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Antiviral Activity of the Zinc Ionophores Pyrithione and Hinokitiol against Picornavirus Infections
B. M. Krenn, E. Gaudernak, B. Holzer, K. Lanke, F. J. M. Van Kuppeveld, J. Seipelt
B. M. Krenn
1Max F. Perutz Laboratories, Medical University of Vienna, Dr. Bohr-Gasse 9/3, 1030 Vienna, Austria
E. Gaudernak
B. Holzer
K. Lanke
2Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, The Netherlands
F. J. M. Van Kuppeveld
J. Seipelt
For correspondence: joachim.seipelt@meduniwien.ac.at
DOI: 10.1128/JVI.01543-08
We have discovered two metal ion binding compounds, pyrithione (PT) and hinokitiol (HK), that efficiently inhibit human rhinovirus, coxsackievirus, and mengovirus multiplication. Early stages of virus infection are unaffected by these compounds. However, the cleavage of the cellular eukaryotic translation initiation factor eIF4GI by the rhinoviral 2A protease was abolished in the presence of PT and HK. We further show that these compounds inhibit picornavirus replication by interfering with proper processing of the viral polyprotein. In addition, we provide evidence that these structurally unrelated compounds lead to a rapid import of extracellular zinc ions into cells. Imported Zn2+ was found to be localized in punctate structures, as well as in mitochondria. The observed elevated level of zinc ions was reversible when the compounds were removed. As the antiviral activity of these compounds requires the continuous presence of the zinc ionophore PT, HK, or pyrrolidine-dithiocarbamate, the requirement for zinc ions for the antiviral activity is further substantiated. Therefore, an increase in intracellular zinc levels provides the basis for a new antipicornavirus mechanism.
Curing virus infections harbors an enormous economic potential, and the search for new antiviral substances is of great interest for worldwide health. We have previously described the commonly used NF-κB inhibitor and metal ion chelator pyrrolidine-dithiocarbamate (PDTC) to significantly inhibit the replication of several picornaviruses such as human rhinovirus (HRV), poliovirus, coxsackievirus, and mengovirus (9, 22). These examples suggest that a common step in the life cycle of these picornaviruses is the target for the antiviral drug. In particular, we have demonstrated that PDTC has negative effects on picornavirus replication by influencing the processing of the viral polyprotein (21, 22).
The antiviral activity of PDTC is not restricted to the family Picornaviridae, since PDTC was shown to prevent the multiplication of human influenza virus, a member of the Orthomyxoviridae (33, 34). However, due to strong differences in the life cycle and host-cell interaction between human influenza virus and picornaviruses, it is likely that entirely different mechanisms might be relevant for the antiviral action of PDTC against these viruses.
Currently, the precise mode of the antiviral action of PDTC is unknown, although several theories have been substantiated with experimental evidence. Antioxidative properties of PDTC are postulated to be the reason for antiviral effects against influenza virus infections (33), which is not the case for human rhinovirus multiplication (9).
We have demonstrated that the antiviral effects of PDTC are metal ion dependent, and, in particular, Zn2+ ions play a pivotal role. To underline the hypothesis that influx of zinc into the cells has antiviral capacity, pyrithione (PT) and hinokitiol (HK) were examined. PT is known to be a zinc ionophore that leads to a rapid increase in intracellular zinc levels (27), and HK is a chelator of divalent metal ions (2).
We provide evidence that both PT and HK inhibit replication of picornaviruses by impairing viral polyprotein processing. The basis of the antiviral activity is dependent upon the availability of zinc ions. We show that the import of extracellular zinc ions is a key feature of the common antiviral property of these compounds.
Cell, media, and reagents.HeLa cells (strain Ohio; European Collection of Cell Cultures, Salisbury, United Kingdom) were cultured in RPMI 1640 supplemented with 10% heat-inactivated fetal calf serum, 2 mM l-glutamine, 100 U/ml penicillin, and 100 μg/ml streptomycin (all obtained from Gibco, Invitrogen, Austria). PDTC (pyrrolidine-dithiocarbamate ammonium salt), pyrithione (2-mercaptopyridine N-oxide sodium salt), Zn-EDTA, Ca-EDTA, Mg-EDTA, and N,N,N′,N′-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN) were purchased from Sigma-Aldrich, Austria. HK (β-thujaplicin) from Calbiochem was dissolved in dimethyl sulfoxide and stored at −20°C.
Virus preparation and titration.Strain HRV2 was obtained from the American Type Culture Collection and routinely grown in suspension cultures of HeLa cells (strain Ohio; Flow Laboratories, McLean, VA) as described previously (31). CVB3 (Nancy strain) was derived from transcription of the p53CVB3/T7 plasmid (36). The mengovirus strain EMCV was obtained upon transfection of in vitro-transcribed RNA from cDNA clone pM16.1 (5).
Virus titers in 50% tissue culture infectious doses (TCID50) were determined according to Reed and Muench (26). From our experience, typical interassay variation is less than ±0.5 log TCID50/ml.
Infection of cells.HeLa cells were grown in six-well plates and infected at 70% confluence with HRV2 with indicated multiplicity of infection (MOI) in RPMI medium supplemented with 2% fetal calf serum, 2 mM l-glutamine, 100 U/ml penicillin, and 100 μg/ml streptomycin. After 2 h of infection, input virus was removed, and cells were washed three times with acidic HEPES buffer and once with phosphate-buffered saline (PBS). For further incubation, infection medium was applied for the indicated amounts of times. If indicated, chemicals were present during parts or the whole period of infection. Whenever HK was used, application of 30 mM MgCl2 was essential to avoid cytotoxicity. Virus production was determined in the supernatants of infected cells by TCID50 determination.
Confluent monolayers of HeLa cells were infected with CVB3 or mengovirus for 30 min. Cells were then washed twice with PBS and cultured in medium at 37°C in the presence or absence of indicated chemicals. At indicated time points, the cells were disrupted by three cycles of freezing and thawing, and virus titers were determined by end point titration.
Cell viability assay.HeLa cells were infected with HRV2 (MOI = 50) or mock infected in the presence or absence of different concentrations of PT or HK-MgCl2. At 24 h postinfection (p.i.), a CellTiter 96 AQueous nonradioactive cell proliferation assay (Promega, WI) was performed according to the manufacturer's protocol. Extinction at 492 nm reflecting cell viability was measured in a Labsystems Multiscan RC plate reader.
Western blot analysis.HeLa cells were infected with HRV2 as described for virus infection. At 0, 2, 4, 6, 8, and 24 h p.i., the medium was removed, and the cells were lysed by the addition of protein sample buffer. Protein extracts were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), electroblotted onto polyvinylidene difluoride membranes, and analyzed using a rabbit polyclonal antibody against eIF4GI (37), as described previously (9).
Pulse-labeling and immunoprecipitation.HeLa cells were preincubated with 10 μM PT or 125 μM HK-30 mM MgCl2 for 30 min and infected with HRV2 (MOI = 50) in the presence of the substances. At 6 h p.i., newly synthesized proteins were labeled with [32S]Met/Cys (Hartmann Analytic, Germany) for 1 hour. At 7, 8, and 9 h p.i., VP2 or VP2-comprising precursor proteins were isolated by immunoprecipitation using the monoclonal VP2-specific 8F5 antibodies (30) and analyzed by SDS-PAGE and autoradiography as described previously (21).
HeLa cells infected with CVB3 (MOI = 50) were incubated with 125 μM PDTC, 75 μM HK-30 mM MgCl2, or 10 μM PT in the presence or absence of 10 μM TPEN. Five hours p.i., cells were starved half an hour prior to 1 h of labeling with [35S]Met/Cys. After labeling, cells were lysed, and cellular extracts were subjected to immunoprecipitation using either antibodies specific for 3D or 3C (kindly provided by C. Cameron, Pennsylvania State University) as described previously (22). Then, the protein pattern was analyzed by SDS-PAGE and autoradiography.
Radioactive zinc uptake studies.HeLa cells in serum-free culture medium (zinc concentration of 0.6 μM as measured by atomic absorption analysis) were incubated with 5 μM 65Zn2+ (0.82 mCi/mg Zn2+; Hartmann Analytic, Germany) in the presence of indicated concentrations of PDTC, PT, or HK-MgCl2. At the indicated time points, the cells were harvested by filtration on GF/C glass fiber filters (Whatman, Maidstone, United Kingdom). To remove extracellular 65Zn2+, filters were washed with a buffer containing EDTA (15 mM HEPES, 100 mM glucose, 150 mM KCl, 1 mM EDTA [pH 7]), and the amount of intracellular 65Zn2+ was determined in a Packard Cobra II γ-counter.
Fluorescence microscopy.HeLa cells grown in μ-slide VI slides (Ibidi, Germany) were loaded with 5 μM FluoZin-3 acetoxymethyl ester (Invitrogen) or 1 μM RhodZin-3 acetoxymethyl ester (Invitrogen) in PBS for 15 min at 37°C. Subsequently, cells were incubated for 1 h in growth medium to allow de-esterification. Then, PDTC, PT, or HK was added to the medium for the indicated incubation times. In some experiments, chemicals were removed after 30 min, and fresh medium was applied for 1 h. Fluorescence was monitored in a live-cell microscope system (Olympus cellR) using fluorescein isothiocyanate settings for FluoZin-3 and Cy3 settings for RhodZin-3. A Hamamatsu Photonics Orca-ER camera was used.
PT and HK inhibit picornavirus multiplication and increase cell viability of infected cells.We have previously discovered that the drug PDTC substantially interferes with the multiplication of several picornaviruses (9, 22). These antiviral effects of PDTC are dependent on metal ions, in particular zinc ions. To further substantiate the hypothesis that zinc ions play a major role in virus inhibition, two structurally different metal ion binding compounds, PT (4, 12, 17, 35) and HK (2, 23, 32), were analyzed regarding their effects on HRV production (Fig. 1). HeLa cells were infected with HRV serotype 2 with an MOI of 20 in the presence or absence of PT or HK. At 24 h p.i., supernatants were collected, and virus titers were determined. The presence of 5 μM and 10 μM PT decreased viral titers by around 3 orders of magnitude (Fig. 1A). Likewise, HK significantly diminished viral multiplication in a dose-dependent manner (Fig. 1B). Similar results were obtained using a different HRV serotype (HRV14) or an alveolar carcinoma cell line (A549) (data not shown).
PT and HK dramatically reduce picornavirus multiplication and increase cell viability. Viral titers of HRV2-infected HeLa cells (MOI = 20) in the presence or absence of indicated concentrations of PT (A) or HK plus 30 mM MgCl2 (B) were determined 24 h p.i. Results for one representative experiment of three experiments are shown. HeLa cells were infected with HRV2 (MOI = 50) or mock infected, and different concentrations of PT (C) or HK-MgCl2 (D) were added. At 24 h p.i., a CellTiter 96 AQueous nonradioactive cell proliferation assay was performed according to the manufacturer's protocol. Extinction at 492 nm reflects cell viability. The means ± standard deviations of quintuples obtained in one representative experiment of three performed are shown. (E) HeLa cells were infected with CVB3 or mengovirus (MOI = 10) and incubated with 10 μM PT or 75 μM HK-30 mM MgCl2, respectively. Virus production of infected cells was determined by TCID50 assay at 24 h p.i. The results for one of two representative experiments are shown. −, control.
To quantify cell viability a colorimetric viability assay was performed. HeLa cells infected with HRV2 showed a significant loss of viability 24 h p.i. (Fig. 1C and D). In contrast, PT (Fig. 1C) and HK (Fig. 1D) retained viability to normal levels at concentrations between 5 μM and 20 μM PT and 62 μM and 125 μM HK, respectively. Based on additional experiments, 50% inhibitory concentrations of 3 μM for PT and 42 μM for HK were determined. Importantly, no cytotoxicity of PT and HK was found in mock-infected HeLa cells (Fig. 1C and D, gray bars) and A549 cells (data not shown) under these conditions. The absence of cytotoxicity is in contrast to reports about proapoptotic activities of PT and HK in other cell lines such as HL-60 cells (15, 19, 20).
It is of great interest to investigate whether PT and HK act specifically for HRV or whether these drugs target a common step in the picornavirus life cycle. Thus, the role of PT and HK during infection with coxsackievirus strain B3 (CVB3) and the mengovirus strain EMCV (which will hereafter be referred to as mengovirus) was examined (Fig. 1E). In a single-round infection experiment with CVB3 or mengovirus, viral titers of around 108 TCID50/ml were obtained. In the presence of PT or HK, the titers were significantly reduced by around 3 and 2 orders of magnitude, respectively. These data are in agreement with the antiviral activities of PDTC against these viruses that were reported previously (22).
PT and HK abolish eIF4GI cleavage and affect viral polyprotein processing.Different steps of the HRV infection in the presence of PT or HK were studied to analyze whether PT and HK act mechanistically similar to PDTC. Early events in the viral life cycle, such as virus entry and uncoating, were not affected by PT and HK (data not shown). A hallmark of rhinovirus infection is the cleavage of the eukaryotic translation initiation factors eIF4GI and eIF4GII by the viral 2Apro (7, 11), leading to the shutoff of host-cell protein synthesis (8). To test whether PT and HK affect eIF4GI cleavage, protein extracts of HRV2-infected cells were analyzed by Western blotting (Fig. 2A). In the absence of PT or HK, around 50% cleavage of eIF4GI was obtained at 4 h p.i. At 6 h and 8 h p.i., eIF4GI was nearly completely processed into its typical cleavage products. In the presence of PT or HK, no significant amounts of eIF4GI cleavage products were found within 24 h of infection. This is in agreement with data obtained with PDTC (9).
PT and HK abolish HRV2-triggered eIF4GI cleavage and affect viral polyprotein processing. (A) HRV2-infected HeLa cells (MOI = 20) were either mock treated or treated with 10 μM PT or 125 μM HK-30 mM MgCl2. After the indicated time points, protein extracts were collected and analyzed by Western blotting using an antibody specific for eIF4GI and its cleavage products. (B) HeLa cells were preincubated with 10 μM PT or 125 μM HK-30 mM MgCl2 for 30 min and infected with HRV2 (MOI = 50) in the presence of the substances. At 6 h p.i., newly synthesized proteins were labeled with [32S]Met/Cys for 1 hour. At the indicated time points, VP2 or VP2-containing precursor proteins were isolated by immunoprecipitation and analyzed by SDS-PAGE and autoradiography. Immunoprecipitation of mock-infected labeled cells did not show any signal. MW, molecular weight in thousands.
As PDTC shows a clear inhibition of viral polyprotein processing (21), P1 processing was also examined in the presence of PT or HK (Fig. 2B) by a pulse-chase labeling experiment, followed by immunoprecipitation with a VP2-specific antibody, 8F5, which pulls down VP2, VP2-containing precursors, and viral proteins bound to VP2 (30). Labeling of viral proteins started at 6 h p.i. for 60 min, and subsequently, cell lysates were prepared every hour. In untreated cells, the processing of the P1 precursor protein was clearly visible between 7 h and 9 h p.i. as a reduction of the amount of the corresponding polyprotein band. At the same time, smaller bands comprising VP2 and VP3 appeared. In the presence of either PT or HK, the processing of the P1 protein was blocked, and no mature VP2 or VP3 products could be detected. Moreover, various intermediate processing products were obtained in the presence of PT or HK, giving an identical picture to the processing defects observed using PDTC (21).
To specifically monitor the activity of 3CDpro, which is responsible for the processing of the P1 region and which autocleaves itself into 3Cpro and 3Dpol, the polyprotein-processing pattern of coxsackievirus infection in the presence of PDTC, PT, and HK was investigated (Fig. 3). CVB3-infected HeLa cells incubated with PDTC, HK, or PT were starved half an hour prior to 1 h of labeling at 5.5 h p.i. Subsequently, immunoprecipitation experiments using polyclonal antibodies raised against CVB3 3Cpro and 3Dpol were performed and analyzed as described above. PDTC, PT, and HK abolished coxsackievirus polyprotein processing into the mature viral proteins 3D and 3C in a similar manner indicating a common antiviral mechanism of all three compounds. The presence of 10 μM of the strong metal ion chelator TPEN restored viral polyprotein processing, suggesting that the observed inhibition is based on the availability of metal ions.
PT and HK abrogate 3D and 3C processing of CVB3. HeLa cells infected with coxsackievirus B3 (MOI = 50) were incubated with 125 μM PDTC, 75 μM HK-30 mM MgCl2, or 10 μM PT in the presence or absence of 10 μM TPEN. At 5 h p.i., cells were starved half an hour prior to 1 h of labeling with [35S]Met/Cys. Harvested cell lysates were subjected to immunoprecipitation using either antibodies specific for 3D (left panel) or 3C (right panel) and then analyzed by SDS-PAGE and autoradiography. Results for a representative experiment are shown. −, TPEN absent; +, TPEN present.
These data indicate that polyprotein processing of picornaviruses is a sensitive step for treatment with zinc ionophores. We have evidence that viruses such as respiratory syncytial virus (belonging to the family of Paramyxoviridae) which do not depend on polyprotein processing during their life cycle are not inhibited by PDTC treatment (data not shown). An unspecific adverse effect of PDTC on general cellular functions that lead to virus inhibition is therefore unlikely.
EDTA abolishes the antipicornavirus effects of PT and HK.We and others have shown that treatment with PDTC or PT leads to a rapid elevation of the concentration of free cytoplasmic Zn2+ ions (6, 22, 16-18). The importance of metal ions was further substantiated by experiments using EDTA as a general extracellular metal ion chelator (Fig. 4). In the presence of 10 μM EDTA, the antiviral properties of PT and HK against HRV2 (Fig. 4A), CVB3 (Fig. 4B), and mengovirus (Fig. 4C) are lost, indicating the involvement of metal ions. By using Zn2+-, Ca2+-, or Mg2+-saturated EDTA (25), we demonstrate that only Zn-EDTA retains the antiviral property of PT or HK. This indicates that the availability of Zn2+ ions is a prerequisite for the antiviral activity of these compounds. None of the EDTA-metal ion complexes alone had any antiviral effect at the concentrations tested.
Zinc ions are responsible for the antiviral property of PT and HK. HeLa cells were infected with HRV2 (MOI = 20) (A), CVB3 (MOI = 10) (B), or mengovirus (MOI = 10) (C) and incubated with 10 μM EDTA or 10 μM of Zn-EDTA, Ca-EDTA, and Mg-EDTA, respectively. If indicated, 10 μM PT (A, B, and C), 125 μM HK-30 mM MgCl2 (A), or 75 μM HK-MgCl2 (B and C) was added at the time of infection. The virus titers in the supernatants of the infected cells were determined by a TCID50 assay at 24 h p.i. and shown as log TCID50/ml. Viral infection without addition of compounds is labeled as "cont." The results for one representative experiment of three are shown.
PDTC, PT, and HK treatments cause a rapid and efficient influx of 65Zn2+ into cells.It is unclear whether PDTC, PT, and HK mobilize zinc ions localized in intracellular storage vesicles or allow extracellular ions to enter the cytoplasm. To directly monitor import of extracellular zinc ions into HeLa cells, we employed radioactive 65Zn2+ to determine the effects of PT, HK, and PDTC on zinc import (Fig. 5A). HeLa cells were incubated for different time periods with 5 μM 65Zn2+ and PDTC, PT, or HK and then harvested by filtration on GF/C glass fiber filters. The amount of intracellular 65Zn2+ was measured by γ-counting of the filter membranes. In the presence of 65Zn2+ alone, no significant increase in radioactivity of the collected cells was measured, whereas the presence of either PT or HK facilitated a threefold increase of intracellular 65Zn2+ within a few minutes. PDTC elevated the intracellular 65Zn2+ level sixfold. These results demonstrate that all three substances facilitate import of extracellular zinc ions via a rapid uptake mechanism.
PDTC, PT, and HK cause import of extracellular 65Zn2+ levels in a dose-dependent manner. (A) HeLa cells in serum-free culture medium were incubated with 5 μM 65Zn2+ and 125 μM PDTC, 10 μM PT, or 125 μM HK-30 mM MgCl2. At the indicated time points, the cells were harvested and washed with a buffer containing EDTA, and the amount of intracellular 65Zn2+ was determined in a Packard Cobra II γ-counter. Statistical variations between different samples are determined to be a maximal ±10% (data not shown). The results for one of three experiments are shown. (B) HeLa cells in serum-free culture medium were incubated with 5 μM 65Zn2+ and various concentrations of PDTC (top panel), PT (middle panel), or HK-MgCl2 (lower panel) for 15 min. Then, the cells were collected and washed, and the amount of intracellular 65Zn2+ was determined as described above. The results for one of five experiments are shown.
As shown in Fig. 5B, this zinc uptake is dose dependent. The presence of more than 15 μM PDTC, 2.5 μM PT, or 62 μM HK caused significant 65Zn2+ uptake after 15 min. It is noteworthy that this concentration range was found to be antiviral (Fig. 1) (9), suggesting that the influx of zinc ions is essential for mediating the common antiviral property of these compounds.
Intracellular localization of zinc ions imported via PT, HK, and PDTC.To directly visualize the ability of PDTC, PT, and HK to increase the intracellular pool of labile Zn2+, specific zinc indicators were used (Fig. 6). FluoZin-3 is a Zn2+-sensitive and -specific fluorescent probe that has no specific cellular localization (14). In cells loaded with FluoZin-3, intracellular fluorescence was minimal (Fig. 6A, top panel) due to a very low level of free zinc ions (24). After induction with 10 μM PT, 125 μM PDTC, or 125 μM HK, a rapid and significant increase in fluorescence was found reflecting an elevation of the intracellular labile "chelatable" zinc level. Noteworthy, these experiments were carried out in normal growth medium and apparently the Zn2+ concentration present in the medium is sufficient to lead to ionophore-mediated zinc ion transport.
Zinc ionophores influence the labile Zn2+ pool. HeLa cells were loaded with 5 μM FluoZin-3 (A) or 1 μM RhodZin-3 (B) in PBS for 15 min at 37°C. After extensive washing and 1 h of de-esterification in medium, zinc uptake was induced by treatment with 125 μM PDTC, 10 μM PT, and 125 μM HK-30 mM MgCl2 in growth medium. If indicated, after 30 min of chemical treatment, ionophores were removed for 1 hour (PDTC + 1 h removal, PT + 1 h removal, HK + 1 h removal). Pictures were taken at the indicated time points by live fluorescence microscopy with 60× optics. Examples of images of three independent experiments were chosen.
The observed punctate pattern of FluoZin-3 fluorescence is in agreement with recent data from rainbow trout cells incubated with high levels of extracellular zinc (24). In a large variety of mammalian cell types, vesicular storage sites for zinc which have been designated "zincosomes" can be detected (1). Zincosomes play a role in detoxifying excess zinc and are suggested to colocalize with endosomal compartments and lysosomes (13).
The uptake of zinc ions is reversible. When the zinc ionophores PDTC, PT, and HK were removed, the fluorescence declined close to background within 1 h (Fig. 6A, bottom panel).
To specifically monitor the free mitochondrial zinc pool, RhodZin-3 was used (28). HeLa cells loaded with RhodZin-3 exhibited a very weak fluorescence, indicating low levels of labile Zn2+ inside the mitochondrial compartment (Fig. 6B). In contrast, upon 20 min of treatment with PDTC, PT, or HK, the signal of RhodZin-3 fluorescence was strongly enhanced. This mitochondrial localized signal was found to be constant over at least 80 min of PT incubation (data not shown). The role of a labile Zn2+ fraction in mitochondria during viral infection is currently unclear and has to be the subject of further studies.
Concluding remarks.Conclusively, all three antiviral substances are potent zinc ionophores increasing the intracellular pool of labile zinc. This strong elevation is constant as long as the zinc ionophores are present but is reversible after removal of PDTC, PT, or HK.
The reversibility of the elevation of free-zinc concentrations is in agreement with data that we had obtained when virus multiplication was monitored in a setup when PT, HK, and PDTC were present for short intervals only. In contrast to the significant viral titer reduction evoked by permanently present PDTC, PT, or HK, a short (1 h) pulse of zinc ionophore treatment between 2 h and 5 h p.i. was not sufficient to significantly reduce viral titers (data not shown). These data indicate that a prolonged presence of ionophores during viral replication is needed to exert antiviral effects. In previous data, we have shown that a clear reduction of virus titer was obtained when PDTC treatment started up to 4 h after infection, continuing to 24 h (9).
In conclusion, we have identified a set of three antiviral compounds against HRV, coxsackievirus, and mengovirus infections, which differ in their chemical structures but appear to use import of zinc ions as a common trigger for exerting their antiviral effect. It was reported that PDTC reduces coxsackievirus B3 replication through inhibition of the ubiquitin-proteasome pathway (29). We tested the proteasome inhibitor MG-132 at nontoxic concentrations for antiviral properties against HRV2 and HRV14. However, functional MG-132 concentrations that cause a massive accumulation of ubiquitinylated proteins within 8 h of incubation were not antiviral (data not shown). Thus, proteasomal inhibition is not likely to be the major cause of the antiviral activity of PDTC, PT, or HK.
Importantly, PDTC, PT, and HK lead to efficient import of zinc ions that are naturally present in the cell culture medium. Uptake of Zn2+ into cells interferes with the viral life cycle. Already in 1974, Butterworth and colleagues have shown that adding high concentrations of zinc ions to cells impairs picornavirus polyprotein processing (3); however, the mechanistic basis still remains incompletely understood. On the one hand, viral proteases might be affected in their functions directly; on the other hand, zinc ions could contribute to folding problems of the viral polyprotein that lead to inseparable precursors. Folding inhibition was recently suggested as a target for antiviral strategies (10).
Several attempts have been employed to create mutants resistant against PDTC during human rhinovirus or influenza virus infections. However, no resistant viruses were obtained, hinting at a cellular mechanism of action which is expected to be similar for HK and PT. On account of these findings, PDTC, PT, and HK may provide an interesting basis for the development of new classes of antipicornaviral therapeutics.
This work was supported by grant LS05-039 of the Vienna Science and Technology Fund to J.S. and by grant NWO-VIDI-6 917.46.305 of The Netherlands Organization for Scientific Research and the M.W. Beijerink Virology Fund from the Royal Netherlands Academy of Sciences to F.J.M.V.K.
We thank C. Cameron (Pennsylvania State University) for the kind gift of antibodies, Andrea Trienoll for technical help, and Hans Goldenberg for helpful discussions.
Received 22 July 2008.
Accepted 6 October 2008.
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Muylle, F. A., D. Adriaensen, W. De Coen, J. P. Timmermans, and R. Blust. 2006. Tracing of labile zinc in live fish hepatocytes using FluoZin-3. Biometals19:437-450.
Perrin, D. D. 1979. Stability constants of metal-ion complexes: organic ligands. Pergamon, Oxford, United Kingdom.
Reed, L. J., and H. Muench. 1938. A simple method of estimating fifty per cent endpoints. Am. J. Hyg.27:493-497.
Sensi, S. L., L. M. Canzoniero, S. P. Yu, H. S. Ying, J. Y. Koh, G. A. Kerchner, and D. W. Choi. 1997. Measurement of intracellular free zinc in living cortical neurons: routes of entry. J. Neurosci.17:9554-9564.
Sensi, S. L., D. Ton-That, J. H. Weiss, A. Rothe, and K. R. Gee. 2003. A new mitochondrial fluorescent zinc sensor. Cell Calcium34:281-284.
Si, X., B. M. McManus, J. Zhang, J. Yuan, C. Cheung, M. Esfandiarei, A. Suarez, A. Morgan, and H. Luo. 2005. Pyrrolidine dithiocarbamate reduces coxsackievirus B3 replication through inhibition of the ubiquitin-proteasome pathway. J. Virol.79:8014-8023.
Skern, T., C. Neubauer, L. Frasel, P. Grundler, W. Sommergruber, M. Zorn, E. Kuechler, and D. Blaas. 1987. A neutralizing epitope on human rhinovirus type 2 includes amino acid residues between 153 and 164 of virus capsid protein VP2. J. Gen. Virol.68:315-323.
Skern, T., W. Sommergruber, D. Blaas, C. Pieler, and E. Kuechler. 1984. Relationship of human rhinovirus strain 2 and poliovirus as indicated by comparison of the polymerase gene regions. Virology136:125-132.
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Uchide, N., and K. Ohyama. 2003. Antiviral function of pyrrolidine dithiocarbamate against influenza virus: the inhibition of viral gene replication and transcription. J. Antimicrob. Chemother.52:8-10.
Uchide, N., K. Ohyama, T. Bessho, B. Yuan, and T. Yamakawa. 2002. Effect of antioxidants on apoptosis induced by influenza virus infection: inhibition of viral gene replication and transcription with pyrrolidine dithiocarbamate. Antiviral Res.56:207-217.
Warner, R. R., J. R. Schwartz, Y. Boissy, and T. L. Dawson, Jr. 2001. Dandruff has an altered stratum corneum ultrastructure that is improved with zinc pyrithione shampoo. J. Am. Acad. Dermatol.45:897-903.
Wessels, E., D. Duijsings, R. A. Notebaart, W. J. Melchers, and F. J. van Kuppeveld. 2005. A proline-rich region in the coxsackievirus 3A protein is required for the protein to inhibit endoplasmic reticulum-to-Golgi transport. J. Virol.79:5163-5173.
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Journal of Virology Dec 2008, 83 (1) 58-64; DOI: 10.1128/JVI.01543-08
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It's an absolute joy to get to team up with Thomas Nelson and Harper Collins Christian Publishing for a brand new Appalachian Romance series!
I've had the HONOR of signing with Harper Collins Christian Publishing for a new historical series – the 1st book releasing summer 2018 from Thomas Nelson!
The story sets sail when a young widow leaves Norway for America to make a new start housekeeping for her late husband's cousins—three rough & tumble brothers who brew cider in the hills of Appalachia. It's a beauty-from-ashes tale, a swoon-worthy romance, and delves deep into the bond and rivalry between brothers.
As the forefront brother can neither hear nor speak, the dearness in this series also lives in writing from the perspective of a Deaf character. Having taken American Sign Language and Deaf studies in my school years, it's an utmost privilege to share the heart of a silent and steady hero as well as the love story that will abound.
A special thank you to my agent, Sandra Bishop, for paving the way, and to the team at Harper Collins for so stoutly believing in me and these books. Also, a very special thank you to all YOU dear readers for celebrating this new adventure and making the writing journey so incredibly special!
You're always such a smile-maker! I'm excited for you to read this one and have been so blessed by your enthusiasm!
what a challange this book must have been and knowing the type author that you are, I am sure this will be an experience like no other to read this story. I like the story and am sure the characters will be fantastic.
Pauline, It truly was! I've written the rough draft and found that getting the Deaf hero's thoughts across proved a unique challenge. Thanks for celebrating with me!
Beth, Thank you so much!!
Biggest thanks!! You've givene me such a smile!
Kathleen – thank you for that beautiful verse. <3 Hour heart is so precious.
I do know and it's such a treasure to me! It's been fun chatting about Thor, Hakon and Aven with you and can't wait for your insights on the pages!
Oh dear. It's still not quite 2017 and I'm already going to have to start a 2018 TBR pile! Such exciting news!
LOL, Katie! I mirror your sentiments exactly. 😉 We'll both be reading all the great 2017 releases and I'm happy to say that I'll have one novella, if not two novellas coming out next year, so maybe one of those can be a nice little appetizer, LOL.
Oh, I am absolutely giddy with excitement!! I'm thrilled for you, Joanne, and can't wait to read this new historical series. It is sure to be extraordinary, as all your stories are.
I agree with Katie, I'm going to have to start a 2018 TBR pile.:) So glad you have another series coming out, will each of the three brothers get their own book?
Joanne: I am over-the-moon thrilled for you, sweet friend! HaPpY dAnCiNg for you!!
Hi Beth! Thank you so much, my friend! Your happy dancing FILLS my heart!
Joanne, I'm so thrilled and excited for you! And for myself as well (whose copy of The Lady and the Lionheart has been languishing in the throes of scant newlywed reading time) as I'm already anticipating reading this series! Congratulations!
I'm absolutely thrilled for you Joanne! That's so exciting for you AND us! The story sounds so fascinating. It's going to be a looooong wait, though. Like Katie, I'm going to have to start a 2018 TBR list. That sounds so far away, but if it goes as fast as 2016 did, it will be here in no time. Congrats! I'm looking forward to some happy reading.
Winnie, It's such a treat to hear that it's already going onto those 2018 TBR lists. 😀 It does seem so long away, but I'll have a novella out this winter with Barbour (The Message in a Bottle romance collection) and hopefully one other little surprise in 2017. 🙂 So glad this series already sounds like one you'll enjoy!! Thanks for celebrating with me!
So happy and proud of Joanne! Looking forward to hearing the wonderful testimonies these stories will inspire in people's lives as your stories always do!
These kind words mean so much! As does your sweet support and enthusiasm over these last few years! THANK YOU.
Thanks, Kim! I'm so glad you're happy 😀 That's the best kind of news for me to ring in this new year. And oh… it does seem far away, doesn't it? I have a hunch that all the great books to come in 2017 will more than pass the time. 😉 Can't wait for you to read this one some day as well!
I am sooooo excited about this! Absolutely cannot wait to read!!!
Hi Sydney!!! Thank you so much, my friend!
It sounds very interesting to me, can't wait to read this.
Jennifer, It's going to be such a joy sharing these stories with you. Thank you!
Exciting News…..Proud for you! I just won Lady/L. on a blog …and am sooo thrilled. I can't wait to read it as well getting some older books of yours to read! Blessings on you and your writing!!
Thank you, Jackie! That means a lot! AND YAY! I am thrilled that you won a copy of Lionheart. I hope you have a great time at the circus with Charlie and Ella!
This series of books sound exciting. I love the setting of the Appalachian Mountains. Your book was great in "The Message in a Bottle Romance Series". Thank you for letting me be part of the Influencer Team.
Brenda, I am so glad you enjoyed the novella and the collection! This one has been really special. We've been so blessed to have you.
And thank you! I'm incredibly excited about this new series and look forward to getting to share the stories with you.
Hello! I just wanted to tell you how much I enjoyed The Lady in the Lionheart. Right now I am trying to get my hands on copies of your other books. I am very excited about this new project! I have always been interesting in sign language (I can do a little, but its more like pidgin English than actual ASL). I find it so fascinating. Can't wait for the release!
Congratulations! I love the honest emotions your stories bring to the surface. They surround the heart with love, acceptance and faith. I can only aspire to be so genuine and joyful. I look forward to your new books. Happy writing!
That's a true compliment, thank you!


text:
Seven Books, and a Universe Worth of Perspective
An all-ages reading list to expand the way you look at the world around you
Out ThereBy Corey S. PowellDecember 30, 2019 6:00 AM
A tour into the world of Really Big Numbers. (Credit: AMS)
For years, I've toyed with doing year-end lists or holiday gift guides. Sure, they are absurdly presumptuous (are the items on this list really the best of everything in the entire world?), but they can also be useful and even inspiring. I've discovered a lot of good books, music, and movies by digging into these little passion products. So for the first time, I'm taking the plunge, putting together a best-of book list.
There are so many great science books out there that I'm taking a slightly unconventional approach. These are not my picks for the best books of 2019; there are already plenty of good lists like that around. Rather, these are books that caught my attention because of their ability to expand your perspective on the world, regardless of your level of scientific expertise.
Think of it as an all-ages reading list for a greater appreciation of the universe in 2020.
Really Big Numbers by Richard Evan Schwartz
Gallery of the Infinite by Richard Evan Schwartz
You might reasonably guess that books written by a professor of mathematics at Brown University and published by the American Mathematical Society (AMS) would plunge really deep into the world of numbers. What you might not guess is that they are tremendous fun. And whimsical. And mostly visual: There is a fair bit of explanatory text in both of these books, but all of the pages are composed in an inviting, colorful comic-book style.
According to the AMS, these books are intended for advanced middle-school students and above, but I had no trouble getting my 10-year-old daughter hooked. She didn't make it all the way through to some of the more advanced concepts, but that's what re-reading (and growing up) is for. Really Big Numbers begins by looking at familiar styles of counting in unfamiliar ways, and quickly skyrockets from checkbook-level numbers to numbers that vastly exceed the quantity of particles in the visible universe (that's about 10 to the 80th power, by my count).
After the first book has you feeling extremely small, or perhaps extremely powerful, you are ready to enter the Gallery of the Infinite. How can you not be fascinated by the idea of a number that never ends, that encompasses everything, that is beyond imagining even though it turns up in mathematics all the time? OK, even if you weren't before, you will be after Schwartz is done with you. In his books, math is magic, imagination, logic, and Play-Doh all rolled into one.
Magnitude: The Scale of the Universe by Kimberly Arcand and Megan Watzke (Black Dog & Leventhal)
While you are going big in numbers, you can add to the fun by going big in physical dimensions, too. I've seen plenty of books that take a visual tour of the universe (and if you are reading this blog, you probably have, too), but I've never seen another book quite like this one. The authors push the concept of scale into every dimension--not just size and distance, but also scales of temperature, pressure, density, even sound. In all, they cover 13 different dimensions, in addition to a helpful primer on units.
You won't find any of the over-familiar Hubble images here, either. The book is entirely illustrated by Katie Peek in a lucid, playful style. It makes the unfamiliar seem familiar, and vice versa, in a thoroughly uplifting way.
The Atom: A Visual Tour by Jack Challoner (MIT Press)
It's strange to think how thoroughly we are cut off from the essential structures of the world. Everything around us is made of atoms, and yet there is no way for us to perceive them directly. This book does a bang-up job of rectifying the situation, expanding the atomic realm into something visually and comprehensibly real. Along the way, veteran science writer Jack Challoner sneaks in a broad overview of physics, chemistry, and materials science, always connecting the theoretical concepts back to tangible examples.
Then, just when you think you know the atoms, the book leaves you with an even stranger idea to ponder: From the perspective of modern quantum theory, all particles are more accurately thought of as excitations in a field, so in a sense there is no such thing as solid matter at all.
Zooming in on DNA with Powers of Ten. (Credit: Eames Office)
Powers of Ten: About the Relative Size of Things in the Universe by Philip and Phylis Morrison, with the office Charles and Ray Eames (Scientific American Press)
No discussion of perspective would be complete without mentioning Powers of Ten, the seminal depiction of the different scales of reality. It began as a gorgeous film by Charles and Ray Eames (itself inspired by an earlier book, Cosmic View, by Kees Boeke). I remember visiting the National Air and Space Museum as a child and watching the film over and over, shivering at the vastness of the cosmos.
Today you can watch Powers of Ten online, as well as the similarly conceived, and similarly beautiful, Cosmic Zoom. Powers of Ten has also been reconceived in a slightly faster-paced, more modern-looking version as Cosmic Eye. Meanwhile, the original Powers of Ten movie begat an equally lyrical book, authored by Philip and Phyllis Morrison. It's now out of print, but readily available used at a reasonable price from all the usual online booksellers.
Astronauts: Women on the Final Frontier by Jim Ottaviani and Maris Wicks (MacMillan, coming out in February but available for pre-order)
Shifting your perspective does not always involve a change in scale or quantity. Sometimes it merely requires adjusting social preconceptions--although merely is an optimistic word, considering how difficult such adjustments tend to be. Astronauts is an illustrated history of the long struggle for women to be accepted as equals in space exploration, from Valentina Tereshkova's childhood dreams of flight to astronaut Mary Cleave's ascent to the top science position within NASA.
The graphic-novel format proves an apt way to tell a tale that balances anger and frustration with generous doses of humor and sweet triumphs. Its only real shortcoming is that the book leaves you wanting more; fortunately, it ends with a helpful bibliography and list of resources. If you enjoy this format, you might want to check out some of Jim Ottaviani's other, similarly perceptive illustrated science histories, including Hawking, Feynman, and Suspended in Language (about Niels Bohr).
The Field Guide to Citizen Science by Darlene Cavalier, Catherine Hoffman, and Caren Cooper (Workman Press, coming out in February but available for pre-order)
Perhaps the most powerful way for science to change your perception of the world is for you to do it yourself. That's the underlying theme of this friendly how-to overview of the citizen science movement. These days, it's not difficult to find a citizen science project to participate in; just Google the term and many projects pop up instantly. The harder part is knowing where to begin, and believing that your own small efforts can make a meaningful contribution to serious research project. This book can help.
The Field Guide is divided by settings rather than by field, to help you find the kind of project that suits your schedule and your lifestyle. Want to work with your community? Your school? Alone, online? Out in the field? There are options for all of these. Darlene Cavalier (who worked for Discover organizing public events) created SciStarter.org, which expands on the resources here. As with every great adventure, you just have to take the first step to get going.
For science news and ideas, follow me on Twitter: @coreyspowell
NASA Wants Your Help Naming Its Mars 2020 Rover
Making Air From Moon Dust: Scientists Create a Prototype Lunar Oxygen Plant
Latest Crew Dragon Test Moves SpaceX Closer to a Crewed Flight
The SciencesThe Physics of Christmas: Wormholes and Other Tricks Santa Might Use to Get His Job Done

redpajama_set_name: RedPajamaCommonCrawl


This Oracle Database 12c R2: Install and Upgrade Workshop gives you detailed information to help you install Oracle Database 12c Release 2 software. Expert Oracle instructors will teach you how to create a container database and provision pluggable databases.
Students will benefit from working with multiple install scenarios in the lab sessions. This will allow the new course to be relevant for both 12c R1 and 12c R2 setups. After the install of the Grid Infrastructure software, the student will then gain experience patching Oracle Software.


Airlines are trying to compromise on every millimeter as the legroom are continuously decreasing. In their bid to extract profit from this expensive industry the pinch is being harshly felt by the passengers.
New Zealand's tourism high season has delivered another success for the industry with one million fans now engaging with the 100% Pure New Zealand Facebook page.
We have additional teams of engineers, electrical staff and volunteers at the airport to minimise the risk of disruption from potential further flooding.Contingency plans have also already been put in place to minimise the risk of potential flooding following disruption earlier this week.
siaIn anticipation of the 2014 sailing season, Holland America Line is launching a new Above and Beyond promotional program that allows guests to take advantage of four special offers, including an onboard spending credit that can be put toward a variety of uses.
Mr Ramu Pillay was personally present at the SURMER Establishment on Christmas Day itself to bring the Christmas spirit to a group of 72 orphans and disadvantaged children living in homes with the Roman Catholic Nuns at Sainte Elizabeth Convent and also at Anse Etoile.
The Travel Association, today released its Travel Trends Report 2014, developed in association with the Foreign and Commonwealth Office. The report predicts cautious optimism in the holiday market for the year ahead with consumers continuing to holiday and planning to spend more than they did in 2013.
Visitors can enjoy the seventh KulturWinter programme in the enchanting setting of the Harz mountains from 31 January to 16 February. During this magical time of year there will be special guided tours and memorable events at castles, theatres, mines and abbeys.
In 2014 Germany is celebrating a very special anniversary: 25 years since the peaceful revolution. To the cry of "We are the people – no violence!" more than 70,000 demonstrators confronted the armed security forces of the East German regime in Leipzig in 1989.
The Hohenbuchau Collection – one of the most exquisite private collections of north European baroque paintings – is on show at the Stuttgart State Gallery until 24 February 2014.
The Black Forest is a popular spot for sled dog enthusiasts, as is evident when the annual international sled dog race comes to Todtmoos.
Singapore budget airline Tigerair has launched direct flights between this city state and Ningbo, a port city in eastern China's Zhejiang Province.
Malaysia Airlines and Japan Airlines have established a new code share destination that took effect starting 24 December 2013. This would give the national carrier access to Vancouver, Canada via Tokyo.
Transport NSWA Transport for NSW spokesperson today announced the NSW Government's planned upgrade of Bankstown Station is one step closer, with planning approval now received for the project.
Fred. Olsen Cruise Lines – voted 'Best Affordable Cruise Line' and runner-up 'Best Cruise Line' in the prestigious 'Cruise International Awards 2013' – will have a team of experts on hand at the Telegraph Cruise Show, to be held at ExCeL in London on Friday 10th, Saturday 11th and Sunday 12th January 2014, ready to inspire and inform visitors on the right kind of Fred. Olsen cruise for them.
With the Kenyan government establishing more trade links with other countries, business travel dominated with 1.5 million departures, 82% of the total, an 11% increase compared with 11%, with Dubai, the Far East and Europe being the key trading partners of Kenya.
As we approach the festive season of Christmas and New Year, surprise your loved ones by a special treat with Yeti Airlines. Yeti Airlines is offering a complimentary stay for two nights at a Hotel in Sauraha when you buy a normal fare return ticket to Bharatpur.
Singapore Airlines (SIA) and the Japan National Tourism Organization (JNTO) have signed their first Memorandum of Understanding (MoU) aimed at boosting tourist arrivals into Japan from Singapore, Malaysia and Indonesia.
China Airlines has been named the "Best Airline in North Asia" by U.S.-based Global Traveler magazine, flying the flag for Taiwan in the highly regarded Global Traveler Tested Reader Survey Awards.
Thai Airways International Public Company Limited (THAI) was recently the winner of two SET Awards for "Outstanding Investor Relations" and for "Outstanding Corporate Social Responsibility" at the SET Awards 2013 ceremony.
Thai Airways International Public Company Limited (THAI), through its THAI Smile business unit, recently operated its inaurual flight from Bangkok to Luang Prabang, in the Lao People's Democratic Republic (Lao PDR).
Qatar Tourism Authority convened its international representation offices and local tourism and hospitality sector stakeholders last week for a Framework Workshop on Strategic Tourism Marketing Initiatives for 2014 and beyond.
In celebration of the 43rd year of the reign of His Majesty Sultan Qaboos, Oman Air is sponsoring a major international exhibition organised by the Oman Society of Fine Arts. 43 Exhibitions in Air will see the work of 43 Omani artists displayed on seven key routes within Oman Air's network of 43 destinations.
A cargo train crashed into makeshift houses in Nairobi's largest slum in Kibera on Sunday morning injuring about 10 people, Kenyan Red Cross officials confirmed. No deaths, however, have been reported till now and the rescue team also allayed fears that many people may have been trapped underneath the rubble of the Sunday's crash.
An Antarctic-bound cruise liner with tourists onboard is awaiting rescue after the ship got trapped in thick sheets of sea ice. The MV Akademik Shokalskiy is a Russian-built ship which is on a tourist trip with about 50 passengers onboard and 20 crew members.
Dense fog disrupted timings of over 100 flights at IGI airport in New Delhi causing inconvenience to the passengers. Dense fog yesterday morning reduced the visibility to below 50 metres at one end of the third runway, virtually shutting the operations on this runway.
A cargo train crashed into makeshift houses in Nairobi's largest slum in Kibera on Sunday morning injuring about 10 people, Kenyan Red Cross officials confirmed.
The enthusiasm of festive season has been hit by weekend ice and snow storm which further caused power cuts in parts of central and northeastern US. The Christmas spirit was further dampened by the flight delays caused due to bad weather.
InterContinental Hotels Group announces the opening of the Holiday Inn Express® Hotel Mountain View – S Palo Alto. The three-story 46-room hotel adds to the IHG portfolio in the Mountain View and Palo Alto areas and is opening after significant investments of over $1 million in renovations by the ownership.
Fewer people are travelling to their rural homes in Zimbabwe this festive season compared with previous years, according to a survey carried out New Ziana.
Fred. Olsen Cruise Lines is offering guests something completely new and different in 2014…its first-ever 'Mystery Cruise'! Departing from Tilbury on 15th November 2014 for 14 nights – on Fred. Olsen's inaugural turnaround call at this Essex port – the mystery is where in the world Black Watch will take you?
Starting December 26, 2013 till January 20, 2014, themed "Togetherness – one day is not enough", five Regal Hotels in Hong Kong will offer daily dining surprises with special menus in their specified restaurants.
The America's hotel industry region recorded positive results in the three key performance metrics when reported in U.S. dollars during November 2013, according to data compiled by STR and STR Global.
A tourist assistance program has been launched in the Peruvian city of Cusco to provide free help and advice to travelers, and to generate donations for local charities and community projects.
Four people were injured when a British Airways Boeing 747 collided into a building at OR Tambo International Airport in Johannesburg, Airports Company South Africa (ACSA) confirmed on Monday.
Metrorail in Cape Town says train services in the Peninsula, the rocky piece of land that juts out into the Atlantic Ocean at the south-western tip of the African continent, are only expected to return to normal on Christmas Day following the derailment of a train on Sunday afternoon as it entered Cape Town Station.
Kenya Airways wishes to inform its customers and the general public that all flights to and from Juba in South Sudan have been suspended between December 24, 2013 and December 31, 2013.
Mozambique Airlines (LAM) has expressed "deep concern and shock" at the findings of the Commission of Inquiry investigating the Nov 29 crash of a LAM Embraer-190 aircraft in northern Namibia.
Cathay Pacific Airways released combined Cathay Pacific and Dragonair traffic figures for November 2013 that show an increase in the number of passengers carried alongside a rise in cargo and mail tonnage.
Sabre, a global technology provider, has appointed Bill Robinson as executive vice president and Chief Human Resources Officer.
Carlson Wagonlit Travel (CWT) UK & Ireland and Travelport have together created an industry-leading global travel solution to help multinational clients benefit from highly-personalised service and the best possible deals wherever they are based.
Travelport announced a new multi-year distribution agreement with FlightCar, a service which lets people parking at the airport to rent their vehicles out to other travelers. Now offering services in San Francisco, Los Angeles and Boston, FlightCar is now bookable to all Worldspan-connected travel agents in the United States.
Dubai Mina Rashid sixth consecutive year in the prestigious World Travel Awards 2013 DP World, the world 's leading cruise port managed voted , the company said in its press release .
Airlines for America (A4A), the industry trade organization for the leading U.S. airlines, today commended the U.S. Senate's confirmation of Jeh Johnson to serve as the next Secretary of the U.S. Department of Homeland Security (DHS).


text:
LAWMA To Complete Rehabilitation Of Lamdfills In Days
byND - August 18, 2021 0
Lagos Waste Management Authority (LAWMA) has rejuvenated its operations around the state, taking full advantage of the new waste collection trucks and the double dino bins injected into its fleet by Mr. Governor, Babajide Sanwo-Olu, in line with his administration's drive towards actualising the second pillar of the 'THEMES' Agenda: Health and Environment.
The huge advantage that the trucks has brought into waste management in recent times cannot be overemphasized, as the capacity to collect, transport and dispose waste has greatly improved, their presence in a ubiquitous manner can be felt in every nook and space of the state and steadily, an hitherto huge waste that adorn the landscape is gradually and steadily disappearing, to the delight and satisfaction of Lagosians.
The narrative is indeed changing and we will take full advantage of this, by not resting on our oars until our primary objective ensuring a sustainably clean environment is achieved.
Another major component of the Authority's operational drive is the landfill rehabilitation.
The major landfills scattered all over the state are currently undergoing rehabilitation process which has really affected our operations and a noticeable feature is the presence of traffic around the areas.
It is of note that the rehabilitation of these landfills, especially capping, road networks, upgrading and the likes actually started around March this year, but unfortunately, activities were greatly hampered due to the rains and the process was forced to stop by the end of April/May, due to the bad and unfriendly weather.
Work has, however, resumed in earnest on the landfills, taking advantage of the August break and we want to assure Lagosians that, in the next ten days, the exercise will be completed and the good news is that, the turn-around time will radically improve and the traffic snarl around those landfills, triggered by the rehabilitation works will disappear.
In equal terms, some of those old LAWMA collection trucks would be boarded to some of the PSP operators, whose trucks were destroyed during the unfortunate EndSARS protest, to support their operations, increase their capacity for better service delivery and optimal performance. A committee has been constituted in this regards in order to ensure transparency and that due process followed, just like the previous one which had already been completed.
The Authority wants to assure Lagosians that it will continue to, not only seek guidance from the Ministry of the Environment and Water Resources from time to time, but also collaborate on formulation of right policies, programmes and directions, in order to ensure a clean cityscape, as well as create a people-friendly and sustainably clean Environment livable for all.
Furthermore, LAWMA will improve and upscale its regulatory role, through constant monitoring of the over 450 PSP operators across the state for efficiency and compliance, our Marine operations; Medical Waste; School Waste; Market operations; Construction, Demolition and Disaster Waste operations (E-waste inclusive); Recycling programme; Waste to Energy; Waste to Wealth and over 15 waste management programmes that the Authority oversees.
The Authority hereby appeal to Lagosians for their understanding, patience and support as we employ all scientific and technological methods to bringing about a sustainably cleaner environment for the good of everyone.
While assuring you of our total commitment to our filial duties and responsibility, we want to use this medium to once again, ask Lagosians and tenements not to dump refuse indiscriminately in unauthorised places, patronise our assigned PSP operators and pay your waste bills promptly, for better and efficient waste management delivery in order to ensure a sustainably cleaner environment.
Akinleye Hakeem Kayode
Assistant Director, Public Affairs
Lagos Waste Management Authority (LAWMA)


text:
Q: MySQL query fails in PostgreSQL Using this query:
users = User.where('confirmed_at is NULL AND confirmation_sent_at <= DATE_SUB(NOW(), INTERVAL ? days)', 1)

In mysql goes okay but in Postgresql it fails with:

PG::SyntaxError: ERROR:  syntax error at or near "1"
    LINE 1: ...AND confirmation_sent_at <= DATE_SUB(NOW(), INTERVAL 1 day))
                                                                 ^
    : SELECT "users".* FROM "users"
      WHERE (confirmed_at is NULL AND confirmation_sent_at <= DATE_SUB(NOW(), INTERVAL 1 day))

I'm trying to understand but missing the context here. Why is the integer 1 not valid in this query?

A: There is no function DATE_SUB() in PostgreSQL, so it cannot work.
This expression would work in Postgres:
... AND confirmation_sent_at <= (now() - interval '1 day')

Or, if confirmation_sent_at is a date:
... AND confirmation_sent_at <= (now()::date - 1)

A: Try...
users = User.where(
    "confirmed_at IS NULL " +
    "AND confirmation_sent_at <= (NOW() - INTERVAL '1 DAY')"
)

redpajama_set_name: RedPajamaStackExchange


Bournemouth is a large coastal resort town on the south coast of England to the east of the Jurassic Coast.
Lewis Tregonwell founded the city in 1810 when the area was just a deserted heathland, visited by fishermen and smugglers.
Bournemouth is now a great destination for holidays because of warm climate and a prominent seaside.


Little is known about the early clients. They seem to have disappeared to form a part of the plebeian mass not long after the founding of the city. 12 But of the patricians themselves much more exact information is available.
Who were the patricians? The conquest theory that the patricians were Sabines, whereas the plebeians were Latins, has been answered, even while it was being promulgated, by research into the origins of the patrician families. Duruy 13 and Fustel de Coulagnes found that they were the cream of the society or neighboring towns who fled to Rome because of the political disturbances in their native places. Heitland 14 believes that the patricians were more largely Sabine and that the plebeians were more largely Latins, but that neither group was homogeneous. Blackmar's 15 idea that those who first settled in Rome established the patrician lines fails to take into consideration that each patron arrived in Rome with his clients. The gens and its dependents came as a unit.
The significant fact was that each patrician family could by marriage enter into connubium with each other, even though they were in some respects mutually strange to each other. This was because of their mutual recognition of common aristocratic backgrounds and status. Furthermore, families continued to come to the center as the city-state grew, and some of these aristocratic newcomers were also recognized as patricians.
However, as will be shown, there was some circulation upward within the plebs. They had, by this time, ceased to constitute a layer in society. In fact, they were never a single social class, as were the patricians, because some of them were rich and illustrious persons from other cities, especially from the eastern Mediterranean.
The plebeian was not always poor. Often he belonged to a family that was originally from another city, which was there rich and influential, and whom the fate of war had transported to Rome without taking away his wealth, or the sentiment of dignity that ordinarily accompanies it.
12. Georg Friedrich Schoeman, Griesche Alterthumer, vol. I (Berlin, 1861) p. 136.
13. Victor Duruy, History of Rome, vol. I. (Boston, 1883) pp. 132 ff.
14. W. E. Heitland, Roman Republic, vol. I (Cambridge, 1909) p. 42.
15. Blackmar, op. cit., p. 251.
16. Edward Gibbon, The Decline and Fall of the Roman Empire, vol. I (Modern Library edition, New York, 1932) p. 525.
17. Pitirim Sorokin, Social Mobility (New York, 1927) p. 148.
18. Fustel de Coulagnes, op. cit., p. 380.
19. Duruy, op. cit., pp. 196 - 197.
20. Fustel de Coulagnes, op. cit., p. 360.


Burgess, Robin (2015) How to deposit research outputs in RADAR. Documentation. The Glasgow School of Art.
This guide provides step by step instructions on how to log in to RADAR, deposit and manage outputs, upload documents and edit your RADAR records.


Camouflage techniques have long been done by secret personnel to conceal them self with surroundings. However, the biggest problem is that if the soldier moved to a different location, they might find it difficult to blend again. This is not like one of the Japanese ninja abilities which are able to refract the body with the environment such as walls, trees, roads, and others. This is very similar to the chameleon's ability to adapt. This ability seems to inspire a team of researchers from China and the United States who have struggled to develop a way to work around this. Unlike in the movie who usually wear a robe or a ring and even drink a drug to make you perfectly invisible but those are quite dangerous, chameleon robot that is successfully created by the researchers at Wuhan University in China is the best thing to get complete transparency to blend into the background well enough so it will not be detected easily.
Researchers from the University of Wuhan in China took the 3D model. This design is covered with plasmonic display and also installed a light sensor detector. This tool will be able to produce in accordance with the color or background conditions that existed at the robot. The plasmonic screen on this robot can generate and change colors quickly. The screen is made of small glass with a hole that has a diameter of 50 nanometers.
Let's start by looking at the nanoscale structure. In order to make it, the researchers wrap the glass with gold nanoparticles, which creates a small dome on each hole. They also use a layer of electrolyte gel with silver ions. Thus, each hole has its nanodome gold. When light hits, these displays will create Plasmon, or ripples of electrons, so that the dome can determine the reflection and the absorption rate of light. The different colors produced when an electric field is connected and incorporates a number of sticks of silver ions into the golden dome.
In short, different colors that exist in the robot's body are generated when electric fields are interconnected and changing the presence of some silver ions. Then, adding light and color detection sensor from the environment in order to adjust the electric field to change color as needed. This is undoubtedly an extremely complex technical phenomenon. However, the uploaded videos showed that robot moves from red to green background color can adapt to its surface in real-time from front to back without moving color transition until the sensor completely moved into the next background color. It became an evident that the mechanical chameleon has every fundamental feature required for active and realistic camouflage.
Scientists are still figuring out exactly how chameleons change color in real life. The latest research shows it is small guanine crystals that exist beneath the skin cells. It seems that by changing the distance between these crystals, the chameleon can change the wavelength of the reflected light. This concept is similar to what they used in chameleon robot – the color changing is depending on the tuning of the electric field in a similar way how the chameleon's body adjusts to its guanine crystals.
Although it is considered cutting-edge, the scientists say that at the moment the color matching of this robot is limited to red, green, and blue. However, they believe this invisible robot will be developed further in order to be able to detect and match any color.
A more advanced system can detect any color. This will fully combine mechanical chameleon capability into surroundings. If a more sophisticated sensor can be miniaturized, then someday this technology could be developed into an adaptive camouflage for military purposes such as vehicle or body armor.
This display still needs a long road and a few jobs to be done before all of that possible. However, it seems that this technology is on its way. Therefore, get ready to see the development of military camouflage.
Be the first to comment on "This Enchanting Chameleon Robot Can Be an Early Development of Military Camouflage System"


Dixons Carphone is a leading electrical and telecommunications retailer and services company in Europe.
The company was looking for packaging solutions to suit multiple skus and sizes while offering superior product protection and an optimum customer experience.
Macfarlane worked closely with Dixons Carphone to review their existing packaging and introduced new ideas that were better catered for their packaging needs. The new packaging has helped Dixons to reduce product damage, decrease transport and administration costs and increase productivity.


text:
Poll: Youth overwhelmingly support Edward Snowden
Photo courtesy Slowking4
A new poll commissioned by the Washington Post and ABC news shows that young people overwhelmingly support Edward Snowden, and don't think he should be prosecuted for blowing the whistle on NSA spying.
Just 35 percent of those under age 30 say he should be charged with a crime, compared with 57 percent of those 30 and up. And 56 percent of young adults say he did the "right thing" in leaking NSA documents. Just 32 percent of their elders agree.
These numbers on majority youth support for Snowden come months after a July 2013 Washington Post/ABC News poll found that most people under 30, unlike their elders, did not prioritize investigation powers over their personal privacy rights.
No matter their age, a vast majority of people surveyed think that the NSA's dragnet surveillance programs violate US person privacy. Very few people think those intrusions are justified.
A whopping 68 percent of Americans think the NSA violates the privacy rights of "some Americans"; only twenty percent of that group think the intrusions are justified. Over half of respondents say the NSA intrudes on their own privacy, ninety percent of whom see this invasion as unjustified.
Unsurprisingly, belief that the NSA is unjustifiably intruding on privacy rights correlates with weaker support for the US government's prosecution of whistleblower Edward Snowden. Among people who believe the NSA is violating rights, 42 percent support the government's prosecution of Snowden under the Espionage Act of 1917. Contrast that with 62 percent support for the prosecution among people who don't worry about the privacy intrusions, or think they aren't happening.
The poll found that opposition to the government's dragnet surveillance operations tacks closely to party affiliation. Democrats, "protective of the Obama administration," are now playing the role of surveillance defender while conservatives "are much more likely than moderates or liberals to think the NSA intrudes on privacy without justification."
Perhaps Democrats need to be reminded that all the information the NSA collects today could be available to a President Rick Santorum or Marco Rubio in 2020? After all, that data center in Utah is awfully large.


text:
from biicode.common.output_stream import Color
from collections import defaultdict
from biicode.common.exception import BiiException
import fnmatch
from biicode.common.model.cells import SimpleCell

def print_deps(out, hive_holder, block_name=None, details=False, files=False):
    ''' Print the general block dependencies '''
    block_holders = {block.block_name: block for block in hive_holder.block_holders}
    # filter block_name
    if block_name is not None:
        try:
            block_holders = {block_name: block_holders[block_name]}
        except KeyError:
            raise BiiException("Block name '%s' not exists" % block_name)

    if files is not None:
        _print_deps_files(out, block_holders, files)
    else:
        _print_deps_details(out, block_holders, details)

def _print_deps_details(out, block_holders, details):
    if details is not None:
        show_details = True
        if not details:
            details = ['*']
    else:
        show_details = False

    def _show_origins():
        if show_details:
            for origin in sorted(origins):
                out.writeln("                %s" % str(origin))

    for block in sorted(block_holders):
        block_holder = block_holders[block]
        out.write(block, Color.BRIGHT_GREEN)
        out.writeln(" depends on:")

        dep_table = block_holder.requirements
        deps_dict = _deps(block_holder)

        for block_name in sorted(deps_dict):
            dict_cell_names = deps_dict[block_name]
            if block == block_name:
                block_version = "%s (self)" % block
                if not details:
                    continue
            else:
                block_version = dep_table.get(block_name, "Error, dep not found")
            out.writeln("       %s" % str(block_version), Color.BRIGHT_CYAN)
            for cell_name in sorted(dict_cell_names):
                if not _check_file_patterns(cell_name, details):
                    continue
                origins = dict_cell_names[cell_name]
                out.writeln("          %s" % cell_name, Color.CYAN)
                _show_origins()

        systems = _system(block_holder)
        unresolveds = _unresolved(block_holder)
        if systems:
            out.writeln("       system:", Color.BRIGHT_YELLOW)
            for system in sorted(systems):
                if not _check_file_patterns(system, details):
                    continue
                origins = systems[system]
                out.writeln("          %s" % system, Color.YELLOW)
                _show_origins()

        if unresolveds:
            out.writeln("       unresolved:", Color.BRIGHT_RED)
            for unresolved in sorted(unresolveds):
                if not _check_file_patterns(unresolved.name, details):
                    continue
                origins = unresolveds[unresolved]
                out.writeln("          %s" % unresolved, Color.RED)
                _show_origins()

def _unresolved(block_holder):
    unresolved = defaultdict(set)
    for cell, _ in block_holder.simple_resources:
        for unr in cell.dependencies.unresolved:
            unresolved[unr].add(cell.name.cell_name)
    return unresolved

def _system(block_holder):
    system = defaultdict(set)
    for cell, _ in block_holder.simple_resources:
        for s in cell.dependencies.system:
            system[s].add(cell.name.cell_name)
    return system

def _deps(block_holder):
    deps = defaultdict(lambda: defaultdict(set))
    for cell, _ in block_holder.simple_resources:
        for s in cell.dependencies.explicit:
            deps[s.block_name][s.cell_name].add("%s (E)" % cell.name.cell_name)
        for s in cell.dependencies.implicit:
            deps[s.block_name][s.cell_name].add("%s (I)" % cell.name.cell_name)
    return deps

def _check_file_patterns(name, patterns):
        if not patterns:
            return True
        for p in patterns:
            if fnmatch.fnmatch(name, p):
                return True
        return False

def _print_deps_files(out, block_holders, files):

    for block in sorted(block_holders):
        block_holder = block_holders[block]
        out.writeln(block, Color.BRIGHT_GREEN)
        cells = {cell.name.cell_name: cell for cell, _ in block_holder.resources.itervalues()}
        for cell_name in sorted(cells):
            if not _check_file_patterns(cell_name, files):
                continue
            cell = cells[cell_name]
            out.writeln("       %s [%s]%s"
                        % (cell_name, cell.type, '[M]' if cell.hasMain else ''),
                        Color.BRIGHT_CYAN)
            if isinstance(cell, SimpleCell):
                for s in sorted(cell.dependencies.explicit):
                    out.writeln("           %s (E)" % s)
                for s in sorted(cell.dependencies.implicit):
                    out.writeln("           %s (I)" % s)
                for s in sorted(cell.dependencies.system):
                    out.writeln("           %s (S)" % s, Color.YELLOW)
                for s in sorted(cell.dependencies.data):
                    out.writeln("           %s (D)" % s, Color.MAGENTA)
                for s in sorted(cell.dependencies.unresolved):
                    out.writeln("           %s (U)" % s, Color.RED)
            else:
                for s in sorted(cell.resource_leaves):
                    out.writeln("           %s (V)" % s.cell_name)

redpajama_set_name: RedPajamaGithub


Dell Inspiron 1200 Driver Download – Computer drivers are generally very small programs which allow your Computer devices to help you talk with your operating-system software programs.Retaining upgraded Computer software programs prevents failures not to mention boosts devices and strategy performance.Dell Inspiron N5110 Drivers Download This page contains the list of device drivers for Dell Inspiron N5110. To download the proper driver, first choose your operating system, then find your device name and click the download button.The drivers in this category is updated weekly, so you can always download the latest DELL Inspiron 1200 drivers here! If you are not sure which one is the exact driver for DELL Inspiron 1200 , you can download our automatically drivers installer utility, please.Dell Inspiron 1200 notebook HLDS GCC-4243N Slim CDRW/DVDROM 24X GBAS v.A103(WIN) for Windows XP/2000 Windows based Flash Utility to update HLDS Slim Combo GCC-4243N 2007-10-30.
Find great deals on eBay for dell inspiron 1200 and dell inspiron 1200 battery. Shop with confidence.Drivers for Dell Inspiron 1200. For this model of laptop we've found 22 devices. Select device for driver's downloading.Dell Inspiron 1200 System BIOS Dell laptops driver Descritpion: Installation Instructions. The file I1200A07.EXE is using the Hard Drive format and is designed to be directly executed from Windows environments.Descarga el driver de Dell para Inspiron 1200. Ayuda y soporte técnico en español.
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Tonight I'm documenting another Cars 3 Mattel 1:55 scale diecast from my collection...this time around, it's Piston Cup racer Chip Gearings (also known by his sponsor, Combustr; No. 11)! I've had this one for almost a whole year and I'm only getting to this review now. Phew! He was released on May 1st last year and was part of the initial launch of Cars 3 toys by Mattel.
Combustr (who's slogan is "The Power of Online Baking") is a brand new sponsor created just for Cars 3 and was not featured on any racers in any of the previous Cars films or shorts. Chip can be seen in Cars 3 very, very briefly (essentially just a quick blur) during some of the opening racing shots of the film. I really wish the camera lingered on some of these racers longer (kind of like in the first Cars), so that you could see all these awesome characters better!
There's a next-gen Combustr racer coming out this year as well, so I'll be posting that as soon as I find him (don't worry, it won't take me a year this time). Not too much to say about this one though! Just another basic and somewhat generic (yet solidly done) racer who uses the made mold as many of the others diecasts.
Believe it or not, Chip can still be found on store shelves to this day. It's crazy! However, if you're looking to add him to your collection and he's not available in your area anymore, you can always visit my direct link to Amazon below.
Let me know your thoughts or any questions you might have. Happy hunting!


text:
YouGov criticised for claim about lifting Covid restrictions in 'England and Wales'
The flags of Wales and England
YouGov has been criticised for a claim about lifting Covid-19 restrictions in England and Wales.
The polling firm suggested that most are "due to be lifted this month" in England and Wales in a survey about public attitudes towards wearing face masks.
Covid rules in England are decided by the UK Government, but in Wales they are decided by the Welsh Government.
This led Labour for an Independent Wales president Bob Lloyd to say that "YouGov has a serious problem with Wales."
Boris Johnson has confirmed today that the final step of lifting coronavirus restrictions in England would happen as planned on 19 July.
These include scrapping the legal requirement to wear face masks and ditching social distancing rules.
However, the Welsh Government has yet to announce what it plans to do and has said that ministers and officials would evaluate data ahead of the next review on 15 July.
The YouGov survey said: "Most remaining Covid restrictions are due to be lifted this month (in England and Wales) or next month (in Scotland).
"Thinking about the current requirement to wear a mask, when most restrictions are lifted do you think…?"
In response Nia Jenkins said: "@YouGov wrongly claiming that Covid restrictions in #Wales will be lifted this month.
"The guidance in Wales is set by the @SeneddCymru @SeneddWales NOT Westminster. @ThatsDevolved."
Barry Suddery said: "For f***'s sake, @YouGov, devolution has been in place for decades! DO. YOUR. RESEARCH!"
'Follow England'
Robert Jenrick, Boris Johnson's Communities Secretary, told The Andrew Marr Show on Sunday that the UK Government wants the other nations of the UK to follow England and lift all legal coronavirus rules on July 19.
He said the Westminster government was going to "work with" Wales, Scotland and Northern Ireland to "try and be as coordinated as possible".
But at a Covid-19 press conference today, Wales' Health Minister, Eluned Morgan has said that Wales will "follow the data rather than the politics".
She added that it was "very clear that we are still in a very difficult situation because case numbers are increasing exponentially in Wales".
"Boris Johnson will do what is right for England and we will do what is right for Wales," she said. She added that "time and time again deadlines have been set in England and missed".
"In an ideal world we would like to move together," she added. "But here we've been following the data and will continue to do that."
Kerry Davies
This is the YouGov that treats Wales as part of the West Midllands, is it not? Madam Zahawi, heater of horses, set it up so take from that what you will.
YouGov is clearly an incompetent organization who should not be trusted to undertake any form of polling.
This happens far too often to be accidental. Somebody needs sacking at Yougov
when you see who the active directors and major shareholders are, YouGov's agenda becomes much more clear.
Brian Coman
Maybe their should be a poll about You Gov ….confusion is still rife.Went to Sainsburys…sign outside read "Shop Alone "..then went home and saw 30,000 people sat together at Wimbledon enjoying a Pimms with food !


text:
Long IslandObituaries
Engineer Stanley Millman, who worked on space missions, dead at 83
From a barren outdoor field in Florida a few miles from the John F. Kennedy Space Center, Plainview engineer Stanley Millman, pictured here, was an eyewitness to the world's most iconic and arguably important space mission in 1969. Millman, of Plainview, a spacecraft troubleshooter, died Nov. 9, 2014 at home after a second battle with non-Hodgkin's lymphoma. He was 83. Newsday's obituary for Stanley Millman
Credit: Millman Family
By DEON J. HAMPTON deon.hampton@newsday.com @deonjhampton Updated December 16, 2014 9:42 PM
From a barren field in Florida a few miles from the John F. Kennedy Space Center, Plainview engineer Stanley Millman was an eyewitness to the world's most iconic and arguably important space mission.
It was there, on July 16, 1969, that his teary eyes never left the historic launch of the Apollo 11 flight as it departed for the moon with astronaut Neil Armstrong as its commander.
Millman, of Plainview, a spacecraft troubleshooter, died Nov. 9 at home after a second battle with non-Hodgkin's lymphoma, his family said. He was 83.
In 1969, millions around the globe watched the black-and-white telecast of the launch. Near the Space Center in Cape Canaveral, residents crowded highways and beaches for a glimpse of the epic moment.
Millman, an engineer who worked on navigational systems for America's space programs troubleshooting spaceships and debriefing astronauts once they returned from orbit, had been invited by NASA to watch the liftoff in the field alongside famous people such as aviator Charles Lindbergh.
"When it [Apollo 11] went up, the Earth shook and your body shook with it. There wasn't a dry eye. We were in absolute awe in what we were watching. It was the experience of a lifetime. . . . It looked like a tremendous bullet shooting up in the sky," said Millman's wife, Claire Millman, 82.
"The resurgence of the cancer [came], and then everything went downhill and I lost him. It's been really unreal," she said.
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Millman was born in the Borough Park section of Brooklyn, where he also attended Boys High School.
The couple married in 1955 after meeting in their late teens while attending Brooklyn College.
On their first day of history class, they coincidentally sat next to each other. "I guess it was meant to be," Claire Millman said.
Millman graduated with a bachelor's degree in 1952, his wife said. He was drafted into the Army in 1953 and served a two-year stint at Fort Huachuca in Sierra Vista, Arizona, where he became a corporal and was awarded a sharpshooting medal.
A math whiz, according to relatives, Millman went on to obtain a master's degree in electrical engineering from Columbia University.
He worked at Syosset-based Kollsman Instrument Corp., an engineering firm, for 19 years.
Eventually, he rose to senior vice president of Bohemia-based ILC Data Device Corp., another engineering firm.
Viewing the Apollo 11 launch was Millman's defining moment, family members said.
"It was an American dream. It was space-age. Dad was an overnight sensation," said his daughter Sherry Purzak, of Plainview.
Other survivors include another daughter, Laurie Millman-Freedman of Leverett, Massachusetts. Burial was at New Montefiore Cemetery in Farmingdale.
By DEON J. HAMPTON deon.hampton@newsday.com	@deonjhampton
Deon J. Hampton joined Newsday in June 2012. He covers Brookhaven Town.
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Sophie V Sugar: You're Fired!
This week's Apprentice task was so simple it could have been put together by anybody – to think up and design a new piece of flat-pack furniture.
Sophie immediately decided to take charge sit back, allowing the rest of the girls to come up with a "multifunctional, sturdy item" to be used "anywhere in the home". This Swiss army knife of a design incorporated a laptop tray, a seating area, a storage area, an ipad easel and, presumably, a kitchen sink.
However, compromise can be a dangerous thing, and on this occasion it left the team with a design nobody wanted and a product which bears an uncanny resemblance (both in form and function) to my wash basket.
Predictably, there was agreement from practically every potential buyer that paying £75 for a box on wheels was a tad excessive, and the Girls lost by a huge margin.
Sophie was once again called back to the boardroom, and without so much as a whimper of protest was quickly despatched by Lord Sugar.