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(May 13, 2011) The Council of Ministers of the Netherlands adopted a proposal on April 29, 2011, to raise the official retirement age to 66 in 2020; at present it is 65. It is estimated that the move would save the government about €700 million (about US$1 billion). Under an informal accord reached between employers and labor unions in 2010, the pensionable age would be linked to average life expectancy. By the year 2025, that age would be 67; by 2040, according to the Dutch Minister of Social Affairs and Employment, Henk Kamp, it would be 68. (René Offermanns, Increase of Pensionable Age from 65 to 66 Proposed, TAX NEWS SERVICE (May 10, 2011), International Bureau of Fiscal Documentation (IBFD) online subscription database; Dutch Retirement 'at 68 by 2040,' RADIO NETHERLANDS WORLDWIDE (Apr. 20, 2011).)
Reportedly, "[t]he impetus for the move is Holland's aging population and increased longevity. Current government population projections indicate that the present ratio of four workers for each pensioner in the Netherlands is expected to decline to two workers for each pensioner by 2040." (Netherlands Cabinet Endorses Proposal to Raise Retirement Age, AGING WORKFORCE NEWS (May 4, 2011).)
In addition, the Council of Ministers proposed increasing the pension accrual period from 35 years to 40, effective January 1, 2013. The annual accrual rate for a final pay system (a plan based on a person's final salary) would be 1.75%, down from 2%; for a career-average wage system (a plan based on conditional, indexed average pay), the rate would be 2%, down from 2.25%. Pension rights that have already accrued would remain unchanged. (Offermanns, supra; The Old Age Pension System in the Netherlands (June 2008); The Principles of the Dutch Pension System: The Problems We Are Facing, A Challenge for Trade Unions, Public Services International website (Nov. 14, 2008); see also Wendy Zeldin, Netherlands: Retirement Age to Rise, GLOBAL LEGAL MONITOR (Dec. 7, 2009).)
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Last updated: 05/13/2011


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Structure and Mechanism in Protein Science: A Guide to Enzyme Catalysis and Protein Folding
Review Caspase inhibitors: viral, cellular and chemical BA Callus* ,1 and DL Vaux 1 Caspases, key mediators of apoptosis, are a structurally related family of cysteine proteases that cleave their substrates at aspartic acid residues either to cause cell death or to activate cytokines as part of an immune response. They can be controlled upstream by the regulation of signals that lead to zymogen activation, or downstream by inhibitors that prevent them from reaching their substrates. This review specifically looks at caspase inhibitors as distinct from caspase regulators: those produced by the cell itself; those whose genes are carried by viruses; and artificial caspase inhibitors used for research and potentially as therapeutics. Cell Death and Differentiation (2007) 14, 73?78. doi:10.1038/sj.cdd.4402034; published online 8 September 2006 The first caspase inhibitor was discovered before caspases were termed ?caspases?, and before caspases were known to be the key executioners of the cell death program. Caspase 1, initially called interleukin 1b converting enzyme (ICE), was identified not because it was involved in cell death, but because it is responsible for cleaving and thereby activating interleukin 1b, a pro-inflammatory cytokine. 1,2 The first caspase inhibitor was cytokine response modifier A (CrmA), a product of cowpox virus that inhibits ICE activity. 3 With the cloning of the CED-3, which is essential for programmed cell death in Caenorhabditis elegans, and recognition of its similarity to ICE, 4 it became clear that caspases were required for cell death in the worm, and therefore that caspase inhibitors might prevent worm cells from killing themselves. Because the mechanisms of pro- grammed cell death in the worm were similar to those for apoptosis of mammalian cells, 5 caspase inhibitors could presumably prevent the death of mammalian cells as well. The only caspase inhibitor known at the time, CrmA, was therefore tested for its ability to prevent cell death, and indeed, it was able to inhibit death of mammalian cells triggered by overexpression of caspase 1. 6 The study of other viruses led to the identification of further caspase inhibitors, and pointed the way to identification of their cellular homologues. As several of the viral caspase inhibitors act through binding of pseudosubstrate loops in the catalytic site, study of viral caspase inhibitors has also provided useful examples for the design of artificial caspase inhibitors. CrmA Viruses that bear genes for caspase inhibitors have been positively selected either because the caspase inhibitors prolong host cell viability, increasing the time for viral replication or because caspase inhibition prevents the generation of inflammatory cytokines as part of the host?s immune response. CrmA inhibits caspase 1, thus preventing the generation of active cytokines interleukin 1b and interleukin 18. 7,8 In addition to inhibiting mammalian cell death caused by artificial overexpression of caspase 1, it was later found that CrmA could inhibit apoptosis triggered by tumour necrosis factor (TNF) treatment or ligation of Fas receptors. 9?12 In retrospect, however, it has turned out this was due to inhibition of caspase 8 by CrmA, rather than by inhibition of caspase 1. In addition to inhibiting caspase 1 with an inhibitory constant (K i ) in the low picomolar (pM) range (Table 1), CrmA can also efficiently inhibit caspase 8 and in humans caspase 10, and can thereby often prevent death of cells signalled by ligation of a subset of the TNF receptor super family members known as ?death receptors? that signal via FADD and caspase 8. 32 CrmA is not a strong inhibitor of other caspases, such as caspase 3, 6 and 7 (K i 4100 nM; Table 1), and is therefore unlikely to be expressed at high enough levels to inhibit these capases in vivo. 8 Although CrmA inhibits caspases, which are cysteine proteases, by structure and mechanism of action it is a member of the serine protease inhibitor (serpin) family, whose other members, as their name implies, inhibit serine pro- teases, rather than cysteine proteases. The pseudosubstrate residues (P 4 -P 1 ) of CrmA, LVAD, bind to the caspases? active sites (Figure 1a). Unbound CrmA is relatively unstable, but is significantly more stable while bound to caspase 1. It is thought that some CrmA molecules are cleaved and subsequently released from caspase 1, whereas other CrmA molecules are not cleaved but form an irreversibly stable complex. 13,33 Received 07.6.06; revised 27.7.06; accepted 27.7.06; Edited by S Kumar; published online 08.9.06 BAC and DLV have no financial interests in any of the companies mentioned in this review. 1 Department of Biochemistry, La Trobe University, Victoria 3086, Australia *Corresponding author: BA Callus, Department of Biochemistry, La Trobe University, Victoria 3086, Australia. Tel: �61 3 9479 1669; Fax: � 61 3 9479 2467; E-mail: email@example.com Keywords: caspase; IAP; apoptosis; protease; p35 Abbreviations: ICE, interleukin 1b converting enzyme; CrmA, cytokine response modifier A; TNF, tumour necrosis factor; IAP, inhibitor of apoptosis protein; BIR, baculoviral IAP repeat Cell Death and Differentiation (2007) 14, 73?78 &2007 Nature Publishing Group All rights reserved 1350-9047/07 $30.00 www.nature.com/cdd P35 The next caspase inhibitor to be identified was, like CrmA, a viral gene product, but it did not come from viruses that infected mammalian hosts, but from a virus that infects the Alfalfa looper, Autographa californica. P35, 34 and the related p49 from Spodoptera littoralis nucleopolyhedrovirus 35 inhibit a broad range of caspases. 14,17,36?38 P35 not only inhibits insect caspases, but also inhibits many mammalian cas- pases, mostly with Kds in the low nanomolar range 14 (Table 1). It is least effective at inhibiting caspases 2 and 9, 39 and is also a relatively weak inhibitor of DRONC, the caspase 9-like initiator caspase from Drosophila, whereas p49 seems capable of inhibiting these caspases as well. To inhibit caspases, p35 is first cleaved at the exposed reactive site loop P 4 -P 1 residues DQMD, but the cleaved polypeptides do not dissociate, as a covalent thiol linkage is formed with the caspase?s catalytic cysteine. 14,40,41 Structural studies of p35 have shown the conformation of this loop and the preceding alpha-helix are essential for caspase inhibition. 36,37 IAPs The first inhibitor of apoptosis protein (IAP) was discovered as baculoviral gene product that could complement Autographa californica nuclear polyhedrosis virus for loss of p35. 42 They, and cellular homologues discovered subsequently, all bear from one to three baculoviral IAP repeats (BIRs), a novel zinc binding fold of about 70 amino acids. 43 Although the first IAP described, OpIAP, is able to inhibit cell death, and able to complement AcNPV for mutation to p35, OpIAP does not directly inhibit the catalytic activity of caspases, but presumably acts upstream to prevent activation of caspase zymogens. 19 NAIP was the first mammalian IAP to be discovered, but rather than having a role in regulation of cell death, it is a Table 1 Specificity of viral and cellular caspase inhibitors Caspase inhibitor Source Target caspase(s) Strength of inhibition (where known) Reference CrmA Cowpox virus Caspase 1 Caspase 8 Caspase 10 K i 4?10 pM K i o340 pM K i 4?17 nM 13?15 P35 Baculovirus Broad spectrum, for example, inhibits caspase 1, 3, 6, 8, 7 and 10 K i s 0.1?9 nM 14,16 P49 Broad spectrum Caspase inhibitor, like p35, but also inhibits initiator caspases DRONC and caspase 9 17,18 OpIAP Baculovirus Does not directly inhibit caspase activity 19 DIAP1 Drosophila DRONC DrICE Powerfully inhibits DRONC activation; activity against DrICE may be weak 20?23 XIAP Mammalian Caspase 3 Caspase 7 Caspase 9 IC50 0.1?2 nM IC50 1?10 nM IC50 10 nM 24?28 cIAP1 Mammalian Does not directly inhibit caspases at physiological concentrations 29 cIAP2 Mammalian Does not directly inhibit caspases at physiological concentrations 29 ILP-2 Human Does not directly inhibit caspases at physiological concentrations 28 ML-IAP Mammalian Does not directly inhibit caspases at physiological concentrations 30 Survivin Mammalian Does not directly inhibit caspases at physiological concentrations 31 NAIP Mammalian Does not directly inhibit caspases at physiological concentrations 29 BRUCE Mammalian Does not directly inhibit caspases at physiological concentrations 29 allosteric inhibition Active allosteric site closed Compound 34 Inactive zymogen-like , allosteric site open Inactive Active catalytic site inhibition z-VAD Inactive CrmA or p35 Inactive a b ,,, Figure 1 Catalytic site and allosteric site inhibition of caspases. (a) The viral inhibitors, CrmA and p35, as well as synthetic peptidic inhibitors for example, z-VAD-fmk, bind as pseudosubstrates to the active catalytic sites (solid circles) of target caspases thereby inhibiting their catalytic activity. (b) Following zymogen activation caspases are in equilibrium between active (allosteric site closed) and ?zymogen-like? inactive (allosteric site open) conformations. Compound 34 (triangle) binds to the open allosteric site in the dimeric interface thereby trapping the enzyme in an inactive state. Inactive catalytic sites are represented with open circles. For simplicity only caspase monomers are shown. See text for details Caspase inhibitors BA Callus and DL Vaux 74 Cell Death and Differentiation member of the NACHT-LRR/NOD-LRR/CATERPILLAR/ CLAN family 44,45 that appears to function in providing innate immunity to infection by bacteria such as Leigonella pneumo- phila. 46,47 Although some initial reports suggested it might be able to inhibit caspases in vitro, subsequent studies have shown NAIP cannot directly inhibit caspases at physiological concentrations. 29 Similarly, although Survivin, an IAP that acts together with aurora kinase B and the inner centromere protein during mitosis, was initially proposed to inhibit caspases, 48 it is no longer thought to be able to do so. 31 XIAP, which bears three BIRs, is the most thoroughly characterized mammalian IAP, and also the most potent inhibitor of cell death in vitro. In interactions involving BIR2 and the flanking region just N-terminal to it (the BIR1/BIR2 linker region), XIAP can inhibit caspase 3 and caspase 7 with low nanomolar efficiency 24?26 (Table 1, Figure 2a). The main interaction involves insertion of an aspartic acid residue from the region flanking BIR2 into the active site of the caspases, but orientation of the inserted peptide is the reverse of that adopted by caspase substrates when they enter the catalytic site. 26 As well as inhibiting caspase 3 and 7 by this mechanism, XIAP can also inhibit caspase 9 by a different mechanism, in which the third BIR binds to the processed amino-terminus of monomeric caspase 9, to prevent its dimerization, which is required for caspase activation. In this way, XIAP inhibits caspase 9 with an IC50 of around 10 nM. 27,28 Like XIAP, cIAP1 and cIAP2 have three BIRs and a RING domain. However, although cIAP1 and cIAP2 are able to bind to caspases, they are not able to inhibit them in physiological circumstances, because their K i are greater than 5mM, 29 so their ability to inhibit apoptosis is probably indirect rather than by the direct inhibition of caspase activity. Possible mechan- isms include: binding to IAP antagonists such as Smac/ Diablo, to reduce the amount available to antagonize XIAP, thereby allowing more XIAP molecules to be free to inhibit caspases; or influencing signalling by NF-kB and MAP kinases, or targeting caspases for ubiquitylation and protea- somal degradation. 29,49 The strongest evidence for a role of IAPs in controlling apoptosis comes not from mammalian experiments but from Drosophila. Whereas deletion of genes for XIAP in the mouse has a very minor phenotype, 50 deletion of DIAP1 in the fly results in massive, lethal apoptosis. 51 However, even though they are similar, DIAP1 and XIAP do not act in precisely the same ways. For example, XIAP inhibits caspase 9 activation by binding, via its BIRs, to N terminally processed caspase 9, thereby stopping it from dimerizing. DIAP1, on the other hand, binds to the unprocessed form of DRONC, the Drosophila homologue of caspase 9 20 (Figure 2b). Although just the BIRs of XIAP are sufficient to inhibit caspase 9 activation, DIAP1 requires not only its BIRs that bind to DRONC, but also the E3 ligase activity of its RING domain in order to neutralize it. 52 DIAP1 can also bind to processed effector caspases such as DrICE and DCP1 via conserved IAP-binding motifs (IBMs) in the neo-amino-termini of the large caspase subunits. 53 Although some groups report DIAP1 inhibits DrICE, 21 another group suggests that, like cIAP1 and cIAP2, DIAP1 may not inhibit the proteolytic activity of effector caspases even while bound to them. 53 Other Caspase Regulators In addition to direct inhibitors of caspase activity, several other regulators of caspases have been described that act up- stream by indirect mechanisms, rather than by directly blocking catalytic activity. Although these regulators are not the focus of this review, they remain nonetheless extremely interesting proteins by virtue of their potential to modulate caspase activity. For example, using the yeast two hybrid system with the pro-domain of caspase 8 as bait, McDonald et al. reported the identification of caspase 8 and 10 associated RING proteins (CARP1 and CARP2) as inhibitors of apoptosis triggered by death receptor ligation. 54 Their mechanism of action is yet not fully elucidated, but it is likely that CARPs (also known as human Ring Finger homologous to IAP type or hRFIs 55 ) do not directly inhibit caspase proteolytic activity, but may prevent dimerization of pro- caspases, preventing their activation, or, because they bear a C-terminal RING domain, they may ubiquitylate caspases 8 and 10 and target them for degradation by the proteasome. Similarly, in Drosophila, proteins such as dBruce, a BIR bearing protein and the RING protein Defense repressor 1 (Dnr1) might also be capable of regulating caspases via as yet undetermined mechanisms. 56,57 XIAP caspase 9 caspase 3/7 Cell death a DIAP1 DRONC DrICE/DCP1 Cell death DIAP1-RING-dependent proteasomal degradation b Figure 2 Caspase inhibition by IAPs. (a) XIAP can bind to the processed end of the large subunit of caspase 9 thereby preventing its dimerization and subsequent activation. XIAP can also bind to the active catalytic sites (solid circles) of effector caspases, caspase 3/7, thereby blocking their activity. (b) DIAP1 neutralizes DRONC by binding to its pro-domain (hatched box) resulting in DIAP1-RING- dependent degradation of DRONC. DIAP1 can also bind to the processed ends of effector caspases, DrICE and DCP1, but may or may not inhibit their activity (indicated with a dashed line). See text for details Caspase inhibitors BA Callus and DL Vaux 75 Cell Death and Differentiation Synthetic Caspase Inhibitors Synthetic caspase inhibitors have been developed both as research tools, and with the hope that they may eventually be used to prevent cell death in the clinic, where they would be of tremendous benefit if they could reduce cell loss in ischaemic vascular diseases, neurodegenerative diseases, and in organ transplant surgery. Because caspases are cysteine proteases, any inhibitors that can react with the catalytic cysteine, for example, iodoacetamide, are also capable of inhibiting caspases. However, inhibitors that are specific for caspases are more useful for research, and only these could be used in the clinic. A number of specific and broad-spectrum peptide caspase inhibitors have been developed, the first based upon caspase substrates, for example, the YVHD cleavage site in pro- IL1b. 58 These inhibitors act as pseudosubstrates for active caspases (Figure 1a) and are therefore competitive inhibitors. Peptides have been linked to chemical groups that serve to block the amino acids and to improve cell permeability, stability and efficacy. These peptide inhibitors range from a single O-methyl-aspartate residue (e.g. benzyloxycar- bonyl-aspartyl(OMe)-fluoromethylketone: Boc-Asp-FMK) to tri-peptides (e.g. Boc-val-ala-asp(OMe)-fluoromethylketone: z-VAD-FMK) and tetrapeptides (e.g. YVAD-FMK). Peptides linked to aldehydes (or nitriles or ketones) are reversible inhibitors (e.g. Ac-DEVD-CHO, Ac-YVAD-CHO) and bind to the catalytic site, but do not irreversibly chemically alter the enzyme. Peptides linked to leaving groups such as halomethylketones (chloro or fluoro), acylomethyl ketones and (phosphinyloxy) methyl ketones are irreversible inhibi- tors. It has been proposed that irreversible inhibitors (e.g. Ac-DVAD-FMK) bind via a thioester linkage to a transition state oxyanion and the carbonyl oxygen occupies an oxyanion hole in the caspase transition state. 59,60 Peptide inhibitors display a wide range of specificity and potency against caspase activity with dissociation constants ranging from pM to low micromolar (mM) concentrations (Table 2). Most synthetic caspase inhibitors are hydrophobic and not very permeable, and could cause nonspecific toxic effects when added at concentrations required to inhibit intracellular caspases. The addition of a carboxy-terminal O-phenoxy group together with an amino-terminal quinolyl group has been reported to significantly improve the efficacy of peptide inhibitors. For example, quinolyl-valyl-O-methylaspartyl-[2,6- difluorophenoxy]-methylketone (Q-VD-OPh) effectively inhi- bits caspase activity at nearly one-tenth the dose required for inhibition by Boc-D-FMK. 61 The improved leaving properties of the carboxy terminal O-phenoxy group makes this inhibitor more reactive with the active cysteine in caspases, explaining the increased effectiveness of Q-VD-OPh compared with inhibitors linked to fluoromethylketones. The amino terminal quinolyl group alone also decreases the dose of peptide inhibitor required for effect, most likely by increasing cell permeability. Derivatives of caspase inhibitors as well as caspase substrates have been used as reagents to assay caspase activity. Most commonly caspase substrates are made in which a colorimetric or fluorescent chemical group is linked to the aspartic acid residue of a peptidic caspase substrate so that colour or fluorescence is produced upon substrate cleavage. For example, in DEVD-AFC and DEVD-AMC the AFC (7-amino-4-trifluoromethyl coumarin) and AMC (amino- 4-methyl coumarin) groups fluoresce following cleavage of the peptide from the substituted coumarin, whereas conjugation to p-nitroanilide (e.g. DEVD-pNA) generates a substrate that allows caspase activity to be determined colorimetrically. Sometimes fluorescent groups (e.g. FITC) are linked to the amino-terminal end of an irreversible peptidic caspase inhibitor, for example, as in FITC-DEVD-FMK. Results using these reagents have to be interpreted with care, because they do not give quantitative signals, and their fluorescence is the same in the presence or absence of active caspases. Rather than becoming fluorescent when they bind to an active caspase, these inhibitors gain specificity because they remain bound to active caspases, whereas the unbound inhibitors are washed away. However, because dead cells are much more permeable than those that are alive, it is possible for much more of the reagent to enter them, so a bright fluorescent signal might be indicative of increased uptake, rather than caspase activity. Indeed, the apparent caspase activity in dying yeast 67 is most likely an artifact owing to the increased permeability of dead cells. 68 Until the effects of synthetic caspase inhibitors are confirmed in cells and ultimately in vivo, caution should be exercised when assigning an inhibitor?s caspase specificity solely on in vitro determined K i s, particularly when the K i s are derived from cleavage assays that utilize non-physiological, Table 2 Specificity of chemical caspase inhibitors Caspase inhibitor Source Target caspase(s) Strength of inhibition (where known) Reference Q-VD-Oph Synthetic peptidic Caspases 1, 3, 8 & 9 IC50 25?400 nM 61 DEVD-CHO Synthetic peptidic Strong inhibitor of caspase 3 and caspase 7 K i o2nM 15 zVAD-FMK Synthetic peptidic Inhibits all caspases, but inhibits caspase 2 very weakly 15 IDN-6556 Synthetic non-peptide, Idun (Pfizer) Broad spectrum irreversible caspase inhibition IC50 25 nM 62 Pralnacasan Synthetic non-peptide (Vertex) Caspase 1 63,64 M867 Synthetic non-peptide (Merck-Frosst) Reversible, selective effector caspase inhibitor K i 1.4 nM (casp 3) K i 8.9 nM (casp 7) 65 Compound 34 Synthetic non-peptide (Sunesis) Targets allosteric site rather than active site Inhibits caspase 1 and caspase 7 and possibly others 66 Caspase inhibitors BA Callus and DL Vaux 76 Cell Death and Differentiation peptide-based substrates. Although in vitro derived K i sdo provide a strong indication of whether an inhibitor is likely to block particular caspases at physiological concentrations, they do not give any indication of possible off-target effects on other enzymes. Ideally, when peptidic caspase inhibitors are used, control experiments should be performed with a compound with the same warhead group, but with a glutamic acid residue in place of the aspartic acid (P1) residue. Drugs Modified peptides generally do not make good pharmaceu- ticals, owing to problems such as proteolysis and poor cellular permeability. In order to develop drugs to inhibit cell death when it occurs inappropriately, such that caused by ischaemic vascular disease or in neurodegenerative disease, pharmaceutical companies have developed non- peptide or peptido-mimetic caspase inhibitors. Most of these act like the peptidic caspase inhibitors, that is, they target the caspase?s catalytic sites. Recently, researchers at Sunesis 66 described a different approach, namely to target a cysteine in the caspase?s allosteric site so that the drug prevents the caspase from adopting the active conformation (Figure 1b). Their Compound 34 was found in a screen for molecules that formed a thiol linkage with a cysteine in the dimeric interface of caspase 1, and it acts in a way remini- scent of the BIR3 domain of XIAP, which inhibits caspase 9 by binding to the dimer interface to prevent dimerization and activation. M867, 65 produced by Merck-Frosst, is a potent reversible caspase inhibitor selective for effector caspases 3 and 7. Although it was able to block many of the manifestations of apoptosis when administered in vivo, it was ineffective at preventing cell death. These results suggest that irreversible inhibitors, and ones that tackle initiator caspases (e.g. caspase 8, caspase 9) or have broad-spectrum activity, would be more effective in vivo. Idun, recently acquired by Pfizer, has produced a number of broad-spectrum caspase inhibitors (IDN-8066, -7503, -7436, -1965, -6556). IDN-6556 is a potent, irreversible, broad- spectrum caspase inhibitor that strongly inhibited Fas- induced apoptosis in vitro, as well as inhibiting liver injury in the mouse in vivo. In a Phase I clinical trial, oral IDN-6556 was able to reduce levels of liver enzymes in the blood in patients with liver disease, presumably by reducing apoptosis of liver cells. 69 It is now is in Phase II trials in patients undergoing liver transplantation, with the hope that it will reduce cell death owing to ischaemia?reperfusion injury. 62 Idun also has described small oxoazepinoindoline caspase inhibitors, IDN-5370 and the more permeable IDN-7866, which prevented apoptosis and promoted the survival of neurons exposed to apoptotic stimuli. 70 IDN-5370 was reported to significantly reduce cortical infarct size in rats subjected to permanent middle cerebral artery occlusion. Vertex produced an orally active non-peptide caspase 1 inhibitor, pralnacasan, and has completed a Phase IIa clinical trial in osteoarthritis. 71 Unfortunately, a phase IIb trial had to be halted because animal toxicology studies showed liver abnormalities after a 9-month exposure to high- doses. Conclusions Our understanding of the mechanisms of action of caspase inhibitors continues to rapidly expand, and new pharmaceu- tical caspase inhibitors are being developed. Although some pharmaceutical companies appear to have ceased their caspase inhibitor projects, and no caspase inhibitors have yet reached phase III trials, there are still grounds to be optimistic that caspase inhibitors will eventually be developed that have wide application in the clinic. In the mean time, study of both synthetic and natural caspase inhibitors has provided many new biological insights, some of which may also turn out to have clinical implications. Study of IAPs, for example, has prompted the development of IAP antagonists that show great promise as inducers of cell death, rather than as cell death inhibitors. Acknowledgements. DLV and BAC are supported by grants from the Australia Research Council and National Health and Medical Research Council. 1. Cerretti DP, Kozlosky CJ, Mosley B, Nelson N, Van NK, Greenstreet TA et al. Molecular cloning of the interleukin-1 beta converting enzyme. Science 1992; 256: 97?100. 2. Thornberry NA, Bull HG, Calaycay JR, Chapman KT, Howard AD, Kostura MJ et al. A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes. Nature 1992; 356: 768?774. 3. Ray CA, Black RA, Kronheim SR, Greenstreet TA, Sleath PR, Salvesen GS et al. Viral inhibition of inflammation: cowpox virus encodes an inhibitor of the interleukin-1 beta converting enzyme. Cell 1992; 69: 597?604. 4. Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz HR. The C. elegans cell death gene ced 3 encodes a protein similar to mammalian interleukin 1 beta converting enzyme. Cell 1993; 75: 641?652. 5. Vaux DL, Weissman IL, Kim SK. Prevention of programmed cell death in Caenorhabditis elegans by human bcl-2. Science 1992; 258: 1955?1957. 6. Miura M, Zhu H, Rotello R, Hartweig EA, Yuan J. Induction of apoptosis in fibroblasts by IL-1b-converting enzyme, a mammalian homolog of the C. elegans cell death gene ced-3. Cell 1993; 75: 653?660. 7. Kamada S, Funahashi Y, Tsujimoto Y. Caspase-4 and caspase-5, members of the ice/ced- 3 family of cysteine proteases, are CrmA-inhibitable proteases. Cell Death Differ 1997; 4: 473?478. 8. Zhou Q, Snipas S, Orth K, Muzio M, Dixit VM, Salvesen GS. Target protease specificity of the viral serpin CrmA ? analysis of five caspases. J Biol Chem 1997; 272: 7797?7800. 9. Chinnaiyan AM, O?Rourke K, Tewari M, Dixit VM. Fadd, a novel death domain-containing protein, interacts with the death domain of fas and initiates apoptosis. Cell 1995; 81: 505?512. 10. Enari M, Hug H, Nagata S. Involvement of an ice-like protease in fas-mediated apoptosis. Nature 1995; 375: 78?81. 11. Miura M, Friedlander RM, Yuan JY. Tumor necrosis factor-induced apoptosis is mediated by a CrmA-sensitive cell death pathway. Proc Natl Acad Sci USA 1995; 92: 8318?8322. 12. Tewari M, Dixit VM. Fas- and tumor necrosis factor-induced apoptosis is inhibited by the poxvirus CrmA gene product. J Biol Chem 1995; 270: 3255?3260. 13. Komiyama T, Ray CA, Pickup DJ, Howard AD, Thornberry NA, Peterson EP et al. Inhibition of interleukin-1-beta converting enzyme by the cowpox virus serpin CrmA ? an example of cross-class inhibition. J Biol Chem 1994; 269: 19331?19337. 14. Zhou Q, Krebs JF, Snipas SJ, Price A, Alnemri ES, Tomaselli KJ et al. Interaction of the baculovirus anti-apoptotic protein p35 with caspases ? specificity, kinetics, and characterization of the caspase/p35 complex. Biochemistry 1998; 37: 10757?10765. 15. Garcia-Calvo M, Peterson EP, Leiting B, Ruel R, Nicholson DW, Thornberry NA. Inhibition of human caspases by peptide-based and macromolecular inhibitors. J Biol Chem 1998; 273: 32608?32613. 16. Xu G, Rich RL, Steegborn C, Min T, Huang Y, Myszka DG et al. Mutational analyses of the p35-caspase interaction. A bowstring kinetic model of caspase inhibition by p35. J Biol Chem 2003; 278: 5455?5461. 17. Jabbour AM, Ekert PG, Coulson EJ, Knight MJ, Ashley DM, Hawkins CJ. The p35 relative, p49, inhibits mammalian and Drosophila caspases including DRONC and protects against apoptosis. Cell Death Differ 2002; 9: 1311?1320. 18. Zoog SJ, Schiller JJ, Wetter JA, Chejanovsky N, Friesen PD. Baculovirus apoptotic suppressor P49 is a substrate inhibitor of initiator caspases resistant to P35 in vivo. EMBO J 2002; 21: 5130?5140. 19. Kaiser WJ, Vucic D, Miller LK. The Drosophila inhibitor of apoptosis D-IAP1 suppresses cell death induced by the caspase drICE. FEBS Lett 1998; 440: 243?248. Caspase inhibitors BA Callus and DL Vaux 77 Cell Death and Differentiation 20. Meier P, Silke J, Leevers SJ, Evan GI. The Drosophila caspase DRONC is regulated by DIAP1. EMBO J 2000; 19: 598?611. 21. Yan N, Wu JW, Chai J, Li W, Shi Y. Molecular mechanisms of DrICE inhibition by DIAP1 and removal of inhibition by Reaper, Hid and Grim. Nat Struct Mol Biol 2004; 11: 420?428. 22. Hawkins CJ, Wang SL, Hay BA. A cloning method to identify caspases and their regulators in yeast: identification of Drosophila IAP1 as an inhibitor of the Drosophila caspase DCP-1. Proc Natl Acad Sci USA 1999; 96: 2885?2890. 23. Hawkins CJ, Yoo SJ, Peterson EP, Wang SL, Vernooy SY, Hay BA. The Drosophila caspase DRONC cleaves following glutamate or aspartate and is regulated by DIAP1, HID, and GRIM. J Biol Chem 2000; 275: 27084?27093. 24. Takahashi R, Deveraux Q, Tamm I, Welsh K, Assamunt N, Salvesen GS et al. A single bir domain of xiap sufficient for inhibiting caspases. J Biol Chem 1998; 273: 7787?7790. 25. Riedl SJ, Renatus M, Schwarzenbacher R, Zhou Q, Sun C, Fesik SW et al. Structural basis for the inhibition of caspase-3 by XIAP. Cell 2001; 104: 791?800. 26. Sun C, Cai M, Gunasekera AH, Meadows RP, Wang H, Chen J et al. NMR structure and mutagenesis of the inhibitor-of-apoptosis protein XIAP. Nature 1999; 401: 818?821. 27. Sun CH, Cai ML, Meadows RP, Xu N, Gunasekera AH, Herrmann J et al. NMR structure and mutagenesis of the third Bir domain of the inhibitor of apoptosis protein XIAP. J Biol Chem 2000; 275: 33777?33781. 28. Shin H, Renatus M, Eckelman BP, Nunes VA, Sampaio CA, Salvesen GS. The BIR domain of IAP-like protein 2 is conformationally unstable: implications for caspase inhibition. Biochem J 2005; 385: 1?10. 29. Eckelman BP, Salvesen GS. The human anti-apoptotic proteins cIAP1 and cIAP2 bind but do not inhibit caspases. J Biol Chem 2006; 281: 3254?3260. 30. Vucic D, Franklin MC, Wallweber HJ, Das K, Eckelman BP, Shin H et al. Engineering ML-IAP to produce an extraordinarily potent caspase 9 inhibitor: implications for Smac-dependent anti-apoptotic activity of ML-IAP. Biochem J 2005; 385: 11?20. 31. Banks DP, Plescia J, Altieri DC, Chen J, Rosenberg SH, Zhang HC et al. Survivin does not inhibit caspase-3 activity. Blood 2000; 96: 4002?4003. 32. Strasser A, O?Connor L, Dixit VM. Apoptosis signaling. Ann Rev Biochem 2000; 69: 217?245. 33. Patston PA, Gettins P, Beechem J, Schapira M. Mechanism of serpin action: evidence that C1 inhibitor functions as a suicide substrate. Biochemistry 1991; 30: 8876?8882. 34. Clem RJ, Fechheimer M, Miller LK. Prevention of apoptosis by a baculovirus gene during infection of insect cells. Science 1991; 254: 1388?1390. 35. Du QS, Lehavi D, Faktor O, Qi YP, Chejanovsky N. Isolation of an apoptosis suppressor gene of the Spodoptera littoralis nucleopolyhedrovirus. J Virol 1999; 73: 1278?1285. 36. Fisher AJ, dela Cruz W, Zoog SJ, Schneider CL, Friesen PD. Crystal structure of baculovirus P35: role of a novel reactive site loon in apoptotic caspase inhibition. EMBO J 1999; 18: 2031?2039. 37. dela Cruz WP, Friesen PD, Fisher AJ. Crystal structure of baculovirus P35 reveals a novel conformational change in the reactive site loop after caspase cleavage. J Biol Chem 2001; 276: 32933?32939. 38. Xu G, Cirilli M, Huang Y, Rich RL, Myszka DG, Wu H. Covalent inhibition revealed by the crystal structure of the caspase-8/p35 complex. Nature 2001; 410: 494?497. 39. Eddins MJ, Lemongello D, Friesen PD, Fisher AJ. Crystallization and low-resolution structure of an effector-caspase/P35 complex: similarities and differences to an initiator- caspase/P35 complex. Acta Crystallogr 2002; 58: 299?302. 40. Bertin J, Mendrysa SM, Lacount DJ, Gaur S, Krebs JF, Armstrong RC et al. Apoptotic suppression by baculovirus p35 involves cleavage by and inhibition of a virus-induced ced- 3/ice-like protease. J Virol 1996; 70: 6251?6259. 41. Bump NJ, Hackett M, Hugunin M, Seshagiri S, Brady K, Chen P et al. Inhibition of ice family proteases by baculovirus antiapoptotic protein p35. Science 1995; 269: 1885?1888. 42. Crook NE, Clem RJ, Miller LK. An apoptosis inhibiting baculovirus gene with a zinc finger like motif. J Virol 1993; 67: 2168?2174. 43. Hinds MG, Norton RS, Vaux DL, Day CL. Solution structure of a baculoviral inhibitor of apoptosis (IAP) repeat. Nat Struct Biol 1999; 6: 648?651. 44. Ting JP, Davis BK. Caterpiller: a novel gene family important in immunity, cell death, and diseases. Ann Rev Immunol 2005; 23: 387?414. 45. Damiano JS, Newman RM, Reed JC. Multiple roles of CLAN (caspase-associated recruitment domain, leucine-rich repeat, and NAIP CIIA HET-E, and TP1-containing protein) in the mammalian innate immune response. J Immunol 2004; 173: 6338?6345. 46. Diez E, Lee SH, Gauthier S, Yaraghi Z, Tremblay M, Vidal S et al. Birc1e is the gene within the Lgn1 locus associated with resistance to Legionella pneumophila. Nat Genet 2003; 33: 55?60. 47. Wright EK, Goodart SA, Growney JD, Hadinoto V, Endrizzi MG, Long EM et al. Naip5 affects host susceptibility to the intracellular pathogen Legionella pneumophila. Curr Biol 2003; 13: 27?36. 48. Li F, Ackermann EJ, Bennett CF, Rothermel AL, Plescia J, Tognin S et al. Pleiotropic cell- division defects and apoptosis induced by interference with survivin function. Nat Cell Biol 1999; 1: 461?466. 49. Vaux DL, Silke J. IAPs, RINGs and ubiquitylation. Nat Rev Mol Cell Biol 2005; 6: 287?297. 50. Harlin H, Reffey SB, Duckett CS, Lindsten T, Thompson CB. Characterization of XIAP- deficient mice. Mol Cell Biol 2001; 21: 3604?3608. 51. Wang SL, Hawkins CJ, Yoo SJ, Muller HAJ, Hay BA. The Drosophila caspase inhibitor DIAP1 is essential for cell survival and is negatively regulated by HID. Cell 1999; 98: 453?463. 52. Wilson R, Goyal L, Ditzel M, Zachariou A, Baker DA, Agapite J et al. The DIAP1 RING finger mediates ubiquitination of Dronc and is indispensable for regulating apoptosis. Nat Cell Biol 2002; 4: 445?450. 53. Tenev T, Zachariou A, Wilson R, Ditzel M, Meier P. IAPs are functionally non-equivalent and regulate effector caspases through distinct mechanisms. Nat Cell Biol 2004; 7: 70?77. 54. McDonald III ER, El-Deiry WS. Suppression of caspase-8- and -10-associated RING proteins results in sensitization to death ligands and inhibition of tumor cell growth. Proc Natl Acad Sci USA 2004; 101: 6170?6175. 55. Sasaki S, Nakamura T, Arakawa H, Mori M, Watanabe T, Nagawa H et al. Isolation and characterization of a novel gene, hRFI, preferentially expressed in esophageal cancer. Oncogene 2002; 21: 5024?5030. 56. Foley E, O?Farrell PH. Functional dissection of an innate immune response by a genome- wide RNAi screen. PLoS Biol 2004; 2: 1091?1106. 57. Vernooy SY, Chow V, Su J, Verbrugghe K, Yang J, Cole S et al. Drosophila Bruce can potently suppress Rpr- and Grim-dependent but not hid-dependent cell death. Curr Biol 2002; 12: 1164?1168. 58. Rano TA, Timkey T, Peterson EP, Rotonda J, Nicholson DW, Becker JW et al. A combinatorial approach for determining protease specificities ? application to interleukin-1- beta converting enzyme (ice). Chem Biol 1997; 4: 149?155. 59. Mittl PR, Di Marco S, Krebs JF, Bai X, Karanewsky DS, Priestle JP et al. Structure of recombinant human CPP32 in complex with the tetrapeptide acetyl-Asp-Val-Ala-Asp fluoromethyl ketone. J Biol Chem 1997; 272: 6539?6547. 60. Walker NPC, Talanian RV, Brady KD, Dang LC, Bump NJ, Ferenz CR et al. Crystal structure of the cysteine protease interleukin-1-b-converting enzyme: A (p20/p10) 2 homodimer. Cell 1994; 78: 343?352. 61. Caserta TM, Smith AN, Gultice AD, Reedy MA, Brown TL. Q-VD-OPh, a broad spectrum caspase inhibitor with potent antiapoptotic properties. Apoptosis 2003; 8: 345?352. 62. Linton SD, Aja T, Armstrong RA, Bai X, Chen LS, Chen N et al. First-in-class pan caspase inhibitor developed for the treatment of liver disease. J Med Chem 2005; 48: 6779?6782. 63. Linton SD. Caspase inhibitors: a pharmaceutical industry perspective. Curr Top Med Chem 2005; 5: 1697?1717. 64. Siegmund B, Zeitz M. Pralnacasan (vertex pharmaceuticals). IDrugs 2003; 6: 154?158. 65. Methot N, Huang J, Coulombe N, Vaillancourt JP, Rasper D, Tam J et al. Differential efficacy of caspase inhibitors on apoptosis markers during sepsis in rats and implication for fractional inhibition requirements for therapeutics. JExpMed2004; 199: 199?207. 66. Scheer JM, Romanowski MJ, Wells JA. A common allosteric site and mechanism in caspases. Proc Natl Acad Sci USA 2006; 103: 7595?7600. 67. Madeo F, Herker E, Maldener C, Wissing S, Lachelt S, Herian M et al. A caspase-related protease regulates apoptosis in yeast. Mol Cell 2002; 9: 911?917. 68. Wysocki R, Kron SJ. Yeast cell death during DNA damage arrest is independent of caspase or reactive oxygen species. J Cell Biol 2004; 166: 311?316. 69. Valentino KL, Gutierrez M, Sanchez R, Winship MJ, Shapiro DA. First clinical trial of a novel caspase inhibitor: anti-apoptotic caspase inhibitor, IDN-6556, improves liver enzymes. Int J Clin Pharmacol Ther 2003; 41: 441?449. 70. Deckwerth TL, Adams LM, Wiessner C, Allegrini PR, Rudin M, Sauter A et al. Long-term protection of brain tissue from cerebral ischemia by peripherally administered peptidomimetic caspase inhibitors. Drug Dev Res 2001; 52: 579?586. 71. Rudolphi K, Gerwin N, Verzijl N, van der Kraan P, van den Berg W. Pralnacasan, an inhibitor of interleukin-1beta converting enzyme, reduces joint damage in two murine models of osteoarthritis. Osteoarthritis Cartilage 2003; 11: 738?746. Caspase inhibitors BA Callus and DL Vaux 78 Cell Death and Differentiation
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Plan on flying this Thanksgiving? Check your flights and arrive early
EUGENE, Ore. -- A southern winter storm could cause Thanksgiving travel problems for tens of millions Americans. The Eugene Airport is expecting its second busiest day ever this Thanksgiving weekend.
"We'll have 1700 passengers through here, a little over that," said Kaitlin Hunter, an official at the Eugene Airport. "So it's about 600 more than we usually do through the airport so we're going to be very busy around here. Security is going to be a little bit slower because there will be a lot of people trying to get through security."
Airport officials suggest passengers arrive two hours before their flight. They also say those with only carry-ons should check in online to save time.


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WASHINGTON (WUSA) -- Being sloppy wet and sticky never felt so sweet.
The 2012 Washington Nationals let loose in the locker room and on their ball field Monday evening, following their 2-0 loss to the Phillies. Because of the Pittsburgh Pirates victory over the Atlanta Braves, the Nats were able to act like college hooligans -- or better yet little leaguers celebrating a title.
Here are a few Nationals players I caught up with during the pandemonium. Their words help describe a scene of joyous chaos, but better yet, six months of compelling baseball that captivated a city -- possibly for the next 10 years.
I'll have a much larger video compilation tomorrow. Until then, enjoy these quotes. I sure did.
Jayson Werth
"This is what it's like being on a good team. And I'm on the good team."
On coming to D.C. - "It was looked at like a gamble. And frowned upon by a lot of people. And I definitely caught a lot of grief for it. But realistically I knew the situation I was going to. I knew all along I wanted to go to place where I had a chance to win for a long time. And it turned out this was probably the best place I could've went."
Bryce Harper
"Being able to enjoy it with these fans in this city...this is so special to me."
"This is only the start of it. We're going to enjoy it tonight but soon, we're really going to get things going."
"This is what I expect every year. I expect to win. This what I do."
John Lannan
"There was a time earlier in the season where I didn't know what was going to happen. Now? It all makes sense."
Stephen Strasburg
"All that matters to me is that we keep on winning. I'm happy to be along for the ride."
Gio Gonzalez
"I don't want to wake up, boys. I'm still dreaming."
Michael Morse
To the fans: "This is as much your win as it is our win."
"We could've folded early. People wanted to write us off after Stras. We are here to stay."
Ryan Zimmerman
"For so long we were the ones at the bottom of the division. Now, our fans have something to be proud of."


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Cajun, blues fest brings a taste of Louisiana to Simi Valley
Families turn out for a taste of the South
The weather was cool. And so was the music Saturday at the 23rd annual Simi Valley Cajun & Blues Music Festival at Rancho Santa Susana Community Park, sponsored by the Rotary Club of Simi Sunrise.
Festivalgoers were all smiles. Some came for the music; some came for the shopping, and some came for the food.
Hilary Matthews, of Burbank, husband John and 12-year-old daughter Ashlyn came for all of it, but particularly the gator.
It was Hilary Matthews' fourth year at the festival and John and Ashlyn's eighth.
"The first thing we did was head over to the food area for the gator on a stick and calamari," Hilary Matthews said.
"I'm going to have a tub of crawfish," John said. "The music is great, too. Everybody loves zydeco."
Hilary said: "The weather is perfect, too. It's usually really hot when we come, so this is really nice. And I've made a lot of purchases: a great pair of retro sunglasses, a dress, some jewelry, fairies, which I always buy from a lady here."
Ashlyn said: "I have on a white tiger hat that has paws that you can stick your hands in. I love the music, too."
Marnie Holohan, of Simi Valley, was doing so much shopping that her 15-year-old son Houston had to drag her away.
"I was doing serious damage," she said.
Houston said: "I'm enjoying the day. But I'm glad she finally left the store. I'm here for the food. I like the music, too."
Bill Elrod, of Camarillo, was dancing up a storm to tunes from Billy Lee & the Swamp Critters.
"I really like Cajun music," Elrod said. "I went to New Orleans about five years ago for Mardi Gras. I'm pacing myself with the dancing, though, because this is an all-day thing."
Not only was the music authentic, but so was the food, which included blackened catfish, jambalaya, gumbo, Louisiana crabcakes, Cajun stew, red beans and rice, alligator and Cajun boiled crawfish.
Frank Tomlinson, of Ocean Fresh Seafood in Simi Valley, was teaching people how to eat the crawfish at the Slap Ya Mama Boiled Crawfish stand.
"You pinch the tail and get the meat out, then suck the head to get the juice out, and that's all part of being at the Simi Valley Cajun Festival without having to go to New Orleans," Tomlinson said.
Lisa Long and her boyfriend drove down from Roseburg, Ore., for the festival. It was their first time to eat crawfish.
"We drove 14 hours to get here," Long said. "Excellent entertainment and excellent food."
There was a lot to do for the kids, as well, including a few bouncies, a rock climbing wall and a craft area.
Members of the Hout family — Tracy, Greg and 7-year-old Murphy — have been coming to the festival from Ojai for eight years.
"We brought Murphy here when he was 4 weeks old the first time," Greg Hout said.
"We spend most of the time at the bouncie," Tracy Hout said.
"But luckily we hear the great music while we're doing it."
Herschel Berger, president of Rotary of Simi Sunrise, was pleased with attendance Saturday.
The festival is the group's biggest fundraiser of the year, benefiting many local organizations, including the Free Clinic of Simi Valley, Meals on Wheels, Many Mansions, the Samaritan Center.
"Our online and pre-sale ticket sales were the highest ever," Berger said.
"By the middle of Sunday, it's going to be rockin'. We're happy because it's for such a good cause.
"We work all year for this. We're very blessed."
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text:
Sully Pinos knows what it's like to bridge the communication gap.
She did it when she was growing up, translating English to Spanish for her parents, who came to the United States from Ecuador before she was born.
She did it on Election Day, when she helped Spanish-speaking York residents find their way to polling locations.
On Thursday, Pinos was at it again.
Only this time she's not being a good daughter or neighbor. Now, helping people is her job.
Pinos, 24, is the district office chief of staff for State Rep. Kevin Schreiber. She is also the only Spanish-speaker on Schreiber's staff.
From 1 to 4 p.m. on the first and third Thursdays of every month, Pinos expects she will be at Centro Hispano Jose Hernandez in York, waiting to answer questions and listen to concerns of Spanish-speaking residents, and connect them with the resources they need.
Although Schreiber was in Harrisburg this Thursday, he plans to be at the center in the future. He doesn't speak Spanish, yet, he explained by phone, but he's learning.
Even if Pinos needs to translate for him, Schreiber said, he plans to sit in on the office hours at Centro Hispano because "part of the job of a representative is to represent their constituents."
The Latino community in York County is fast-growing, he said. "It's a segment of the community we want to reach out to, make sure they're getting the services they require."
A language barrier should not be a barrier to those resources, Schreiber said.
Pinos said the hope is to connect with between 500 and 1,000 people during the first year of the Spanish-speaking mobile office hours.
Jose D. Colon-Bones, board president of the Centro Hispano, said it's helpful to residents for Pinos and Schreiber to come into the community.
"We are pretty much in the heart of the Latino community," Colon-Bones said of the center's location in the 200 block of East Princess Street. People feel comfortable coming to the resource center, but might feel a little intimidated visiting Schreiber's local office in the York Government Offices, Colon-Bones said.
Schreiber will be able to help residents with a multitude of requests, including health care information, birth certificate applications, property tax and rent rebate programs.
For a full list of constituent service, visit www.pahouse.com/Schreiber or Rep. Kevin Schreiber's Facebook page.


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Latest Weather Blog
"Predicted Global Warming-1700s"
In the late 1700s, many scholars were debating whether human activities were changing the earth's climate. As noted in a previous column, Thomas Jefferson and his colleague, Harvard professor Samuel Williams, wrote; "A change in our climate is taking place...both heats and colds are much more moderate within the memory of the middle-aged. When settlers enter a township their first business is to cut down trees, clear lands and sow grains." It was their belief that the surface of the earth became warm and dry and as settlements increased, the effects are more extensive. Dr. Noah Webster believed that the clearing of lands welcomed more sun, thus the changeover from forest to field changes the heat balance. Webster's reflections were noted by Helmut Landsberg 170 years later.


text:
Narrow your search
The service lets passengers find cheap rides from one city to another in 19 countries. But Brazil, not the US, is next on the company's expansion list, CEO Frédéric Mazzella says.
The loudest protest so far against smartphone-era car services involves burning tires, blocked traffic, riot police and an assault on a celebrity taking an Uber ride from the airport.
The city's iconic black cabs brought roads to a standstill in a protest against what drivers see as unfair regulation of the industry.
Spanish activists held a rally this past weekend to protest an upcoming law that levies heavy fines for assembling in front of government buildings. Instead of human bodies, 2,000 holograms showed up to make their holo-voices heard.
On today's show, Ashley and Khail check out a Spanish hologram protest, a stop-motion animated short where every frame was 3D-printed and a new patent from Boeing that might help you sleep better on long flights. #TDProtest
Technically Incorrect: Because you are evil and she is an artist, Qinmin Liu wants you to buy a gold Apple Watch and give it to her, so that she can make art.
The ride-sharing app's drivers in the US and London are complaining about fee hikes, fare cuts and the lack of a tip option.
When the pop superstar pulled her music off the streaming music service last year, her protest ended up acquainting a whole new group of people with Spotify, CEO Daniel Ek says.
It can't sit still as Chinese competitor Didi Kuaidi makes bold moves. One way for Uber to get drivers' attention: Pay them big bonuses.
A commercial court orders Uber to shut down its low-cost service in the Belgian capital within 21 days.


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The patterns rendered by this program are calculated by simulating
the effect of light refracting through water. The water surface is
made tileable in both space and time. This means that you seamlessly
can tile individual rendered images both horizontally and vertically.
It also means that a full generated animation sequence will loop in
The rendered images can for example be used as realtime textures
for games and animations but can also be used as light textures for
film production, advertising renderings and architectural scene
All prices are given excluding VAT. Purchases within EU will add VAT.


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Frequently Asked Questions
Frequently Asked Questions
Shafer maintains two direct mail lists: one for Hillside Select and one called our "Napa Valley List," which offers the other wines in our portfolio.
The "Napa Valley List," which makes available Red Shoulder Ranch Chardonnay, Merlot, One Point Five Cabernet Sauvignon and Relentless, is currently open. The "Hillside Select List" is closed, however, you can sign up for the Waiting List to be added as spots become available. To sign up for one or both of these lists, please click here.
Yes, to those whose names are active on one or both of our mailing lists or who purchase wine at the winery and live in states to which such shipments are legal. That list currently includes: Alaska (wet counties only), California, Colorado, Connecticut, District of Columbia, Florida, Georgia, Hawaii, Idaho, Illinois, Iowa, Kansas, Maryland, Maine, Michigan, Minnesota, Missouri, Montana, Nebraska, Nevada, New Hampshire, New Jersey, New Mexico, New York, North Carolina, Ohio, Oregon, South Carolina, Tennessee, Texas, Vermont, Virginia, Washington, Wisconsin, and Wyoming.
The direct shipping issue continues to change as more and more states pass related legislation. Up-to-date information is available at www.freethegrapes.org.
Because of high temperatures, shipments of wine ordered during summer months may be delayed until fall. This is to protect your wine from heat damage, which can easily occur while sitting in a hot delivery truck.
In specific situations, however, we are able to ship via FedEx Cold Chain. This is a seasonal refrigerated transport solution that our fulfillment house has used with success. The wines are picked up at their facility in a temperature controlled truck, sorted, and consolidated at a temperature-controlled facility and then loaded onto temperature controlled line haul vehicles.
The truck, though, that delivers the wine from your local FedEx hub is not temperature controlled. Given that, we only ship via FedEx Cold Chain in areas where delivery is guaranteed by 10:30 AM (some areas cannot guarantee delivery until much later in the day).
For this method of delivery to be successful, there MUST be an adult available to receive and sign for the delivery on the specified day. Shipping to a business address is preferable.
Also note, using the Cold Chain system takes some time, in most cases at least 10 days from the time your order is placed. The order must be in our fulfillment company's system by Friday before noon for pick up by FedEx the following Friday. Delivery is made on either Tuesday or Wednesday following the FedEx Friday pickup.
Frequently Asked Questions
Approximate number of years from vintage date Shafer considers optimum:
Optimum drinking Length of Aging
Red Shoulder Ranch® Chardonnay Release - 5 years
Merlot Release - 8 years
Napa Valley Cabernet Sauvignon Release - 10 years
Relentless® Release - 15 years
Hillside Select® Cabernet Sauvignon Release - 20 years
Click here for the complete Hillside Select tasting notes.
Wines in larger format bottles age more slowly. Remember, all of Shafer's wines are made to be immediately drinkable upon release.
Frequently Asked Questions
Frequently Asked Questions
Frequently Asked Questions
What is a Diam cork?
A Diam cork is made from 100% real cork that is ground and run through a process that, at the molecular level, eliminates TCA (the chemical compound that causes wines to be "corked") and other microbial contaminants that produce off flavors. Wine corks are produced in France from this clean ground cork using an FDA-approved, food-grade binding agent. For more details on the process visit this URL: http://www.diam-closures.com/Process-en
Why is Shafer using Diam corks?
We don't want a single bottle of Shafer wine to be corked. Ever. Over the past 30 years we have gone to extraordinary lengths to eliminate the presence of TCA in the natural corks we used and have been 98% to 99% successful. That's not good enough. We want to be 100% TCA-free and using this cork will get us there.
What do you like about Diam corks?
We have tested Diam corks in trials for seven years and have come to believe the company's guarantee that its corks are 100 percent free of TCA. In addition, these corks offer something else that natural corks cannot – a guarantee of the amount of oxygen the cork allows into the bottle. This is referred to as Oxygen Transfer Rate (OTR). Natural corks, by contrast, have inconsistent density and permeability, which means a variable amount of oxygen is allowed into the bottle. Using a Diam cork ensures that your wine won't be "over the hill" before its time.
Why are Diam corks used in your Chardonnay but not the other wines?
We have tested these corks for seven years and we like the results. Our Chardonnay is a wine that we know most consumers enjoy within two to three years of release. We continue to test these corks to see how they perform in terms of long-term aging. We won't know those results for a few more years but given what we've seen so far, we expect to be using Diam corks in our red wines in the future.
How are Diam different from other composite corks?
Unlike other composite corks, Diam uses a safe, clean process to eliminate TCA from ground natural cork – it's the same process used to remove caffeine from coffee beans. Also, Diam engineers its corks to guarantee a consistent rate at which oxygen is allowed into the bottle over time. This ensures that every bottle will age in your cellar at a similar rate.
Can Diam corks be recycled like natural corks?
Yes. Most corks collected in recycling bins are re-purposed to make cork flooring, as such, Diam is perfectly useful.
Can I trust the Diam corks in your wines?
Yes. We have tested these corks for seven years and would not use them it we did not fully believe they are what's best for the wine.


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Gallery Folders
Eyapi - Species infoOverviewEyapi - Species info by Kamirah
My Characters
Personal artwork
Carpet Kitty
Other adoptables
I played the games I used for these adoptables, Idk if you want me to link back or not but here: piperleefrance.deviantart.com/…
can you note me your brush settings please? thank you if you do!
Your art's soo awesome!
>sub> too bad you don't do art trades probably! </sub>
good job you champion
Omg I love them all!
You're gallery is magnificent!!!! C:
your work is beautiful. i wish i could draw that well on the computer.
Love all your work it's amazing I want to add all your art work to my favourite
Your artwork is fantastic!!
I like it
So cute!!
Don't you have any free art that I can have?


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The Wine
Fotinos History
Contact Us
George and Vivian Fotinos welcome you to the Fotinos Vineyard web site.
For over 40 years, the Fotinos family has nurtured this vineyard which produces some of
the finest wine grapes in the Napa Valley.
The vineyard is located on the Old Sonoma Road, just south of Buhman Creek in the
Carneros region of Napa Valley. The vineyard is dedicated to growing Pinot Noir grapes,
exclusively. Pinot Noir clones consist of Dijon UC 115, Pommard, and Calera Selection.
The combination of mild climate, soil and grape combine to produce superior quality
grapes. These grapes are sought after by several of the leading wineries in the
George brings a great respect for nature and love of the earth to his farming
efforts. He learned the fine art of viticulture from his father Christos, who immigrated
from the Greek island of Lefkas in 1910. Once he began growing his own grapes with his
brother Tom in 1969, George educated himself in modern viticulture and wine-making
techniques, thus bringing together the Old World and California styles.
The Fotinos Vineyard has grown and developed along with George and Vivian and their
family. Their daughters, Angela, Margaret, and Elaine, have shared their father's
interest in farming and have worked alongside him over the years.
If you share our love of wine and would like to purchase some of our pinot
noir, feel free to contact us.


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If you have a question about studying as a postgraduate that isn't answered here, contact us:
International students - visit Coming to Cardiff, our dedicated questions area for students from outside the UK.
This is an externally hosted beta service offered by Google.
Download, view online or request a paper copy.
Cardiff University is a member of the Russell Group of Universities
Cardiff University is a registered charity No. 1136855
Copyright © Cardiff University


text:
Dow Drops Back Below 12,000 On Greek Default Fears
A banner for Pandora Media Inc., the online-radio company, hangs in... News PhotoBusiness,Corporate Business,Day 1,Economy,Finance,Hanging,Horizontal,International Landmark,New York City,New York Stock Exchange,Pandora - Jewelry,Stock Market,The Internet,Trading,USA,WalkingPhotographer Spencer PlattCollection: Getty Images News 2011 Getty ImagesNEW YORK, NY - JUNE 15: A banner for Pandora Media Inc., the online-radio company, hangs in front of the New York Stock Exchange walk on its first day of trading as a public company on June 15, 2011 in New York City. Pandora stock rose as much as 63 percent to $26 following its debut on the New York Stock Exchange, under the symbol P. Reversing much of the previous day's gains, stocks fell Wednesday as more news emerged about the fragility of the American and global economy. The Dow Jones Industrial Average fell 88 points, or 0.8%, to 11987 in morning trading. (Photo by Spencer Platt/Getty Images)


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Despite a recent blast of chilly weather, it's been a mild Oklahoma winter, which has prematurely stirred my inner grill-master from hibernation.
Don't let cold weather stop you from making your grill marks in winter
Oh, you wicked, wicked global warming, er, climate change.
While we've had plenty of sunshine and some splashes of springlike weather, it's still a little too chilly to cook out after 5 p.m. — certainly after dark.
Never fear: The cast-iron griddle I got a couple of Christmases ago from my in-laws is here.
The kids have gotten to where they actually like burgers made on the flat side of the griddle better than, pause for dramatic effect, those cooked on grill. Gasp ... Protestations of disbelief ... Curse words and raised, shaking fists from my friends at American Propane.
All right, all right, I'm not trying to convert anyone away from using the outdoor cookers the good Lord gave us. But alternatives are great.
The reason the grill is in no danger is because the cast-iron griddle works great on anything you can grill, but not everything you cook on the grill is optimal for homes without industrial vent hoods.
A rib-eye steak cooked on your griddle will fill your house with smoke faster than a Cheech and Chong film festival. Burgers aren't much better.
Enter pork chops. And at the top of the pork chop hierarchy is the Porterhouse pork chop, a dense cut that includes tenderloin. Unlike the Porterhouse steak, the pork chop is very lean. So, it needs a flavor boost, perhaps even gravy.
Continue reading this story on the...
Griddled Porterhouse Pork Chops with Blood Oranges
4 Porterhouse pork chops, 3½ to 4 pounds
2 small onions, sliced very thin
2 cloves garlic mashed in 2 teaspoons salt until paste
2 cups chicken stock or reduced-
1½ teaspoon smoked paprika
1 teaspoon garlic powder
1 teaspoon onion powder
1 teaspoon kosher salt
1 teaspoon toasted fresh ground
¼ teaspoon chile de arbol or cayenne pepper
1 or 2 blood oranges, sliced thick
Garlic-Onion Gravy
¼ cup mix of olive oil and bacon drippings
1/3 cup all-purpose flour
1 tablespoon fresh thyme
2 teaspoons salt
2 teaspoons fresh ground black pepper


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- Infowars - http://www.infowars.com -
Greek conservatives New Democracy 'in narrow poll lead'
Posted By kurtnimmo On June 17, 2012 @ 12:36 pm In Global Crisis,Old Infowars Posts Style,Tile | Comments Disabled
June 17, 2012
Editor's note: If we are to believe exit polls, the Greek people want austerity, lower standards of living, increased suicide rates, and approve of the prospect that unelected EU bureaucrats and IMF loan sharks can determine their fate.
Greece's right-wing New Democracy party has a narrow lead over its left-wing rivals after parliamentary elections, exit polls suggest.
New Democracy, which broadly supports a European bailout deal, was one to two percentage points ahead of Syriza, which opposes the measure.
The outcome could decide Greece's future inside the euro.
Article printed from Infowars: http://www.infowars.com
URL to article: http://www.infowars.com/greek-conservatives-new-democracy-in-narrow-poll-lead/
Click here to print.
Copyright © 2015 Infowars. All rights reserved.


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My lack of posts here lately is shameful, I know. I've been so so busy, and finally have a little calm (which won't last long.) Hopefully, I'll be posting here more often this winter.
I have some exciting news!
I'll be presenting 6 new pieces for Buy Some Damn Art in a week from today. (You may remember the show Yelena and I had together last year.) I'll be posting full images next week, but for now- here are some snippets of my upcoming show. All of the original works will be for sale starting August 27 on the Buy Some Damn Art site.


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On this page you will find important information about Evans Excavating based in Paoli, IN, like the address, contact person and details, as well as the email address and home page.
Evans Excavating
Excavating Contractor
For travel by car, directions from your location to Evans Excavating at 46 West County Road 250 North in Paoli, IN will be displayed via link >>my route<< below the map.
Evans Excavating, Excavating Contractor in 46 W County Road 250 N, Paoli, Indiana 47454.
Mailing send it to the following address of Evans Excavating:
For questions regarding Evans Excavating you can call the following numbers, or find the appropriate contact on the homepage of Evans Excavating.
To request more information about Evans Excavating from abroad please call the international phone number +1.812.723.4559 under which you will be able to speak with the appropriate contact person.
Please send written inquiries and notices to Evans Excavating from abroad to the international fax number or to the company email address. Call displayed telephone number to ask for respective email address of Evans Excavating.
Here are some other interesting Excavating Contractors from Paoli, the County Orange and the U.S. State Indiana are listed:


text:
Ryan Suter, barring the unforeseen, is going to test the free-agent market.
The Nashville Predators' All-Star defenseman can sign with another team on July 1.
"Unless something changes in the hear future, he's going to take a peek at July 1," GM David Poile told The Tennessean. "We're going to be in consistent contact with him, and I'm certainly hoping, as he said to me a week ago, that he's not going to make a sudden decision … and we're going to have some conversations after he has talked to these different teams."
Poile added that he doesn't want to trade Suter's negotiating rights. It had been speculated that Poile would flip the 27-year-old for draft picks before free agency starts. Agent Neil Sheehy called a previous report that Suter had given the Predators a list of teams he'd accept at trade to "100 percent untrue," according to the Minneapolis Star Tribune.
"We've never entertained any offers for him," Poile said. "He has never said he doesn't want to play for us. He just said he wants to take a look."
Suter doesn't just represent the best defenseman in his class. His future with Nashville is also vital to the franchise's ability to re-sign captain Shea Weber, who is also Suter's blue-line partner.
The Detroit Red Wings have long been speculated as the leader's for Suter's services—and now it appears that they will indeed get the opportunity to talk to him.


text: I thought this would be an appropriate title for this month's blog since the weather is cooling down! Although it is cutesy, it is true. Dogs are like snowflakes. I came to this conclusion the other day while I was walking my clients' dogs. Every dog needs love, attention, food, and water- they are similar in that way, just as humans are. However, each one of the dogs I walk are different; they all have their own personality and character; each little soul is special in its own way. This is important to remember as a dog walker and pet sitter. Dog walking isn't as simple as leashing the dog and walking him or her and providing fresh water. There is no cookie cutter way of walking a dog; there is so much more! Depending on the dog's size and personality, you may need a basic harness, gentle leader, harness with a martingale loop on the chest, etc. Some dogs may be more comfortable walking on a certain side depending on their sight and hearing. As a dog walker, part of my job is to assess how the dog behaves, plays, obeys, and commands. Then after getting to know the dog, I'll know best how to walk him or her. Some dogs also need different kinds of attention when their owners are away, too. I used to teach elementary school, and at the beginning of each year, the children would enter my classroom on the first day of first grade differently. Some children were excited, some scared, some nervous and sad. This is exactly how dogs are when they experience something different and away from their parents. Some are excited and happy to be with anyone who will give them a belly rub, some need to be distracted with a toy, and some need gentle cuddling. Once we know how the dogs we care for react in different situations, then we are able to care for them in the best way possible, because dogs are special and unique…just like snowflakes.


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Fifth Gear Automotive
7301 W 118th Pl, Broomfield, CO 80020 Map & directions
Call Now: (303) 502-9031
"The work was fast, and the price was reasonable."
"They have done wonderful work for me, they started doing American and foreign cars."
"They did good work, I can trust them and I have recommended several friends to them."
"I have used them for years, and their quality of service is really good. They are very reliable and I trust..."
"They provide good service, they did exactly what was needed for my truck."
"They worked very hard to fix the problem, I don't think most mechanics would try as hard as they did."
"They are a great company and they are very trustworthy."
" I've been with them for many years and I always go back. I'm very satisfied. They treat me well when I go..."
About Fifth Gear Automotive
RepairPal's Comprehensive Evaluation
Assessment Summary
Andy opened Fifth Gear Automotive in 1982 and has been serving the Broomfield area ever since. The shop moved into their brand new building at its current location in 2001. They have a very experienced team of five technicians who have an astonishing 100 years of experience between them. Combine this with their excellent tooling, factory level diagnostic equipment, and top-notch customer service, and you have the complete package. Fifth Gear is also AAA approved, a Bosch Authorized Service Center, and an emissions testing and repair facility. During our survey of their recent customers this RepairPal Certified shop was described as reliable, honest, and convenient. Amenities include a local shuttle service, WiFi Internet access, and after hours vehicle drop off.
Message from the Shop
We are a full service repair shop that's AAA approved.We are a member of BBB, a "Bosch Authorized Service Center", We employ ASE certified Techs. 5th Gear started in 1981 in Norhglenn and now is located in Broomfield,Colorado.
We also have been licensed by the State of Colorado to do Diesel Emission Tests. We service most makes and models and use dealer level equipment to fix and repair the vehicles we service. Please feel free to come bye or call us a call.
Auto Makes We Service
Quality Affiliations
|Check Engine Light
|Muffler & Exhaust
|Oil Change & Lube
|Scheduled Maintenance
|Service & Repair
|Timing Belts
|Tire Sales/Repair
|Transmission Repair
|AAA Member Discount
|Child Friendly
|Early Bird Dropoff
|Heated Waiting Room
|Service Guarantee
|Shopping Nearby
|Wireless Internet
Customer Reviews 20 verified reviews (21 total)20 Sort by: Date | Helpful
It seems like they have changed ownership in the last couple years. There was a guy who was running everything who I don't really see anymore. It would have been nice to know about what happened because I kept wondering where he was. The new guys are ok, but I have missed the main guy. For a couple years, he just hasn't been there.
Dear Holly,
My name is Andy and the owner of 5th Gear for over thirty years now. Ive been taking more time off since my son Tris is up front and helping me run the company.Thank you for asking. Andy
We have gone in there to ask them to check something out and they were like, "you don't need that done, or we will do it for free." Andy is his name we like him. We have gone through them for years. We like them, and wouldn't go through any one else. They have always done a really good job. If you need a repair they will tell you, If it can wait they will tell you that you don't need it done now. They were just friendly.
i took my honda accord to one of those shops that specialize in brakes. I was shocked at the quote, and amount of work my car needed, What happened that low cost brake job? I said forget it. One of my coworkers told me about 5th gear, What a difference, they saved me money and were very professional.
Get Directions


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By ajcolores
Posted in IndustryMusic | Tags : Arizona, gadsen, gadsen records, indie, music, Phoenix, Record Label
Disclosure are excited to announced their 1st official US release Disclosure - The Singles out on April 30th. The multi-instrumentalists are bringing their infectious UK garage + 2-step sound stateside & are finishing up their current US run of dates which included well received sets at SXSW, Ultra Music Fest & Coachella.
The 4-song EP will feature previously released singles including their breakout single "Latch" featuring British singer Sam Smith, their hit "White Noise" with AlunaGeorge & the future-bass heavy HudMo remix. Also on the EP will be the brand new track " You & Me" with songstress Eliza Doolittle.
Their debut full-length Settle, drops this summer on June 3rd.


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CAKMAKOVA Advocates main activities are providing legal and attorney services to domestic and foreign business clients.
Our team is comprised of experienced attorneys at law and associates who are dedicated to the efficient, professional and effective resolution of the legal matters and protection of the rights and legal interests of our clients in all areas of the law.
We provide highly professional services and have the necessary personnel and organizational resources which can properly respond to the needs and dynamics of the everyday working of the business entities in accordance with their demands.


text:
Join us in Austin December 16 - 17
for Scientific Software Days
Scientific Software Days is an ongoing meeting of users and producers of scientific software, with presentations by scientific software tool makers and the users of their tools.
The complete schedule of events is available here.
Featured Presentations
The Seventh Annual Software Days keynote address will be given by Neil Chue Hong, director of the Software Sustainability Institute.
Mr. Chue Hong will speak on Putting the User Back into Software Sustainability
We will also feature a presentation by James Howison of the Information Institute of the University of Texas, on Scientific Software Production: Incentives and Collaboration
On Tuesday Dec 17, tutorials will be offered on "Python for Data Analysis", and on "High Performance and High Throughput with R".
There is no cost for attendance. Unfortunately, registration has been closed.
More details are available here.
Scientific Software Days is sponsored by the Jackson School of Geosciences, Texas Advanced Computing Center, and the Insitute for Computational Engineering and Sciences, with funding from XSEDE, the Extreme Science and Engineering Discovery Environment program.


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Vast factory farms a step closer
Posted by Stevie at 05/19/2011
Vast factory farms a step closer after ministers order research into 'sustainable intensification' of the livestock industry
Chia at 05/24/2011 11:07:16
Thank you for sharing this link.
Rooibos at 06/16/2011 18:50:19
Eating other animals will never be "sustainable." I just love it how that word has become code for shoving everything that moves up our faces not because we "need" to, but because we simply want to. Ridiculous. Not fooled!
You need to be logged in or registered to post.


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Michal Golan's Confetti Cross Necklace
Availability: In Stock and Ready To Ship
Israeli-born Michal Golan's Middle Eastern background is reflected in this colorful, eclectic necklace handcrafted in her New York studio with jewelers enamel, Swarovski crystals and glass beads hand set in gold-plated brass. 2 in. cross on 18 in. chain with 4 in. extender.
Certificate of Authenticity Included


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Nahle as transportation, aviation principal
Stantec recently hired Andy Nahle to serve as a principal in its transportation practice and lead of its California aviation services.
Bringing nearly 27 years of industry experience to the position – including 20 years with the U.S. Federal Aviation Administration – Nahle will be focused on further developing a regional presence with the company's established aviation sector niche.
Based from Stantec's Los Angeles office, Nahle will identify business development opportunities throughout California to support the aviation industry in the construction management, project management and engineering disciplines.
Nahle has served with National Association of Air Traffic Controllers as the organization's president and National Legislative Committee Chairman. Additionally, he has served as chairman for the Air Transport Technical Group for the American Society of Civil Engineers, Los Angeles Section.
HOK in Los Angeles adds Seeger, promotes Bruce
Chuck Seeger has joined the Los Angeles office of HOK office as vice president and director of planning and landscape architecture. Seeger will lead the master planning, urban design and landscape architecture practice at HOK Los Angeles and will work across HOK's 23 offices, including overseas locations.
With more than 25 years of experience in master planning and urban design in the corporate, institutional, retail/entertainment/mixed-use and community planning markets, Seeger's responsibilities at HOK Los Angeles will include cultivating new business relationships, managing current clients, coordinating community outreach efforts and gaining approvals for entitlements.
Meanwhile, HOK reports that James R. Bruce, Jr., vice president and senior aviation planner, has been promoted to regional leader, aviation and transportation. In his new position, Bruce will serve as the aviation and transportation sector leader in Los Angeles, overseeing HOK's diverse portfolio of ongoing projects, including the Anaheim Regional Transportation Intermodal Center and the 12-year modernization of the Honolulu International Airport.
T.Y. Lin hires Cornell as associate vp and aviation director
T.Y. Lin International has named Steven B. Cornell , P.E., associate vice president and west region aviation director.
Cornell, who will be based in San Diego, is responsible for TYLI's aviation line of business in the West. The aviation LOB provides complete planning, design and project management services for aviation facilities that range in size from major international air carrier airports to regional airports and general aviation facilities.
Cornell brings over 26 years of engineering knowledge and extensive aviation industry expertise to TYLI. He joins the company from the San Diego County Regional Airport Authority, where he was most recently the director in charge of the $1.0 billion Terminal Development Program. Prior to his position with SDCRAA, he worked as an aviation consultant, providing planning, design, program, and construction management services for private, public, and military airport clients at facilities around the world.
Gafcon promotes Duveen
Construction management and consulting firm Gafcon Inc. has promoted Robin Duveen , a 20-year construction industry veteran, to vice president of operations.
Duveen, who has been with Gafcon for 13 years, has served as project executive for Gafcon's Irvine office as well as division manager for Gafcon's Los Angeles office. He also served as Gafcon's program manager for the $335-million Sweetwater Union High School District bond program.
Based in Gafcon's downtown San Diego headquarters, Duveen will manage operations within Gafcon's corporate office, branch offices and project sites.


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*But I agree with RckJmes in that I don't think that 2 minutes of running would give him 30 mins talk time. It just doesn't seem possible.
It might be possible if the cell phone has low enough power consumption.
*Also, I thought it was bad for a battery to be charged and then sit for a while and then charged again. I thought you were suppose to drain the battery fully before you recharge it again. This seems like it would drain the battery over time.
This is true of NiCd batteries. Most cell phones use Li ion or NiMh.
Yes, I'm lame. Don't remind me.
really, those sci fairs are hard
yes its possiple to charge a cell phone for 30 mins in 2 mins!
Hamsters run fast
And once again LordJonathan...you crack me up! EWW
Maybe that is his sister.
If this is true, and he got a C, he was so gypped.
-------------------------------------------------Time is like a knife..... slowly and relentlesly.... cuts the cored of life.You! Off My Planet!! (My Homepage)
I think you miss the point of science fairs. They aren't trade shows, it's not like this guy is thinking about trying to sell these things. They are just organized activities where young people are encouraged to demonstrate their technical knowledge concerning any given area of science. In this case he just came up with a cute way to demonstrate an example of electrical engendering.
If you've already got an I-Am-Bored.com account,click here to sign in.
If you don't have an account yet,
Click Here to Create a Free Account


text:
Information for Publishers & Copyright registration benefits
NLI works on behalf of Ireland's newspaper publishers to ensure that the copyright in the content of their newspapers is respected, and ensures those wishing to reproduce articles/extracts for commercial purposes must be properly licensed.
Since NLI's establishment, the number of licences issued annually has grown year on year.
NLI delivers a revenue stream to publishers for the reproduction of their titles at no cost to the publisher.
Membership of NLI grants the publisher the right to copy from a fellow member's titles for internal management purposes.
Collective Rights Management societies offer publishers the best option to protect their rights.
Publishers assign NLI the copyright subsisting in original works appearing in published editions of their newspapers and mandate NLI to license other parties to reproduce those newspapers or extracts, on certain terms. The publisher retains all other rights.


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Maybelline Dream Smooth Mousse Review and Swatches
Much to my utter delight Mayeblline Dream Smooth Mousse is available for purchase in US drugstores. When I originally told you about this foundation it was only available within Europe and I thought maybe we'd have to wait as far as Fall to see it here but yay! It's been released and is available now at your local drugstores (and on sale in most cases Buy 1, Get 1 50% Off all Maybelline).
Jump ahead to hear the good word.
A retake on Maybelline Dream Mousse Foundation in compact form with a whipped formula that provides a super soft, matte finish with a weightless feel!
Maybelline Dream Smooth Mousse comes housed in a new compact design. Where as before you had to dip your hands into a pot of Maybelline Dream Mousse Foundation, you now have the option of purchasing Dream Smooth in compact format. The foundation is housed in a screw top compact with a flip top that reveals a mirror and sponge. The top unscrews and reveals the foundation beneath.
Now knowing the original whipped formula, I somehow assumed that this would sport an airy, whipped like texture but that's really not the case at all. This formula is more of a traditional cream foundation but with a creamier formula. If you have dry skin, chances are you'll love how creamy and hydrating this feels on the skin. The formula glides on effortlessly, blends out flawlessly, and creates a nice smooth surface for makeup. The included sponge works great to apply or you can apply with a foundation brush.
I didn't feel the finish was completely matte but more dewy to the touch. It wears comfortably on my face and feels quite weightless.
Although the formula is weightless you can easily over do it and end up with a mask-like look and feel. So do be aware when blending. A little goes a long way as the product is very pigmented so build up slowly…I've made the mistake of layering it on WAY to thickly.
Color selections are the worst since many contain a fair bit of beige. Beige in my foundation tends to make my skin look old, tired, and dull. I tried Classic Ivory and even this was crazy beige (it's the 2nd lightest shade).
The cream formula is quite gorgeous as it's a cross between a cream and whipped up mousse (leans more towards cream) however it proceeds to oxidize fairly quickly on my skin even after proper prepping and priming.
I'm not a big expert on large pores but I can imagine this could cause general woe with larger pores since the formula is rich and even though it claims a matte finish, I felt it was more dewy to the touch so it might cause more of an greasy feel for those with oily skin.
- Anyone with dry skin.
- Women who like cream foundation!
- Anyone who's looking for an inexpensive dupe to Urban Decay's Surreal Skin Cream to Powder Foundation.
- Anyone looking for foundation that can be worn lighter and built up to full coverage.
- Oily skin types or those with larger pores (because of reasons described above).
- Anyone seeking a matte finish (Just didn't feel like this was fully matte, perhaps semi-matte).
- Anyone who has a problem with foundations that oxidize easily.
- Anyone who isn't BEIGE (Jebus when will the drugstores get the shade selection right on foundations?)
I could deal with many of the bad things I said about this before but the fact that I can't find a single flattering shades is unforgivable. I'm not beige Maybelline! The overall feel of the product is very nice and I liked working with it but I just wish it didn't make my skin look so dull and tired, the shades are just wrong for me sadly.
Not really bad but not really good either.
Indecisive about this one!
Probably worth a shot if you're dead curious. You can always return it, if you hate it.
One anyone's wish list?
Anyone try already?
What did you think?
Curious minds!
This product was purchased by the Muse for review purposes.
Read my full disclosure statement here.
6/23/10 13:02 Steelnpurple:
Ah I had this on my to-try list but still haven't got around to it.
Will pick it up shortly and try it out.
I am an official sucker for creamy products. LOL!
6/23/10 13:48 Steelnpurple:
Will do!
6/25/10 11:40 Steelnpurple:
I do like it. A lot. It looks fab actually!
I HATE the colour selection, with a passion.
I like the foundation. A lot. LOL!
The lightest available here (no 20) is a tad too dark but I'll make it work since it's summer.
I don't have any issues with my pores showing up more than I'd like, but the liines in the forehead = FAIL. lol..
So overall I do like it!
6/23/10 13:13 Phyrra:
Why can't drugstore foundations ever come in neutral light colors? Everything is too beige, too yellow, too dark, too orange.
7/1/10 13:52 Ashley:
I have the SAME problem. I got this in Creamy Natural and it seems to be working well. The undertone isn't as pink as I thought it would be. The first one I bought (can't remember name) was way to yellow.
6/23/10 13:38 ndoodles:
I have so much trouble finding my foundation color from the drugstores! But glad to know that the texture is great!
6/23/10 14:13 Womble:
we dont have this in the UK we have dream matte mousse, and dream creamy foundation, which is more like mac studio tech then mousse i think this is it under a different name
6/23/10 14:22 Anitacska:
We do have it. 😉 No mirror though!
6/23/10 14:23 Courtney:
How does this compare with the Covergirl TrueBlend Whipped Foundation that you reviewed awhile ago? Do you like the Covergirl or the Maybelline better? just curious.
6/23/10 16:04 Nicole:
Great review, as always. I just thought to comment that you put "Final Thoughts" instead of "Who Might Not Like It."
6/23/10 17:37 Dana:
Hey musey
This is not a replacement to dream matte mousse. Its a smooth creamy version. They are likely going to be releasing a new improved version of the dream matte mousse with different and less silicones.
6/24/10 20:53 Dana:
ok thank you. I was just confused when you said before you had to dip finger in a small pot etc. Sorry and thanks!
6/25/10 1:01 se7ens7ars:
Actually u did mention "dipping your hands in a pot…" here's what u said, "dip your hands into a pot of Maybelline Dream Mousse Foundation." Just saying so no one gets misunderstood : ->
6/23/10 18:08 angela:
i hate this! it did not work for me
6/23/10 20:24 Delphine:
I'm a fair skinned East Asian. I tried the two lightest shades and they both made me look drunk, AND they're both too dark for my skin. It was awful.
Not only that, I felt the foundation smelled bad and felt greasy.
Bleh. I had to toss both foundations I got.
Now I only use BB cream.
6/23/10 22:16 Courtney:
You both have piqued my curiosity. I may have to make a trip to the Bobbi Brown counter this weekend.
6/24/10 3:29 em:
I love dream creamy! I don't know if we have diffrent shades in europe but I have fair skin and the lightest shade was totally good for me 😮 its called 004 light porcelain
6/25/10 15:38 Delphine:
I checked, we don't have that shade. The palest we have in the US is light ivory. For the liquid version it's porcelain ivory.
I have a yellow understone so make up with pink understones look really horrible on me and they appear darker than my skin when they may be the right shade.
6/25/10 19:18 Charmaine:
I tested this at CVS, and ITA, the stuff feels fantastic, but the shades are funky. I'm SE Asian, and VERY yellow-toned, so it's really hard for me to find stuff that actually matches. I would love to buy this just cuz I like the way it feels, even though the color and formula aren't quite for me [oil slick and some big pores, bleah], I would just wear it in the house, lol!
6/25/10 22:58 Tohnia:
the original Dream Matte Mousse was HORRIBLE for me! The colour selection was awful (the closest shade made me look gray! No joke!), and it rubbed off on EVERYTHING. I might try this, but after my experience last time, I may pass.
6/29/10 18:27 jen:
I just got this and there is no mirror (you mentioned a mirror). also, i dont think it's ever intended on being a matte finish. its quite the opposite and will compliment the maybeline line! I hate the matte mousse, this one is its opposite lil' sister! love it! my tone is neutral, but the 240 natural beige works for me.
7/8/10 0:35 CuriousAboutDreamMousseSmooth:
I was wondering if you know which colors would work best for a person with light skin and yellow undertones?
8/2/10 19:19 Cindy:
I'm going to have to try this. I like the regular mousse foundation ok ,but it does accentuate dry skin. I've been miffed at Maybelline since they discontinued their shine Free foundation a few years ago.
8/19/10 20:46 Danielle:
I do have yellow undertones in my skin, so this stuff matches my skin color perfectly. It's great for my dry skin too.
8/24/10 23:23 Trebbles:
i totally agree with you Danielle. I have dry patches around my nose but this doesn't cake up like the revlon foundation I have. Since I got a tan over the summer I'm a shade darker than usual so Classic Ivory matches my skin perfectly for now anyways.
10/16/10 16:16 sania:
i'm 17 year old biracial (black and white) girl. i have a complexion similar to singer Rhianna. So, its hard to find a color to match me, and not to mention i have blemishes because of acne in pre-teen years.
the color selection is horrible ! i usually settle for honey beige in other foundations. everything here was too dark or too light. i ended up settling for natural beige, I love the creamy fill of it and how it feels so smooth on your skin ! i agree with everything you said. Great review
10/20/10 16:53 Naomi:
I really like it. The only problem is that it smears clothing whenever I happen to touch my face. I have both dry and greasy skin which is bad. So I don't know what kind of foundation I should get but I this foundation so far is the best I've had.
11/21/10 9:37 Melissa:
this SUCKS!!! it makes me look like a crackhead. good coverage but wears off FAST and makes my forehead look SOO oily! gross. my momma said i havent been lookin half as pretty since i bought it lol
12/22/10 0:16 Ashley Beau:
Hello! I really want to try this foundation…. I have fair skin with yellow undertones….. Which one of the shades would you think I need to use?
2/12/11 14:28 m-dot:
I just bought this and tried it out this morning. I like it. I have very dry skin and some acne spots on my cheeks and it covered it right up w/out feeling like a paint job. I'm african american and between Halle Berry and Ashanti's complexion. Caramels are always too dark for me so i was happy to find a honey beige that wasn't to chalky looking. It looks perfect face to face but does photograph a little lighter. But for the texture, finish, and price it's a go!
5/28/11 22:05 Emily:
Hi Muse! I really enjoy your reviews and posts on Dr. Who (love Dr. Who!!) I just wanna say that this foundation is suppose to a hydrating/dewy finish version for dry skin, unlike the matte mousse which is matte for oily skin.
6/15/11 18:49 Yaz:
Lol. Thank God I'm kind of beige.
7/31/13 8:55 Caygri:
what color is it?