encephalopathy . Arg-178 is a highly conserved position in the ITPase structure and is one of the residues that form the SHR signature sequence for ITPase. It is thought to have a major role in substrate selectivity as it is postulated to interact with the nucleobase of incoming (d)ITP at two positions  (see above). This particular variant has been predicted to result in a nonfunctional protein by multiple software programs . Additionally, a site-directed mutagenesis study has identified this position as essential for ITPase activity both in vitro and in vivo .
The two additional single nucleotide variants do not affect protein structure. The common c.124 + 21A > C variant is an intronic substitution that prevents the canonical spliceosome reaction . Substitution of adenine at this position is thought to destroy the preferred branch point in the splicing reaction, resulting in an alternative splicing event that is less efficient, therefore reducing expression of the ITPA gene . The recently identified g.19176G > A variant is also thought to alter ITPA expression . This particular variant is located in the 3′-untranslated region (3′-UTR) of the ITPA transcript. It has been hypothesized that this variant affects mRNA metabolism and/or translation resulting in a higher level of ITPase expression .
ITPase is thought to have a direct role in metabolism of thiopurine drugs . Thiopurines such as azathioprine and 6-mercaptopurine are prodrugs and require enzymatic bioactivation to undergo ribosylation and phosphorylation to become the active nucleotide form. In the active form, thiopurines are antimetabolites which act by replacing guanosine containing nucleotides in physiological processes. Hence, thiopurines can disrupt multiple biologic pathways such as DNA and RNA metabolism, purine metabolism, and stimulate pro-apoptotic pathways (see references [56, 57] for review). One intermediate in this pathway, 6-thio-inosine 5′-triphosphate (6-TITP), has a structure nearly identical to ITP (see Fig. 4 for comparison of nucleobases). 6-TITP has been shown to be a substrate for ITPase . This result suggests that the drug may enter a futile cycle of phosphorylation by kinase enzymes to the triphosphate form, and hydrolysis by ITPase back to the monophosphate form. Therefore, the end result is that the ITPase enzyme acts to reduce an intermediate in the pathway, and subsequently the amount of active form of the drug present in human cells (Fig. 5a).
Ribavirin is also activated by intracellular kinases to form a nucleoside triphosphate (Fig. 5b) [52, 58]. In this case, the ribonucleoside triphosphate becomes a substrate for the replicative RNA-dependent RNA polymerase and it is incorporated into the viral genome. Incorporation into the viral genome is thought to lead to chromosomal degradation and a reduced viral load for the host. To date, ITPase has not been demonstrated to have a direct role in ribavirin metabolism (although evidence suggests it may ), however it is thought to modulate overall nucleotide pools and ITPA status can affect treatment outcomes as discussed below .
Several groups have shown that ITPA variation correlates with increased toxicity to thiopurines [53, 54, 56, 59–61]. Thiopurine therapy is widespread. Thiopurines, such as azathioprine or 6-mercaptopurine, are immunosuppressants that are commonly administered to organ transplant recipients , and patients undergoing treatment for inflammatory bowel disease , ulcerative colitis , Crohn's Disease  and a variety of cancers [66–68]. For patients harboring ITPA variation, common side effects included rash, flu-like symptoms, pancreatitis, life threatening myelosuppression, and hepatotoxicity. Toxicity presumably occurs due to an increase of thiol-containing NTPs. Because these side effects can be quite devastating to the patient, dosage alteration or discontinuation of treatment is common for individuals with ITPA polymorphism [53, 59] (see references [36, 56, 57] for review). As a result, researchers have suggested including pre-therapeutic screening of patients for ITPA polymorphism to minimize the occurrence of drug toxicity [69–71]. Importantly, not all ITPA polymorphism is associated with thiopurine toxicity. For example, one group found that heterozygosity for the c.94C > A (p.Pro32Thr) allele was associated with adverse drug reactions, but both hetero- and homozygosity for the c.124 + 21A > C allele was not .
An alternative approach to alleviating thiopurine toxicity is to prescribed 6-thioguanine in place of azathioprine or 6-mercaptopurine. Bioactivation of 6-thioguanine proceeds via a thio-GMP intermediate (6-TGMP), rather than a thio-IMP intermediate (6-TIMP), thus by-passing the ITPase reaction (see Fig. 5a) . Substitution with 6-thioguanine has been used successfully in a cohort of Crohn's disease patients who demonstrated resistant to 6-mercaptopurine therapy .
One caveat to the involvement of ITPase in thiopurine toxicity is that some studies have not found a correlation between ITPA variation and thiopurine toxicity [73–76]. The conflicting data underscores the fact that many different gene products have a role in thiopurine metabolism (at least 20), and phenotypic variation among patients may mask effects of ITPA variation in certain studies . Indeed, studies that do not find a correlation between ITPA variation and drug toxicity identify small sample size, ethnicity, drug interactions and the retrospective nature of their studies as shortcomings [73, 74, 76, 77]. In 2014, Matimba et al. used a "three-tiered" experimental strategy to overcome some of the shortcomings associated with clinical studies. This allowed them to positively identify and functionally validate an association between ITPA variation and an altered thiopurine response phenotype .
In 2010 and following studies, the c.94C > A (p.Pro32Thr) variant was shown to delay the development of anemia in patients treated for chronic hepatitis [52, 78, 79]. For the 170 million people affected with hepatitis C worldwide, one of the potential side effects for the standard treatment of pegylated interferon alpha and ribavirin is hemolytic anemia . In a follow up study, researchers found that individuals harboring either the c.94C > A (p.Pro32Thr) or c.124 + 21A > C variations not only had delayed development of anemia, but also had a decreased need for ribavin dose reduction . Recently, methods have been developed to use ITPase activity as an accurate predictor for the development of anemia during ribavirin treatment . Based on these findings, it has been suggested that status of the ITPA locus, or ITPase activity, should be considered for patients beginning hepatitis C therapies which include ribavirin [51, 81–83]. In fact, an ITPA SNP-based index has been developed to advise healthcare workers in maximizing the tolerability of treatment regimen for patients with chronic hepatitis C .
While the mechanism for the protective effect of ITPA polymorphism is under debate, it seems likely that modulation of nucleotide pools plays a role. Ribavirin-induced anemia is thought to result from decreased erythrocyte ATP levels, which in turn affects ATP-dependent oxidative metabolism  and reduces the levels of GTP in the cell . However, it has been speculated that for individuals with reduced ITPase activity, a rise in intracellular ITP concentrations might allow ITP to replace GTP as a cosubstrate for the adenylosuccinate synthetase reaction, thus allowing ATP biosynthesis to continue . The rise in ATP levels subsequently allows GTP biosynthesis to continue. Therefore, an increased ITP concentration may allow erythrocyte nucleotide pools to maintain a more normal level which lowers the incidence of hemolytic anemia . One caveat to this hypothesis is that adenylosuccinate synthetase activity has not been demonstrated in erythrocytes .
The mode of action of ribavirin requires bioactivation to the nucleotide ribavirin 5′-triphosphate (RBV-TP), which is subsequently incorporated in the viral genome and interferes with replication [52, 58]. Individuals with variant ITPA phenotypes have increased levels of RBV-TP in their red blood cells . Importantly, the level of RBV-TP in cells corresponded to ITPA status, i.e. genotypes predicted to have lower ITPase activity had greater levels of RBV-TP . Ribavirin has an electronegative oxygen (carbonyl) in approximately the same location as the 6-position carbonyl in inosine  (see Fig. 4). Taken together, it is likely that RBV-TP is a substrate for ITPase, but this has not been directly demonstrated in the current literature.
Overall, it appears that ITPA variation would alter the monophosphate to triphosphate ratio of ribavirin containing nucleotides. Consequently, it is possible that the mechanism for the observed delay in onset of anemia for patients with ITPA variation may involve a reduction in the level of the monophosphate form, or an increase in the level of the triphosphate form of ribavirin. Furthermore, the role of nucleoside diphosphate kinase should be considered. This enzyme is active in erythrocytes  and its reversible and promiscuous ping-pong mechanism essentially allows any NTP to provide the phosphorylation power to quickly convert any NDP into its corresponding NTP . Therefore, in the case of ITPA variation, the rise in ITP and RBV-TP levels is expected to contribute to the pool of ATP equivalents in the cell.
ITPA variation has also been associated with reduced relapse risk and achieving sustained virological response (SVR) for hepatitis C patients . Rembeck et al. found that for patients receiving a conventional 800 mg daily ribavirin dose and peginterferon-2α, those that had an ITPA status which was predicted to result in ITPase activity that was 60 % or less than wild-type, both relapse rate and SVR were favorably impacted. Importantly, the researchers observed no statistical difference in hemoglobin levels among patients achieving or not achieving SVR, suggesting that protection against onset of anemia is not related to an improved rate of SVR. For patients harboring ITPA variation, the authors suggested that imbalances in the NTP pools such as increased levels of ITP, along with decreased levels of GTP (due to inhibition of inosine monophosphate dehydrogenase by ribavirin) may result in increased incorporation of ITP into the viral genome. In turn, the increased level of inosine in viral RNA may trigger reduction of the viral load via an innate immune response .
Kevelam et al. recently identified recessive ITPA mutation as a cause of early infantile encephalopathy . The researchers used magnetic resonance imaging (MRI) and whole exome sequencing (WES) to link very rare, recessive mutation of the ITPA gene to a unique MRI pattern. Seven patients were identified who presented severe progressive microcephaly, seizures and developmental delays shortly after birth. Sadly, six of the seven patients died before 2.5 years of age. Cardiac abnormalities and severely reduced erythrocyte and fibroblast ITPase activity was observed, but purine and pyrimidine urine profiles were normal . These phenotypes are consistent with high levels of brain and cardiac ITPA expression . The homozygous genetic variation observed included gene deletions, as well as nonsense, frameshift and missense mutations . All but the latter was predicted to significantly alter the primary structure of the resulting protein. In the case of the missense mutation, a nonfunctional protein with a substitution of Arg-178 with cysteine was predicted. An R178C substitution would alter a key residue in the substrate specificity pocket and this substitution is predicted to affect the ability of this residue to hydrogen bond with the 6-position keto oxygen of ITP (see above and Fig. 3) and would most likely reduce affinity for ITP . Alternatively, because this point mutation introduces an additional cysteine residue into the primary protein structure, it is possible that improper disulfide bonds could form with one of the seven other cysteine residues during protein maturation. Perusal of x-ray crystallographic data  suggests that native ITPase quaternary structure does not contain any disulfide bonds, however, position 178 is in close proximity to Cys-116 in a neighboring beta strand (personal observation). Preliminary work with the R178C mutant ITPase indicates this protein has a low level of solubility when overexpressed in E. coli cells (unpublished data), however the occurrence of disulfide bond formation is not known. Because ITPase has been shown to be activated with DTT [5, 28], it is possible cysteine redox chemistry has a role in the enzyme structure and/or chemistry.
Recently, the ITPA gene has been identified as a susceptibility gene for young-onset tuberculosis (TB) . Here, the researchers used next-generation sequencing (NGS) to identify single nucleotide polymorphisms in young TB patients from multi-case families and found two ITPA polymorphisms (g.19176G > A and c.94C > A (p.Pro32Thr)) to be associated with young TB patients. The g.19176G > A variant showed the strongest association. This variant is located in the 3′-UTR of the ITPA gene and it is hypothesized to modulate ITPA expression at the posttranscriptional level. In silico eQTL analysis using lymphoblastoid expression profile data indicates an increased level of expression for the minor 'A' allele form of this variant. Subsequently, it was hypothesized that a lower level of expression for the major 'G' allele may render individuals harboring this allele more susceptible to TB infection. Similarly, c.94C > A (p.Pro32Thr) polymorphism, which would cause reduced ITPase activity (see above), is also linked to increased susceptibility. Considering that the thymus is among the human tissues with highest ITPA expression , these results suggest that ITPase may have a role in the host immune system upon onset and progression of TB . Therefore, this study introduces the idea that overexpression of the ITPA gene may have a protective effect.
Vanderheiden first identified patients with an abnormal accumulation of erythrocyte ITP in the 1960s and suggested that these patients were ITPase deficient [88, 89]. In 2002 a report indicated that erythrocytes from c.94C > A (p.Pro32Thr) homozygous individuals showed 0 % ITPase activity, and, it was noted that there appeared to be no biological consequence of this absence . Today it is clear that ITPase has an essential role in purine metabolism . This is underscored by the fact that ITPase is so highly conserved among all branches of biology , and expressed in all mammalian tissues assayed . The role of the protein in specific tissues appears to differ and measurement of activity in one specific tissue does not necessarily reflect activity of the whole organism. For instance, one study determined that low erythrocyte ITPase activity did correlate with lower activity in white blood cells and platelets, but the overall level of activity was considerably higher for these cells . Over time, more and more reports revealed significant relationships between ITPA variation and altered drug regimen outcomes [52, 59–61, 78, 79]. Today, with two examples of lethality due to severe homozygous ITPA defects (Itpa knockout mouse data  and infantile encephalopathy data ), along with an example of increased fitness due to potential ITPA overexpression (TB susceptibility data ), it seems more likely that there is a spectrum of ITPA-related disease as Kevelam et al suggested . Hence, most ITPA variation results in modulated ITPA expression/activity, rather than absence of ITPase, therefore, use of term "ITPase deficiency" in the literature to describe the majority of ITPA polymorphism appears to be a historical inaccuracy.
Considering that the current data indicates the phenotypic spectrum of ITPA defects ranges from mild drug toxicity to infantile death, it seems likely that therapies will emerge to modulate ITPase activity. Advances in DNA sequencing techniques, such as WES and NGS, and reduced cost of sequencing is likely to identify an increased number of instances where ITPA status contributes to neurological and cardiac disease as well as complications associated with inflammation, the immune system or other unknown ITPA-related diseases. Given the widespread use of thiopurines, and magnitude of individuals infected with hepatitis C, while considering that roughly one third of the world population has ITPA polymorphism, it seems plausible that development of these therapies will be met with considerable need.
Above, I have outlined examples where ITPA polymorphism/mutation is detrimental to patient outcomes (thiopurine toxicity/infantile death) and examples indicating that ITPA polymorphism is beneficial to patient outcomes (reduced anemia in hepatitis C patients, young-onset TB). Current treatment for the pharmacological related conditions includes dose modification, treatment of the side effects or discontinuation of the drug [54, 91]. Below, I will outline strategies which have potential to prevent the occurrence of negative outcomes for these patients. Therefore, ITPase serves as an interesting drug target because there is a need for both positive and negative modulation.
With the development of improved gene delivery systems, and gene editing tools one can envision a day when a bioengineered ITPase (with increased activity and improved substrate discrimination) or gene editing system (to enhance/correct ITPase function), can be delivered to a patient suffering from cardiac or neurological maladies due to very rare and severe mutation, or even possibly patients suffering from thiopurine toxicity due to common polymorphism. In the cell, this scenario would exacerbate existing ITPase activity and cause a much greater increase in specificity for (d)ITP or 6-TITP over the canonical (d)NTPs, thus reducing time spent with the unproductive binding and catalysis of adenine and guanine containing nucleotides. In E.coli cells, ITP levels are about 200 μM, whereas ATP and GTP are approximately 50- and 25-fold greater, respectively . K M values for ITPase with these substrates follow the same trend [2, 12]. Therefore, alteration of kinetic constants via protein engineering should result in improved ability of ITPase to discriminate between canonical and noncanonical purine containing nucleotides. This is expected to greatly enhance the ability of the enzyme to clear cells of excess (d)ITP or drug metabolite.
Towards this goal, we have identified three gain-of-function mutants . Most notably, the E22A mutant shows a nearly two-fold enhancement in ITP hydrolyzing activity compared to wild-type, with a two- and five-fold decrease in hydrolyzing activity with GTP and ATP, respectively, compared to wild-type. Overall, we observe a roughly 10-fold enhancement over wild-type for discrimination between ITP and ATP. X-ray crystallography data suggests Glu-22 does not directly interact with the incoming nucleotide , but rather has an organizing role in the specificity pocket such as orienting the essential Arg-178 as discussed above (Fig. 3). Unfortunately, this protein has reduced stability in vivo and cannot complement ITPase defects in E. coli. Similarly, the K172A mutant exhibits a two-fold increase in ITP hydrolyzing activity and a greater than two-fold decrease in ATP or GTP hydrolyzing activity. In vivo, this mutant is more stable than the E22A mutant and it does have an ability to partially complement ITPase defects in E. coli . Detailed biochemical and modeling data with these mutants will provide a platform for protein engineering experiments to continue improving ITPase activity and/or substrate discrimination with the aim of developing therapies to reverse thiopurine toxicity, neurological disorders, TB susceptibility and emerging ITPA-related disorders in patients affected by ITPA polymorphism.
In the case of the c.94C > A (p.Pro32Thr) ITPase, a portion of the reduction in enzyme activity has been attributed to reduced protein stability and rate of catalysis [33–35] (see above). This substitution affects an exterior loop of the protein, and substitution with an amino acid that does not have a tertiary peptide amine, renders the loop more flexible. Therefore, it has been speculated that a small molecule could be designed which would bind to this region of the protein and help stabilize this exterior loop .
Because reduced ITPase activity results in improved outcomes for patients undergoing ribavirin treatment , it is plausible that competitive ITPase inhibitors could be developed to help reduce anemia in individuals not affected by ITPA polymorphism. Therefore, molecules which inhibit ITPase activity are expected to have clinical significance. Considering that that the substrate specificity pocket has exquisite complementarity to the nucleobase of ITP and strongly favors electronegativity at the 6-position , competitive inhibitor molecule design should focus on nucleotides or nucleobases where the nucleobase has chemical properties similar to hypoxanthine. Alternatively, irreversible inhibitors could be designed to have structures that covalently attach to residues lining this pocket, or have such low dissociation constants that they irreversibly bind to this pocket. Because of the unique role ITPase has in the cell, the landscape of the substrate specificity site is expected to be unique, which would reduce the likelihood of cross-reactivity with ATP- and GTPases. Noncleavable substrates, such as inosine containing phosphoramidites, may prove advantageous as well, but would have greater difficulty entering the cell .
One confounding fact of ITPase biochemistry is that substrate inhibition has been demonstrated for two mammalian homologs with elevated concentrations of substrate [2, 5, 28]. Although substrate inhibition was first demonstrated over 45 years ago , the significance of this mechanism remains unknown. It seems likely this effect may be due to specific biochemical roles for ITPase in purine metabolism in certain tissues at certain times. Currently there is at least one example which indicates that ITPase is not subject to substrate inhibition in vivo , suggesting that a cellular component can reverse this phenomenon. To date this issue remains completely unresolved in the literature. Regardless, the effect of substrate inhibition with purified/recombinant ITPase is strong and renders mammalian ITPase nearly inactive when ITP concentrations are in the high micromolar range . In fact, substrate inhibition occurs at elevated levels of ATP (unpublished observations) and GTP  as well. Overall, the possibility of negative allosteric binding sites should be considered when designing small molecule inhibitors for ITPase. Design of competitive and noncompetitive inhibitory molecules awaits more rigorous biochemical characterization and molecular modelling of ITPase.
Recent studies demonstrate disparate examples of disease related to ITPA polymorphism/mutation. Recent biochemical studies have begun to elucidate the mechanism ITPase uses to discriminate between canonical and noncanonical purine containing NTPs, and determine the underlying mechanism of disease state. In general, ITPase is an understudied protein and a knowledge gap exists in the basic science of ITPase biochemistry. Currently, seven ITPA variants/mutants are known to affect clinical outcomes. ITPA status can have beneficial or detrimental consequences, depending on the clinical setting. Drug toxicity occurs in patients with ITPA variation undergoing thiopurine therapy, whereas development of anemia in the treatment of hepatitis C is delayed for individuals with ITPA polymorphism. The current understanding is that these individuals retain a functional enzyme, however, the enzyme expression is reduced (c.124 + 21A > C), and in some cases catalysis and stability is reduced as well (c.94C > A (p.Pro32Thr)). To date, several preliminary reports have indicated a need to determine ITPA status, or enzyme activity, prior to treatment for conditions where ITPA status has been shown to affect patient outcomes, however, no large scale prospective cohort studies have been performed to validate these results. ITPase enzyme activity is directly related to ITPA status, and individuals harboring homozygous ITPA variation experience the greatest effects. Instances of mutation, where the protein length (c.264-607_295 + 1267del1906, c.359_366dupTCAGCACC, c.452G > A (p.Trp151Stop)) and/or functionality (c.532C > T (p.Arg178Cys)) is grossly altered are very rare and homozygosity results in infantile encephalopathy and lethality. On the other hand, ITPA variation which is predicted to increase protein expression is thought to reduce susceptibility to tuberculosis. Consideration of these examples suggests that there is a spectrum of ITPA-related disease. Future studies concerning both positive and negative modulation of ITPase activity will meet the needs of patients suffering from ITPA-related disease.
This work was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R15GM112121.
NEB wrote the review. NEB read and approved the final manuscript.
The author approves the manuscript for publication.
dbSNP: Short Genetic Variations. National Center for Biotechnology Information, Bethesda, MD. 2016. http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?showRare=on&chooseRs=doublehit&go=Go&locusId=3704. Accessed 20 Oct 2016.
Jimmerson LC, Urban TJ, Truesdale A, Baouchi-Mokrane F, Kottilil S, Meissner EG, Sims Z, Langness JA, Hodara A, Aquilante CL et al. Variant ITPA phenotypes are associated with increased ribavirin triphosphate levels. J Clin Pharmacol. 2016. http://dx.doi.org/10.1002/jcph.783.


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Flower power earrings. These earrings are made out of 15×7 crystal navette stones in the form of three drops. The earrings have a clip finding to attach them to the ear. Drop of earring is 13cm. Width of earring is 4cm.


Server racks typically have front and rear doors that are perforated or solid. The fully enclosed server rack mount cabinet is the most expensive rack type due to the amount of metal use.
The perforated doors allow for proper ventilation of the electronics in the rackmount cabinet. The current standard for ventilation is a minimum of 63% perforated on both the front and rear doors of the rack mount cabinet. Filler panels are typically used to help minimize air recirculation. If the rack cabinet has a solid door, then additional equipment must be installed in the rack to provide adequate ventilation. Racks with solid doors typically have fans in the top and air enters the rack from the floor.
The fully enclosed server rack provides the highest level of security for the equipment. Typically the front and rear doors have a lock to prevent unauthorized access to the equipment. The side panels of the rack mount cabinet can be easily removed in most models which allows access to cabling or power distribution units which are sometimes installed in the Zero-U space in the sides of rack cabinets.
Most modern rack enclosures have adjustable EIA rails for equipment attachment. These rails have mounting holes on a pattern by EIA-310. Racks have one of three hole types: square, round, or threaded. Most racks have adjustable rails, allowing the mounting depth and equipment position to be adjusted.
Rack cabinets are more difficult to route cabling due to limited access. Since the racks have rear doors, wires are typically routed out the top to overhead trays, or the wires are routed out the bottom and below a raised floor. Most racks have limited space in the sides to allow cabling from the front to rear.
Does my rack need fans for cooling?
This entry was posted on Thursday, October 11th, 2007 at 10:46 am	and is filed under Racks. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.
Unfortunately our Cabinets start at $879. Your best bet is going to be a used or refurbished Cabinet.
Would love to see more spec's on rack enclosures such as the typical (standard) height (RU) and depth (inches).


Claiming the "Baby Benz" title from the Mercedes-Benz C-Class when it was first introduced for the 2015 model year, the Mercedes-Benz CLA is the most affordable option within the Mercedes-Benz lineup, but rest assured, it delivers an experience worthy of the Silver Star.
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Durable and incredibly versatile, the Mercedes-Benz GLC (formerly the GLK) has the maneuverability of a car and the utility of and SUV. With a fun-to-drive experience behind the wheel, capable towing, and configurable passenger and cargo space, the GLC is a top choice among midsize crossovers.
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Tens of Thousands Expected for DC Demonstration Against Darfur Genocide
StoryApril 28, 2006
On Sunday, tens of thousands are expected to gather in Washington for a demonstration against the ongoing genocide in Sudan. We speak with Joe Madison president of the Sudan Campaign. [includes rush transcript]
Joe Madison, president of the Sudan Campaign. He will serve as the emcee for the Rally to Stop Genocide in Washington DC this Sunday. He is also the host of the radio show The Black Eagle.
AMY GOODMAN: We turn now to Washington, D.C. We're joined by Joe Madison. He's President of the Sudan Campaign, served as emcee on Sunday for another major protest that will be taking place, the rally to stop genocide in Sudan. He's also the host of the radio show The Black Eagle. He joins us on the line from his radio studio in Maryland. Welcome to Democracy Now!, Joe Madison.
JOE MADISON: Hi, Amy. Thank you for having me again. I really appreciate it.
AMY GOODMAN: It's good to have you with us. Talk about the protests that you're going to be a part of on Sunday.
JOE MADISON: It's actually a rally. It's a wake-up call. Here's what the mission is. Several years ago, when this whole thing started, when we first started talking about it, long before anyone was even — even knew where Darfur was or Southern Sudan, the President of the United States had a briefing on Rwanda. And in the pages, in the margins of the briefing pages, he wrote "not on my watch." Well, guess what. It has happened on his watch. Darfur is the 21st century's first genocide.
And so, Sunday, individual members of Congress on both sides of the aisle, because they do have a unison agreement, a resolution saying that it is genocide. The administration has declared it is genocide. The problem is that we're all disappointed that they really haven't done enough to stop the genocide. So the purpose of the rally is to bring students together, Republicans, Democrats, conservatives, liberals, to say, "Not on my watch. We will stop this genocide." The U.N. has a responsibility. NATO may have a responsibility. We all have a responsibility.
AMY GOODMAN: And specifically, you're calling for what, for Congress to do, for people to do?
JOE MADISON: Well, first of all, the survivors of the genocide have to be protected from this genocide, so that some two million of them can leave various parts of Chad. Many have now gone into Southern Sudan. As a matter of fact, I'll be leaving Monday for a ten-day fact-finding mission to Southern Sudan and parts of Darfur hopefully, even though people aren't allowed in. But we'll be going into those regions of Sudan, because now Darfurians are filtering with their families down into Southern Sudan, which was torn up by a war 20 years ago.
There has to be justice for those who, in fact, who were involved in the crime of genocide. And there has to also — we have to also hold China and Russia accountable, because they have continually blocked efforts to try and end this genocide. China imports — I think Sudanese oil is like the seventh largest import that China has. And Russia is currently selling MiGs and other weapons to Sudan. These — and finally, there must be a special envoy, someone with a status that can go in and negotiate a peace for this conflict.
AMY GOODMAN: Joe Madison, we just have 30 seconds. The U.N. is saying today, it will cut food rations for more than six million people in Sudan, half of them in Darfur, due to a severe lack of funds.
JOE MADISON: This is absolutely amazing. Absolutely crazy. And I'm telling you, it is racist in nature. It is sad, because if I came on your show today and told you that there were two million people starving to death as we speak, right now, and that there are over 400,000 who are dead and counting, and this is happening in western Germany or the southern part of France, there would not be this type of reaction from the U.N. or any other governmental body.
AMY GOODMAN: Well, Joe Madison, I want to thank you very much for being with us, President of the Sudan Campaign. He will serve as emcee for the rally to stop genocide in Sudan this Sunday. I want to thank you for joining us, and now you can go back to your radio show.
Raging Grannies Acquitted in New York
NEXTRaging Grannies Acquitted in New York

redpajama_set_name: RedPajamaCommonCrawl


text:
Boneseed (Chrysanthemoides monilifera ssp. monilifera)
Boneseed (Chrysanthemoides monilifera ssp. monilifera), this time profiling the presence of this invasive shrub aster in the inner metropolitan.
The photographs here show the species throughout escarpment areas of Yarra Bend Park (2-6), on nearby exposed scarps of the Merri Creek (7-8), and along the Clifton Hill-Jolimont railway corridor in Abbotsford (1, 9) and East Melbourne (10).
Although Yarra Bend Park is one of Melbourne's iconic natural spaces, the superficial splendour of the river corridor belies a history of disturbance. From 1836, when cattle driven overland from NSW first crossed the river at Dights Falls, much of the parkland was extensively grazed and trampled, exploited by timber harvesters and otherwise remade.
Construction of Yarra Boulevard in the 1930s introduced retaining walls, reshaped slopes and may perhaps have included an intentional introduction of Boneseed to the parklands (if it did not merely arrive in bird droppings from nearby gardens). Boneseed appears to have been first recorded in the park in 1946, and the steep dry escarpments, denuded of much of their indigenous ground cover by a century of grazing but in some areas supporting a regenerating woodland canopy, have proven ideal for the species, allowing it to lurk, survive and rebound from cycles of weed management.
A 2000 plan by Parks Victoria reported that Boneseed in the park had been restricted to scattered individuals, that its numbers were decreasing and that the then-current control program was limiting its spread. Today, there are hundreds if not thousands of Boneseed plants along the Yarra River from Fairfield Pipe Bridge to Kanes Bridge.
Despite decades of work, no introduced biocontrol for Boneseed has achieved success in Australia. Meanwhile, the fragility of labour-based manual control is on full display this spring, devastation manifest in endless floodplain acres of Angled Onion and in these lurid golden scarps. An automatic moralism will get us nowhere with this, another species that is now part of the furniture.
Boneseed (Chrysanthemoides monilfera ssp. monilifera)
Magnoliopsida > Asteraneae > Asterales > Asteraceae > Chrysanthemoides > Chrysanthemoides monilifera > Chrysanthemoides monilifera ssp. monilifera > Boneseed (Chrysanthemoides monilifera ssp. monilifera)
Search for information about Chrysanthemoides monilifera ssp. monilifera in the Flora of Victoria
View information and occurrences of Chrysanthemoides monilifera ssp. monilifera on the Atlas of Living Australia
One thought on "Boneseed (Chrysanthemoides monilifera ssp. monilifera)"
October 20, 2020 at 6:17 PM	Reply
I've been pulling these intermittently until this year and the real problem is now the inaccessible places where the the seedbank survives:
– Dangerously steep banks along the river
– Along the freeway reserve/roadside
– Roadside – Kew Boulevard (private or council responsibility)
I think this can be controlled again if the above places can be accessed – anyone else interested?


text:
Q: Is Hom$(V, W) \simeq V^* \otimes W$ naturally? When $V, W$ are finite dimensional linear spaces, I think Hom$(V, W) \simeq V^* \otimes W$, but is this isomorphism independent of the choice of basis?

A: Yes: take the map $V^* \otimes W \rightarrow \mathrm{Hom}(V,W)$ defined as $\alpha \otimes w \mapsto (v \mapsto \alpha(v)w).$

redpajama_set_name: RedPajamaStackExchange


text:
57 user 121 critic
I'm a Cyborg, But That's OK (2006)
Ssa-i-bo-geu-ji-man-gwen-chan-a (original title)
Not Rated | 1h 45min | Comedy, Drama, Romance | 7 December 2006 (South Korea)
1 VIDEO | 76 IMAGES
A girl who thinks she is a combat cyborg checks into a mental hospital, where she encounters other psychotics. Eventually, she falls for a man who thinks he can steal people's souls.
Seo-kyeong Jeong (as Seo-gyeong Jeong), Chan-wook Park
Soo-jung Lim, Rain, Seong-hun Cheon | See full cast & crew »
57 user | 121 critic
Park Chan-wook interview: The Handmaiden, film critics
13 April 2017 | Den of Geek
Chan-wook Park Starts New Movie, Lesbian Drama 'Fingersmith'
24 June 2015 | Rope Of Silicon
Soundtrack For Park Chan-Wook's 'Oldboy' Gets Vinyl Reissue, Executive Produced By Nicolas Winding Refn
03 September 2014 | The Playlist
100 Most Popular Korean Movies
Plan to Watch (Asian Movies)
To See: 2006
Search for "I'm a Cyborg, But That's OK" on Amazon.com
Title: I'm a Cyborg, But That's OK (2006)
Weird, Funny, Creative
What Is Your Favorite South Korean Movie of the 21st Century?
Best sci-fi movie from outside the USA?
8 wins & 8 nominations. See more awards »
Thirst (2009)
Through a failed medical experiment, a priest is stricken with vampirism and is forced to abandon his ascetic ways.
Stars: Kang-ho Song, Ok-bin Kim, Hee-jin Choi
Lady Vengeance (2005)
After being wrongfully imprisoned for thirteen years and having her child taken away from her, a woman seeks revenge through increasingly brutal means.
Stars: Yeong-ae Lee, Min-sik Choi, Shi-hoo Kim
Sympathy for Mr. Vengeance (2002)
Action | Drama | Thriller
A recently laid off factory worker kidnaps his former boss' friend's daughter, hoping to use the ransom money to pay for his sister's kidney transplant.
Stars: Kang-ho Song, Ha-kyun Shin, Doona Bae
Joint Security Area (2000)
After a shooting incident at the North/South Korean border/DMZ leaves 2 North Korean soldiers dead, a neutral Swiss/Swedish team investigates, what actually happened.
Stars: Yeong-ae Lee, Byung-Hun Lee, Kang-ho Song
Three... Extremes (2004)
An Asian cross-cultural trilogy of horror films from accomplished indie directors.
Directors: Fruit Chan, Takashi Miike, and 1 more credit »
Stars: Bai Ling, Byung-Hun Lee, Kyoko Hasegawa
After India's father dies, her Uncle Charlie, whom she never knew existed, comes to live with her and her unstable mother. She comes to suspect this mysterious, charming man has ulterior motives and becomes increasingly infatuated with him.
Stars: Mia Wasikowska, Nicole Kidman, Matthew Goode
Bitter Sweet Seoul (2014)
Documentary | Drama
This documentary is a crowdsourced film about life in the Korean megalopolis.
Directors: Chan-kyong Park, Chan-wook Park
If You Were Me (2003)
Several of Korea's most acclaimed filmmakers, including Park Chan-wook (OLDBOY), explore the nature of discrimination in this provocative anthology.
Directors: Jae-eun Jeong, Chan-wook Park, and 4 more credits »
Stars: Jong-hak Baek, Jeong-su Byeon, Ha-eun Jeon
Saminjo (1997)
A suicidal saxophonist is pushed over the edge after he discovers his wife's infidelity.
Stars: Seon-kyeong Jeong, Bu-seon Kim, Min-jong Kim
Night Fishing (2011)
Short | Fantasy
A fisherman becomes entangled in his line when he catches something unexpected.
Stars: Jung-hyun Lee, Kwang-rok Oh
60 Seconds of Solitude in Year Zero (2011)
The film is a collection of one-minute short films created by 60 filmmakers from around the world on the theme of the death of cinema.
Directors: Phie Ambo, Shinji Aoyama, and 29 more credits »
The Moon Is... The Sun's Dream (1992)
Crime | Romance | Thriller
A gangster in Busan is caught having an affair with his boss's mistress. The two decide to run off with the organizations money, leading to dire circumstances.
Stars: Eun-hee Bang, Seung-Chul Lee, Hyun-Hee Nah
Soo-jung Lim ... Cha Young-goon
Rain ... Park Il-sun
Seong-hun Cheon ... Hwang Kyu-Seok
Hee-jin Choi ... Choi Seul-gi
Joo-hee Eun ... Son Eun-Young
Yoo-rang Joo ... Radio announcer
Park Jun-Myun ... Wang Kop-Dan
Byeong-ok Kim ... Judge
Jung-yong Lee ... Young-Goon's uncle
Yong-nyeo Lee ... Young-goon's mother
Dal-su Oh ... Shin Duk-cheon
Byeong-eun Park ... Kim Jun-Beop
Ho-jeong Yu ... Il-sun's mother
A young woman who believes she's a cyborg hears voices and harms herself while at work making radios. She's hospitalized in a mental institution where she eats nothing and talks to inanimate objects. She's Young-goon, granddaughter of a woman who thought she was a mouse (and whose dentures Young-goon wears) and a mother who's a butcher without much social grace. Young-goon comes to the attention of Il-sun, a ping-pong playing patient at the institution who makes it his goal to get her to eat. Will he succeed? Which way does sanity lie? Written by <jhailey@hotmail.com>
six word title | female protagonist | female mental patient | female cyborg | south korea | See All (33) »
Not Rated | See all certifications »
Official site [Germany] | Official site [South Korea] | See more »
7 December 2006 (South Korea) See more »
I'm a Cyborg, But That's OK See more »
Joy Fund, Moho Film See more »
Did not get a US theatrical release. See more »
Park Il-sun: More than our socks are wet.
I'm a Cyborg, But That's OK
26 July 2008 | by TheFluffyKnight – See all my reviews
Cha Young-goon thinks she's a cyborg. She works in a factory, where the employees all wear bright red and sit in neat, identical rows. One day, she slits her wrist and inserts an electrical cable into the wound in an attempt to recharge herself. Unsurprisingly, she is committed to a mental hospital.
The hospital is coloured in a similar stylistic vein, with lovely pastel shades of primary colours. It's all very different from writer/director's Park Chan-wook's previous films; his bleak Sympathy for Mr. Vengeance fades into black and white half way through the film. I'm a Cyborg, But That's OK is definitely a radical departure, although it does retain Park's visual quirkiness.
Young-goon has Cher-like hair, and wide, innocent eyes; we instantly fall in love with her. Once committed, she begins talking to vending machines and strip lights, using her grandmother's dentures. She also refuses to eat, preferring instead to lick batteries. This attracts the attention of mask-wearing Park Il-sun, fellow patient and kleptomaniac. But Il-sun is not your average, run-of-the-mill pickpocket; he steals the intangible, such as memories, table tennis skill, or politeness.
It is not long before Young-goon enlists Il-sun to steal her sympathy. You see, Young-goon needs to rescue her grandmother, who has also been committed, and kill the doctors holding her prisoner. But she can't stop worrying that her victims have grandmothers of their own. And, as we all know, sympathy is one of the seven deadly robotic sins. (The others include thankfulness, hesitation, and useless daydreaming.) It's all very strange. Refreshingly strange, in fact. Two odd highlights are a yodelling interlude, and an extended Peckinpah-style bloodbath, complete with finger guns. The unusual plot and set pieces are complemented by an equally unusual look. Park's idiosyncratic visual flair translates well from the darkness and violence of his vengeance trilogy, to the lighter world of this romantic comedy. The mental hospital looks like no hospital I've ever seen, with bright green padded rooms, deep red maintenance corridors, and even a hiccupping grandfather clock. The CGI, whether due to budget constraints or artistic choice, has that artificial quality seen all too often, but here it adds to the films carefully crafted aesthetic. It's almost as if we're seeing the hospital through the eyes of the patients; everything seems not quite real. Or perhaps too real.
There is a shaky start, though. Throughout the first half of the film, as we are amused by Young-goon's robotic shenanigans, we are also distanced from her. I'm a Cyborg's charming eccentricities threaten to overwhelm the proceedings, bury the characters in their own strangeness. Thankfully, the really quite genuine relationship between Young-goon and Il-sun injects some much needed humanity, and as the film progresses, we begin to learn more of, and sympathise with, Young-goon's plight.
I'm a Cyborg is one of those rare and welcome films that you cannot help but smile through. Young-goon's innocent eyes, the hospital's pastel-coloured walls, the glorious flights of fancy; it all makes for one of the most charming, and definitely the oddest, romantic comedy I have seen in a long time. Odd in the good way, though.


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How did the UK national press portray Bulgarians and Romanians prior to the lifting of transitional controls on 1 January 2014?
Duration: 0:27:08 | Added: 27 Oct 2014
William Allen, Migration Observatory, COMPAS, University of Oxford, gives a talk for the COMPAS Breakfast Briefing series.
On 1 January 2014, transitional controls placed on Bulgarians and Romanians wanting to work in the UK were lifted. From 1 December 2012 to 1 December 2013, arguably a crucial time in the run-up to this important change, UK national newspapers discussed the potential magnitude, impacts, and composition of migrants from these countries. But how did the British national press portray these groups? What kinds of issues were raised in relation to people from these countries? This briefing will explore these questions using new research from The Migration Observatory, Bulgarians and Romanians in the British National Press: 1 December 2012 – 1 December 2013. Analysing the language used by different sections of the UK national press (tabloids and broadsheets) to describe Bulgarians and Romanians over an entire year reveals clear differences in the kinds of words used to refer to each group. Furthermore, it uncovers a range of numerical figures referring to anticipated numbers of migrants that circulated in the press, despite a continuing lack of official data.
Centre on Migration, Policy and Society (COMPAS)
The mission of COMPAS is to conduct high quality research in order to develop theory and knowledge, inform policy-making and public debate, and engage users of research within the field of migration.
The mobility of people is now firmly recognised as a key dimension shaping society today, but the relationship between migration and societal change is only partly understood. Research at the Centre on Migration, Policy and Society (COMPAS), core funded by the Economic and Social Research...
<iframe width="640" height="400" src="http://podcasts.ox.ac.uk/embed/355d6fbfbea327174d8c" frameborder="0" allowfullscreen></iframe>


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Download Jewel - Propaganda - A Secret Wish (Vinyl, LP, Album) album flac mp3
By Kajile
Label: Island Records - 207 027,Island Records - 207 027-620,ZTT - 207 027,ZTT - 207 027-620 • Series: Action Series - 13 • Format: Vinyl LP, Album • Country: Europe • Genre: Electronic • Style: Synth-pop
Released in an outer sleeve; and an inner sleeve with a montage of images and photos on one side (with quotes from texts and the titles of the tracks scattered through the montage), and on the other side a band photo, tracklisting, list of band members, credits, and two large chunks of text quoted from Walter Benjamin's "On The Concept Of History" and Franco Moretti's "Signs taken for wonders.
Slightly different to this Euro version: Propaganda - A Secret Wish No picture inner sleeve and the back of the sleeve is a bit different: right upper corner: bar code is above the format and distribution codes (instead of other way around) - layout of information underneath /5(30).
The album was originally released on Trevor Horn's ZTT Records, also famous for its Frankie Goes To Hollywood releases. Both the singles "Duel" and "" were huge hits. The track "p:Machinery" was featured in an episode of the TV show Miami Vice, exactly the right place for an 80's Synthpop band.
A Secret Wish is the debut album by German synthpop band Propaganda. Released by ZTT Records in , it was produced by Stephen Lipson under the supervision of label boss Trevor Horn. The singles "Duel" and "Dr. Mabuse" were both Top 30 UK chart : Synth-pop, new wave.
· The g vinyl LP package includes a 6-page booklet and 12"x12" artcard whilst the hardback CD mediabook format boasts a page booklet, with both formats featuring Ian Peel's newly-written and extensively-researched sleevenotes which tell the story of the players, the craft, the impact and the legacy of this much-loved album through interviews with band members Ralf Dörper & .
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Mubar says:
An absolute MONSTER of an opening track and one of the best curtain-raisers to any album ever. What distinguished A Secret Wish from other albums released at the same time was that there were two distinct versions - one on vinyl and one on CD/5().


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FCC Gives Initial OK To New Internet Traffic Rules
Demonstrators protest outside the Federal Communications Commission Thursday. The agency voted to open new proposed rules for public comment, including a discussion of whether "paid prioritization" should be banned.
New rules for how Internet traffic is governed were officially unveiled and approved for public comment following a 3-2 vote Thursday by members of the Federal Communications Commission.
The Associated Press notes that the new rules "could set standards for Internet providers who wish to create paid priority fast lanes on their networks."
Update at 1:25 p.m. ET: More Details About The FCC Vote And Plan
"This proposal does not provide or mandate paid prioritization," FCC Chairman Tom Wheeler said at a news conference this afternoon. He said that it only asks questions about paid pathways, instead of authorizing them.
The briefing was contentious at times, with Wheeler growing frustrated by what he called overly hypothetical questions.
"I buy a pipe, I buy a pathway," Wheeler said, using his own arrangement with his Internet provider as an example. "Nobody can mess with that."
He added, "I'm saying there's a path to the Internet — I bought it!"
The commission's 3-2 vote this morning had its Republican members voting against and its Democrats voting in favor (see the proceedings in archived video at C-SPAN).
Asked by a reporter about a "rift" between the commissioners, Wheeler said, "Everybody got it three weeks early. There were a couple of early 'noes.' "
He also said he has "a hard time associating myself" with comments made by Republican commissioners at today's session.
While several protesters announced their presence at the meeting, FCC special counsel Gigi Sohn tweeted, "no protesters were arrested during #NetNeutrality presentation. They were simply escorted out of the room."
The FCC hasn't yet released the full text of the proposal, which was prompted by Wheeler's proposal for an Open Internet in February.
The agency handed out a guide today to what it calls "Protecting and Promoting the Open Internet." The guide was then posted online by Alex Howard of the blog E Pluribus Unum.
The document says the proposal "asks whether paid prioritization arrangements, or 'fast lanes,' can be banned outright."
It also asks "whether broadband providers should be required to disclose specific network practices, performance characteristics (e.g., effective upload and download speeds, latency and packet loss) and/or terms and conditions of service to end users (e.g., data caps)."
Washington Post tech writer Brian Fung, who has followed the net neutrality issue closely, tweets, "yes, there may be a fast and slow lane. But the FCC says consumers will effectively choose how slow 'slow' means."
That idea is the crux of Fung's story for the Post, which cites Wheeler's statement during today's hearing that "If a network operator slowed the speed of service below that which the consumer bought, it would be commercially unreasonable and therefore prohibited."
The net neutrality issue has been lobbied heavily by industry and consumer groups. Public comments on the proposal are due on July 15. The FCC has posted a link for people to use to email their input on its "Open Internet" proposal; a Web page explains the full process.
Here's a quick summary of what's at stake, from NPR's Laura Sydell:
"FCC Chairman Wheeler says he is dedicated to making certain everyone's content gets to consumers without interruption; but an initial version of the proposed rules suggested it might be OK for Internet service providers like Comcast to charge a content producer like CNN extra if it wanted to reach viewers faster."
In a nod to the intense public interest in the question, Commissioner Mignon Clyburn said in a round of speeches before the vote that even her mother had gotten in touch about it. "When my mother calls with public policy concerns, I know there's a problem," she said.
Clyburn went on to lay out the issue and to say that American consumers will have a chance to weigh in on the proposal.
"I support an open Internet," Commissioner Jessica Rosenworcel said. "But I would have done this differently." Saying that the Internet is now a powerful force in Americans' lives, Rosenworcel said the rules change was contemplated without enough input.
Some commissioners, such as Ajit Paik, announced their dissent before the vote, stating, "I respectfully dissent."
Commissioner Michael O'Rielly sought to eviscerate the rules notice, saying its flaws include a lack of cost-benefit analysis. He said the proposed net neutrality rules would stifle creativity without providing any benefit to consumers.
After O'Rielly spoke, the proceeding was briefly interrupted by a protester who yelled, "I speak on behalf of the Internet generation!" She continued to speak, calling for a free and open Internet, earning applause from some of those in attendance.
Before the vote, FCC Chairman Tom Wheeler said that the rules proposal needs to be judged on its content, not on the rumors that have circulated. He also sought to allay concerns that the new rules would create a "fast lane" and a "slow lane" online.
"Nothing in this proposal authorizes paid prioritization," Wheeler said, "despite what has been incorrectly stated today."
Noting that previous efforts to change the Internet's rules had been blocked in court, Wheeler said that the FCC is moving "to surmount that opposition."


/Pricing and Terms /What are integrations?
TrackDuck works as a complementary tool to various project management tools, collaboration platforms and content management systems. The list of integrations that TrackDuck supports is being currently updated.


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Daphne Bradford is a media producer, grassroots organizer, and a nationally recognized innovative educator and technology evangelist. A native of South Los Angeles, she spent her early childhood years in Compton and Inglewood, California, graduating from the all-girls high school St. Mary's Academy. With the dream of becoming a real estate mogul and Wall Street financier, Daphne earned a degree in finance from Cal State Long Beach, becoming a real estate agent and earning her stockbrokers license at the infamous Shearson Lehman Brothers.
Leaving Wall Street behind to take care of her ailing grandfather, Daphne embarked on a modeling career with the encouragement of her mother. She entered a modeling contest for a beer company sponsored by the now-defunct KACE 103.9FM radio station owned by football Hall of Famer Willie Davis, thus beginning her radio career as a morning show producer and DJ. With a goal of becoming one of the top radio producers and on-air personalities, Daphne interviewed entertainers and politicians and appeared on the Oprah Winfrey Show covering the 1992 riots in Los Angeles. When KACE was sold, Daphne was hired at low-powered KJLH 102.3FM, the last remaining black-owned radio station in Los Angeles which is still owned by legendary entertainer Stevie Wonder. She went to KJLH hoping to bridge entertainment and education and become a gospel music evangelist, until she experienced her #MeToo moment which derailed her dreams.
After stints at Fox and Sony, Daphne got back into broadcasting working with legendary syndicated radio pioneer Lee Bailey. She was the gospel music editor for Inside Gospel where she conducted one of the last radio interviews with civil rights icon Rosa Parks. That was the catalyst for Daphne's new calling in life; the establishment of the non-profit organization Mother Of Many (M.O.M.) and her syndicated radio production company Queen James Entertainment. These two entrepreneurial and grass roots organizing ventures took her to Locke High School in Watts where she began teaching radio, music and video production, in partnership with music industry songwriter and infamous educator Reggie Andrews. Her dream of bridging entertainment and education led to Daphne becoming one of the most celebrated teachers in the nation with recognition from Apple, Microsoft, Google and being honored as a White House Champion of Change by President Barack Obama.


On Saturday the 26th of November, an age old tradition will return to Memorial Stadium. The Boilermakers will be rolling into town to partake in the 91st annual Old Oaken Bucket.
It is true that IU vs. Purdue football games have occurred since 1891, however, the Old Oaken Bucket was established in 1925 to better celebrate the schools' rivalry. Two men, IU alum Dr. Clarence Jones and Purdue alum Russel Gray, believed the winner of the football game should be adorned with a trophy to showcase at their school. They did not want just any generic trophy: they needed something special. The two visited a rural Indiana farm in search for such a prize and returned with a wooden bucket used to collect water from a well. What other kind of trophy is most fit for Indiana football?
The bucket was presented to the Presidents of IU and Purdue at the game in 1925. It was said that whoever won would have a bronze block in the shape of their school's letter attached to the bucket. Coincidentally, the first Old Oaken Bucket ended in a tie, so the letters "IP" were the first bronze decorations; they hang proudly on the handle of this treasured prize.
Every year, a new letter is attached. So far, Purdue leads 72-40-6, however, IU has dominated the game for the past three years and is looking for another victory this season. So make sure you're either at Memorial Stadium or watching the game on TV on Saturday to see who will take home the Old Oaken Bucket this year!


Careerpilot can be at the centre of a school/college's careers plan for Y7 - Y13.
Careerpilot is a free to use website co-funded by 20 universities in the South of England.
Careerpilot can sit in the centre of a school or college careers provision/plan for young people from Y7 - Y13.
You can see suggested Careerpilot activities for each year group here.
It can also be a central source of information and support to the designated Careers Leader, teachers/tutors and parents.
Careerpilot offers a student site with information on the full range of choices at 14, 16 and 18 and information on19 job sectors linked to 100s of job profiles which include labour-market information. The Career Tools enable young people to personalise and save their choices and record their learning from the activities they do, including from employer encounters or work experience. Their record moves up with them as they go through the school/college.
The site has a Reporting Zone where school/college Careers Leaders and other school/college staff can monitor the choices students make. The Reporting Zone can also be used to record reports from one to one guidance sessions/tutor meetings, etc. You can view a sample Careerpilot Student Report here.
The site also includes an Adviser and Parent Zone.


Friday night's championship match between "Set an Example" and "Volley Storm" could have been anyone's game. The first set showed a different side from both teams hungry for a championship. "Volley Storm" played lights out, making all the right choices and getting the ball to either Audrey or Joe. They were dominant on offense and digging balls left and right!
In the second set "Set an Example" was able to regroup. Milan (player of the game) started off with 4 points in a row (3 kills and 1 block) putting his team up early 4-0. He had a strong presence at the net with his blocking, forcing the hitters for "Volley Storm" to maneuver around him. "Volley Storm" didn't give up easily though; at one point, they were up by 6 points in the latter stage of set 2. But, Milan rallied his team to get on a good serving run and take back the match, leveling it up at 17-17. It was sideout volleyball for the next few rallies until "Set an Example" edged out their opponent to win the match 21-19. They definitely showed heart in that match and showed the entire gym they didn't want to go home. A lot of cheers and excitement from everyone watching, as well as players on the court.
The third and final set started in favor of "Volley Storm" from the get-go, with "Set an Example" unable to keep momentum early on. But, Milan pushed his team really hard with some great defense. Audrey and Joe were hitting from everywhere on the court and playing incredibly aggressive for "Volley Storm" but "Set an Example" stuck with it and dug deep to gain a lead. At around 18-10 "Volley Storm" went on a service run, rattling off 6 straight points with solid serves and excellent transition balls when it was sent back over.
After a side out "Set an Example" pushed the score to 19-16, with Volley Storm continuing to apply pressure closing the gap to within 1 (19-18). Ultimately though our champs would close out the last two points, first due to a service error and then with a great point after a long rally after "Volley Storm" called a timeout to regroup.
All in all a great season! Congrats to "Set an Example" on the fantastic win!


Most of you—our clients—are "best practitioners" in the art of online merchandising and search marketing. You invest in search engine optimization. You constantly refine your Web site search and navigation. We'd like to calibrate how far along you are in integrating your search marketing efforts to provide the optimal findability, navigation, and results for prospects and customers. So please take our Search-Driven Marketing Strategy Survey. And forward this link to your colleagues to take as well. You'll find Sue Aldrich's questions provocative. As you respond to her queries, I'm sure you'll begin to realize that there may be things you should be doing that you hadn't really thought about yet. We'll publish the survey results shortly and offer our analysis and recommendations about what you can do to make it easier for customers to find your products and services in order to meet their needs.


A prominent gang leader escaped from his United Kingdom prison cell after being temporarily released in order to celebrate Christmas Day with his family.
Blake Donnellan, a 31 year old male inmate and gang leader, went missing on December 25th, 2011.
"Donnellan was convicted of conspiracy to supply drugs along with Craig Harbar, Steven Armstrong, Neil Hazelwood and Terence Gray" (Burrows, 2017, n.p.).
Police caught them stopped on the A38, travelling from Manchester to Plymouth. As suspected, police discovered immense amounts of cocaine and other drugs.
"During their trial… there were indications the gang were making fortnightly deliveries from Manchester to Plymouth which could have totalled 56kg of cocaine worth £2.8 million over a seven-month period" (Burrows, 2017, n.p.), says Recorder Nicolas Gerasimidis. The prosecution described Donnellan as the "area manager" which added an additional 15 years to his sentence. The rest of the gang members received prison sentences ranging from two to eight years (Burrows, 2017).
After being sentenced to 15 years of jail time for "heading up a multi-million pound cocaine operation" (Burrows, 2017, n.p.), Donnellan decided to breakout and has been on the run ever since. His last known whereabouts were in Bude, Cornwall, England, UK. He had close links to Plymouth and Manchester as well.
It seemed highly unlikely that Donnellan would ever go back to Cornwall, Plymouth, or Manchester because of his easy recognition. He is too well known around there; it would take only one person to spot him and Donnellan would be back behind bars.


In other words, we don't start over; we begin again right where we are, with the opportunity to make things better in our lives.
As we begin this new year, are you excited about the possibilities of new beginnings? The beginning of a new year is much like fresh snow: everything is covered under a blanket of white. What kind of tracks will you make this year?
I remember as a kid how much fun it was making angels in the snow. I remember the joy and thrill of making forts and tunnels in the snow. How many of us apply the same amount of gusto to our lives today? As kids we just enjoyed the day. We didn't worry that our masterpieces would melt and disappear. The conditions didn't have to be perfect. We didn't worry about how much time we had. Whatever we built or what fun we had was perfect exactly the way it was.
High-fiving 3-Day participants after getting soaked in the ice bucket challenge in Philadelphia this summer.
Wouldn't it be magical to bring some of that wonder back into our lives today as adults? Every time I get wound up with stuff I have to do, my husband gently cups my face and simply says, "It's time to put your mind on third grade." As a child, you knew the value of being in the moment. Today many of us are so geared up we view ourselves as production robots doing more and more all the time. Society tells us that doing more and having more equals success. These are all important but our quality of life is key to peaceful living. If I don't complete my list of "things to do" my value as a human being won't diminish. We are all infinitely valuable, but life will march on whether or not we get that PowerPoint presentation done.
The new year is a good time to reflect, and is certainly an excellent time to plan and decide what you are going to do and accomplish this year. I also encourage you to think and ponder about who you want to be this year. Many times we get so caught up in doing that we forget who we are being and who we are becoming.
What will 2015 be about for you? Will life be a grand adventure or will it be more of the same? Chances are if you do the same things as last year you will get the same result.
Is there an area of your life that could use a new beginning? Could your health use a new beginning, or your relationship with your spouse? Could your career or business use a jolt of new energy? Set your intention and steer yourself in that direction.