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[
"Introduction {#s1}\n============\n\nProteoglycans (PGs) constitute an own entity of glycoproteins, where the core proteins are substituted with glycosaminoglycan (GAG) chains. ",
"There are several types of GAG-chains, where chondroitin sulphate (CS) is one of the major types. ",
"CS-chains are unbranched and contain a variable number of negatively charged sulphate groups which are important for their function [@pone.0020616-Hascall1], [@pone.0020616-Kjellen1]. ",
"Almost all mammalian cells synthesize PGs, and these are either secreted or cell associated. ",
"PGs synthesized from monocytes and macrophages are mainly substituted with CS-chains (CSPG) [@pone.0020616-Edwards1]--[@pone.0020616-UhlinHansen1]. ",
"When monocytes are stimulated and differentiated to macrophages, both the biosynthesis and the secretion of CSPG are increased [@pone.0020616-UhlinHansen1]. ",
"The human monocyte cell line THP-1 secretes PGs such as serglycin, versican and perlecan [@pone.0020616-Makatsori1], [@pone.0020616-ynebrten1]. ",
"The biological role of the secreted PGs such as serglycin from macrophages is not clear, but it has been shown that they bind to other molecules released from the cells through interaction with the GAG-chains, suggesting that serglycin and other PGs may act as a kind of carrier molecule [@pone.0020616-Kolset4], [@pone.0020616-Metkar1]. ",
"It has also been reported that serglycin is constitutively produced by multiple myeloma plasma cells and can inhibit the bone mineralization process [@pone.0020616-Theocharis1].",
"\n\nThe family of matrix metalloproteinases (MMPs) consists of approximately 25 different secreted and membrane-bound mammalian enzymes. ",
"They are zinc and calcium dependent, and together the MMPs are able to degrade most extracellular matrix (ECM) proteins. ",
"In addition they can process and regulate the activity of a large amount of non-ECM proteins such as growth factors, cytokines, chemokines, cell receptors, serine proteinase inhibitors as well as other MMPs [@pone.0020616-Butler1]--[@pone.0020616-Strongin1]. ",
"Thus, MMPs have complicated biological functions playing a role in both normal and pathological conditions [@pone.0020616-Nagase1], [@pone.0020616-Cawston1]--[@pone.0020616-HadlerOlsen1].",
"\n\nAll MMPs are built up of various modules, including a pro- and a catalytic domain. ",
"In addition, all the secreted MMPs with the exception of the two matrilysins (MMP-7/-26) also contain a C-terminal hemopexin-like domain [@pone.0020616-Nagase1], [@pone.0020616-Ra1]. ",
"Secreted MMPs bind to ECM proteins, PGs as well as cell membranes [@pone.0020616-Woessner1]. ",
"The two gelatinases MMP-2 and MMP-9 contain a unique inserted domain in their catalytic region, i.e. a module containing three fibronectin II-like repeats (FnII). ",
"This domain is similar but not identical in the two gelatinases, and is involved in the binding of denatured collagens, elastin and native collagen. ",
"The three FnII-like repeats in the catalytic site of MMP-2 and MMP-9 may facilitate the localization of these enzymes to connective tissue matrices. ",
"They also appear to be of importance for the degradation of macromolecules such as elastin, gelatin and collagens IV, V and XI, but do not influence the degradation of chromogenic substrates [@pone.0020616-Allan1]--[@pone.0020616-Xu2].",
"\n\nMMP-9 (92 kDa gelatinase) is produced by a variety of cell lines, including monocytes and macrophages. ",
"MMP-9 is produced as a monomer as well as various dimer forms [@pone.0020616-Goldberg1]--[@pone.0020616-Winberg1]. ",
"The homo- and several of the hetero-dimer forms are reduction sensitive. ",
"Hence, the proteins are either covalently linked to each other through disulfide bonds or a very strong reversible interaction where intramolecular disulfide bonds are essential. ",
"We discovered that THP-1 cells produced a new type of reduction sensitive heteromer, where 10--15% of the total amount of proMMP-9 synthesized was linked to the core protein of one or several CSPGs [@pone.0020616-Winberg1]. ",
"The binding of proMMP-9 to a CSPG alters several biochemical properties of the enzyme [@pone.0020616-Malla2], [@pone.0020616-Winberg2]. ",
"Among these properties are the ability to be activated by organomercurial compounds as well as its binding to collagens and gelatins through the three FnII repeats in the enzymes catalytic region. ",
"It was shown that the CSPG core protein hides and prevents binding of collagen and gelatin to the enzymes FnII domain.",
"\n\nThe aim of the present investigation was to determine whether different compounds known to stimulate the synthesis of proMMP-9 and CSPGs also can increase the syntheses of proMMP-9/CSPG heteromers in THP-1 cells, and to what extent various PKCs are involved. ",
"Our results revealed that only PMA significantly increased the biosynthesis of the heteromers and that a Rottlerin sensitive pathway is involved.",
"\n\nMaterials and Methods {#s2}\n=====================\n\nMaterials {#s2a}\n---------\n\nFormaldehyde, TRIS, urea, DMSO and sodium acetate were from Merck. ",
"Trichloroacetic acid (TCA), Ethanolamine and EDTA were from Fluka. ",
"Acrylamide, Coomassie Brilliant Blue G-250 and Triton X-100 were from BDH. ",
"Safranin O (no.",
"S-2255), cetylpyridinuim chloride, phorbol 12-myristate 13-acetate (PMA), blue dextran, Hepes, Brij-35, alkaline phosphatase-conjugated antibodies, chondroitin sulphate C, gelatin, bovine serum albumine (BSA), LPS, Concanavalin A (ConA), Sigma Fast Protease inhibitor cocktail tablets, primers and the JumpStart™Red Taq® PCR reaction mix were purchased from Sigma. ",
"IL-1α and IL-1β were from R&D Systems, while PGE~2~ (prostaglandin E~2~) was from Cayman Chemicals. ",
"Proteinase free chondroitin ABC lyase (cABC) was from Seikagaku Kogyo Co. Gelatin-Sepharose, Q-Sepharose, Superose 6 (HR 10/30), Sephadex G-50 (fine), Amplify and ^14^C-labeled Rainbow™ protein molecular weight standards were from GE-Healthcare. ",
"Ultima Gold XR, \\[^35^S\\]sulphate and \\[^3^H\\]glucosamine were obtained from Perkin Elmer. ",
"DC Protein Assay and unlabeled molecular weight standards were from BioRad. ",
"Magic Marker molecular weight standards and pre-casted polyacrylamide gels (NuPAGE Novex 4--12% Bis-Tris gels) for Western blotting were from Invitrogen. ",
"Solution cell proliferation assay (Cell Titer 96AQueous One) was from Promega. ",
"Rabbit polyclonal antibody against human PKCα, rabbit monoclonal antibodies against human Phospho-MAPKAPK-2 (Thr222) and PKCε were from Cell Signaling Technology. ",
"Western Blotting Luminol Reagent, HRP-conjugated donkey anti-goat secondary antibody, rabbit polyclonal antibodies against human ERK2, PKC βI, βII, δ and goat polyclonal antibody against human PKCθ were from Santa Cruz Biotechnology. ",
"Rabbit polyclonal antibody against PKD3 was a kind gift from Dr. Johan Van Lint, Catholic University, Leuven, Belgium. ",
"HRP-conjugated goat anti-rabbit secondary antibody was from Southern Biotech. ",
"MCSF (macrophage colony stimulating factor), TNF-α, bFGF, IL-3, IL-6, Gö6983, Gö6976 and Rottlerin were from Calbiochem. ",
"NucleoSpin RNAII kit was from Macherey-Nagel. ",
"iScript cDNA synthesis kit and DC Protein assay kit was from Bio-Rad. ",
"Kodak Scientific imaging film, X-OMAT AR was from Kodak.",
"\n\nBiosynthesis of proMMP-9/CSPG heteromer, proMMP-9 and CSPGs {#s2b}\n-----------------------------------------------------------\n\nThe human leukemic monocyte cell-line THP-1 was a kind gift from Dr. K. Nilsson, Department of Pathology, Uppsala University, Sweden. ",
"The cells were cultured in RPMI 1640 medium with 10% fetal bovine serum, 50 µg/ml of streptomycin, and 100 units/ml of penicillin. ",
"To investigate the effect of various biological compounds on the biosynthesis of proMMP-9/CSPG heteromer, proMMP-9 and CSPGs, cells were washed 3 times in serum-free medium and then cultured for 72 h in serum-free RPMI 1640 medium with or without the following compounds; PMA (10^−9^--10^−5^ M); IL-1α (1--200 ng/ml), IL-1β (1--200 ng/ml), IL-3 (1--200 ng/ml), IL-6 (1--200 ng/ml), LPS (1--5000 ng/ml), ConA (1--200 µM; 26--5200 µg/ml), TNF-α (1--200 ng/ml), bFGF (1--200 ng/ml), PGE~2~ (1--200 ng/ml), MCSF (1--200 ng/ml). ",
"In all cases, control cells contained the same amount of DMSO as the cells treated with the various biological compounds. ",
"Conditioned medium was harvested and loose cells were removed by centrifugation at 1000 rpm for 10 min. ",
"CSPG and proMMP-9/CSPG heteromers were thereafter isolated and detected as described below. ",
"To determine proMMP-9 the enzyme was detected directly in the harvested medium by gelatin zymography.",
"\n\nPreparation of cytosol and plasma membranes {#s2c}\n-------------------------------------------\n\nSixty million cells treated with or without PMA (10^−7^ M) and Rottlerin (5 µM) were incubated in serum-free RPMI 1640 medium for 8 hr as described above. ",
"Adherent cells (PMA treated) were scraped off and suspended in PBS. ",
"Cells were thereafter pelleted for 10 min at 2000 rpm and re-suspended in 50 mM Tris-HCl buffer pH 8.0 containing 5 mM CaCl~2~ and 1x proteinase inhibitor cocktail along with 10 mM EDTA. ",
"Cells were homogenized with a glass homogenizer and the cytosol fraction was separated from plasma membrane, intact cells and organelles by centrifugation (50,000xg for 1 h). ",
"The supernatant fraction (cytosol) was collected and the pellet was dissolved in 20 mM Tris-HCl buffer pH 7.4 containing 8.7% sucrose, 1x proteinase inhibitor cocktail along with 10 mM EDTA and thereafter layered on the top of a 38.5% sucrose cushion prior to centrifugation (100,000xg, 1 h). ",
"The plasma membrane fraction was collected from the interface, pelleted by centrifugation (100,000xg, 1 h), and re-suspended in 50 mM Tris-HCl buffer pH 8.0 containing 5 mM CaCl~2~, 1x proteinase inhibitor cocktail along with 10 mM EDTA [@pone.0020616-Loennechen1], [@pone.0020616-Mathisen1]. ",
"All steps were performed at 4°C. ",
"The cytosol and plasma membrane fractions were frozen and stored at −70°C. ",
"The amount of protein in the cytosol and membrane fractions was determined by the DC Protein assay kit using BSA as a standard. ",
"Four independent measurements were performed on each cytosol and membrane preparation, and the standard deviation of the determined protein concentrations was less than 10%.",
"\n\nRNA isolation and reverse transcriptase-polymerase chain reaction (RT-PCR) {#s2d}\n--------------------------------------------------------------------------\n\nTotal RNA was isolated using the NucleoSpin RNAII kit according to the manufacturer\\'s protocol. ",
"Two µg of RNA was reverse-transcribed using iScript cDNA synthesis kit. ",
"The primers for PCR were: PKCα forward: 5′-atccgcagtggaatgagtcctttacat-3′; PKCα reverse: 5′-ttggaaggttgtttcctgtcttcagag-3′; PKCβI forward: 5′-ctgtggaactgactcccactg-3′; PKCβI reverse: 5′-atactgaagcattttggtatc-3′; PKCβII forward: 5′-gaccgatttttcacccgcca-3′; PKCβII reverse: 5′-ccatctcatagagatgctcc-3′; PKCγ forward: 5′-cacgaagtcaagagccacaa-3′; PKCγ reverse: 5′-tagctatgcaggcggaactt-3′; PKCδ forward: 5′-caactacatgagccccacct-3′; PKCδ reverse: 5′-gaggctctctgggtgacttg-3′; PKCε forward: 5′-gatgcagaaggtcactgcaa-3′; PKCε reverse: 5′-gtcgtcatggaggatggact-3′; PKCξ forward: 5′-gttatcgatgggatggatgg-3′; PKCξ reverse: 5′-gcaccagctctttcttcacc-3′; PKCη forward: 5′-gaacagaggttcgggatcaa-3′; PKCη reverse: 5′-atatttccgggttggagacc-3′; PKCθ forward: 5′-acaaacagggctaccagtgc-3′; PKCθ reverse: 5′-atgccacatgcatcacactt-3′; PKCι forward: 5′-tacggccaggagatacaacc-3′; PKCι reverse: 5′-tcggagctcccaacaatatc-3′; PKCµ/PKD1 forward: 5′-acggcactattggagattgg-3′; PKCµ/PKD1 reverse: 5′-tgaccacattttctcccaca-3′; PKD2 forward: 5′-gccctcacggtgcactcctatc-3′; PKD2 reverse: 5′-tgacaccggagtcctctgact-3′; PKCυ/PKD3 forward: 5′-atttgtctacaagtatctctgt-3′; PKCυ/PKD3 reverse: 5′-ctgaccacatatctagggaacg-3′. The PCR cycling conditions were 35 times at 94°C for 30 sec, 55--60°C for 30 sec and 72°C for 30 sec. ",
"PCR was performed using JumpStart™Red Taq® PCR reaction mix. ",
"PCR products were visualized on an ethidium bromide-stained agarose gel.",
"\n\nCell Toxicity and Viability Assays {#s2e}\n----------------------------------\n\nCell viability tests were performed in 96-well plates, where 6×10^4^ cells/well were incubated with increasing concentrations of different cytokines, growth factors, lectins, lipopolysaccharides, PMA and PKC inhibitors in 100 µl serum-free RPMI 1640 media for 8 to 72 h. At the end of incubation, cells were washed in PBS and then 100 µl serum-free RPMI 1640 media containing 20 µL of 3-(4,5-dimethythizol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt (CellTiter 96 AQueous One Solution) was added to each well and further incubated for 1 or 4 h at 37°C and then the absorbance at 490 nm was determined in a plate reader (VersaMax™, Molecular Devices Corp) according to the manufacturer\\'s protocol. ",
"Absorbance of control cultures (which was not significantly altered after 72 h of incubation in serum-free conditions) was defined as 100% and compared with that of treated cultures. ",
"It was also determined to which extent PMA and the PKC inhibitor Rottlerin were toxic to the cells by using the Trypan Blue test. ",
"Briefly, 4×10^5^ cells were added to each well in 12 well plates (0.6 ml/well) and incubated for 12--72 h in the presence or absence of different concentrations of PMA and Rottlerin. ",
"Cells were thereafter harvested, mixed with Trypan Blue and counted in a Bürker chamber. ",
"To harvest PMA treated cells, a rubber scraper was used to detach the cells from the well.",
"\n\nBiosynthetic radiolabelling of GAG-chains {#s2f}\n-----------------------------------------\n\nTo determine the effect of the various biological compounds on the biosynthesis of CSPG, radioactive labelling was performed by incubating 0.8×10^6^ cells in 1 ml with \\[^35^S\\]sulphate (50 µCi/ml) for 72 h. To determine the effect of Rottlerin in the presence and absence of PMA (10^−7^ M), GAG-chains were labelled with either 50 µCi/ml of \\[^35^S\\]sulphate or 10 µCi/ml of \\[^3^H\\]glucosamine by incubating 1×10^6^ THP-1 cells for 8 and 23 h in 0.5 ml of serum-free RPMI 1640 medium containing 50 µg/ml of streptomycin and 100 units/ml of penicillin. ",
"Conditioned medium and cells were thereafter separated through centrifugation at 2000 rpm for 10 min. ",
"The cell-free conditioned medium and the obtained cell lysates were then applied to a Sephadex G-50 column in order to separate free \\[^35^S\\]sulphate or free \\[^3^H\\]glucosamine from CSPG-labelled with \\[^35^S\\]sulphate or \\[^3^H\\]glucosamine. ",
"The radioactively labelled CSPG in the media or in the purified material was thereafter counted in a liquid scintillation spectrometer or applied to SDS-PAGE followed by autoradiography.",
"\n\nDetection of PG-bound CS-chains {#s2g}\n-------------------------------\n\nPG-bound CS-chains were quantified spectrophotometrically by the Safranin O method as described previously [@pone.0020616-Winberg1].",
"\n\nIsolation of secreted CSPG and proMMP-9/CSPG heteromers {#s2h}\n-------------------------------------------------------\n\nSecreted PG and the proMMP-9/PG heteromers were isolated by Q-Sepharose anion-exchange chromatography as described previously [@pone.0020616-Winberg1].",
"\n\nIsolation and detection of radioactive labelled CSPG and free CS chains {#s2i}\n-----------------------------------------------------------------------\n\nTo determine the size of CSPGs isolated from Rottlerin-treated and untreated cells, as well as CS-chains released from CSPGs, Q-Sepharose purified \\[^35^S\\]sulphate and \\[^3^H\\]glucosamine labelled CSPG were applied to a Superose 6 (HR19/30) column. ",
"The latter column was run in 50 mM sodium acetate, 4M guanidine and 0.15 M NaCl, pH 6.0 and markers for void (V~0~) and total volume (V~t~) were blue dextran and free \\[^35^S\\]sulphate, respectively. ",
"Furthermore, to determine if a size difference between the CSPGs isolated from Rottlerin-treated and untreated cells could be detected on SDS-PAGE, ^35^S-labelled CSPG (30000 cpm/well) was subjected to SDS-PAGE using either a 4--12% gradient gel or a 7.5% gel (as in the zymography experiments but without added gelatin). ",
"After the electrophoresis, the gel was soaked in Amplify and dried and \\[^35^S\\]CSPG was detected with autoradiography.",
"\n\nPurification of proMMP-9 from the THP-1 cells {#s2j}\n---------------------------------------------\n\nThe proMMP-9 in conditioned medium from the THP-1 cells was partly purified as described previously [@pone.0020616-Malla2].",
"\n\nChondroitin ABC lyase (cABC) treatment {#s2k}\n--------------------------------------\n\nThe PG bound CS-chains were removed by digestion for 2 h at 37°C with 0.2--1.0 units of cABC/ml in 0.05 M Tris-HCl, pH 8.0, containing 0.05 M sodium acetate.",
"\n\nGelatin zymography {#s2l}\n------------------\n\nSDS-substrate PAGE was done as described previously [@pone.0020616-Winberg1] with gels (7.5 cm × 8.5 cm × 0.75 mm) containing 0.1% (w/v) gelatin in both the stacking and separating gel, 4 and 7.5% (w/v) of polyacrylamide, respectively. ",
"Gelatinase activity was evident as cleared (unstained) regions, and the area of these regions was quantified by the GelBase/GelBlot™ Pro computer program from Ultra Violet Products.",
"\n\nWestern immunoblotting analysis of PKC and PKD isoforms {#s2m}\n-------------------------------------------------------\n\nImmunoreactive PKC and PKD isoforms were determined by immunoblotting of cytosol and plasma membrane preparations subjected to SDS-PAGE (NuPAGE Novex 4--12% Bis-Tris gels) before electroblotting to a polyvinyl difluoride (PVDF) membrane. ",
"Cytosolic and plasma membrane preparations were obtained as described above and a given amount of protein was loaded to the gels. ",
"After blockage of non-specific binding sites with non-fat milk in TBS-T (150 mM NaCl, 0.25% Tween-20, 20 mM Tris-HCL, pH 7.4) for 1 h at room temperature, a specified amount of cytosol and plasma membrane were incubated with antibodies against the PKC and PKD isoforms over night at 4°C. ",
"One blot for each PKC isoenzyme was also incubated with an antibody against ERK2 as an additional loading control. ",
"ERK2 has been shown to be unaffected by PMA and rottlerin [@pone.0020616-Bain1], [@pone.0020616-Kontny1] and is located both in the cytosol and at the plasma membrane [@pone.0020616-Kim1]. ",
"After the incubation with primary antibodies, the PVDF membranes were washed in TBS-T 3×5 min, and incubated with HRP-conjugated donkey anti-goat secondary antibody or goat anti-rabbit secondary antibody for 1 h and washed 3×5 min with TBS-T before visualization using a Western Blotting Luminol Reagent. ",
"The intensity of immunoblot bands was measured using a Luminescent Image Analyzer LAS-3000 with MultiGauge software version 3.0 (Fujifilm, Tokyo, Japan).",
"\n\nStatistical analysis {#s2n}\n--------------------\n\nIn all cases, at least three independent cell experiments were performed. ",
"Assays on all harvested media and cell fractions were performed in triplicate or more (unless otherwise stated) with data presented as mean ± S.D., using the Student *t* test.",
"\n\nResults {#s3}\n=======\n\nCell morphology and viability {#s3a}\n-----------------------------\n\nUntreated THP-1 cells cultured on plastic had a spherical morphology and were non-adherent. ",
"When the cells were exposed to the tumour promoting phorbol ester PMA they became adherent, more flattened and spread with pseudopodia. ",
"The other compounds used did not induce the same morphological changes. ",
"Similar observations for PMA treated THP-1 cells were previously described by Van Ranst and coworkers [@pone.0020616-VanRanst1].",
"\n\nPrior to examining the effect of the various compounds on the THP-1 cells synthesis of proMMP-9/CSPG heteromer, proMMP-9 and CSPG, we determined to which extent these compounds affected the cell viability. ",
"For this purpose two different methods were used, the MTS and Trypan Blue exclusion test. ",
"At the concentrations used (see methods), none of the following compounds (IL-1α, IL-1β, IL-3, IL-6, PGE~2~, TNF-α, bFGF and LPS) had any effect on the viability based on the MTS test. ",
"In contrast to this, a decrease in viability was observed when the cells were exposed to MCSF, ConA and PMA ([Fig. ",
"1A](#pone-0020616-g001){ref-type=\"fig\"}). ",
"In the case of PMA, the Trypan Blue exclusion test verified that PMA was slightly toxic to the cells. ",
"Four independent experiments where the THP-1 cells were cultured in the absence or presence of 10^−7^ M PMA for 24, 48 and 72 h resulted in 69±12, 55±12 and 56±14% (mean ± SD) of living cells in PMA exposed cultures. ",
"The percentage of dead cells (mean ± SD from four independent experiments) after 24, 48 and 72 h were 5±2, 6±3 and 8±5 in control cultures and 31±5, 45±13 and 44±6 in PMA exposed cultures.",
"\n\n{#pone-0020616-g001}\n\nThe two PKC inhibitors Gö6976 (25 nM) and Gö6983 (25 and 100 nM) had no effect on the cell viability neither in the absence or presence of 10^−7^ M PMA using the MTS test (data not shown). ",
"However, time- and dose-dependent studies with the PKC inhibitor Rottlerin in the absence or presence of PMA showed that Rottlerin was toxic for the cells as monitored by the MTS and the Trypan blue exclusion tests ([Figs. ",
"1B and C](#pone-0020616-g001){ref-type=\"fig\"})\n\nPMA stimulates the biosynthesis of the proMMP-9/CSPG heteromer in a time and concentration dependent manner {#s3b}\n-----------------------------------------------------------------------------------------------------------\n\nPMA is known to stimulate monocytic cell lines to increase the synthesis of MMPs [@pone.0020616-VanRanst1]--[@pone.0020616-Zhou1]. ",
"We therefore determined to what extent PMA could stimulate the biosynthesis of the proMMP-9/CSPG heteromer by THP-1 cells. ",
"In several independent experiments the biosynthesis of the proMMP-9/CSPG heteromers increased with increasing PMA concentrations with a peak at 10^−7^ M, and thereafter decreases with increasing PMA concentrations ([Fig. ",
"2A](#pone-0020616-g002){ref-type=\"fig\"}).",
"\n\n{ref-type=\"sec\"}. ",
"In (**A**), cells were incubated for 72 h in the presence of various concentrations of PMA as indicated. ",
"In (**B**), cells were incubated for various time periods (as indicated) in the absence or presence of 10^−7^ M PMA. ",
"The samples (containing CSPG and proMMP-9/CSPG complex) from cells not exposed to PMA were five times more concentrated than the samples from the PMA treated cells when applied to the gel. ",
"In (**C**), cells were either incubated for 72 h in the absence (−) or presence (+) of 10^−7^ M PMA at serum free conditions, or pre-incubated for 3 h in the absence (−) or presence (+) of 10^−7^ M PMA and/or 10% fetal calf serum. ",
"After the pre-incubation, cells were washed three times in PBS and thereafter incubated in serum free medium for 72 h. Arrowhead shows the border between the separating and stacking gel, and arrows show the position of the proMMP-9/CSPG complexes. ",
"Purified proMMP-9 was used as a standard and the position of the 225 kDa homodimer form is shown at the left. ",
"The gels are representative for several similar experiments.](pone.0020616.g002){#pone-0020616-g002}\n\nTo study the time dependency of the accumulation of the proMMP-9/CSPG heteromer in the culture medium, cells were cultured in the absence or presence of PMA (10^−7^ M) for 8 to 72 h before the amount of proMMP-9/CSPG heteromers was determined as described in [Materials and Methods](#s2){ref-type=\"sec\"}. [",
"Figure 2B](#pone-0020616-g002){ref-type=\"fig\"} shows that the heteromer can be detected already after 12 h from both untreated and PMA-treated cells, and that the amount of heteromer increased with time for at least 72 h. In other experiments with more material loaded to the gelatin zymography gel, it was shown that the complex could be detected already after 8 h from both untreated and PMA treated cells (data not shown).",
"\n\nAs it was shown that the proMMP-9/CSPG heteromer accumulated with time for at least 72 h in the PMA exposed cells, the question arise whether it is necessary with a continuous exposure to the phorbol ester. ",
"Cells were therefore primed with PMA for 3 h prior to the incubation for 72 h in the absence of PMA. ",
"In control cultures, PMA was present during the entire 72 h period. ",
"The cells produced comparable amounts of the heteromer whether the PMA was removed after 3 h or not ([Fig. ",
"2C](#pone-0020616-g002){ref-type=\"fig\"}). ",
"Likewise, whether pre-incubation of the cells with PMA occurred in serum or serum-free media had no detectable effect on the biosynthesis of the heteromer ([Fig. ",
"2C](#pone-0020616-g002){ref-type=\"fig\"}).",
"\n\nPMA stimulation affected the biosynthesis of the two components of the proMMP-9/CSPG heteromer differently {#s3c}\n----------------------------------------------------------------------------------------------------------\n\nPMA stimulation of the THP-1 cells resulted in a concentration ([Fig. ",
"3A](#pone-0020616-g003){ref-type=\"fig\"}) and time ([Fig. ",
"3B](#pone-0020616-g003){ref-type=\"fig\"}) dependent increase of proMMP-9 in the cell conditioned media. ",
"Likewise, the PMA induced synthesis of proMMP-9 continued after the removal of the phorbol ester ([Fig. ",
"3C](#pone-0020616-g003){ref-type=\"fig\"}). ",
"Whether pre-incubation of the cells with PMA occurred in serum or serum-free media had no detectable effect on the biosynthesis of the proMMP-9 monomer and homodimer ([Fig. ",
"3C](#pone-0020616-g003){ref-type=\"fig\"}).",
"\n\n![",
"Synthesis of proMMP-9 and CSPG in the absence and presence of PMA.\\\n**A**--**C**: Typical gelatin zymographies of 20 times diluted conditioned medium from THP-1 cells. **",
"A**: Cells were incubated for 72 h in the presence of various concentrations of PMA as indicated. **",
"B**: Cells were incubated for various time periods (as indicated) in the absence or presence of 10^−7^ M and 10^−5^ M PMA. **",
"C**: Cells were either incubated for 72 h in the absence (−) or presence (+) of 10^−7^ M PMA at serum free conditions, or pre-incubated for 3 h in the absence (−) or presence (+) of 10^−7^ M PMA and/or 10% fetal calf serum. ",
"After the pre-incubation, cells were washed three times in PBS and thereafter incubated in serum free medium for 72 h. **A--C**: The position of proMMP-9 homodimer (225 kDa), monomer (92 kDa) and proMMP-2 (72 kDa) standards is indicated. **",
"D** and **E**: Conditioned medium from THP-1 cells incubated with \\[^35^S\\]sulphate was passed over a G-50 Sepharose column in order to separate labelled macromolecules from free \\[^35^S\\]sulphate. ",
"The amount of labelled macromolecules was determined by counting the entire pass through fraction in a liquid scintillation spectrometer. **",
"D**: Cells were incubated in the absence or presence of various concentrations of PMA for 72 h as indicated and in (**E**) the cells were incubated for various time periods in the absence or presence of 10^−7^ M PMA. (**",
"D**: upper and lower panel) Results (mean ± s.d) were normalized against the control (without PMA). ",
"Lower panel, results were in addition normalized against the number of viable cells. **",
"E**: Results (mean ± s.d) are presented as cpm (upper panel) and cpm/viable cells (lower panel). ",
"The results in (**D**) and (**E**) are from a typical experiment with four parallels in (D) and three parallels in (E), where \\*p\\<0.05 compared to control without PMA.](pone.0020616.g003){#pone-0020616-g003}\n\nIn contrast to the PMA-induced increase in proMMP-9 and proMMP-9/CSPG synthesis, PMA reduced the amount of \\[^35^S\\]CSPG secreted into the medium in a concentration dependent manner ([Fig. ",
"3D](#pone-0020616-g003){ref-type=\"fig\"}, upper panel). ",
"However when the amount of secreted \\[^35^S\\]CSPG was normalized against the number of viable cells, a slight increase was observed in the PMA exposed cell cultures ([Fig. ",
"3D](#pone-0020616-g003){ref-type=\"fig\"}, lower panel). ",
"In both untreated and PMA treated cells, approximately 90% of the CSPG synthesized was secreted into the culture medium. ",
"The amount of CSPG in the culture medium increased with time in both the untreated and PMA treated cells. ",
"After 72 h the conditioned culture medium from control cells contained approximately 2.5 times more \\[^35^S\\]CSPG than the culture medium from PMA treated cells ([Fig. ",
"3E](#pone-0020616-g003){ref-type=\"fig\"}, upper panel). ",
"However when the amount of CSPG was normalized against the number of viable cells, a slight increase in \\[^35^S\\]CSPG was found in the culture medium from PMA treated cells at all time points ([Fig. ",
"3E](#pone-0020616-g003){ref-type=\"fig\"}, lower panel).",
"\n\nUntreated and PMA treated THP-1 cells express various PKC mRNA isoforms {#s3d}\n-----------------------------------------------------------------------\n\nPreviously it has been shown that undifferentiated THP-1 cells express the classical PKC isoforms α and β, novel PKC isoforms δ and ε and the atypical PKC ζ [@pone.0020616-Schwende1]. ",
"The same authors showed that PMA changed the expression of some of these PKC isoforms. ",
"As PMA is known to induce activation of various classical and novel PKC isoforms [@pone.0020616-Ron1], we have reinvestigated at the mRNA level which isoforms are produced by THP-1 cells in the presence and absence of PMA. ",
"This has extended the list of PKC isoforms present in these cells. ",
"As shown in [Figure 4](#pone-0020616-g004){ref-type=\"fig\"}, both untreated and PMA treated THP-1 cells contained mRNA for classical PKC isoforms α, βI and βII, novel PKC isoforms δ, ε and θ, atypical PKC ζ and ι as well as for PKD3 (PKCυ). ",
"The signals for PKC isoforms θ and γ were weak, and no mRNA could be detected for the PKC η, and the PKD isoforms 1 (PKC μ) and 2 ([Fig. ",
"4](#pone-0020616-g004){ref-type=\"fig\"}). ",
"As also shown in [Figure 4](#pone-0020616-g004){ref-type=\"fig\"}, exposure to PMA did not seem to affect the mRNA levels of the PKC isoforms in THP-1 cells.",
"\n\n{ref-type=\"sec\"}. ",
"Ladder is a marker with DNA fragments of known size (in bp).](pone.0020616.g004){#pone-0020616-g004}\n\nRottlerin blocks the biosynthesis of proMMP-9/CSPG, proMMP-9 and CSPG {#s3e}\n---------------------------------------------------------------------\n\nWe tested to what extent inhibitors of various PKC isoforms could block the PMA induced biosynthesis of the proMMP-9/CSPG complex. ",
"Neither 25 nM Gö6976 (inhibits PKC α, β1 and μ) nor 25--100 nM Gö6983 (inhibits PKC α, β1, γ, δ and ζ) affected the PMA induced biosynthesis of the proMMP-9/CSPG complex ([Fig. ",
"5A](#pone-0020616-g005){ref-type=\"fig\"}). ",
"Furthermore, these two PKC inhibitors did not affect the biosynthesis of the proMMP-9 monomer and homodimer ([Fig. ",
"5B](#pone-0020616-g005){ref-type=\"fig\"}).",
"\n\n{ref-type=\"sec\"} prior to gelatin zymography. ",
"To determine the effect of the inhibitors on the synthesised proMMP-9 (**B, D**), the harvested medium was diluted 20 times and then applied to gelatin zymography. ",
"Arrowhead shows the border between the separating and stacking gel and the position of purified proMMP-9 monomer (92 kDa) and proMMP-9 homodimer (225 kDa) used as a standard (Std) is shown.](pone.0020616.g005){#pone-0020616-g005}\n\nIn contrast to this, Rottlerin which is reported to be a specific inhibitor of the novel PKC δ and PKC θ [@pone.0020616-Kontny1], [@pone.0020616-Gschwendt1], [@pone.0020616-Springael1] blocked the biosynthesis of both the proMMP-9/CSPG complex and the proMMP-9 monomer (92 kDa) and homodimer (225 kDa). ",
"Rottlerin at a concentration of 5 µM blocked the synthesis in both the untreated and PMA treated cells ([Fig. ",
"5C and D](#pone-0020616-g005){ref-type=\"fig\"}). ",
"Since Rottlerin is toxic when THP-1 cells were exposed to the substance for more than 12 h ([Fig. ",
"1C](#pone-0020616-g001){ref-type=\"fig\"}), the culture medium containing proMMP-9/CSPG heteromer and the proMMP-9 monomer/homodimer was recovered after 12 h in these experiments.",
"\n\nWe have previously shown that ∼0.1% of the total amount of CSPGs sythesized by the THP-1 cells are proMMP-9/CSPG heteromers [@pone.0020616-Malla2]. ",
"Therefore, biosynthetic labelling of the CS-chains with either \\[^35^S\\]sulphate or \\[^3^H\\]glucosamine in the absence or presence of PMA and Rottlerin will reflect the latter compounds effect on the cells biosynthesis of CSPGs. ",
"The results revealed that the biosynthesis of the second component of the complex, the CSPG, was also inhibited by Rottlerin in a concentration dependent manner. ",
"As shown in [figures 6](#pone-0020616-g006){ref-type=\"fig\"}(A) and 6(B), the conditioned culture medium from cells exposed to Rottlerin contained less amounts of the \\[^35^S\\]sulphate and \\[^3^H\\]glucosamine labelled macromolecules than medium from cells not treated with Rottlerin. ",
"This effect of Rottlerin was seen in both the untreated and PMA treated cells. ",
"Since PGs are highly negatively charged molecules, the radioactively labelled macromolecules were subjected to Q-Sepharose chromatography. ",
"As shown in [Figure 6C](#pone-0020616-g006){ref-type=\"fig\"} (upper panel), all the ^35^S-labelled material was PGs as it was eluted with 0.7 M NaCl. ",
"Rottlerin did not affect the position of the eluted material, indicating that it did not affect the sulphate density of the GAG-chains. ",
"The use of ^3^H-labelled glucosamine showed that the majority of the radioactive sugar is incorporated in the PGs ([Fig. ",
"6C](#pone-0020616-g006){ref-type=\"fig\"}, lower panel), but a small amount is also eluted at around 0.3 M NaCl which is most likely hyaluronan and non-PG glycoproteins. ",
"The fractions eluted from the Q-Sepharose column at the position of PGs (∼0.7 M NaCl) were pooled and divided in three parts. ",
"One was treated with cABC to degrade CS-chains, another was treated with NaOH to liberate the CS-chains from the core protein and the third part was untreated (control). ",
"These fractions were applied to a Superose 6 column. ",
"As seen in [Figures 6(D)](#pone-0020616-g006){ref-type=\"fig\"} and 6(E), cABC totally degraded the GAG-chains to disaccharides showing that the radioactively labelled PGs were substituted with CS-chains. ",
"Furthermore, Rottlerin did not affect the type of GAG-chains synthesized. ",
"However, the size of the PGs synthesized by Rottlerin exposed cells was smaller than the PGs synthesized by the control cells. ",
"NaOH treatment of the material shows that also the size of the CS-chains was smaller in the Rottlerin treated material. ",
"Since free CS-chains with a molecular size less than 15 kDa would be expected to elute from the Q-Sepharose column at a lower NaCl concentration than CS-chains with equal charge density but with molecular size \\>20 kDa [@pone.0020616-Hallen1], [@pone.0020616-Kolset5], several experiments were performed with material from both the control and Rottlerin-exposed cells where the CSPG had been treated or not treated with NaOH. [",
"Figure 6F](#pone-0020616-g006){ref-type=\"fig\"} shows that the elution profile of the free CS-chains of the Rottlerin-treated and untreated materials superimposed on the corresponding intact PGs. ",
"In all cases, gel filtration on a Superose 6 column revealed that the CSPG from the Rottlerin exposed cells had a reduced size compared to the CSPG from the untreated cells, although the reduction in size varied from experiment to experiment. ",
"Thus, if there were some free CS-chains in the Rottlerin-treated material it was not possible to separate these chains from intact CSPGs by Q-Sepharose column chromatography at least during the conditions used in the present work. ",
"The reduced size of the CSPG from Rottlerin exposed cells compared to CSPG from the control cells was not detected when \\[^35^S\\]CSPG was subjected to SDS-PAGE (7.5% acrylamide) followed by autoradiography ([Fig. ",
"6F](#pone-0020616-g006){ref-type=\"fig\"}, upper panel). ",
"Both bands appeared at the top of the separating gel at a position that corresponded with the proMMP-9/CSPG complex seen in gelatin zymography. ",
"However when a 4--12% gradient gel was used, the reduced size of the CSPG from Rottlerin exposed cells was detected in spite of the smeared bands that appear due to the heterogenous size of the CS-chains ([Fig. ",
"6F](#pone-0020616-g006){ref-type=\"fig\"}, lower panel). ",
"In summary, Rottlerin treatment of the THP-1 cells was followed by a reduced synthesis of the proMMP-9/CSPG heteromer, both components in the heteromer as well as a reduced size of the CSPG and its CS chains.",
"\n\n![",
"Effect of Rottlerin on biosynthesis and molecular size of CSPG and the CS-chains.\\\n**A, B**: Cells in the absence (control) or presence of 10^−7^ M PMA were incubated with increasing concentrations of Rottlerin for 8 h and 23 h in serum free medium containing either \\[^35^S\\]sulphate (**A**) or \\[^3^H\\]glucosamine (**B**). ",
"A typical experiment is shown, where the results (total cpm not adjusted to the amount of living cells) are presented as mean ± s.d. (",
"n = 2). **",
"C**--**F**: Cells were incubated for 24 h in serum free medium containing either \\[^35^S\\]sulphate or \\[^3^H\\]glucosamine. **",
"C**: \\[^35^S\\]sulphate and \\[^3^H\\]glucosamine labelled macromolecules were applied to Q-Sepharose chromatography and the bound CSPG were eluted with a 0.15--1.5 M NaCl gradient (\\-\\-\\--) as shown in the upper graph. ",
"○, absence of Rottlerin; Δ, presence of 1 µM Rottlerin. **",
"D, E**: Eluted CSPG from the Q-Sepharose column was either untreated (solid line) or treated with cABC (\\-\\--) or 0.5 M NaOH (^.......^) prior to application on a Superose 6 gel chromatography column as described in [Material and Methods](#s2){ref-type=\"sec\"}. ",
"Cont., ",
"control without Rottlerin; Rotl., ",
"presence of 1 µM Rottlerin and Fr.",
"No., ",
"fraction number. **",
"F**: \\[^35^S\\]CSPG (•) and free \\[^35^S\\]CS-chains (○) from control and Rottlerin-treated cells were subjected to Q-Sepharose chromatography as in (C). ",
"Arrow shows the elution position of shark cartilage CS. **",
"G**: \\[^35^S\\]Sulphate labelled CSPG (isolated from control, PMA (10^−7^ M) and Rottlerin treated cells) was subjected to SDS-PAGE (upper panel: 4% stacking gel and 7.5% separating gel; lower panel: 4--12% gradient gel) followed by autoradiography (see [Materials and Methods](#s2){ref-type=\"sec\"}). ",
"An equal amount of radioactivity (based on scintillation counting) was loaded to each well in order to be able to compare the bands. ",
"Arrowhead shows the border between the separating and stacking gel and the position of molecular size markers are shown. ",
"Small arrow shows the bottom of the application well.](pone.0020616.g006){#pone-0020616-g006}\n\nRottlerin inhibits the activation of several PKC isoforms {#s3f}\n---------------------------------------------------------\n\nThe inhibitory effect of Rottlerin on the biosynthesis of proMMP-9, CSPG and proMMP-9/CSPG heteromer may be due to inhibition of PKC activation or factors downstream to PKC. ",
"We have therefore determined the amount of PKC in the cytosol and the plasma membrane fraction of untreated and PMA treated THP-1 cells. ",
"To ensure equal loading, the total amount of cytosol and membrane proteins were determined as described in [Materials and Methods](#s2){ref-type=\"sec\"}. ",
"As shown in [figure 7](#pone-0020616-g007){ref-type=\"fig\"}, PMA treatment of the cells resulted in decreased amounts of the classical and the novel PKCs in the cytosol as expected. ",
"PMA treatment resulted also in increased amounts of some PKCs to the plasma membranes. ",
"The presence of 5.0 µM Rottlerin resulted in a slight decrease in the amounts of the PKC isoenzymes δ, ε, θ and υ (PKD3; 100 kDa) bound to the plasma membranes in the PMA treated cells ([Fig. ",
"7](#pone-0020616-g007){ref-type=\"fig\"}). ",
"In the presence of Rottlerin, the PKC isoenzymes ε and θ showed a small increase in the cytosol of the PMA treated cells. ",
"In cells not exposed to PMA, the presence of Rottlerin resulted in a slightly increased amount of the PKC isoenzymes δ, ε and θ in the cytosol and a minor decrease in the plasma membrane ([Fig. ",
"7](#pone-0020616-g007){ref-type=\"fig\"}). ",
"MAPKAPK-2 is a mitogen-activated protein kinase expressed in THP-1 cells [@pone.0020616-Hendriks1]. ",
"Because PMA also can stimulate the activity of MAPKAPK-2 [@pone.0020616-Chevalier1], [@pone.0020616-Zu1], and Rottlerin is a potent inhibitor of MAPKAPK-2 (IC~50~ = 5.4 µM; [@pone.0020616-Davies1]), we examined whether PMA activated MAPKAPK-2 in THP-1 cells. ",
"No phosphorylation of MAPKAPK-2 at Thr-222 was detected in control cells or cell exposed to PMA, indicating that PMA did not activate MAPKAPK-2 in these cells (data not shown).",
"\n\n{#pone-0020616-g007}\n\nSeveral factors that have an effect on either the MMP-9 or CSPG biosynthesis have no or little effect on the biosynthesis of the proMMP-9/CSPG heteromer {#s3g}\n--------------------------------------------------------------------------------------------------------------------------------------------------------\n\nIn order to determine to what extent the heteromer biosynthesis could be induced by other biological factors than PMA, we investigated the effect of factors known to enhance MMP synthesis in various cell lines. ",
"Neither of the investigated factors did trigger a significant change in the synthesis of the proMMP-9/CSPG heteromer ([Fig. ",
"8A](#pone-0020616-g008){ref-type=\"fig\"}), although most of these compounds (TNF-α, M-CSF, IL-1α, IL-1β, IL-3, IL-6, LPS, PGE~2~ and ConA) caused an increase in the biosynthesis of proMMP-9 in a concentration dependent manner (data not shown). ",
"However, their stimulatory effect on proMMP-9 synthesis was 5--20 times less than the effect of PMA. ",
"No effect on the proMMP-9 synthesis was obtained with bFGF (data not shown).",
"\n\n{ref-type=\"sec\"}. ",
"Arrowhead shows the border between the separating and stacking gel and arrow shows the position of the 300 kDa proMMP-9/CSPG heteromer. ",
"The position of the pro-MMP-9 homodimer (225 kDa) is shown. **",
"B**: Cells were incubated with \\[^35^S\\]sulphate. ",
"The harvested serum free medium (open bars) and the lysed cell preparations (grey bars) were passed over a G-50 Sepharose column in order to separate labelled macromolecules from free \\[^35^S\\]sulphate. ",
"The entire pass through fraction that contains the labelled macromolecules was then counted in a liquid scintillation spectrometer. ",
"All results (mean ± s.d) were normalized against the controls, i.e. the synthesis in absence of added compounds. ",
"In lower panel with ConA and MCSF, the results were in addition normalized against the number of viable cells. ",
"The results in (**B**) are from a typical experiment with four parallels.](pone.0020616.g008){#pone-0020616-g008}\n\nConA reduced, whereas TNF-α, M-CSF, IL-3, IL-6 slightly increased the \\[^35^S\\]CSPG released into the culture media ([Fig. ",
"8B](#pone-0020616-g008){ref-type=\"fig\"}, upper panel). ",
"However, when the released \\[^35^S\\]CSPG was normalized against the number of viable cells, a large increase in the CSPG was observed ([Fig. ",
"8B](#pone-0020616-g008){ref-type=\"fig\"}, lower panel). ",
"No change in released CSPG occurred when the cells were exposed to LPS, bFGF, IL-1α, IL-1β or PGE~2~ (data not shown). ",
"Only ConA increased cell associated \\[^35^S\\]CSPG, while the other compounds showed a decrease or no change in cell associated CSPG ([Fig. ",
"8B](#pone-0020616-g008){ref-type=\"fig\"}).",
"\n\nDiscussion {#s4}\n==========\n\nPreviously we have shown that THP-1 cells produce a reduction sensitive complex between proMMP-9 and a CSPG core protein which may influence the tissue localization of the enzyme [@pone.0020616-Winberg1]. ",
"The formation of the proMMP-9/CSPG complex affects several properties of the enzyme, including activation and binding to collagen I and gelatin [@pone.0020616-Malla2], [@pone.0020616-Winberg2]. ",
"Furthermore, we have shown that the CSPG core protein binds to both the hemopexin domain and the fibronectin-like repeats in the catalytic domain of the enzyme. ",
"The latter interaction prevented the enzyme from binding directly to collagen and gelatin [@pone.0020616-Malla2], which is important for the gelatinases ability to degrade gelatin [@pone.0020616-Allan1]--[@pone.0020616-Xu2]. ",
"An increasing number of studies reveal that processing and degradation of protein and peptide substrates by various MMPs requires that the substrates not only interact with the active site but also regions outside the active site, referred to as noncatalytic sites or exosites [@pone.0020616-Murphy2]--[@pone.0020616-Overall2]. ",
"In addition, the cellular and tissue localization of an individual MMP along with available substrates in its immediate environment may either prevent or promote disease progression [@pone.0020616-Cawston1], [@pone.0020616-Duffy1]--[@pone.0020616-Rundhaug1]. ",
"With respect to development of new drugs, it is therefore important to consider whether an enzyme or enzyme activity represent a target or anti-target. ",
"The development of new inhibitors against MMPs requires knowledge of specific exosites for different substrates and whether a given MMP forms complexes with other molecules that either block such exosites or create new exosites that may involve both the MMP and its binding partner. ",
"In the present study our aim was to determine how different factors, known to affect the synthesis of MMP-9 or CSPG, influence the formation of the proMMP-9/CSPG complex in THP-1 cells. ",
"Knowledge of how various factors affect the cellular synthesis of this complex and its individual components is important for the understanding of putative biological conditions promoting complex formation, as well as insight in the mechanism behind the formation of the complex.",
"\n\nIn the present work it is shown that 10^−9^ to 10^−7^ M PMA strongly upregulates the THP-1 cells synthesis of the proMMP-9/CSPG heteromer and the proMMP-9 monomer and homodimer. ",
"However, these concentrations of PMA were also associated with some cell death. ",
"In a previous study on THP-1 cells [@pone.0020616-VanRanst1] it was shown that PMA (10^−9^--10^−7^ M) induced the synthesis of MMP-9 in a time and concentration dependent manner similar to the observations in the present work. ",
"In contrast to our work, the authors did not observe that PMA induced differentiation was accompanied by any cell death. ",
"The reason for this discrepancy is not known. ",
"The observed cell death in the present work may suggest that the PMA induced increase in secreted proMMP-9/CSPG, proMMP-9 and CSPG is a result of release of intracellular stored molecules from dying cells. ",
"Several independent facts strongly argue against this possibility. (",
"1) THP-1 cells and other monocytic cell lines do not store MMPs or other secretory proteins in granules. (",
"2) Van Ranst and coworkers [@pone.0020616-VanRanst1] showed that PMA treatment of THP-1 cells resulted in a steady state increase in MMP-9 mRNA for at least up to 48 h corresponding to the increase in secreted MMP-9. (",
"3) In the present work it is shown that only 10% of the synthesized CSPG is associated with the cells, which confirms that CSPG is constitutively secreted in monocytes and macrophages [@pone.0020616-UhlinHansen1]. (",
"4) Gelatin zymography of lysed THP-1 cells shows a band at around 80 kDa that is approximately 100 times more intense than the 92 kDa MMP-9 band (data not shown). ",
"This 80 kDa band is not seen in the cell conditioned media. ",
"Therefore, it can be concluded that the effect of PMA on the amount of the proMMP-9/CSPG heteromer, proMMP-9 and CSPG secreted into the conditioned medium is due to an altered biosynthesis, which will be discussed below.",
"\n\nIn this study we show that the proMMP-9/CSPG complex, proMMP-9 and CSPG increases with time in the cell conditioned media from both unstimulated and PMA stimulated THP-1 cells. ",
"Whether PMA was removed already after three hours, or if it was present during the entire incubation time of 72 h did not affect the synthesis of the proMMP-9/CSPG complex and proMMP-9. ",
"Previously it has been shown for some cell types that prolonged incubation with PMA desensitizes cells and results in a down regulation of activated PKCs [@pone.0020616-Liu1]. ",
"The present work shows that prolonged incubation of THP-1 cells with PMA does not necessarily down regulate the PKCs and other factors involved in the induction of the cells synthesis of the proMMP-9/CSPG complex and proMMP-9. ",
"As extended exposure of cells to Rottlerin was toxic at concentrations above 5 µM, we could not incubate the cells in the presence of this compound for more than 8 hours in order to detect any effect on the activation of PKCs. ",
"However, this will give a reliable picture on the role of PKC isoenzymes in the synthesis of the proMMP-9/CSPG complex and proMMP-9 since it was sufficient to prime the cells for three hours with PMA in order to induce a prolonged increase in the cell synthesis of MMP-9 and its complex with CSPG.",
"\n\nAs PMA induces activation of the classical and novel PKCs [@pone.0020616-Ron1], [@pone.0020616-Liu1], it can be assumed that one or several of these PKCs are involved in the PMA induced changes in the synthesis of proMMP-9/CSPG, proMMP-9, and CSPG by THP-1 cells. ",
"This assumption is supported by a previous work on THP-1 cells where it was shown that PMA induced synthesis of MMP-9 was not due to activation of PKA or increase in intracellular calcium [@pone.0020616-VanRanst1]. ",
"Treatment of the THP-1 cells with the PKC inhibitors Gö6976 and Gö6983 reveals that the PMA induced synthesis of proMMP-9 and its complex with CSPG is independent of the PMA induced activation of PKC α, β or δ. ",
"Hence, the PMA induced synthesis is most likely due to the activation of one or several of the PKC isoforms ε, θ or υ (PKD3).",
"\n\nRottlerin inhibited the synthesis of the proMMP-9/CSPG heteromer, proMMP-9 and CSPG in both the PMA treated and untreated THP-1 cells. ",
"Previously it has been shown that Rottlerin influences various cellular processes such as mitochondrial respiration [@pone.0020616-Soltoff1], cell growth and viability [@pone.0020616-Parmer1], cell cycle distribution [@pone.0020616-Parmer1], generation of superoxide [@pone.0020616-Takizawa1], signalling events and cytokine production [@pone.0020616-Kontny1] as well as macropinocytosis [@pone.0020616-Sarkar1]. ",
"Rottlerin has been assumed to be a specific inhibitor of the two novel PKCs δ and θ [@pone.0020616-Kontny1], [@pone.0020616-Gschwendt1], [@pone.0020616-Springael1], although this has been disputed [@pone.0020616-Davies1], [@pone.0020616-Soltoff1]. ",
"Activation of PKC is known to be associated with phosphorylation and transfer of the activated enzyme from the cytosol to various membrane fractions. ",
"The nature of the membrane fraction to which an activated PKC is translocated depends on the stimulatory conditions used [@pone.0020616-Mosior1]--[@pone.0020616-Shirai2]. ",
"Analysis of both the cytosol and the plasma membrane fraction should reveal whether or not Rottlerin inhibits the activation of a given PKC isoform. ",
"Inhibition should result in a decreased amount of the PKC in the plasma membrane fraction (if the activated form is bound to this membrane fraction) and an increased amount in the cytosol fraction. ",
"In the present study we show that under the conditions used, 5 µM Rottlerin inhibited the synthesis of the MMP-9/CSPG heteromer and proMMP-9. ",
"However, Rottlerin only slightly reduced the PMA induced activation of the PKC isoforms δ, θ and υ (PKD3) as well as the activated forms of PKC δ, θ and ε in the PMA untreated THP-1 cells. ",
"Thus it is not possible to conclude whether or to what extent these PKC isoenzymes are involved in the PMA induced synthesis of proMMP-9 and its complex with CSPG. ",
"Furthermore, PMA did not cause phosphorylation/activation of MAPKAPK-2, jeopardizing a role of MAPKAPK2 in PMA-triggered proMMP-9/CSPG synthesis. ",
"Therefore, the Rottlerin sensitivity of the synthesis of MMP-9 and its complex formation with CSPG in both the unstimulated and PMA stimulated cells may be due to Rottlerin acting on enzymes downstream the PKC isoforms δ, θ, ε and υ (PKD3) and/or on an alternative PMA induced PKC independent pathway. ",
"Indeed, Rottlerin has been demonstrated to inhibit the enzymatic activity of several other protein kinases [@pone.0020616-Bain1] and PMA can enhance expression of several proteins in what was suggested to be in a PKC-independent pathway [@pone.0020616-Conquer1]--[@pone.0020616-Malakooti1].",
"\n\nAs for the synthesis of MMP-9, the synthesis of CSPG was reduced in the presence of Rottlerin. ",
"However, the synthesis of CSPG was reduced at concentrations of Rottlerin (0.5 to 1.0 µM) that did not affect the synthesis of the MMP-9/CSPG heteromer and proMMP-9. ",
"This suggests that the signalling pathway involved in the synthesis of CSPG is different from the one involved in the synthesis of the proMMP-9/CSPG heteromer and proMMP-9. ",
"Furthermore, at least a part of the Rottlerin induced reduction in CSPG ([Figs. ",
"6A,B](#pone-0020616-g006){ref-type=\"fig\"}) can be ascribed to the formation of PG core proteins containing shorter CS-chains compared to untreated controls. ",
"This was reflected in CSPG molecules with smaller molecular mass than the CSPGs produced in the absence of Rottlerin ([Figs. ",
"6D and E](#pone-0020616-g006){ref-type=\"fig\"}). ",
"Although the Rottlerin treated cells produced CSPGs with shorter CS-chains, there was no significant difference in charge density between the CSPGs from the untreated and Rottlerin treated cells. ",
"This was demonstrated by a similar elution profile from the Q-Sepharose column, where the CSPG from both the Rottlerin-treated and untreated cells were eluted at approximately 0.7 M NaCl ([Fig. ",
"6C](#pone-0020616-g006){ref-type=\"fig\"}). ",
"This suggests that Rottlerin inhibits one or several of the enzymes involved in CS-chain elongation and termination. ",
"In contrast to this, it appears that Rottlerin has no effect on the enzymes involved in the glycosylation of proMMP-9, as gelatin zymography of cell conditioned media did not reveal active bands with lower molecular mass than 92 kDa, but only less amounts of the 92 kDa form. ",
"There was no reduction in the amount of proMMP-9/CSPG heteromer formed in the presence of 1.0 µM Rottlerin compared to control ([Fig. ",
"5C](#pone-0020616-g005){ref-type=\"fig\"}). ",
"This suggests that Rottlerin only affected the size of CS-chains bound to the PG core proteins but had no effect on the amount or types of core proteins produced, or at least no changes in those PGs involved in the complex formation with proMMP-9.",
"\n\nPMA mimics diacylglycerol and in addition to the activation of the classical and novel PKCs, the Raf/MEK/ERK, JNK, p38/MAPKAPK2 and NFκB pathways can also be activated [@pone.0020616-Brose1]-[@pone.0020616-Traore1]. ",
"This results in the regulation of several genes, such as MMP-9, TNF-α, IL-1β and PGE~2~ [@pone.0020616-VanRanst1], [@pone.0020616-Schwende1], [@pone.0020616-Dieter1], [@pone.0020616-Siljander1]. ",
"Several of the compounds used like LPS, ConA, M-CSF and IL-1β are known to activate at least one of the following regulators and transcription factors, TNF-α, NFκB, IRAK, ERK 1/2, p38, JNK, SAPK and PGE~2~ [@pone.0020616-Kontny1], [@pone.0020616-Cuschieri1]--[@pone.0020616-Turner1]. ",
"Of the compounds used in the present work, PMA induced the largest increase in the synthesis of proMMP-9 and was the only agent that stimulated the synthesis of the proMMP-9/CSPG complex. ",
"This suggests that the pathways induced by TNF-α, M-CSF, IL-1α, IL-1β, IL-3, IL-6, LPS, PGE~2~ and ConA alone are not sufficient to increase the synthesis of the proMMP-9/CSPG complex in THP-1 cells. ",
"The difference in response between PMA and the other compounds mentioned above may be due to different types of CSPG core proteins synthesized and/or the synthesis of other molecules which prevent proMMP-9/CSPG complex formation. ",
"Several studies have shown a synergetic effect between various factors such as cytokines, growth factors and lipopolysaccharides in the regulation of MMPs [@pone.0020616-Cawston2]--[@pone.0020616-Uttamsingh1]. ",
"Therefore, it cannot be excluded that several of the compounds used in the present study must act together in order to stimulate the synthesis of the proMMP-9/CSPG complex.",
"\n\nOur previous studies have revealed that the assembly of proMMP-9 and the core protein of one or several CSPGs must occur either inside the cells during the synthesis or in the extracellular microenvironment [@pone.0020616-Winberg1]. ",
"Recently we have found that the proMMP-9/CSPG complex can be reconstituted *in vitro*, and that the strong reduction sensitive interaction between the two molecules was not due to a disulfide bridge between the molecules (Malla N et al, unpublished). ",
"In all tissues, including tumours, there is a mixture of different cell types. ",
"If the proMMP-9/CSPG complex also can be formed in the extracellular environment, different cell types may contribute to the formation of this complex by producing one or both of the components of the heteromer. ",
"Thus the presence of a given CSPG in a tissue may affect the localization of proMMP-9. ",
"Since we previously showed the formation of the proMMP-9/CSPG complex affects several properties of the enzyme, including activation and binding to collagen I and gelatin [@pone.0020616-Malla2], [@pone.0020616-Winberg2], the presence of a given CSPG in a tissue may also influence the activation and the proteolytic capacity of the enzyme. ",
"Based on our knowledge of MMP-9 and PGs in physiological and pathological processes, as well as the role of exosites in substrate cleavage [@pone.0020616-Kolset2], [@pone.0020616-Theocharis1], [@pone.0020616-Malla1], [@pone.0020616-Bannikov1]--[@pone.0020616-Yan1], one can not underestimate the putative biological role of an MMP-9/CSPG complex.",
"\n\nThe authors thank Dr. J. Van Lint for kindly providing the anti-PKD3 antibodies and Dr. K. Nilsson for the kind gift of the THP-1 cell line.",
"\n\n**Competing Interests:**The authors have declared that no competing interests exist.",
"\n\n**Funding:**This work was supported in part by grants from The Research Council of Norway, The Norwegian Cancer Society, and The Erna and Olav Aakre Foundation for Cancer Research. ",
"The funders had no role in the study design, data collection, analysis, decision to publish or preparation of the manuscript.",
"\n\n[^1]: Conceived and designed the experiments: NM EB UM LU-H J-OW. ",
"Performed the experiments: NM EB. ",
"Analyzed the data: NM EB UM LU-H J-OW. ",
"Contributed reagents/materials/analysis tools: UM LU-H J-OW. ",
"Wrote the paper: NM UM LU-H J-OW.",
"\n"
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[
"Weitgehend von der Öffentlichkeit unbeachtet hat sich am vergangenen Freitag der Bundesrat mit dem Entwurf eines erweiterten TK-Endgerätegesetzes beschäftigt und zu diesem Stellung genommen. ",
"Gegenstand ist ein Gesetzentwurf, der allen Verbrauchern eine freie Gerätewahl für den Internet-Zugang ermöglichen soll.",
"\n\nAuslöser sind Netzbetreiber und Provider, die \"ausschließlich eigene Router am Breitbandanschluss von Verbrauchern zulassen\", schreibt das federführende Bundesministerium für Wirtschaft und Energie (BMWi). ",
"Zugleich will das BMWi mit dem Entwurf mehr Wettbewerb schaffen. ",
"Zu den schwarzen Schafen der Branche gehören überwiegend Kabelnetzbetreiber wie Unity Media, aber auch Telefónica und andere DSL-Anbieter.",
"\n\nGegen freie Gerätewahl\n\nNachdem die EU und zuletzt auch das Bundeskabinett den Gesetzentwurf zur freien Routerwahl beschlossen hatten, schien die Verabschiedung im Bundesrat nur noch Formsache. ",
"Doch nun reicht der Bundesrat den Entwurf mit seiner Stellungnahme praktisch an das BMWi zurück. ",
"Mit der Stellungnahme zweifelt er zwei Kernpunkte des Entwurfs an – bezeichnenderweise gerade die beiden, die die freie Gerätewahl unabhängig von der Anschlussart gewährleisten sollen. ",
"Mit dem ersten Punkt bittet der Bundesrat zu prüfen, ob \"für den Anschluss von Telekommunikationsendeinrichtungen an das öffentliche Telefonnetz nach § 11 Absatz 3 FTEG die Festlegung weitergehender Anforderungen erforderlich ist\".",
"\n\nDas klingt gerade so, als hätten die Abgeordneten des Bundesrats die zahlreichen Diskussionen und fachlich begründeten Entscheidungen der letzten Monate nicht mitbekommen. ",
"Die Definition neuer Anforderungen, musste das BMWi nach zäher Diskussion mit der Bundesnetzagentur in Angriff nehmen, um das Ziel der Koalition, eben die freie Routerwahl zu erreichen. ",
"Die Bundesnetzagentur wollte den Routerzwang ursprünglich mit einer einfachen Richtlinie abschaffen, weigerte sich dann jedoch. ",
"Fast wäre dabei das Ziel der Koalition ins Gegenteil verdreht worden. ",
"Resultat des Zwists ist nun der Gesetzentwurf.",
"\n\nBundesrat als Büttel\n\nDer zweite Prüfauftrag macht deutlich, auf welchen und wessen Vorstellungen die erneuten Einwände gründen. ",
"Darin fragt der Bundesrat, ob \"die Definition des Endpunkts des öffentlichen Telefonnetzes als passiver Netzabschlusspunkt nach § 45d Absatz 1 TKG an die technischen Gegebenheiten von Fibre-to-the-Home-Netzen sowie von Kabelnetzen angepasst ist oder ob die Definition entsprechend erweitert werden muss\".",
"\n\nÜbersetzt heisst das: Der Bundesrat folgt den Argumenten von Netzbetreibern, die sich händeringend eine abweichende Definition des Netzabschlusspunkts für Kabel- und Glasfasernetze wünschen. ",
"Letztlich hängt nämlich die freie Gerätewahl an der Position des Netzabschlusspunkts: Liegt dieser in der Hand des Netzbetreibers, kann er frei über ihn verfügen und damit den Teilnehmern den Router vorschreiben.",
"\n\nManche Netzbetreiber verfechten diesen Ansatz energisch, weil sie Hotline-Kosten sparen, zusätzliche Einnahmen über den Geräteverkauf erzielen und über die Nutzung von Diensten nach Gutsherrenart verfügen können (z. B. WLAN nur gegen zusätzliche Gebühren freischalten). ",
"Stichhaltige technische Begründungen haben sie in der Diskussion bisher nicht gebracht – aber zahlreiche vorgebracht, die einer näheren Prüfung nicht standhielten.",
"\n\nDer aktuelle Gesetzentwurf folgt hingegen der allgemein anerkannten und technisch fundierten Auffassung, nach der der Abschlusspunkt nicht zum Netz des Betreibers gehört und damit der Teilnehmer selbst entscheidet, welchen Router er daran betreiben will.",
"\n\nWirtschaftsausschuss und technischer Sachverstand\n\nMit den Prüfaufträgen folgt der Bundesrat einer Beschlussempfehlung vom 11. ",
"September. ",
"Diese hatte eigenartigerweise der Wirtschaftsausschuss des Bundesrats vorgelegt. ",
"Von einem Wirtschaftsausschuss würde man technischen Sachverstand jedoch nicht ohne Weiteres erwarten. ",
"Der Inhalt der Empfehlung eignet sich denn auch nicht, Sachverstand zu unterstellen. ",
"Die Autoren führen darin keine eigenen Einwände ins Feld, sondern zittieren nicht genannte \"Branchenverbände\", offenbar ohne deren Einwände selbst hinreichend zu prüfen.",
"\n\nStellvertretend für mehrere technisch unzulängliche Argumentationsversuche gegen den Gesetzentwurf seien hier zwei Beispiele aufgeführt: Durch die Verwendung inkompatibler Endgeräte könne laut dem Ausschuss \"die Erreichung der vertraglich vereinbarten Datenübertragungsrate nicht sichergestellt werden\" und \"durch die Verwendung nicht funktionaler Endgeräte\" könnten \"Störungen im Telekommunikationsnetz des Netzbetreibers verursacht werden\".",
"\n\nUm die Punkte zu widerlegen, genügt indes schon ein wenig Erfahrung. ",
"Beispielsweise sichern sich Netzbetreiber und Provider ohnehin schon vertraglich gegen Leistungseinschränkungen ab, die durch externe Faktoren verursacht werden könnten – oder mit anderen Worten: Sie billigen schon jetzt Geschwindigkeitseinbußen und weisen die Verantwortung dafür von sich. ",
"Das betrifft beispielsweise die Leistung von Verbindungsnetzen, aber auch die Leistung der Gegenstelle, also die vom Teilnehmer eingesetzte Hard- und Software.",
"\n\nWas den Einwand angeht, die Netze seien durch Störungen gefährdet, muss man sich lediglich vor Augen führen, dass für den ISDN- und DSL-Bereich die freie Gerätewahl seit Jahrzehnten gilt. ",
"Und im Mobilfunkbereich ist die Anzahl der verschiedenen, frei am Markt erhätlichen Geräte schier unüberschaubar. ",
"Bisher sind keine durch fehlerhafte oder inkompatible Endgeräte hervorgerufene Störungen der Netze bekannt geworden. ",
"Im Ausland laufen jedoch seit Jahren schon diverse Kabelnetze mit Routern vom freien Markt, etwa in den USA.",
"\n\nAmnesie und Widersprüche\n\nGleichwohl registrieren Betreiber auch in Kabelnetzen Fehler und Ausfälle. ",
"Diese rühren aber hauptsächlich von mechanisch und elektrisch mangelhaften Anschlusskabeln, Dosen und Verteileranlagen, von elektromagnetischer Strahlung etwa durch den Amateurfunk oder LTE-Mobilfunk, teilweise auch noch von älteren, in der Bandbreite nicht angepassten Verstärkern.",
"\n\nAber die sachlich klarsten Argumente, die den Betrieb frei gewählter Router stützten, liefern sogar die Kabelnetzbetreiber selbst. ",
"Diese stecken in den Spezifikationen für Kommunikationsgeräte, die eine Störungsfreiheit von den Produkten fordern. ",
"Für Geräte, die an Kabelnetzen betrieben werden (also im Betreibernetz oder beim Teilnehmer), gibt es teils eigene Spezifikationen. ",
"Ein Beispiel ist der ITU-Standard J.112 G.112 (Abschnitt 4.2.2, Compatibility with other services und Abschnitt 4.2.3, Fault isolation impact on other users). ",
"Ein Kabel-Endgerät darf damit explizit keine Dienste auf dem Koaxialkabel negativ beeinflussen. ",
"Solche Normen entwickeln Netzbetreiber zusammen mit Herstellern unter dem Dach von Normungsinstituten und danach fertigen Chip-Hersteller, Netzwerkzulieferer und Engerätehersteller auch Router.",
"\n\n[Update]: 29.9.2015, 10:09, ITU-Spezifikation korrigiert, Link ergänzt [/Update] (dz)"
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"Top 10 Tom Cruise Performances\n\n10. \"",
"Knight and Day\" (2010)\n\nThe role: Lovestruck spy Roy MillerNominated for: nothingWon: nothingThoughts: No, this isn't a joke. ",
"Cruise is on full tilt in \"Knight and Day,\" the absolute commitment really striking amid the chaos of a mediocre (if over-maligned) action comedy. ",
"And that's been a hallmark of Cruise's career, turning nothing into something. ",
"It's what carried him through four \"Mission: Impossible\" movies and here, it was just fun to watch."
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[
"Log in\n\nSearch\n\nCrass politicking threatens Ontarians' retirement security: Unifor\n\nTORONTO, July 30, 2015 /CNW/ - Unifor is reiterating its call on the\nConservative government to support the creation of a provincial pension\nplan.",
"\n\n\"Prime Minister Harper's refusal to enter a service agreement to support\nthe implementation of the Ontario Retirement Pension Plan (ORPP) is\nundermining the retirement security and democratic will of the people\nof Ontario,\" said Ontario Regional Director Katha Fortier.",
"\n\nToday, the Ontario government called on the federal government\nto reverse its position not to help implement the ORPP, noting that\nthere are at least 28 CRA administered programs and 88 data exchange\nagreements that exist between the federal and provincial governments.",
"\n\n\"This is not a special request,\" said Fortier. \"",
"Establishing a contract\nwith the federal government to assist with the implementation of the\nORPP would be similar to at least 100 other current contracts. ",
"It is\nvery upsetting to see the crassest political games threaten Ontarians'\nretirement security.\"",
"\n\nUnifor has been a strong supporter of the ORPP, as a first step to\nexpanding the CPP. ",
"The Harper government has opposed any plan to expand\npublic pensions.",
"\n\nFortier said Unifor will continue to push for a mandatory, universal,\ndefined benefit ORPP that mirrors the CPP/QPP.",
"\n\nFor more on Unifor's ORPP and CPP efforts, go to\nunifor.org/pensionscampaign.",
"\n\nUnifor is Canada's largest union in the private sector, representing\nmore than 305,000 workers, including 158,000 in Ontario. ",
"It was formed\nLabour Day weekend 2013 when the Canadian Auto Workers and the\nCommunications, Energy and Paperworkers union merged."
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"Q:\n\nfatal error: Destructor cannot take arguments\n\ni'am newbie in programming...\ni try to call webservice from android. ",
"but i have fatal error there.",
"\n1.this is android coding \npublic class UserFunction {\n private JSONParser jsonParser;\n\n private static String LoginURL=\"http://10.0.2.2/android/include/index.php\";\n private static String RegisterURL=\"http://10.0.2.2/android/include/index.php\";\n\n private static String login_tag=\"login\";\n private static String register_tag=\"register\";\n\n public UserFunction(){\n jsonParser=new JSONParser();\n }\n\n public JSONObject loginUser(String email, String password){\n //building parameter\n List<NameValuePair> params= new ArrayList<NameValuePair>();\n params.add(new BasicNameValuePair(\"tag\", login_tag));\n params.add(new BasicNameValuePair(\"email\", email));\n params.add(new BasicNameValuePair(\"password\", password));\n JSONObject json=jsonParser.getJSONFromUrl(LoginURL, params);\n\n return json;\n }\n\n public JSONObject registerUser(String email, String name, String password){\n //building parameter\n List<NameValuePair> params= new ArrayList<NameValuePair>();\n params.add(new BasicNameValuePair(\"tag\", login_tag));\n params.add(new BasicNameValuePair(\"name\", name));\n params.add(new BasicNameValuePair(\"email\", email));\n params.add(new BasicNameValuePair(\"password\", password));\n //getting JSONObject\n JSONObject json=jsonParser.getJSONFromUrl(RegisterURL, params);\n\n return json;\n }\n\n public boolean isUserLoggedIn(Context context){\n DatabaseHandler db= new DatabaseHandler(context);\n int count=db.getRowCount();\n if(count>0){\n return true;\n }\n return false;\n }\n\n public boolean logoutUser(Context context){\n DatabaseHandler db=new DatabaseHandler(context);\n db.resetTable();\n return false; \n }\n}\n\n2.this is index.php\nif(isset($_POST['tag'])&& $_POST['tag'] !",
"=''){\n //get tag\n $tag=$_POST['tag'];\n\n //include DB handler\n require_once ('DB_Functions.php');//ganti include\n $db=new DB_Functions();\n\n //response array\n $response=array (\"tag\"=> $tag, \"Success\"=>0, \"error\"=>0);\n\n //check 4 tag type\n if($tag='login'){\n //req type is check login\n $email=$_POST['email'];\n $password=$_POST['password'];\n\n //check 4 user\n $user=$db->GetUserByEmailAndPassword($email, $password);\n if($user !",
"=false){\n /* user found\n * echo JSON with Success =1 */\n $response [\"Success\"]=1;\n $response[\"uid\"]=$user[\"unique_id\"];\n $response [\"user\"][\"name\"]=$user[\"name\"];\n $response[\"user\"][\"email\"]=$user[\"email\"];\n $response [\"user\"][\"created_at\"]=$user[\"created_at\"];\n $response[\"user\"][\"updated_at\"]=$user[\"updated_at\"];\n echo json_encode($response);\n }\n else{\n /* user not found\n * echo JSON with error =1 */\n $response [\"Error\"]=1;\n $response[\"error_msg\"]=\"INCORRECT EMAIL OR PASSWORD!!!\";",
"\n echo json_encode($response);\n }\n }\n else if($tag=='register'){\n //req type is register new user\n $name=$_POST['name'];\n $email=$_POST['email'];\n $password=$_POST['password'];\n\n //check if user already existed\n if($db->IsUserExisted($email)){\n //user is already existed - error response\n $response[\"error\"]=2;\n $response[\"error_msg\"]=\"USER IS ALREADY EXISTS\";\n echo json_encode($response);\n }\n else{\n //store user\n $user=$db->StoreUser($name, $email, $password);\n if($user){\n //user stored successfull\n $response [\"Success\"]=1;\n $response[\"uid\"]=$user[\"unique_id\"];\n $response [\"user\"][\"name\"]=$user[\"name\"];\n $response[\"user\"][\"email\"]=$user[\"email\"];\n $response [\"user\"][\"created_at\"]=$user[\"created_at\"];\n $response[\"user\"][\"updated_at\"]=$user[\"updated_at\"];\n echo json_encode($response);\n }\n else{\n //user failed to store\n $response [\"Error\"]=1;\n $response[\"error_msg\"]=\"ERROR OCCURED IN REGISTRATION\";\n echo json_encode($response);\n }\n }\n }\n else{\n echo \"INVALID REQUEST\";\n }\n }\n else{\n echo \"ACCESS DENIED\";\n }\n?",
">\n\n3. ",
"this is DB_Functions.php\n<?",
"php\n class DB_Functions{\n private $db;\n /*constructor*/\n function __construct($db){\n require_once ('DB_Connect.php');//ganti include\n /*connecting DB*/\n $this->db= new DB_Connect();\n $this->db->connect();\n }\n /*destructor*/\n function __destruct($db){\n }\n\n /*\n *storing new user\n *returning user detail\n */\n\n public function StoreUser($name, $email, $password){\n $uuid= uniqid('',true);\n $hash= $this->hashSSHA($password);\n $encrypted_password= $hash[\"encrypted\"]; //encripted password\n $salt=$hash[\"salt\"];//salt\n $result=mysql_query(\"INSERT INTO account_users(unique_id, name, email, encrypted_password, salt, created_at) VALUES ('$uuid','$name','$email','$encrypted_password','$salt',NOW())\");\n /*check for succesfull store*/\n if($result){\n /*get user detail*/\n $uid= mysql_insert_id();\n $result= mysql_query(\"SELECT * FROM account_users WHERE uid='$uid'\");\n /*return user detail*/\n return mysql_fetch_array($result);\n }\n else{\n return false;\n }\n }\n /*\n *get user by email & password\n */\n\n public function GetUserByEmailAndPassword($email, $password){\n $result=mysql_query(\"SELECT * FROM account_users WHERE email='$email'\") or die (mysql_error());\n //check 4 result\n $no_of_rows=mysql_num_rows($result);\n if($no_of_rows>0){\n $result=mysql_fetch_array($result);\n $salt=$result['salt'];\n $encrypted_password=$result['encrypted_password'];\n $hash=$this->checkhashSSHA($salt, $password);\n //check pass equality\n if($encrypted_password==$hash){\n //user auth are correct\n return $result;\n }\n }\n else{\n //user not found\n return false;\n }\n }\n\n /*\n *check user existed or not\n */\n public function IsUserExisted($email){\n $result=mysql_query(\"SELECT email FROM account_users WHERE email='$email'\");\n $no_of_rows=mysql_num_rows($result);\n if($no_of_rows>0){\n //user existed\n return true;\n }\n else{\n //user not existed\n return false;\n }\n }\n /*\n *encrypting pass\n *@param pass\n *return salt & encrpted pass\n */\n public function hashSHHA($password){\n $salt=sha1(rand());\n $salt=substr($salt, 0, 10);\n $encrypted= base64_encode(sha1($password.$salt, true).$salt);\n $hash=array(\"salt\"=> $salt, \"encrypted\"=> $encrypted);\n return $hash();\n }\n /*\n *decrypting pass\n *@param salt, pass\n *return hash string\n */\n public function CheckHashSSHA($salt, $password){\n $hash=base64_encode(sha1($password.$salt, true).$salt);\n return $hash;\n }\n\n }\n?",
">\n\n4. ",
"and the last this is the error when i run the android code\n07-18 02:07:59.393: D/dalvikvm(541): GC_EXPLICIT freed 3420 objects / 314064 bytes in 340ms\n07-18 02:08:08.802: E/JSON(541): <br />n<b>Fatal error</b>: Destructor DB_Functions::__destruct() cannot take arguments in <b>C:\\xampp\\htdocs\\android\\include\\DB_Functions.php</b> on line <b>13</b><br />n\n07-18 02:08:08.802: E/JSON PARSER(541): Error parsing dataorg.json.",
"JSONException: Value <br of type java.lang.",
"String cannot be converted to JSONObject\n07-18 02:08:08.802: W/System.err(541): java.lang.",
"NullPointerException\n07-18 02:08:08.812: W/System.err(541): at com.androidTA.androidclient.",
"RegisterActivity$1.onClick(RegisterActivity.java:58)\n07-18 02:08:08.812: W/System.err(541): at android.view.",
"View.performClick(View.java:2408)\n07-18 02:08:08.812: W/System.err(541): at android.view.",
"View$PerformClick.run(View.java:8816)\n07-18 02:08:08.812: W/System.err(541): at android.os.",
"Handler.handleCallback(Handler.java:587)\n07-18 02:08:08.812: W/System.err(541): at android.os.",
"Handler.dispatchMessage(Handler.java:92)\n07-18 02:08:08.812: W/System.err(541): at android.os.",
"Looper.loop(Looper.java:123)\n07-18 02:08:08.812: W/System.err(541): at android.app.",
"ActivityThread.main(ActivityThread.java:4627)\n07-18 02:08:08.822: W/System.err(541): at java.lang.reflect.",
"Method.invokeNative(Native Method)\n07-18 02:08:08.858: W/System.err(541): at java.lang.reflect.",
"Method.invoke(Method.java:521)\n07-18 02:08:08.858: W/System.err(541): at com.android.internal.os.",
"ZygoteInit$MethodAndArgsCaller.run(ZygoteInit.java:868)\n07-18 02:08:08.858: W/System.err(541): at com.android.internal.os.",
"ZygoteInit.main(ZygoteInit.java:626)\n07-18 02:08:08.862: W/System.err(541): at dalvik.system.",
"NativeStart.main(Native Method)\n\ni've problem with the destruct function..., please anyone help me solve this..., a very big thanks for your solution,,, :)\n\nA:\n\nJust remove the $db parameter from your destructor. ",
"It should look like this.",
"\n/*destructor*/\nfunction __destruct(){\n}\n\nIf you need to access the database from the destructor, you can always use $this->db since you've already initialised that in the constructor.",
"\nIn addition to that, you should really remove the $db parameter from the constructor as well. ",
"It's not being used, and you don't pass any arguments when you construct the DB_functions object in index.php.",
"\n\n"
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[
"I'm a fan of Five Below.",
"\n\nComparative sizes, Covert and Alpha\n\n\n\nCovert Hero\n\nThis is a small single shot pistol, about 8\" long, similar to the Exact Strike and similar pistols. ",
"It primes the top of the tail, like most in this space, and features a spring-back on the pull. ",
"The mold features three colors of plastic with the model name and \"DART BLASTER\" as part of the mold on the left side. ",
"The only paint is the line's \"Target Hero\" logo on both sides of the slide. ",
"The plastic feels surprisingly solid for its price. ",
"It's thick enough to not flex when squeezed, though not quite up to the level of the most recent Buzz Bee or Dart Zone releases. ",
"The mold makes this piece feel more decorated than it is. ",
"It would make for a solid prop.",
"\n\n\n\n\n\nOn the ergo side, well, it is small. ",
"I would put this in line with most similar blasters. ",
"It isn't uncomfortable, but my pinky falls right off the end of the handle. ",
"The prime is a little stiff, I'm unsure my seven year old could manage it. ",
"One semi-interesting feature is the included, but optional, single dart storage loop that can be attached to either side of the blaster. ",
"You can see it just in front of the zip tie in the photo above.",
"\n\n\n\n\n\nThe Hero, Butterfly'd\n\nAlpha Hero\n\nThe Alpha pistol is a large single shot pistol more in line with the scale of most magazine pistols and revolvers on the market. ",
"Like the Covert, it is a top tail prime with a spring return. ",
"The Alpha forgoes paint and instead has stickers for both the branding and the model label. \"",
"DART BLASTER\" and \"AMMO\" are molded on the left side. ",
"Aside from that step down, it is a similarly attractive pistol. ",
"The mold deco does a lot to make up for the lack of paint.",
"\n\nAlpha Hero, Butterfly'd\n\nThe Darts\n\nThe Darts are your bog standard Elite-alikes. ",
"In my barely scientific testing I found the performance was in line with the elites I shot as a comparison. ",
"For variety, I tested with the Covert's darts, Buzz Bee Precise Pros, Buzz Buzz Bee Long Distance, and Glowstrike Elites from the Covert, a Tactical Storm, and an Eradicator. ",
"I lost light before running the Alpha and will update when that comes through. ",
"The Covert averaged between 25 and 32 feet with all but the Long Distance darts, which were roughly ten feet longer. ",
"Comparatively, the Tactical Storm and Eradicator averaged about twice that.",
"\n\n\n\n\n\nSummary\n\nThese are solid looking, if low performing pistols. ",
"For $4 and $5 respectively, there isn't much outside of a Buzz Bee clearance that can compete. ",
"The darts line up well enough with Elite performance and at half the price of most brands, as good as you'll see on the shelf.",
"\n\n\n\n\n\nDo you have these? ",
"What do you think?",
"\n\n\n\n\n\n\n\n\n\n\n\n\n\nI enjoy a good treasure hunt. ",
"Maybe it's silly, but I have a fun time wandering in and seeing what shows up.",
"On my most recent trip I had a bit of luck and ran into this line. ",
"The line appears to be called, simply, Hero . ",
"It consists of four products, colored in both red and blue colors. ",
"Blasters come in the smaller Covert and Alpha model pistols, along with color coordinated 40 packs of darts. ",
"A somewhat unusual addition, over to the right, paintball style masks with an operational light.",
"I picked up one of each of the blasters. ",
"Here's what I found.",
"This is a troublesome blaster to open, everything internally is held in place by friction or pressure. ",
"Once opened, springs jump. ",
"The plunger is middling sized, and lubed with what looks to be petroleum jelly. ",
"It was applied very sloppily, even blocking up the air restrictor. ",
"No doubt this impacted performance.",
"Internally, they are nearly identical, including what a problem they are to open. ",
"The Alpha's plunger was much cleaner than the Covert's leaving me to wonder which was the anomaly."
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"Style Glossary: Paperbag Pants\n\nHigh-waist pants that have a gathered waistband, usually tied by a sash or belt made of the same fabric. ",
"The term originated because this new style of pant looks like the top of a paper bag. ",
"Skirts can also have the same paperbag-like detail. ",
"The moniker isn't appealing, but paperbag pants look great on tall girls who seek a comfortable androgynous look.",
"\n\noh and i was lying, these pants are hideous. ",
"honestly, this is fashion? ",
"i'm disappointed. ",
"this is why i dont get involved with this kind of crap. ",
"But dont get me wrong, if i ever wanted to walk down the street looking like a stripper hobo i would buy you, paperbag pants."
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"This invention relates to gas turbine engines for aircraft and means for reclaiming surplus fuel captured in the fuel manifold system incident engine shutdown.",
"\nThis invention serves to solve the problem described in U.S. Pat. ",
"No. ",
"3,841,089 granted to Herbert Clark on Oct. 15, 1974. ",
"As noted this patent describes a system that reclaims surplus fuel by collecting the fuel trapped in the fuel lines (nozzles, manifold, valve, etc.) ",
"upon the engine shutdown and inserting the fuel back into the fuel system by the continuous operation of a jet pump motivated by fuel upon starting the engine. ",
"However, the system described in U.S. Pat. ",
"No. ",
"3,841,089, supra, incurs two distinct situations which may not in certain applications be tolerable. ",
"These are (1) the heat added to the fuel occasioned by the continuous operation of the injector pump and (2) the size of the drain tank which is dictated by the flow capacity of the jet pump and the amount of surplus fuel needed to be stored. ",
"If the engine is stopped and restarted a number of times for any of a number of reasons, as say for an abortive take-off and the capacity of the pump does not permit complete emptying of the drain tank in the allocated time, hence, the drain tank must be large enough to accommodate additional surplus fuel collected in the fuel system upon additional shutdowns. ",
"Obviously, repeated number of stop-go situations contemplated would dictate the storage capacity and 2 or 3 or better such go arounds are not unusual.",
"\nWe have found that we can obviate the problems noted above, completely eliminate the jet pump and reclaim surplus fuel by a system that is characterized as being automatic, repeatable, and relatively simple with a relatively small drain tank, sized sufficiently cterized as being automatic, repeatable, and relatively simple with a relatively small drain tank, sized sufficiently to remove only the surplus fuel trapped in the fuel system for one stop-go situation. ",
"In addition this invention affords the following advantages to name but a few:\nThe system is completely isolated from the engine fuel system during all ground and flight operation of the aircraft.",
"\nThe system is independent of and requires no alteration of the engine fuel system and/or starter.",
"\nThe unit provides visual indication of whether or not the operation of waste fuel disposal system is satisfactory."
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"Hey guys,\n\tI'm wondering if either of you can locate transaction diagrams for these projects.",
"\n\tI can't locate any of the ECS working files (don't know what Hilgert did relative to\n\tthe move). ",
" \n\n\tLet me know,\n\tmk"
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"mobiletry Click each state to learn about an at risk species that lives there Mammal Insect Bird Amphibian Fish Reptile Mollusk Marine mammal Crustacean AK AL AZ AR CA CO CT DE FL GA HI ID IN KS IL IA KY LA ME MD MI MS MA MN MO NE NV MT NH NJ NM NY ND OH NC OK PA RI OR SC TX UT SD TN VT VA WA WV WI WY SOREN WALLJASPER, NG STAFF TEXT: NATASHA DALY, NG STAFF SOURCE: US FISH AND WILDLIFE SERVICE ENVIRONMENTAL CONSERVATION ONLINE SYSTEM HOVER OVER A STATE TO LEARN ABOUT AN AT RISK SPECIES THAT LIVES THERE SOREN WALLJASPER, NG STAFF. ",
"TEXT: NATASHA DALY, NG STAFF SOURCE: US FISH AND WILDLIFE SERVICE ENVIRONMENTAL CONSERVATION ONLINE SYSTEM MANY SPECIES RANGE DATA COMPILED BY COUNTY\n\nThe Wyoming toad may be North America’s most endangered amphibian. ",
"Disease and habitat loss drove the lumpy, spotted toad into such rapid decline in the 20th century that by 1984, there were only about 16 wild toads left, all in a single county just west of Laramie, Wyoming. ",
"By 1991, they were declared extinct in the wild.",
"\n\nNow, thanks to complex captive breeding and release efforts, the Wyoming toad seems to be making a comeback.",
"\n\nYou may have never heard of the Wyoming toad. ",
"In fact, many Laramie residents have never heard of it either.",
"\n\nBut stories like this play out all over the nation, from the masked bobwhite quail of Arizona’s Sonora Desert, once abundant and now almost extinct in the wild, to the Salt Creek tiger beetle, one of the rarest insects in America. ",
"Its beleaguered population lives in marshland in just one Nebraska county.",
"\n\nOften when we think of endangered species, iconic symbols of conservation come to mind: the Bengal tiger, the orangutan, the blue whale. ",
"But endangered species are in our own backyards as well: 719 animals in the United States are listed as endangered or threatened under the federal Endangered Species Act. ",
"All are vital to their ecosystems. ",
"When one species disappears, that loss risks imperiling the food chain of its entire biosphere.",
"\n\n“Every species that’s protected is potentially the greatest underdog story of all time,” says Christina Meister, a public affairs specialist at the U.S. Fish and Wildlife Service.",
"\n\nThe service maintains a publicly accessible database of every federally listed endangered animal species present in each U.S. state.",
"\n\nCalifornia has 113 endangered animals—the most in the country. ",
"Vermont has four—the fewest. ",
"Vermont, of course, is a fraction the size of California, which plays a large role in the discrepancy of endangered species present, but there are other factors at play too that make certain states likely to have higher numbers of endangered species.",
"\n\nCalifornia, says Valerie Fellows, spokesperson at Fish and Wildlife Service, is home to many diverse habitats. ",
"The species in these unique environments have evolved over millennia to live and thrive in very small ranges. ",
"Disruptions to these specific ecosystems, whether by drought or by wildfire or by hunting, are felt acutely, because the species simply aren’t spread out enough to resist.",
"\n\nHawaii is another state that has a high number of endangered animal species, with 79. ",
"Because many species in Hawaii are endemic, or native only to the state, they’re hit hard when there is a threat, Fellows says.",
"\n\nInvasive species in particular are a problem on the Hawaiian islands. ",
"Non-native mongooses, which feed on bird eggs, have had “disastrous effects across the board” for forest-dwelling birds in the state, she says.",
"\n\nInvasive species are also an issue in Florida, according to Fellows. ",
"Like Hawaii, Florida’s balmy, foliage-rich ecosystem is welcoming for foreign species that come to the state—and then never leave. ",
"There are so many invasive snakes in Florida, says Fellows, that they’ve reduced some mammal populations in the state by 95 percent. “",
"Racoons squirrels, rabbits…the snakes have eaten everything,” she says.",
"\n\n“There are species that have teetered on the brink of extinction, and it's only been through the help of people [that we’ve] been able to bring them back,” says Meister.",
"\n\nThis interactive map highlights a different—and often little known—endangered animal found in every U.S. state. ",
"Some, like the Devil’s Hole pupfish, are found only in a single geothermal pool in a limestone cavern. ",
"Others, like the northern long-eared bat, have ranges spanning 37 states. (",
"Click here if you do not see the map on the page).",
"\n\nImperiled creatures come in all shapes and sizes. ",
"Maybe the one we’ve listed for your state is one you’ve never even heard of."
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"Live\n\n• Hillary Clinton picks Virginia Sen. Tim Kaine as her No. ",
"2\n\n• How did people respond to Donald Trump’s convention? ",
"Watch our daily tracking poll\n\n• Watch and read Trump’s full speech, annotated by us\n\nAnd sign up for our free daily politics newsletter for news and analysis in your inbox."
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"\n\nReferences\n\nCategory:Villages in Wałcz County"
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"2011-09-20\n\nI found it difficult to find examples on the use of PyMeta2, an implememtation of the OMeta language in Python. ",
"I mamaged to put together a small example myself on how to parse a PGP public key block and extract the DSA key.",
"\n\n2011-09-16\n\nThe core parts are a HMC6352 compass module connected to a 3.3V Arduino Pro Mini. ",
"A ULN2803 with eight Darlington drivers supply power to the vibrators positioned at even intervals around the belt. ",
"Everything is powered by a 9V battery.",
"\n\nI found some sample code to read the bearing from the compass, and then added the vibrator control myself."
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"Watch and share this groundbreaking edition of the most banned broadcast in the world! ",
"Also, watch Owen Shroyer, Rex Jones and crew deliver live updates from the D.C. swamp.",
"\n\nThe Emergency Election Sale is now live! ",
"Get 30% to 60% off our most popular products today!"
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"Devices for the controlled infusion of fluids into bodies are known in the art, see for example U.S. Pat. ",
"Nos. ",
"4,150,672 to Whitney et al or 3,923,060 to Ellenwood. ",
"The '672 patent teaches a fluid injection apparatus to be worn by the person while the '060 patent describes an implantable device to dispense a medication.",
"\nDevices are available to dispense insulin into a person on a timed basis that is expected to correspond with the need by the individual for the medication. ",
"Problems with various known techniques for injecting a fluid into a body is their complexity, lack of adaptability to the physical movements of the person and the need to provide conveniently installed replacements as the fluid supply is depleted on the currently installed device."
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"Kate Buesing, 36, used a force computer system to access secret records before passing on information\n\nA crooked WPC who accessed confidential police records to help a friend's brother with his court case has been sacked.",
"\n\nKate Buesing, 36, used a force computer system to access secret records before passing on information to her best friend Samantha Cope.",
"\n\nBuesing, of Evesham, Worcestershire - who served with West Mercia Police for 14 years - then provided details to Samantha's brother James about an assault complaint his wife made against him in October 2014.",
"\n\nShe was convicted in August of two charges of obtaining personal data and disclosing the data to another person.",
"\n\nThe disgraced officer was ordered to pay £500 for each offence at Warwick Crown Court.",
"\n\nShe has now been axed by the force following a Special Case Fast Track Hearing, conducted by Chief Constable Anthony Bangham on Wednesday.",
"\n\nThe hearing found that she breached the standards of professional behaviour, in particular those relating to 'confidentiality, orders and instructions and discreditable conduct.'",
"\n\nBuesing, of Evesham, Worcestershire, was previously convicted of two charges of obtaining personal data and disclosing the data to another person\n\nSuperintendent Helena Bennett, head of professional standards for West Mercia Police, said: 'The misconduct hearing found that the behaviour of PC Buesing fell below the standards we expect from our officers and staff and amounted to gross misconduct and it is for this reason she was dismissed without notice.'",
"\n\nSentencing her at the time Judge Stephen Eyre QC told Buesing she had betrayed the trust of the public.",
"\n\nHe added: 'The public give information, sensitive personal information, to the police service which is kept in trust.",
"\n\n'You deliberately, foolishly, to help a friend, breached that trust\n\n'You looked at the computer system simply to help out a friend, knowing you were giving her information to assist her brother in a family matter which was nothing to do with you.",
"\n\n'It was a serious dereliction of duty.'",
"\n\nThe disgraced officer was ordered to pay £500 for each offence at Warwick Crown Court on August 31\n\nAndrew Wallace, prosecuting, told the court Samantha Cope's brother James and his wife Jodie were going through divorce proceedings and a related family court matter in October 2014.",
"\n\nOn October 6 Jodie reported to other police officers that she had been assaulted a couple of years earlier by James throwing a glass at her, which hit her in the face.",
"\n\nMr Cope wanted to know the reason for police attending the house after his wife told him it was just to do with shed break-ins.",
"\n\nMr Wallace said: 'James Cope was not satisfied with what Jodie told him.",
"\n\n'He got his sister to get her friend to do some digging around for him.'",
"\n\nRichard Gibbs, defending, said: 'As a serving police officer, there will be obvious consequences and repercussions.'",
"\n\nBuesing will have the opportunity to appeal the verdict of the police misconduct hearing."
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"The More You Woe\n\nMay 15, 2019\n\nclick me for the comic secret words"
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"Q:\n\nAurelia - ValidationController always returns true\n\nI've made a wizard with aurelia and I want to check the input values when the user hits the next button.",
"\n@autoinject()\nexport class settingsWizard {\nsteps: Step[];\nactiveStep: Step;\nvalController: ValidationController;\n\nconstructor(private i18n: I18N, private http: HttpClient, public wizard: Wizard, private log: Logger, private router: Router, private controllerFactory: ValidationControllerFactory) {\n this.steps = [\n new Step(1, this.i18n.tr(\"route1\"), PLATFORM.moduleName('./steps/step1')),\n new Step(2, this.i18n.tr(\"route2\"), PLATFORM.moduleName('./steps/step2')),\n new Step(3, this.i18n.tr(\"route3\"), PLATFORM.moduleName('./steps/step3')),\n new Step(4, this.i18n.tr(\"route4\"), PLATFORM.moduleName('./steps/step4')),\n ];\n\n ValidationRules\n .ensure('availableTotalTime').required().on(this.wizard.plannedTime);\n //.ensureObject()\n //.satisfies((x: IQualityRate) => x.numberOfProducedQuantity > x.rejects)\n //.withMessage(this.i18n.tr('quality-rate.rejectsHigherThanProducedQuantity'))\n //.on(wizard.qualityRate);\n\n this.valController = controllerFactory.createForCurrentScope();\n this.valController.validateTrigger = validateTrigger.manual;\n}\n\nhere's the nextButton event:\n nextStep() {\n this.valController.validate().then(result => {\n if (result.valid) {\n if (this.activeStep.id !",
"== this.steps.length) {\n this.activeStep = this.steps[this.activeStep.id];\n }\n }\n });\n}\n\nMy aurelia ValidationController always returns result.valid = true even though availableTotalTime is undefined. ",
"What am I doing wrong?",
"\n\nA:\n\nYou might be assuming that the ValidationRules api automatically causes objects to be validated, but it only stores the rules on the object's prototype. ",
"\nThe ValidationController only validates objects which are either explicitly (1) or implicitly (2) registered, or directly provided (3) to it.",
"\n1. ",
"Register \"implicitly\"\nAny property in a view that has the & validate binding behavior on it will be validated whenever you call controller.validate() in the same viewmodel.",
"\n2. ",
"Register explicitly\nLikewise, controller.addObject(this.wizard.plannedTime) will cause that object (and all its properties) to be validated on subsequent calls to .validate()\n3. ",
"Provide a ValidateInstruction\nthis.valController.validate({\n object: this.wizard.plannedTime,\n // optional: propertyName: ...,\n // optional: rules: ...\n});\n\nThis gives you the highest degree of control. ",
"It will only validate the object you pass in, and nothing else. ",
"Also it won't register the object, so subsequent calls to .validate() will not automatically validate it again.",
"\nYou'll probably either want to go with option 2 or 3, depending on other concerns.",
"\n\n"
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"Q:\n\nFormat + Editor for book writing\n\nA friend of mine is going to write a book. ",
"Therefore he is looking for an easy WYSIWYG solution. ",
"First I recommended latex, but this would be a bit to hard to learn. ",
"A big part of the book is finished and saved in a odt-format but for the publishing he has to offer more \"powerful\" formats (latex, xslt, ..). ",
"We tried the following:\n\nLatex - LyX: Ok, lyx is great, but it was a bit too complicated and we had to fight against bugs.",
"\nMarkdown (with latex export) : The book will contain a lot of tables (big ones) and so it wouldn't be the best experience.",
"\nLibre Office: There are latex export tools, but they're very bad.",
"\n\nThe best solution (by now) is Sigil (ePub-format) - but tables are not supported yet.",
"\nSo I am looking for a format and a good wysiwyg editor. ",
"Only a few functions are needed (heading, bold, kursiv, underline, tables and picture integration).",
"\n\nA:\n\nGiven that your friend is over 70 and apparently not IT oriented, I would recommend sticking to something he already knows. ",
"If he already uses and is familar with MS Word, then stick with that. ",
"\nIf he is planning to self-publish, there are tools that can convert a Word document to the appropriate e-book format. ",
"Amazon's Kindle Direct Publishing does this through an online interface that doesn't require any extra software or any special steps. ",
"It may not always format the finished product perfectly, but it's usually pretty good. ",
"There are also people who will convert the finished product to different e-book formats, and usually pretty cheap. ",
"For example, I know a few who will convert a Word document into four different formats for about $50. ",
"That's a lot easier than buying and learning new software.",
"\nIf he is going to self-publish in print format, then the printer will most likely be able to work with him to make sure everything turns out okay. ",
"They may even have certain formatting changes that they will request or require in order to ensure everything turns out okay, but they should be able to provide assistance with that. ",
"Here again, if he needs to change the formatting to accomodate the printer, there are people who will do the work for hire.",
"\n\nA:\n\nIf \"he\" is going to self-publish then the real question to ask is what format his target audience will want to use?",
"\nSecond, perhaps the format he thinks he requires is not really required. ",
"Some readers don't read the same way some writers think they do. ",
"\n\n"
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"Health reform: is routinely collected electronic information fit for purpose?",
"\nLittle has been reported about the completeness and accuracy of data in existing Australian clinical information systems. ",
"We examined the accuracy of the diagnoses of some chronic diseases in an ED information system (EDIS), a module of the NSW Health electronic medical record (EMR), and the consistency of the reports generated by the EMR. ",
"A list of ED attendees and those admitted was generated from the EDIS, using specific (e.g. angina) and possible clinical terms (e.g. chest pain) for the selected chronic diseases. ",
"This EDIS list was validated with an audit of discharge summaries, and compared with a list generated, using similar specific and possible Systematized Nomenclature of Medicine-Clinical Terms (SNOMED-CT), from the underlying EMR database. ",
"Of the 33,115 ED attendees, 2559 had diabetes mellitus (DM), cardiovascular disease or asthma/chronic obstructive pulmonary disease; of these 2559, 876 were admitted. ",
"Discharge summaries were missing for 12-15% of patients. ",
"Only three-quarters or fewer of the diagnoses were confirmed by the discharge summary audit, best for DM and worst for cardiovascular disease. ",
"Proportion of agreement between the lists generated from the EDIS and EMR was best for DM and worst for asthma/chronic obstructive pulmonary disease. ",
"Possible reasons for this discrepancy are technical, such as use of different extraction terms or system inconsistency; or clinical, such as data entry, decision-making, professional behaviour and organizational performance. ",
"Variations in information quality and consistency of the EDIS/EMR raise concerns about the 'fitness for purpose' of the information for care and planning, information sharing, research and quality assurance."
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"「Windows 10」へのアップグレードによってデータの消失やPCの不具合が生じたとして、イリノイ州在住の3人の原告が中心となってMicrosoftに集団訴訟を提起した。",
"\n\nMicrosoftは2年前にWindows 10へのアップグレード推奨を開始し、それ以来、ユーザーをこの最新OSに乗り換えさせようとする同社への不満がたびたび報じられてきた。不満の声が相次いだのは、Microsoftが「Windows 7」以降のOSを使用するユーザーに、Windows 10へのアップグレードを無償提供していた1年間だ。無償提供は2016年7月に終了している。",
"\n\n\n\nWindows 10\n\n提供：Microsoft Windows 10提供：Microsoft\n\nこの一連の騒動に、新たに集団訴訟が加わった。この訴訟ではMicrosoftに対し、ユーザーの時間と金を奪い、苦痛を与えたと訴えている。Windows 10へのアップグレードに伴い、技術サポートやソフトウェアの不具合、ハードウェアの交換といった問題への対応を余儀なくされたというのが、その主張だ。",
"\n\n今回の訴訟には100人以上が加わり、費用と利息を除いて計500万ドル超の損害賠償を求めている。",
"\n\n代表原告のStephanie Watson氏は、Windows 10へのアップグレードを選択していないにもかかわらずアップグレードが実行され、仕事関連のデータを失ったと述べている。同氏はその後、Best Buyのサービス部門Geek Squadにマシンの修理を依頼したが、問題解決に「完全に成功」することはなく、代わりのマシンを購入する結果になったという。",
"\n\n訴状では、Windows 10は米国の法律では消費者向け製品にあたり、また、Microsoftはアップグレードがデータの消失やハードウェアの破損を招く恐れがあると認識していたと主張されている。",
"\n\n原告側は訴訟を通じて、アップグレードによるデータの消失やハードウェアの破損の恐れがあったことや、Microsoftがソフトウェアに互換性がない可能性について知っていたことなど、複数の主張の立証を目指す。",
"\n\n対するMicrosoftは米ZDNetの取材に対し、Windows 10への無償アップグレードプログラムでは、アップグレードしない選択肢を顧客に提供していたと述べている。",
"\n\n意外なことではないが、Windows 10へのアップグレードに関する苦情が殺到したことから、Microsoftは消費者が最も不満に感じた事柄を把握しており、次期アップデート「Creators Update」ではユーザーにより多くの選択肢を提供すると約束している。"
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"Serpiginous hypopigmentation secondary to intra-articular corticosteroid injection.",
"\nCorticosteroids have been a mainstay of therapy for the treatment of many inflammatory diseases for well over 50 years. ",
"Cutaneous side effects of local corticosteroid therapy include striae, thinning of the skin, hypopigmentation, and atrophy, which are well known complications of this treatment modality.",
"Herein, we present an unusual cutaneous adverse side effect rarely seen in intra-articular corticosteroid injections."
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"Q:\n\napi test with postman in angular project\n\nI want to test my api for resister which is post type it contain username, email, password, phone number. ",
"I really don't know how to test api in postman. ",
"It should be authorization type of no-auth. ",
"After this I have to validate or test api for login then it generate some key then I have to use this key to test other api's. ",
"\n\nA:\n\ni believe to test post api withpostman\nfirst you need to put the route of your api and the type of http in your case POST\nthen go to header tab and add this header(under key/value):-\nContent-Type :application/json\nthen under body tab select row option and insert valid json as below\n{\n \"username\": \"Omar Shabro\",\n \"email\": \"o4@o.com\",\n \"phone\": \"0599\"\n\n}\n\n"
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"Many individuals are dissatisfied with their current tooth color. ",
"Thus, there is a desire for whiter teeth and one means to achieve whiter teeth is the use of tooth whitening products.",
"\nIt is known in the literature that the visual perception of a white substance can be altered through the deposition of an optical brightener, blue pigment or blue dye, especially one for which the hue angle (in the CIELAB scale) of the reflected or emitted light is between 200 to 320 degrees. ",
"This effect is commonly used in laundry detergent products to make white clothes appear “whiter” to the human eye. ",
"The same concept has been applied to tooth whitening as well. ",
"The natural off-white or yellow color of teeth can be made to appear whiter through the deposition of a blue substance onto teeth. ",
"Using pigments with a deposition aid, i.e., high molecular weight Gantrez® type polymers (copolymers of maleic anhydride and with methyl vinylether) in toothpaste to make teeth look whiter is disclosed in EP 1935395B1.",
"\nDentifrice formulations comprising peroxide are known and useful for cleaning and whitening teeth. ",
"The peroxide can bleach the teeth, remove stains, and kill cariogenic bacteria. ",
"However, peroxide compounds are highly reactive, and consequently difficult to formulate. ",
"Moreover, hydrogen peroxide can spontaneously decompose to form oxygen gas (O2) and water, so that on storage, the dentifrice containers may bloat, burst or leak, and the remaining formulation will not have enough peroxide remaining to clean and whiten teeth effectively. ",
"Some dentifrices initially comprise very high levels of peroxide, which decomposes over time, so that the exact amount of peroxide delivered on application is variable and largely depends on how long and under what conditions the dentifrice has been stored.",
"\nDue to the color bleaching property of hydrogen peroxide, products containing hydrogen peroxide are usually clear or off white.",
"\nThere is thus a need for improved color stable whitening oral compositions which effectively stabilizes both hydrogen peroxide and pigment that are suitable for everyday consumer use."
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"Production of palatinose using Serratia plymuthica cells immobilized in chitosan.",
"\nIn recent decades, the production of palatinose has aroused great interest since this structural isomer of sucrose has interesting potential. ",
"We describe a simple and effective method of immobilizing Serratia plymuthica cells in chitosan. ",
"The sucrose isomerase activity of immobilized preparations was enhanced many times by activation with fresh nutrient medium and subsequent drying. ",
"The preparations obtained were physically very stable with high enzyme activity and excellent operational stability. ",
"The effect of temperature, pH and substrate concentration on enzyme activity of the immobilized cells was investigated. ",
"Using immobilized cells, a complete conversion of sucrose (40% solution) into palatinose was achieved in 4 h in a \"batch\"-type enzyme reactor. ",
"The use of free or immobilized cells had no effect on the composition of the solution, in particular the sugar content. ",
"The palatinose content was 80% and that of trehalulose 7%."
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"A new initiative in northwestern Wisconsin aims to help farmers' markets get their food to local buyers.",
"\n\nAn AgriBusiness Academy hopes to build on regional demand for locally grown food.",
"\n\nAndrea Huggenvik, with the Northwest Wisconsin Workforce Investment Board, said the new academy will help farmers meet demand from local buyers.",
"\n\n\"They’re really looking to purchase food from local farmers and are sometimes struggling to have enough farmers to produce enough food that they need,\" she said\n\nHuggenvik said the academy will cover business plans, contracts and what foods local buyers want.",
"\n\nSign up for daily news! ",
"Stay informed with WPR's email newsletter.",
"\n\nChequamegon Food Co-op general manager Harold Vanselow said they’ve committed to buying 20 percent of their food locally by 2020.",
"\n\n\"In the produce department, we are close to that goal,\" he said. \"",
"In all other departments, we are further away from that goal.\"",
"\n\nVanselow said they’re in competition with people buying directly from farmers. ",
"He said there’s also a need for regional food processing and storage.",
"\n\nAround 20 businesses in 15 counties across northwestern Wisconsin and northeastern Minnesota have committed to buying 20 percent of their food locally by 2020 under the Superior Compact in the last two years.",
"\n\nThe AgriBusiness Academy is funded by a Wisconsin Forward grant and will be held on three Saturdays this fall -- Oct. 24, Nov. 7 and Nov. 14 -- at Wisconsin Indianhead Technical College in Ashland."
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"We knew it! ",
"The latest installment of James Corden’s Carpool Karaoke will feature Hamilton’s certified genius Lin-Manuel Miranda, along with a slew of Broadway faves. ",
"The segment is scheduled to air on June 6 on The Late Late Show.",
"\n\n\n\nJoining the pair will be six-time Tony winner Audra McDonald (Shuffle Along), Jesse Tyler Ferguson (Fully Committed), along with Tony winner and 2016 Tony nominee Jane Krakowski (She Loves Me).",
"\n\n\n\nTony winner Corden is set to host the 2016 Tony Awards on June 12.",
"\n\n\n\nWe might just be hyperventilating with excitement speculating about which numbers will be on their playlist right now. ",
"Who can't wait to be in the room car where it happens?!"
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"Q:\n\nrender not defined in php\n\nI'm a beginner in html and react. ",
"I make front -end in this project. ",
"I don 't know why he said Uncaught ReferenceError: render_partner is not defined\n at partner:1570\nindex.blade.php\n\n@extends('layouts.app')\r\n\r\n@section('content')\r\n <div id=\"role\">\r\n </div>\r\n <script type=\"text/javascript\">\r\n var test = {\r\n name: 'Partners',\r\n url: 'partners',\r\n order: [{\r\n field: 'id',\r\n direction: 'desc'\r\n }],\r\n fields: [\r\n //{\r\n //field_name: 'reference_id',\r\n //display_name: 'numero de référence',\r\n //type: 'select'\r\n //},\r\n {\r\n field_name: 'lastupdate',\r\n display_name: 'dernière mise à jour',\r\n type: 'date',\r\n index:false\r\n },\r\n //{\r\n // field_name: 'dataconfirm',\r\n // display_name: 'data confirmé',\r\n // type: 'boolean',\r\n // index:false\r\n //},\r\n {\r\n field_name: 'businesspartnersname',\r\n display_name: 'nom du partner',\r\n type: 'text'\r\n },\r\n {\r\n field_name: 'legalform_id',\r\n display_name: 'statut legal',\r\n type: 'select',\r\n source:{\r\n url: 'legalforms.select'\r\n }\r\n },\r\n {\r\n field_name: 'globallocationnumber',\r\n display_name: 'globallocationnumber',\r\n type: 'integer',\r\n index:false\r\n },\r\n {\r\n field_name: 'street',\r\n display_name: 'Nom de la rue',\r\n type: 'text',\r\n index:false\r\n },\r\n {\r\n field_name: 'streetnumber',\r\n display_name: 'Numero de la rue',\r\n type: 'text',\r\n index:false\r\n },\r\n {\r\n field_name: 'box',\r\n display_name: 'Nom de la boite',\r\n type: 'text',\r\n index:false\r\n },\r\n {\r\n field_name: 'address2',\r\n display_name: 'Seconde addresse',\r\n type: 'text',\r\n index:false\r\n },\r\n {\r\n field_name: 'zipcode',\r\n display_name: 'code postal',\r\n type: 'text',\r\n index:false\r\n },\r\n {\r\n field_name: 'state',\r\n display_name: 'Ville',\r\n type: 'text',\r\n index:false\r\n }\r\n ]\r\n };\r\n var role = false; \r\n //render_resource(test, $('#role').get()[0]);\r\n render_partner(test, $('#role').get()[0]);\r\n </script>\r\n <Button onClick=this.refs.partner.render_partner()>myButton</Button>\r\n <script href=\"../component/partner\" ></script>\r\n@endsection\n\npartner.jsx\n\nimport React, {Component} from 'react';\r\nimport React from 'react'\r\nimport ReactDOM from 'react-dom'\r\nimport {HashRouter as Router, Route} from 'react-router-dom'\r\nimport PropTypes from 'prop-types'\r\nimport {ResourceRetriever, Requests} from './retriever.jsx'\r\nimport {TableDefault, TableEdit} from './table.jsx'\r\nimport {LinkButton} from './button.jsx'\r\nimport Form from './form.jsx'\r\nimport {MainLayout, HeaderLayout, BodyLayout} from './layouts.jsx'\r\nimport route from 'ziggy'\r\nimport { Ziggy } from 'ziggy'\r\nimport {render} from 'react-dom'\r\n\r\nconst OnlineSubPartner = PartnerRetriever(TableEdit)\r\n\r\nclass Partner extends React.",
"Component {\r\n\r\nrender() {\r\n let routes = {\r\n index: \"/\",\r\n create: \"/create\",\r\n edit: \"/edit/:id\"\r\n }\r\n let count=0\r\n let name =\"\"\r\n if (this.props.count !",
"== undefined || this.props.count) {\r\n count=Object.keys(this.props.data).length\r\n name = this.props.name + \" (# = \" + count + \")\"\r\n } else {\r\n name = this.props.name\r\n }\r\n //console.log(\"phh1 resource props = \", this.props)\r\n \r\n return (\r\n <Router>\r\n <MainLayout>\r\n <HeaderLayout name={name}>\r\n <Route path={routes.index}\r\n exact\r\n render={() => (\r\n this.props.readonly ? ",
"\r\n null : \r\n <LinkButton to={routes.create}\r\n className=\"btn-primary pull-right\"\r\n style={{marginTop: '-10px', marginBottom: '5px'}}\r\n label=\"Ajouter\" />)} />\r\n </HeaderLayout>\r\n <BodyLayout>\r\n <Route path={routes.index}\r\n exact\r\n render={() => <TableDefault {...this.props}\r\n openEditRoute={(data) => \"edit/\" + data.id}\r\n openPrintRoute={(data) => \"print/\" + data.id} />} />\r\n <Route path={routes.create}\r\n render={() => <Form {...this.props}\r\n closeRoute={routes.index}\r\n submitRequest={data => this.props.requests.store(data)}\r\n closeOnSave\r\n data={{}} />} />\r\n <Route path={routes.edit}\r\n render={(props) => {\r\n let data = this.props.data.filter((row) => row.id == props.match.params.id)[0]\r\n return (\r\n <div>\r\n <Form {...this.props}\r\n closeRoute={routes.index}\r\n submitRequest={this.props.requests.update}\r\n closeOnSave={this.props.subpartner ? ",
"false : true}\r\n data={data} />\r\n {this.props.subpartner && <OnlineSubPartner {...this.props.subpartner}\r\n id={data.id} parenturl={this.props.url} />}\r\n </div>\r\n )}} />\r\n </BodyLayout>\r\n </MainLayout>\r\n </Router>\r\n )\r\n\r\n}\r\n} \r\n\r\nPartner.propTypes = {\r\n name: PropTypes.string.isRequired,\r\n readonly: PropTypes.bool,\r\n requests: PropTypes.instanceOf(Requests).isRequired,\r\n data: PropTypes.arrayOf(PropTypes.object).isRequired,\r\n subpartner: PropTypes.object\r\n}\r\n\r\nexport default function render_partner(partner, mp, subpartner) {\r\n const OnlinePartner = PartnerRetriever(Partner)\r\n ReactDOM.render(<OnlinePartner {...partner} subpartner={subpartner} />, mp)\n\nrend_resource work with a another jsx that i take to make this. ",
"I think the problem is in the jsx with the sub and the partner but i don't see where\n\nA:\n\nThe problem was the import in app.js\n\n"
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[
"/************************************************************\n * <bsn.cl fy=2014 v=onl>\n *\n * Copyright 2014 Big Switch Networks, Inc.\n * Copyright 2014 Accton Technology Corporation.",
"\n *\n * Licensed under the Eclipse Public License, Version 1.0 (the\n * \"License\"); you may not use this file except in compliance\n * with the License. ",
"You may obtain a copy of the License at\n *\n * http://www.eclipse.org/legal/epl-v10.html\n *\n * Unless required by applicable law or agreed to in writing,\n * software distributed under the License is distributed on an\n * \"AS IS\" BASIS, WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND,\n * either express or implied. ",
"See the License for the specific\n * language governing permissions and limitations under the\n * License.",
"\n *\n * </bsn.cl>\n ************************************************************\n *\n * Thermal Sensor Platform Implementation.",
"\n *\n ***********************************************************/\n#include <onlplib/file.h>\n#include <onlp/platformi/thermali.h>\n#include \"platform_lib.h\"\n\n#define VALIDATE(_id) \\\n do { \\\n if(!ONLP_OID_IS_THERMAL(_id)) { \\\n return ONLP_STATUS_E_INVALID; \\\n } \\\n } while(0)\n\nstatic char* devfiles__[] = /* must map with onlp_thermal_id */\n{\n NULL,\n NULL, /* CPU_CORE files */\n \"/sys/bus/i2c/devices/10-0048*temp1_input\",\n \"/sys/bus/i2c/devices/10-0049*temp1_input\",\n \"/sys/bus/i2c/devices/10-004a*temp1_input\",\n \"/sys/bus/i2c/devices/10-004b*temp1_input\",\n \"/sys/bus/i2c/devices/18-005b*psu_temp1_input\",\n \"/sys/bus/i2c/devices/17-0058*psu_temp1_input\",\t\n};\n\nstatic char* cpu_coretemp_files[] =\n {\n \"/sys/devices/platform/coretemp.0*temp2_input\",\n \"/sys/devices/platform/coretemp.0*temp3_input\",\n \"/sys/devices/platform/coretemp.0*temp4_input\",\n \"/sys/devices/platform/coretemp.0*temp5_input\",\n NULL,\n };\n\n/* Static values */\nstatic onlp_thermal_info_t linfo[] = {\n\t{ }, /* Not used */\n\t{ { ONLP_THERMAL_ID_CREATE(THERMAL_CPU_CORE), \"CPU Core\", 0}, \n ONLP_THERMAL_STATUS_PRESENT,\n ONLP_THERMAL_CAPS_ALL, 0, ONLP_THERMAL_THRESHOLD_INIT_DEFAULTS\n },\t\n\t{ { ONLP_THERMAL_ID_CREATE(THERMAL_1_ON_MAIN_BROAD), \"LM75-1-48\", 0}, \n ONLP_THERMAL_STATUS_PRESENT,\n ONLP_THERMAL_CAPS_ALL, 0, ONLP_THERMAL_THRESHOLD_INIT_DEFAULTS\n },\n\t{ { ONLP_THERMAL_ID_CREATE(THERMAL_2_ON_MAIN_BROAD), \"LM75-2-49\", 0}, \n ONLP_THERMAL_STATUS_PRESENT,\n ONLP_THERMAL_CAPS_ALL, 0, ONLP_THERMAL_THRESHOLD_INIT_DEFAULTS\n },\n\t{ { ONLP_THERMAL_ID_CREATE(THERMAL_3_ON_MAIN_BROAD), \"LM75-3-4A\", 0}, \n ONLP_THERMAL_STATUS_PRESENT,\n ONLP_THERMAL_CAPS_ALL, 0, ONLP_THERMAL_THRESHOLD_INIT_DEFAULTS\n },\n\t{ { ONLP_THERMAL_ID_CREATE(THERMAL_4_ON_MAIN_BROAD), \"LM75-3-4B\", 0}, \n ONLP_THERMAL_STATUS_PRESENT,\n ONLP_THERMAL_CAPS_ALL, 0, ONLP_THERMAL_THRESHOLD_INIT_DEFAULTS\n },\n\t{ { ONLP_THERMAL_ID_CREATE(THERMAL_1_ON_PSU1), \"PSU-1 Thermal Sensor 1\", ONLP_PSU_ID_CREATE(PSU1_ID)}, \n ONLP_THERMAL_STATUS_PRESENT,\n ONLP_THERMAL_CAPS_ALL, 0, ONLP_THERMAL_THRESHOLD_INIT_DEFAULTS\n },\n\t{ { ONLP_THERMAL_ID_CREATE(THERMAL_1_ON_PSU2), \"PSU-2 Thermal Sensor 1\", ONLP_PSU_ID_CREATE(PSU2_ID)}, \n ONLP_THERMAL_STATUS_PRESENT,\n ONLP_THERMAL_CAPS_ALL, 0, ONLP_THERMAL_THRESHOLD_INIT_DEFAULTS\n }\n};\n\n/*\n * This will be called to intiialize the thermali subsystem.",
"\n */\nint\nonlp_thermali_init(void)\n{\n return ONLP_STATUS_OK;\n}\n\n/*\n * Retrieve the information structure for the given thermal OID.",
"\n *\n * If the OID is invalid, return ONLP_E_STATUS_INVALID.",
"\n * If an unexpected error occurs, return ONLP_E_STATUS_INTERNAL.",
"\n * Otherwise, return ONLP_STATUS_OK with the OID's information.",
"\n *\n * Note -- it is expected that you fill out the information\n * structure even if the sensor described by the OID is not present.",
"\n */\nint\nonlp_thermali_info_get(onlp_oid_t id, onlp_thermal_info_t* info)\n{\n int tid;\n VALIDATE(id);\n\t\n tid = ONLP_OID_ID_GET(id);\n\t\n /* Set the onlp_oid_hdr_t and capabilities */\t\t\n *info = linfo[tid];\n\n if(tid == THERMAL_CPU_CORE) {\n int rv = onlp_file_read_int_max(&info->mcelsius, cpu_coretemp_files);\n return rv;\n }\n\n return onlp_file_read_int(&info->mcelsius, devfiles__[tid]);\n}\n\n"
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[
"In just under 30 minutes, Peter Schiff and Doug Casey muse on many facets of the crumbling edifice of the status quo that is our current world.",
"\n\nFrom Gold's relatively imminent rise to $5,000 and beyond, to investor ignorance of reality, Casey & Schiff swing from discussions of the US as political entity going forward to 'escape from America' plans for personal and wealth assets, and the realization that the biggest casualty (of US indebtedness), aside from individual liberty, is the value of the dollar - as taxing the middle class is unpopular with both parties - leaving only one route for the government - the inflation tax. ",
"Owning gold, silver, and foreign assets is preferred and while the rest of the world is also printing, the US is likely to beat them all.",
"\n\nPeople \"are clueless with respect to the true state of the global economy,\" with regard to inflation, fiat currencies, and specifically what will happen to the dollar. ",
"The conversation is wide-ranging and absolutely must-see as they remind market-watchers that \"the whole thing is artificial,\" as you can't just keep printing money and monetizing debt without the dollar imploding with monetary policy descending (along with its trillion dollar coin) into 'Three Stooges' comedy.",
"\n\n\n\nThe conversation weaves to some endgame discussions which bring Peter to discuss his father, who he sees as a political prisoner, and his views on the future...\n\n\"the biggest change that is coming to the global economy is a realignment of global living standards.\"",
"\n\nThere is something here for everyone...\n\n\n\n"
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"DACA - Important to Contact Your Congressional Representatives\n\n~~President Trump has ordered an end to the Obama-era executive action that shields young undocumented immigrants from deportation, calling the program an “amnesty-first approach” and urging Congress to replace it with legislation before it begins phasing out on March 5, 2018.",
"\nIn my first life after college, long before I started Tankoos Reporting Company, I was a Spanish teacher. ",
"Majoring in Spanish at Queens College of the City of New York, I was required to take many classes related to the history or Spain and Latin America, as well as Spanish literature, in addition to, of course, learning how to speak the language.",
"\n\nOne fact that jumps out at everyone who has ever studied the history of Spain is that, the country lost its economic status in the world and slid downhill rather quickly, after 1492, the year Queen Isabella and King Ferdinand decided to expel the Jews. ",
"The Inquisition took care of all of those who chose not to leave. ",
"The expulsion of the Jews had been the pet project of Father Tomas de Torquemada, the head of the Spanish Inquisition.",
"\n\nThe Expulsion of the Jews was a disaster for Spain, psychologically, intellectually and economically. ",
"It boosted the legitimacy of the Spanish Inquisition, whose stifling effect would be felt by the society until the 19th century. ",
"It also stripped 2% of Spain’s most urbane, educated and affluent inhabitants. ",
"At a time when Europe’s economy was shifting from agrarian to industrial, Spain could not afford this loss. ",
"The effect was compounded when the Spanish Inquisition managed to have 300,000 Muslims expelled a century later. ",
"Such a massive exodus would be an enormous loss for any country at the time – but especially for Spain, which was only a third the size of France.",
"\n\nIt seems to me that if our President or the Conservatives in our government who support the cancellation of DACA studied and understood history or economics, they would realize that the immigrants who fall under DACA are an important part of the middle class here in the United States, and that sending them back to countries they barely remember will cause more than a small ripple in our economy. ",
"If our congressional representatives choose to ignore the humanitarian effects of what they are doing, they certainly should not choose to ignore the economic problems that will follow.",
"\n\nWrite to your congressional representatives and try to impress upon them the importance of passing legislation that will grant undocumented immigrants who are losing the protection of DACA a path to citizenship.",
"\n\nThe following article is from CNN online:\n\n(CNN)The Trump administration on Tuesday formally announced the end of DACA -- a program that had protected nearly 800,000 young undocumented immigrants brought to the US as children from deportation.",
"\n\nThe Department of Homeland Security will stop processing any new applications for the program as of Tuesday and rescinded the Obama administration policy, Deferred Action for Childhood Arrivals.",
"\n\"I am here today to announce that the program known as DACA that was effectuated under the Obama administration is being rescinded,\" Attorney General Jeff Sessions said Tuesday at the Justice Department.",
"\n\nIn the five years since DACA was enacted, the nearly 800,000 individuals who have received the protections have started families, pursued careers and studied in schools and universities across the United States. ",
"The business community and education community at large has joined Democrats and many moderate Republicans in supporting the program, citing the contributions to society from the population and the sympathetic fact that many Dreamers have never known another home than the US.",
"\n\nIn a statement after his agencies and attorney general announced the decision, President Donald Trump blamed former President Barack Obama for creating the program through executive authority and urged Congress to come up with a solution.",
"\n\"It is now time for Congress to act!\" ",
"he said.",
"\n\nTrump said that winding down the program would be more considerate than letting the courts end it, but emphasized he stands by his \"America First\" agenda.",
"\n\n\"As I've said before, we will resolve the DACA issue with heart and compassion -- but through the lawful Democratic process -- while at the same time ensuring that any immigration reform we adopt provides enduring benefits for the American citizens we were elected to serve,\" Trump said. \"",
"We must also have heart and compassion for unemployed, struggling and forgotten Americans.\"",
"\nThe administration also announced a plan to continue renewing permits for anyone whose status expires in the next six months, giving Congress time to act before any currently protected individuals lose their ability to work, study and live without fear in the US.",
"\n\nThe Trump administration pitched the move as the \"least disruptive\" option available after facing a threat from 10 conservative state attorneys general to challenge the program in court, according to senior administration officials briefing reporters on the move during a conference call conducted on condition of anonymity.",
"\n\nCNN Money: Ending DACA hits U.S. economy where it hurts\nSessions had determined that the program would not be likely to withstand that court challenge, he said.",
"\n\n\"The Department of Justice cannot defend this overreach,\" Sessions said. \"",
"There is nothing compassionate about the failure to enforce immigration laws. ",
"Enforcing the law saves lives, protects communities and taxpayers, and prevents human suffering. ",
"Failure to enforce the laws in the past has put our nation at risk of crime, violence and even terrorism. ",
"The compassionate thing is to end the lawlessness, (and) enforce our laws.\"",
"\n\nCongress faces deadline\nThe move sets a clock for Congress to act to preserve the program's protections before the DACA recipients begin losing their status March 5, 2018.",
"\n\nIn a statement, House Speaker Paul Ryan reiterated his aspiration that Congress will reach a solution in time.",
"\n\n\"It is my hope that the House and Senate, with the president's leadership, will be able to find consensus on a permanent legislative solution that includes ensuring that those who have done nothing wrong can still contribute as a valued part of this great country,\" Ryan said.",
"\nNo one's DACA status will be revoked before it expires, administration officials said, and any applications already received by Tuesday will be processed.",
"\n\nAnyone who's status expires by March 5 has one month to apply for a new two-year permit, and those applications will be processed.",
"\n\nIf Congress were not to act, and DACA begins to expire, nearly 300,000 people could begin to lose their status in 2018, and more than 320,000 would lose their status from January to August 2019. ",
"More than 200,000 recipients have their DACA expiring in the window that DHS will allow renewal.",
"\nSpeaking with reporters on a conference call on condition of anonymity, DHS did not rule out that anyone with expired DACA would then be subject to deportation. ",
"Immigration and Customs Enforcement said they will continue to prioritize for enforcement people with criminal records, people who re-enter the US illegally and\n\nThe officials placed the onus on Congress to make any changes to the system\nthose with final orders of removal.",
"\n\nBut officials said there will be no formal guidance that former DACA recipients are not eligible for deportation, and ICE officers in the field who encounter them will be making a case-by-case judgment as to whether to arrest that individual and process them for deportation.",
"\nThe administration insisted its approach was designed to offer some security to DACA recipients, emphasizing that if it had allowed the courts to decide the issue, then would have been risking an immediate and abrupt end to DACA at the hands of a judge.",
"\n\nBut it also was made clear that once DACA begins to expire, if Congress doesn't act, then people formerly protected \"would be like any other person who's in the country illegally,\" according to a senior DHS official.",
"\n\nAll of the information provided to the government by DACA applicants will remain in the DHS system. ",
"US Citizenship and Immigration Services, which administers the program, will give that information to ICE if requested if \"there's a significant law enforcement or national security interest,\" an official said.",
"\n\nWhile they won't be specifically targeted, DHS said, they could be arrested and deported if they are encountered by ICE officers. ",
"And their information, which they provided extensively for their DACA applications, will continue to reside in DHS systems and could be accessed if officers feel it's necessary in the course of an investigation.",
"\n\nDHS said it had on plans to issue formal guidelines on how former DACA recipients -- or their information -- will be treated beyond the current operating procedures of DHS.",
"\n\n\"To be clear, what ICE is doing now is what Congress intended, we're actually enforcing the law the way it is written,\" said a senior ICE official. \"(",
"This is t)he first President who's asked us to enforce the law the way it is written and not asked us to have some executive interpretation of the law.\"",
"\n\n0 Comments\n\nPost new comment\n\nComment: *\n\nCAPTCHA\n\nDue to spam, all comments require approval before posting. ",
"Please only submit your comment once and fill out the CAPTCHA. ",
"Thank you."
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[
"米Appleは7月7日（現地時間）、公式オンラインストアApple Storeに、ストアで販売するサードパーティー製iPhone／iPadケースの品質テストを紹介するページを開設した。",
"\n\nApple Storeに並ぶケースは、すべてAppleの厳格なテストをパスしたものだけなので、どのケースでも端末に完璧にフィットすると保証している。",
"\n\nオンラインストアに追加されたケースの品質テスト紹介ページ\n\nページのトップの写真は、公式オンラインストアで「限定」タグが付いているロジクールの「Hinge Case for iPad Air 2」だ。",
"\n\nこのページでは、Appleがケースメーカーに対し、本体のデザイン、カメラ、音響性能、Touch IDなどの各種センサー、通信機能を損なわないように設計するよう厳しい基準を設け、検証していることを説明している。",
"\n\nAppleが周辺機器メーカー向け認証プログラム「MFi ライセンスプログラム（Made For iPhone/iPad/iPod）」をサードパーティーに課していることは知られているが、一般向けの公式ページで品質テストについて紹介するのは初めてのことだ。",
"\n\n米9TO5Macによると、Appleは近く、実店舗のApple Storeで販売するサードパーティー製周辺機器の種類を現在より減らし、販売する製品についてはそのパッケージをAppleがデザインしたものに統一する計画という。",
"\n\n一連の変化には、7月1日付で新設の役職、「Chief Design Officer（CDO、最高デザイン責任者）」に就任したジョナサン・アイブ氏の意向が反映されているようだ。Apple公式サイトの同氏のプロフィールには「Appleにおけるすべてのデザインの責任者」であり、「すべてのデザイン」にはパッケージングや小売店も含まれている。"
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[
"Washington Nationals vs. Atlanta Braves Betting Preview\n\nThe streaking Atlanta Braves will go for their sixth consecutive victory when they play host to the Washington Nationals at SunTrust Park. ",
"Mid-Atlantic Sports Network will showcase the matchup and the game is scheduled to get underway at 7:35 p.m. ET.",
"\n\nWashington Nationals at Atlanta Braves Odds\n\nVegas has listed Washington (-140) as the favorite over Atlanta (+130). ",
"Bettors can wager on the game’s total with odds sitting at -110 for over eight runs and -110 for under eight. ",
"The game’s current runline odds sit at +105 for taking the Nationals -1.5 runs and -125 for the Braves +1.5.",
"\n\nThe Braves are 82-64 straight up (SU) and 75-70 against the spread (ATS). ",
"They’ve gained 20.4 units for moneyline bettors and 1.2 units (ATS). ",
"Atlanta has covered the spread five times in its last seven games and the total went over in four of those seven. ",
"The Nationals have gone 74-73 SU this year and are 68-78 ATS. ",
"In total, the team’s lost 22.6 units for moneyline gamblers and 13.4 units ATS. ",
"Washington has covered the spread five times in its last seven games and the over has hit in five of those seven.",
"\n\nBraves games have an over/under record of 68-71-6 in 2018. ",
"Washington has been a decent under bet with a total record of 67-76-3.",
"\n\nRight-hander Max Scherzer is projected to start for Washington. ",
"Scherzer is 17-6 with a 2.31 ERA and 271 strikeouts. ",
"He’s 2-1 with 30 strikeouts and a 1.67 ERA against Atlanta this year (four starts).",
"\n\nThe Braves are turning to righty Kevin Gausman (9-10, 3.89 ERA), who has 134 strikeouts and 43 walks to his credit as well as a WHIP of 1.29. ",
"Gausman is 0-0 with three strikeouts and a 3.00 ERA in one start against Washington this year.",
"\n\nAtlanta’s pitchers have allowed 4.0 runs per game overall this season as a unit. ",
"Its starters have an ERA of 3.47, a WHIP of 1.22 and a strikeouts-per-nine of 8.6. ",
"The bullpen has a 4.04 ERA, 1.37 WHIP and 9.0 K/9. ",
"In 63 games against NL East opponents, Braves starters have an ERA of 2.97 and the bullpen’s ERA is 2.85.",
"\n\nAtlanta’s hitters are putting up 4.7 runs per contest, including 5.1 per game against divisional foes and 4.8 per game over their last five. ",
"The team has slashed .269/.352/.485 over its last five matchups and is 5-0 SU during that stretch.",
"\n\nRight fielder Nick Markakis and first baseman Freddie Freeman have led the Braves’ batters this year. ",
"Markakis is slashing .306/.371/.457 with 14 home runs, 88 RBIs and 75 runs scored, and Freeman is batting .307 with 21 homers, 85 RBIs and 89 runs.",
"\n\nIn the visiting dugout, Washington’s pitchers have allowed 4.2 runs per game and its starting pitchers own a 4.03 ERA, 1.24 WHIP and 8.91 K/9. ",
"The bullpen has logged an ERA of 3.90, along with a WHIP of 1.24.",
"\n\nThe Nationals offense has slashed .252/.332/.415 on its way to 4.7 runs scored per game in 2018, including 5.3 runs per game against divisional foes and 4.8 per game over the team’s last five outings (4-1 SU).",
"\n\nShortstop Trea Turner and third baseman Anthony Rendon have led Washington’s hitters. ",
"The speedy Turner is slashing .267/.337/.405 with 17 home runs, 63 RBIs, 90 runs and 38 steals, while Rendon is hitting .295/.359/.503 with 19 homers, 71 RBIs and 77 runs scored.",
"\n\nThe Nationals have lost 6.5 units and are 52-55 ATS when facing a right-handed starting pitcher this season. ",
"The over has cashed in 48 of those games, compared to 57 that’ve hit the under in such games. ",
"On the other hand, the Braves have netted 21.6 units and are 57-45 ATS when facing a right-handed starting pitcher. ",
"The over’s hit in 46 of those games, compared to 51 that’ve gone under.",
"\n\nBetDSI Resources\n\nAge Verification\n\nApart from self-exclusion options, BetDSI works to ensure that the age limits for gambling are respected and all customers meet the legal gambling age of 18 years old. ",
"We carry out age verification tests to prevent minors from engaging in gambling activities.",
"\n\nJurisdiction\n\nBetDSI offers online betting services for a global client base. ",
"Please check with your jurisdiction to verify if online gambling is legal in you territory.",
"\n\nAddiction\n\nIn the event a player feels they have a gambling addiction. ",
"BetDSI would prefer to be informed of the situation. ",
"BetDSI will immediately close the account and cease all activity on the specified account."
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"News and Media\n\nAssociation News\n\nHere are the latest Association News\n\nThe Think Blue Kitesurf World Cup 2014 kicked off today with registration and an impressive opening ceremony that presented all of the registered riders by home country, in front of an enthusiastic crowd. ",
"In total, 116 riders representing 28 nationalities registered to compete.",
"\n\nLocated on the expansive beaches of St. Peter-Ording, Germany, this event is undoubtedly considered the biggest and most well attended kiteboarding event to date. ",
"For the past eight years it has been known to deliver all the spectacular action and suspense that only a world-class event could. ",
"Over the course of the next ten days, riders will do battle in the disciplines of freestyle and slalom to compete for €47,000 in prize money.",
"\n\nIn the freestyle division, former freestyle World Champion Youri Zoon (NL) is present after a two-event hiatus due to a knee injury, as well as Alberto Rondina, (IT) who has taken some time off from competition. ",
"Also present are last year’s winners Marc Jacobs (NZ) and Karolina Winkowska (PL) who are surely motivated to win for the second year in a row. ",
"Liam Whaley (ES) will also fight for a spot at the top, fresh off his win at the PKRA Fuerteventura and a recent second place finish in Egypt.",
"\n\nWith slalom as the second discipline, the top riders on the planet are present and will showcase their skills and strive for top placements at this major event. ",
"Definitely, the top-ranked Julien Kerneur (FR), Ozzie Smith (SA) and Ariel Corniel (DR) along with and Bryan Lake (US) will offer up some of the most incredible racing action seen this year. ",
"Furthermore, female frontrunners Katja Roose (NL) and Bibiana Magaji (EE) and Eliska Parma (AT) are also in attendance, and plan to make a strong showing, while others will try to claim the top titles.",
"\n\nAs in years past, this event in St Peter-Ording attracts thousands of kiting enthusiasts, industry members, and international media and press, as top riders and hungry up and comers face-off in this prestigious event. ",
"First on the competition schedule is the freestyle trials with fifty men competing for ten spots remaining in the main event. ",
"For the women, twelve girls will be battling for only five spots remaining."
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"#----------------------------------------------------------------------------------------------\n# Auto-generated from:\n# <http://www.digitaluk.co.uk/coveragechecker/main/tradeexport/ZE2 9EL/NA/0/>\n#----------------------------------------------------------------------------------------------\n# location and provider: UK, Bressay\n# date (yyyy-mm-dd) : 2014-03-25\n#\n#----------------------------------------------------------------------------------------------\n[C28 BBC A]\n\tDELIVERY_SYSTEM = DVBT\n\tFREQUENCY = 530000000\n\tBANDWIDTH_HZ = 8000000\n\tCODE_RATE_HP = 2/3\n\tCODE_RATE_LP = NONE\n\tMODULATION = QAM/64\n\tTRANSMISSION_MODE = 8K\n\tGUARD_INTERVAL = 1/32\n\tHIERARCHY = NONE\n\tINVERSION = AUTO\n\n[C25 D3&4]\n\tDELIVERY_SYSTEM = DVBT\n\tFREQUENCY = 506000000\n\tBANDWIDTH_HZ = 8000000\n\tCODE_RATE_HP = 2/3\n\tCODE_RATE_LP = NONE\n\tMODULATION = QAM/64\n\tTRANSMISSION_MODE = 8K\n\tGUARD_INTERVAL = 1/32\n\tHIERARCHY = NONE\n\tINVERSION = AUTO\n\n[C27 SDN]\n\tDELIVERY_SYSTEM = DVBT\n\tFREQUENCY = 522000000\n\tBANDWIDTH_HZ = 8000000\n\tCODE_RATE_HP = 3/4\n\tCODE_RATE_LP = NONE\n\tMODULATION = QAM/64\n\tTRANSMISSION_MODE = 8K\n\tGUARD_INTERVAL = 1/32\n\tHIERARCHY = NONE\n\tINVERSION = AUTO\n\n[C24 ARQ A]\n\tDELIVERY_SYSTEM = DVBT\n\tFREQUENCY = 498000000\n\tBANDWIDTH_HZ = 8000000\n\tCODE_RATE_HP = 3/4\n\tCODE_RATE_LP = NONE\n\tMODULATION = QAM/64\n\tTRANSMISSION_MODE = 8K\n\tGUARD_INTERVAL = 1/32\n\tHIERARCHY = NONE\n\tINVERSION = AUTO\n\n[C21+ ARQ B]\n\tDELIVERY_SYSTEM = DVBT\n\tFREQUENCY = 474167000\n\tBANDWIDTH_HZ = 8000000\n\tCODE_RATE_HP = 3/4\n\tCODE_RATE_LP = NONE\n\tMODULATION = QAM/64\n\tTRANSMISSION_MODE = 8K\n\tGUARD_INTERVAL = 1/32\n\tHIERARCHY = NONE\n\tINVERSION = AUTO\n\n[C22+ BBC B HD]\n\tDELIVERY_SYSTEM = DVBT2\n\tFREQUENCY = 482167000\n\tBANDWIDTH_HZ = 8000000\n\tCODE_RATE_HP = 2/3\n\tCODE_RATE_LP = NONE\n\tMODULATION = QAM/256\n\tTRANSMISSION_MODE = 32K\n\tGUARD_INTERVAL = 1/128\n\tHIERARCHY = NONE\n\tSTREAM_ID = 0\n\tINVERSION = AUTO\n\n"
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[
"Q:\n\nSpecifying relative path to :r command in sqlcmd mode\n\nA) Suppose you have four .sql files (script1.sql,script2.sql,script3.sql,script4.sql ) in say in a folder c:\\scripts.",
"\nB) Create a main script file (Main.sql) with the following, please note I have given relative path for scripts.",
"\n:r script1.sql\n:r script2.sql\n:r script3.sql\n:r script4.sql\n\nSave the Main.sql in c:\\scripts itself.",
"\nC) Create a batch file named \"ExecuteScripts.bat\" with the following:-\nSQLCMD -E -d<YourDatabaseName> -ic:\\Scripts\\Main.sql\nPAUSE\n\nWhen I run the batch file, its unable to script1.sql file. ",
"When i give full path C:\\scripts\\script1.sql, it works fine but I don't want to hardcode the path here.",
"\nIs it possible to achieve this using sqlcmd?",
"\n\nA:\n\n@echo off\npushd \"c:\\scripts\"\nSQLCMD -E -d<YourDatabaseName> -iMain.sql\npopd\nPAUSE\n\nOr if all the sql scripts are in the same folder as your batch script, then:\n@echo off\npushd \"%~dp0\"\nSQLCMD -E -d<YourDatabaseName> -iMain.sql\npopd\nPAUSE\n\nThe last version allows your scripts to run properly, no matter where they reside.",
"\n\n"
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"Interaction of phospholipid liposomes with plasma membrane isolated from alveolar type II cells: effect of pulmonary surfactant protein A.\nPulmonary surfactant protein A (SP-A) augments the uptake of phospholipid liposomes containing dipalmitoylphosphatidylcholine (DPPC) by alveolar type II cells. ",
"The SP-A-mediated uptake process of lipids by type II cells have not been well understood. ",
"In the present study we investigated the SP-A-mediated interaction of phospholipids with plasma membrane isolated from alveolar type II cells. ",
"SP-A increased the amount of liposomes containing radiolabeled DPPC associated with type II cell plasma membrane by 4-fold compared to the control without SP-A when analyzed by sucrose density gradient centrifugation. ",
"This effect is dependent upon the SP-A concentration. ",
"The enhancement was inhibited by anti-SP-A antibody and EGTA. ",
"When type II cell plasma membrane and liposomes containing [14C]DPPC and [3H]triolein were coincubated with or without SP-A, analysis on sucrose density gradients revealed that the profiles of [14C]DPPC and [3H]triolein in each fraction were almost identical with or without SP-A, indicating that SP-A mediates the binding of liposomes to plasma membrane but not transfer of DPPC. ",
"SP-A increased the association of liposomes containing DPPC with the membrane by 2-fold more than that containing 1-palmitoyl-2-linoleoyl-phosphatidylcholine (PLPC). ",
"SP-A induced aggregation of phospholipid liposomes containing PLPC as well as those containing DPPC, but the final turbidity of DPPC liposomes aggregated by SP-A was only by 15% greater than that of PLPC liposomes. ",
"The amount of DPPC liposomes associated with the plasma membrane derived from type II cells was 2-fold greater than that from liver. ",
"We speculate that the SP-A-mediated interaction of lipids with type II cell plasma membrane may contribute, in part, to the lipid uptake process by type II cells."
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"pile_set_name": "PubMed Abstracts"
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"Acute transient memory loss.",
"\nAnterograde amnesia refers to the inability to form new memories. ",
"Alcoholic blackout, benzodiazepine-induced amnesia and transient global amnesia are three disorders that result in acute transient memory loss. ",
"These disorders may be difficult to recognize, because the memory loss is not usually accompanied by other symptoms of neurologic impairment."
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"set(BASELINE ${ITK_DATA_ROOT}/Baseline/Segmentation)\nset(TEMP ${ITK_BINARY_DIR}/Testing/Temporary)\n\nitk_add_test(NAME ConfidenceConnectedWhiteTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/ConfidenceConnectedWhiteTest.png}\n ${TEMP}/ConfidenceConnectedWhiteTest.png\n $<TARGET_FILE:ConfidenceConnected>\n ${ITK_SOURCE_DIR}/Examples/Data/BrainProtonDensitySlice.png\n ${TEMP}/ConfidenceConnectedWhiteTest.png\n 60 116\n)\n\nitk_add_test(NAME ConfidenceConnectedVentricleTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/ConfidenceConnectedVentricleTest.png}\n ${TEMP}/ConfidenceConnectedVentricleTest.png\n $<TARGET_FILE:ConfidenceConnected>\n ${ITK_SOURCE_DIR}/Examples/Data/BrainProtonDensitySlice.png\n ${TEMP}/ConfidenceConnectedVentricleTest.png\n 81 112\n)\n\nitk_add_test(NAME ConfidenceConnectedGrayTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/ConfidenceConnectedGrayTest.png}\n ${TEMP}/ConfidenceConnectedGrayTest.png\n $<TARGET_FILE:ConfidenceConnected>\n ${ITK_SOURCE_DIR}/Examples/Data/BrainProtonDensitySlice.png\n ${TEMP}/ConfidenceConnectedGrayTest.png\n 107 69\n)\n\nitk_add_test(NAME ConnectedThresholdWhiteTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/ConnectedThresholdWhiteTest.png}\n ${TEMP}/ConnectedThresholdWhiteTest.png\n $<TARGET_FILE:ConnectedThresholdImageFilter>\n ${ITK_SOURCE_DIR}/Examples/Data/BrainProtonDensitySlice.png\n ${TEMP}/ConnectedThresholdWhiteTest.png\n 60 116 150 180\n)\n\nitk_add_test(NAME ConnectedThresholdVentricleTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/ConnectedThresholdVentricleTest.png}\n ${TEMP}/ConnectedThresholdVentricleTest.png\n $<TARGET_FILE:ConnectedThresholdImageFilter>\n ${ITK_SOURCE_DIR}/Examples/Data/BrainProtonDensitySlice.png\n ${TEMP}/ConnectedThresholdVentricleTest.png\n 81 112 210 250\n)\n\nitk_add_test(NAME ConnectedThresholdGrayTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/ConnectedThresholdGrayTest.png}\n ${TEMP}/ConnectedThresholdGrayTest.png\n $<TARGET_FILE:ConnectedThresholdImageFilter>\n ${ITK_SOURCE_DIR}/Examples/Data/BrainProtonDensitySlice.png\n ${TEMP}/ConnectedThresholdGrayTest.png\n 107 69 180 210\n)\n\nitk_add_test(NAME FastMarchingLeftVentricleTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/FastMarchingLeftVentricleTest.png,:}\n ${TEMP}/FastMarchingLeftVentricleTest.png\n $<TARGET_FILE:FastMarchingImageFilter>\n ${ITK_SOURCE_DIR}/Examples/Data/BrainProtonDensitySlice.png\n ${TEMP}/FastMarchingLeftVentricleTest.png\n 81 114 1.0 -0.5 3.0 100 100 debug1.png debug2.png debug3.png\n)\n\nitk_add_test(NAME FastMarchingRightVentricleTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/FastMarchingRightVentricleTest.png,:}\n ${TEMP}/FastMarchingRightVentricleTest.png\n $<TARGET_FILE:FastMarchingImageFilter>\n ${ITK_SOURCE_DIR}/Examples/Data/BrainProtonDensitySlice.png\n ${TEMP}/FastMarchingRightVentricleTest.png\n 99 114 1.0 -0.5 3.0 100 100 debug1.png debug2.png debug3.png\n)\n\nitk_add_test(NAME FastMarchingWhiteMatterTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/FastMarchingWhiteMatterTest.png,:}\n ${TEMP}/FastMarchingWhiteMatterTest.png\n $<TARGET_FILE:FastMarchingImageFilter>\n ${ITK_SOURCE_DIR}/Examples/Data/BrainProtonDensitySlice.png\n ${TEMP}/FastMarchingWhiteMatterTest.png\n 56 92 1.0 -0.3 2.0 200 100 debug1.png debug2.png debug3.png\n)\n\nitk_add_test(NAME FastMarchingGrayMatterTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/FastMarchingGrayMatterTest.png,:}\n ${TEMP}/FastMarchingGrayMatterTest.png\n $<TARGET_FILE:FastMarchingImageFilter>\n ${ITK_SOURCE_DIR}/Examples/Data/BrainProtonDensitySlice.png\n ${TEMP}/FastMarchingGrayMatterTest.png\n 40 90 .5 -0.3 2.0 200 100 debug1.png debug2.png debug3.png\n)\n\nitk_add_test(NAME GeodesicActiveContourLeftVentricleTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/GeodesicActiveContourLeftVentricleTest.png,:}\n ${TEMP}/GeodesicActiveContourLeftVentricleTest.png\n $<TARGET_FILE:GeodesicActiveContourImageFilter>\n ${ITK_SOURCE_DIR}/Examples/Data/BrainProtonDensitySlice.png\n ${TEMP}/GeodesicActiveContourLeftVentricleTest.png\n 81 114 5.0 1.0 -0.5 3.0 2.0\n)\n\nitk_add_test(NAME GeodesicActiveContourRightVentricleTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/GeodesicActiveContourRightVentricleTest.png,:}\n ${TEMP}/GeodesicActiveContourRightVentricleTest.png\n $<TARGET_FILE:GeodesicActiveContourImageFilter>\n ${ITK_SOURCE_DIR}/Examples/Data/BrainProtonDensitySlice.png\n ${TEMP}/GeodesicActiveContourRightVentricleTest.png\n 99 114 5.0 1.0 -0.5 3.0 2.0\n)\n\nitk_add_test(NAME GeodesicActiveContourWhiteMatterTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/GeodesicActiveContourWhiteMatterTest.png,:}\n ${TEMP}/GeodesicActiveContourWhiteMatterTest.png\n $<TARGET_FILE:GeodesicActiveContourImageFilter>\n ${ITK_SOURCE_DIR}/Examples/Data/BrainProtonDensitySlice.png\n ${TEMP}/GeodesicActiveContourWhiteMatterTest.png\n 56 92 5.0 1.0 -0.3 2.0 10.0\n)\n\nitk_add_test(NAME GeodesicActiveContourGrayMatterTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/GeodesicActiveContourGrayMatterTest.png,:}\n ${TEMP}/GeodesicActiveContourGrayMatterTest.png\n $<TARGET_FILE:GeodesicActiveContourImageFilter>\n ${ITK_SOURCE_DIR}/Examples/Data/BrainProtonDensitySlice.png\n ${TEMP}/GeodesicActiveContourGrayMatterTest.png\n 40 90 5.0 .5 -0.3 2.0 10.0\n)\n\nitk_add_test(NAME ShapeDetectionLevelSetLeftVentricleTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/ShapeDetectionLevelSetLeftVentricleTest.png,:}\n ${TEMP}/ShapeDetectionLevelSetLeftVentricleTest.png\n $<TARGET_FILE:ShapeDetectionLevelSetFilter>\n ${ITK_SOURCE_DIR}/Examples/Data/BrainProtonDensitySlice.png\n ${TEMP}/ShapeDetectionLevelSetLeftVentricleTest.png\n 81 114 5.0 1.0 -0.5 3.0 0.05 1.0\n)\n\nitk_add_test(NAME ShapeDetectionLevelSetRightVentricleTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/ShapeDetectionLevelSetRightVentricleTest.png,:}\n ${TEMP}/ShapeDetectionLevelSetRightVentricleTest.png\n $<TARGET_FILE:ShapeDetectionLevelSetFilter>\n ${ITK_SOURCE_DIR}/Examples/Data/BrainProtonDensitySlice.png\n ${TEMP}/ShapeDetectionLevelSetRightVentricleTest.png\n 99 114 5.0 1.0 -0.5 3.0 0.05 1.0\n)\n\nitk_add_test(NAME ShapeDetectionLevelSetWhiteMatterTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/ShapeDetectionLevelSetWhiteMatterTest.png,:}\n ${TEMP}/ShapeDetectionLevelSetWhiteMatterTest.png\n $<TARGET_FILE:ShapeDetectionLevelSetFilter>\n ${ITK_SOURCE_DIR}/Examples/Data/BrainProtonDensitySlice.png\n ${TEMP}/ShapeDetectionLevelSetWhiteMatterTest.png\n 56 92 5.0 1.0 -0.3 2.0 0.05 1.0\n)\n\nitk_add_test(NAME ShapeDetectionLevelSetGrayMatterTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/ShapeDetectionLevelSetGrayMatterTest.png,:}\n ${TEMP}/ShapeDetectionLevelSetGrayMatterTest.png\n $<TARGET_FILE:ShapeDetectionLevelSetFilter>\n ${ITK_SOURCE_DIR}/Examples/Data/BrainProtonDensitySlice.png\n ${TEMP}/ShapeDetectionLevelSetGrayMatterTest.png\n 40 90 5.0 1.0 -0.3 2.0 0.05 1.0\n)\n\nitk_add_test(NAME ThresholdSegmentationLevelSetVentricleTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/ThresholdSegmentationLevelSetVentricleTest.png,:}\n ${TEMP}/ThresholdSegmentationLevelSetVentricleTest.png\n $<TARGET_FILE:ThresholdSegmentationLevelSetImageFilter>\n ${ITK_SOURCE_DIR}/Examples/Data/BrainProtonDensitySlice.png\n ${TEMP}/ThresholdSegmentationLevelSetVentricleTest.png\n 81 112 5 210 250\n)\n\nitk_add_test(NAME ThresholdSegmentationLevelSetWhiteMatterTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/ThresholdSegmentationLevelSetWhiteMatterTest.png,:}\n ${TEMP}/ThresholdSegmentationLevelSetWhiteMatterTest.png\n --compareNumberOfPixelsTolerance 40\n $<TARGET_FILE:ThresholdSegmentationLevelSetImageFilter>\n ${ITK_SOURCE_DIR}/Examples/Data/BrainProtonDensitySlice.png\n ${TEMP}/ThresholdSegmentationLevelSetWhiteMatterTest.png\n 60 116 5 150 180\n)\n\nitk_add_test(NAME ThresholdSegmentationLevelSetGrayMatterTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/ThresholdSegmentationLevelSetGrayMatterTest.png,:}\n ${TEMP}/ThresholdSegmentationLevelSetGrayMatterTest.png\n $<TARGET_FILE:ThresholdSegmentationLevelSetImageFilter>\n ${ITK_SOURCE_DIR}/Examples/Data/BrainProtonDensitySlice.png\n ${TEMP}/ThresholdSegmentationLevelSetGrayMatterTest.png\n 107 69 5 180 210\n)\n\nitk_add_test(NAME VectorConfidenceConnectedTest1 COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/VectorConfidenceConnected1.png}\n ${TEMP}/VectorConfidenceConnected1.png\n $<TARGET_FILE:VectorConfidenceConnected>\n ${ITK_SOURCE_DIR}/Examples/Data/VisibleWomanEyeSlice.png\n ${TEMP}/VectorConfidenceConnected1.png\n 70 120 7 1\n)\n\nitk_add_test(NAME VectorConfidenceConnectedTest2 COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/VectorConfidenceConnected2.png}\n ${TEMP}/VectorConfidenceConnected2.png\n $<TARGET_FILE:VectorConfidenceConnected>\n ${ITK_SOURCE_DIR}/Examples/Data/VisibleWomanEyeSlice.png\n ${TEMP}/VectorConfidenceConnected2.png\n 23 93 7 1\n)\n\nitk_add_test(NAME VectorConfidenceConnectedTest3 COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/VectorConfidenceConnected3.png}\n ${TEMP}/VectorConfidenceConnected3.png\n $<TARGET_FILE:VectorConfidenceConnected>\n ${ITK_SOURCE_DIR}/Examples/Data/VisibleWomanEyeSlice.png\n ${TEMP}/VectorConfidenceConnected3.png\n 66 66 3 1\n)\n\n\nitk_add_test(NAME CannySegmentationLevelSetImageFilterTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/CannySegmentationLevelSetImageFilterTest.png}\n ${TEMP}/CannySegmentationLevelSetImageFilterTest.png\n $<TARGET_FILE:CannySegmentationLevelSetImageFilter>\n ${ITK_SOURCE_DIR}/Examples/Data/BrainProtonDensitySlice.png\n DATA{${BASELINE}/ThresholdSegmentationLevelSetVentricle.png}\n ${TEMP}/CannySegmentationLevelSetImageFilterTest.png\n 7 0.1 -10.0 127.5 10000\n)\n\nitk_add_test(NAME GeodesicActiveContourShapePriorCallosumTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/GeodesicActiveContourShapePriorCallosumTest.png}\n ${TEMP}/GeodesicActiveContourShapePriorCallosumTest.png\n $<TARGET_FILE:GeodesicActiveContourShapePriorLevelSetImageFilter>\n ${ITK_SOURCE_DIR}/Examples/Data/BrainMidSagittalSlice.png\n ${TEMP}/GeodesicActiveContourShapePriorCallosumTest.png\n 120 85 60 102 88 83 6 1.0 0.5 0.02\n ${ITK_SOURCE_DIR}/Examples/Data/CorpusCallosumMeanShape.mha 3\n ${ITK_SOURCE_DIR}/Examples/Data/CorpusCallosumMode%d.mha 10 0\n)\n\nitk_add_test(NAME NeighborhoodConnectedWhiteTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/NeighborhoodConnectedWhiteTest.png}\n ${TEMP}/NeighborhoodConnectedWhiteTest.png\n $<TARGET_FILE:NeighborhoodConnectedImageFilter>\n ${ITK_SOURCE_DIR}/Examples/Data/BrainProtonDensitySlice.png\n ${TEMP}/NeighborhoodConnectedWhiteTest.png\n 60 116 150 180\n)\n\nitk_add_test(NAME NeighborhoodConnectedVentricleTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/NeighborhoodConnectedVentricleTest.png}\n ${TEMP}/NeighborhoodConnectedVentricleTest.png\n $<TARGET_FILE:NeighborhoodConnectedImageFilter>\n ${ITK_SOURCE_DIR}/Examples/Data/BrainProtonDensitySlice.png\n ${TEMP}/NeighborhoodConnectedVentricleTest.png\n 81 112 210 250\n)\n\nitk_add_test(NAME NeighborhoodConnectedGrayTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/NeighborhoodConnectedGrayTest.png}\n ${TEMP}/NeighborhoodConnectedGrayTest.png\n $<TARGET_FILE:NeighborhoodConnectedImageFilter>\n ${ITK_SOURCE_DIR}/Examples/Data/BrainProtonDensitySlice.png\n ${TEMP}/NeighborhoodConnectedGrayTest.png\n 107 69 180 210\n)\n\nitk_add_test(NAME IsolatedConnectedTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/IsolatedConnectedTest.png}\n ${TEMP}/IsolatedConnectedTest.png\n $<TARGET_FILE:IsolatedConnectedImageFilter>\n ${ITK_SOURCE_DIR}/Examples/Data/BrainProtonDensitySlice.png\n ${TEMP}/IsolatedConnectedTest.png\n 61 140 150 63 43\n)\n\nitk_add_test(NAME RelabelComponentImageFilterTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/RelabelComponentImageFilter.png}\n ${TEMP}/RelabelComponentImageFilter.png\n $<TARGET_FILE:RelabelComponentImageFilter>\n ${ITK_SOURCE_DIR}/Examples/Data/WatershedSegmentation.png\n ${TEMP}/RelabelComponentImageFilter.png\n)\n\nitk_add_test(NAME WatershedSegmentation1Test1 COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/WatershedSegmentation1Test1.png}\n ${TEMP}/WatershedSegmentation1Test1.png\n $<TARGET_FILE:WatershedSegmentation1>\n ${ITK_SOURCE_DIR}/Examples/Data/VisibleWomanEyeSlice.png\n ${TEMP}/WatershedSegmentation1Test1.png\n 2.0 10 0.0 0.05 1\n)\n\nitk_add_test(NAME WatershedSegmentation1Test2 COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/WatershedSegmentation1Test2.png}\n ${TEMP}/WatershedSegmentation1Test2.png\n $<TARGET_FILE:WatershedSegmentation1>\n ${ITK_SOURCE_DIR}/Examples/Data/VisibleWomanEyeSlice.png\n ${TEMP}/WatershedSegmentation1Test2.png\n 2.0 10 0.001 0.15 0\n)\n\nitk_add_test(NAME CurvesLevelSetImageFilterTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/CurvesLevelSetImageFilterTest.png}\n ${TEMP}/CurvesLevelSetImageFilterTest.png\n $<TARGET_FILE:CurvesLevelSetImageFilter>\n ${ITK_SOURCE_DIR}/Examples/Data/BrainProtonDensitySlice.png\n ${TEMP}/CurvesLevelSetImageFilterTest.png\n 81 114 5.0 1.0 -0.5 3.0 2.0\n)\n\nitk_add_test(NAME HoughTransformTwo2DLinesTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/HoughTransformTwoLinesTest.png}\n ${TEMP}/HoughTransformTwoLinesTest.png\n $<TARGET_FILE:HoughTransform2DLinesImageFilter>\n ${ITK_SOURCE_DIR}/Examples/Data/HoughTransformTwoLines.png\n ${TEMP}/HoughTransformTwoLinesTest.png\n 2 5 10\n)\n\nitk_add_test(NAME HoughTransformTwo2DCirclesTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/HoughTransformTwoCirclesTest.png}\n ${TEMP}/HoughTransformTwoCirclesTest.png\n $<TARGET_FILE:HoughTransform2DCirclesImageFilter>\n ${ITK_SOURCE_DIR}/Examples/Data/HoughTransformTwoCircles.png\n ${TEMP}/HoughTransformTwoCirclesTest.png\n 2 6 20 3.14 10 5 1.5\n)\n\nitk_add_test(NAME LaplacianSegmentationLevelSetImageFilterTest COMMAND ${ITK_TEST_DRIVER}\n --compare DATA{${BASELINE}/LaplacianSegmentationLevelSetImageFilter.png}\n ${TEMP}/LaplacianSegmentationLevelSetImageFilter.png\n $<TARGET_FILE:LaplacianSegmentationLevelSetImageFilter>\n ${ITK_SOURCE_DIR}/Examples/Data/BrainProtonDensitySlice.png\n DATA{${BASELINE}/ThresholdSegmentationLevelSetVentricle.png}\n ${TEMP}/LaplacianSegmentationLevelSetImageFilter.png\n 10 2.0 1 127.5 15\n)\n"
] | {
"pile_set_name": "Github"
} | [
0.003043844310601645
] | 0.003044 | 5 |
[
"/*\n LUFA Library\n Copyright (C) Dean Camera, 2015.",
"\n\n dean [at] fourwalledcubicle [dot] com\n www.lufa-lib.org\n*/\n\n/*\n Copyright 2015 Dean Camera (dean [at] fourwalledcubicle [dot] com)\n\n Permission to use, copy, modify, distribute, and sell this\n software and its documentation for any purpose is hereby granted\n without fee, provided that the above copyright notice appear in\n all copies and that both that the copyright notice and this\n permission notice and warranty disclaimer appear in supporting\n documentation, and that the name of the author not be used in\n advertising or publicity pertaining to distribution of the\n software without specific, written prior permission.",
"\n\n The author disclaims all warranties with regard to this\n software, including all implied warranties of merchantability\n and fitness. ",
" In no event shall the author be liable for any\n special, indirect or consequential damages or any damages\n whatsoever resulting from loss of use, data or profits, whether\n in an action of contract, negligence or other tortious action,\n arising out of or in connection with the use or performance of\n this software.",
"\n*/\n\n#include \"../../../../Common/Common.h\"\n#if (ARCH == ARCH_UC3)\n\n#define __INCLUDE_FROM_USB_DRIVER\n#define __INCLUDE_FROM_USB_CONTROLLER_C\n#include \"../USBController.h\"\n\n#if defined(USB_CAN_BE_BOTH)\nvolatile uint8_t USB_CurrentMode = USB_MODE_None;\n#endif\n\n#if !",
"defined(USE_STATIC_OPTIONS)\nvolatile uint8_t USB_Options;\n#endif\n\nvoid USB_Init(\n #if defined(USB_CAN_BE_BOTH)\n const uint8_t Mode\n #endif\n\n #if (defined(USB_CAN_BE_BOTH) && !",
"defined(USE_STATIC_OPTIONS))\n ,\n #elif (!",
"defined(USB_CAN_BE_BOTH) && defined(USE_STATIC_OPTIONS))\n void\n #endif\n\n #if !",
"defined(USE_STATIC_OPTIONS)\n const uint8_t Options\n #endif\n )\n{\n\t#if !",
"defined(USE_STATIC_OPTIONS)\n\tUSB_Options = Options;\n\t#endif\n\n\t#if defined(USB_CAN_BE_BOTH)\n\tif (Mode == USB_MODE_UID)\n\t{\n\t\tAVR32_USBB.USBCON.uide = true;\n\t\tUSB_INT_Enable(USB_INT_IDTI);\n\t\tUSB_CurrentMode = USB_GetUSBModeFromUID();\n\t}\n\telse\n\t{\n\t\tAVR32_USBB.USBCON.uide = false;\n\t\tUSB_CurrentMode = Mode;\n\t}\n\t#else\n\tAVR32_USBB.USBCON.uide = false;\n\t#endif\n\n\tUSB_IsInitialized = true;\n\n\tUSB_ResetInterface();\n}\n\nvoid USB_Disable(void)\n{\n\tUSB_INT_DisableAllInterrupts();\n\tUSB_INT_ClearAllInterrupts();\n\n\tUSB_Detach();\n\tUSB_Controller_Disable();\n\n\tUSB_OTGPAD_Off();\n\n\t#if defined(USB_CAN_BE_BOTH)\n\tUSB_CurrentMode = USB_MODE_None;\n\t#endif\n\n\tAVR32_PM.GCCTRL[3].cen = false;\n\n\tUSB_IsInitialized = false;\n}\n\nvoid USB_ResetInterface(void)\n{\n\t#if defined(USB_CAN_BE_BOTH)\n\tbool UIDModeSelectEnabled = AVR32_USBB.USBCON.uide;\n\t#endif\n\n\tAVR32_PM.GCCTRL[AVR32_PM_GCLK_USBB].pllsel = !(",
"USB_Options & USB_OPT_GCLK_SRC_OSC);\n\tAVR32_PM.GCCTRL[AVR32_PM_GCLK_USBB].oscsel = !(",
"USB_Options & USB_OPT_GCLK_CHANNEL_0);\n\tAVR32_PM.GCCTRL[AVR32_PM_GCLK_USBB].diven = (F_USB !",
"= USB_CLOCK_REQUIRED_FREQ);\n\tAVR32_PM.GCCTRL[AVR32_PM_GCLK_USBB].div = (F_USB == USB_CLOCK_REQUIRED_FREQ) ? ",
"0 : (uint32_t)((F_USB / USB_CLOCK_REQUIRED_FREQ / 2) - 1);\n\tAVR32_PM.GCCTRL[AVR32_PM_GCLK_USBB].cen = true;\n\n\tUSB_INT_DisableAllInterrupts();\n\tUSB_INT_ClearAllInterrupts();\n\n\tUSB_Controller_Reset();\n\n\t#if defined(USB_CAN_BE_BOTH)\n\tif (UIDModeSelectEnabled)\n\t USB_INT_Enable(USB_INT_IDTI);\n\t#endif\n\n\tUSB_CLK_Unfreeze();\n\n\tif (USB_CurrentMode == USB_MODE_Device)\n\t{\n\t\t#if defined(USB_CAN_BE_DEVICE)\n\t\tAVR32_USBB.USBCON.uimod = true;\n\n\t\tUSB_Init_Device();\n\t\t#endif\n\t}\n\telse if (USB_CurrentMode == USB_MODE_Host)\n\t{\n\t\t#if defined(INVERTED_VBUS_ENABLE_LINE)\n\t\tAVR32_USBB.USBCON.vbuspo = true;\n\t\t#endif\n\n\t\t#if defined(USB_CAN_BE_HOST)\n\t\tAVR32_USBB.USBCON.uimod = false;\n\n\t\tUSB_Init_Host();\n\t\t#endif\n\t}\n\n\tUSB_OTGPAD_On();\n}\n\n#if defined(USB_CAN_BE_DEVICE)\nstatic void USB_Init_Device(void)\n{\n\tUSB_DeviceState = DEVICE_STATE_Unattached;\n\tUSB_Device_ConfigurationNumber = 0;\n\n\t#if !",
"defined(NO_DEVICE_REMOTE_WAKEUP)\n\tUSB_Device_RemoteWakeupEnabled = false;\n\t#endif\n\n\t#if !",
"defined(NO_DEVICE_SELF_POWER)\n\tUSB_Device_CurrentlySelfPowered = false;\n\t#endif\n\n\t#if !",
"defined(FIXED_CONTROL_ENDPOINT_SIZE)\n\tUSB_Descriptor_Device_t* DeviceDescriptorPtr;\n\n\tif (CALLBACK_USB_GetDescriptor((DTYPE_Device << 8), 0, (void*)&DeviceDescriptorPtr) !",
"= NO_DESCRIPTOR)\n\t USB_Device_ControlEndpointSize = DeviceDescriptorPtr->Endpoint0Size;\n\t#endif\n\n\tif (USB_Options & USB_DEVICE_OPT_LOWSPEED)\n\t{\n\t\tUSB_Device_SetLowSpeed();\n\t}\n\telse\n\t{\n\t\t#if defined(USB_DEVICE_OPT_HIGHSPEED)\n\t\tif (USB_Options & USB_DEVICE_OPT_HIGHSPEED)\n\t\t USB_Device_SetHighSpeed();\n\t\telse\n\t\t USB_Device_SetFullSpeed();\n\t\t#else\n\t\tUSB_Device_SetFullSpeed();\n\t\t#endif\n\t}\n\n\tUSB_INT_Enable(USB_INT_VBUSTI);\n\n\tEndpoint_ConfigureEndpoint(ENDPOINT_CONTROLEP, EP_TYPE_CONTROL,\n\t\t\t\t\t\t\t USB_Device_ControlEndpointSize, 1);\n\n\tUSB_INT_Clear(USB_INT_SUSPI);\n\tUSB_INT_Enable(USB_INT_SUSPI);\n\tUSB_INT_Enable(USB_INT_EORSTI);\n\n\tUSB_Attach();\n}\n#endif\n\n#if defined(USB_CAN_BE_HOST)\nstatic void USB_Init_Host(void)\n{\n\tUSB_HostState = HOST_STATE_Unattached;\n\tUSB_Host_ConfigurationNumber = 0;\n\tUSB_Host_ControlPipeSize = PIPE_CONTROLPIPE_DEFAULT_SIZE;\n\n\tUSB_Host_HostMode_On();\n\n\tUSB_Host_VBUS_Auto_On();\n\n\tUSB_INT_Enable(USB_INT_DCONNI);\n\tUSB_INT_Enable(USB_INT_BCERRI);\n\n\tUSB_Attach();\n}\n#endif\n\n#endif\n"
] | {
"pile_set_name": "Github"
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[
"In vitro synthesized small interfering RNAs elicit RNA interference in african trypanosomes: an in vitro and in vivo analysis.",
"\nRNA interference (RNAi) describes an epigenetic gene silencing reaction by which gene-specific double-stranded RNA acts as a trigger to induce the ribonucleolytic degradation of homologous transcripts. ",
"RNAi in African trypanosomes has been shown to be involved in regulating the transcript abundance of retroposons, and the process currently represents the method of choice in gene function studies of the parasite. ",
"However, little is known concerning the mechanistic and structural aspects of the processing reaction. ",
"This is in part due to the absence of a trypanosome-specific RNAi in vitro system. ",
"Here we demonstrate that both the Dicer and the RNA-induced silencing complex steps of the RNAi reaction pathway can be monitored in vitro using cell-free trypanosome extracts. ",
"The two in vitro activities and the generated small interfering RNAs (siRNAs) are characterized by features known from other organisms, and we demonstrate that chemically as well as enzymatically synthesized siRNAs are functional in the parasite. ",
"Thus, the transfection of synthetic siRNAs can be used to rapidly monitor gene knockdown phenotypes in Trypanosoma brucei, which should be helpful in genome-wide, RNAi-based screening experiments."
] | {
"pile_set_name": "PubMed Abstracts"
} | [
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0.0049261083743842365,
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0.005649717514124294,
0,
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] | 0.002314 | 5 |
[
"Inspiring Surfaces\n\nWith over 40 years in the business and more than 2 million sq. ",
"ft. ",
"of materials in stock, Iberia Tiles is the go-to place in Miami to find the highest-quality porcelain tiles and stones from Italy and Spain.",
"\n\nIberia Tiles is the main choice of top architects and designers both for residential and commercial projects throughout the world. ",
"In South Florida, you can find Iberia Tiles materials at Brickell City Centre’s exterior and pools designed by Arquitectonica, Icon Brickell’s recreational deck renovation, the new building façade at FIU, Miami Bay Club, Sereno Residences, 1010 Brickell and Oceana. ",
"Architect Juan Brugo from Nu Space specified their tiles both at the O Residences and Nine Island high-rise building projects, just as architect RA Shaw did in his Cascade beachfront villa in the Turks & Caicos. ",
"Other important projects include the Yves Saint Laurent stores, including the flagship location on 57th Avenue in New York, and Ecuador International Airport.",
"\n\nThe secret to their success largely comes from their commitment to providing the finest selection of tile and stone available. “",
"We always attend the top international trade shows including the Cersaie and Marmomacc expos in Italy, Cevisama in Spain and Coverings here in the U.S.,” says CEO Carlos Ferrando. “",
"We look for the last trends then bring them to the architects and designers in South Florida.” ",
"As such, the best manufacturers around the world offer Iberia Tiles their best collections because they prefer Iberia Tiles as the showroom for their products. “",
"We are a provider of the finest porcelain and stone from all around the world, but especially from Italy and Spain,” continues Ferrando. “",
"We have exclusive rights to some of the most recognized high-end brands like Florim, Vogue, Inalco and Rosa Gres, to name a few. ",
"Additionally, we invest in developing our own designs with our own brand produced by the finest manufacturers in Spain and Italy.”",
"\n\nA good example of their extensive selection of superior surface materials are the porcelain slabs which are currently trending, including the ultra-large sizes 40 in. ",
"x 40 in., ",
"48 in. ",
"x 48 in., ",
"40 in. ",
"x 100 in., ",
"48 in. ",
"x 96 in., ",
"etc. ",
"up to their 128 in. ",
"x 60 in. ",
"porcelain slabs for indoor and outdoor countertops. “",
"By getting porcelain slabs instead of natural stone, you are eliminating the hassle of maintenance and polishing your floors,” says Ferrando. “",
"In addition, by going with porcelain you know exactly what you’re getting. ",
"The colors are more reliable and you will make the installer’s life a lot easier. ",
"Larger format tiles give the impression of a bigger room and more space.”",
"\n\nUpon arrival, customers are first greeted at the entrance, where they are offered some of Iberia Tiles’ famous coffee or another beverage of choice. ",
"The Iberia Tiles team then works to get an understanding of what the client is looking for and shows them several of the best options selected by the experienced sales associates. ",
"After the customers select the potential options, the team then shows examples of previous projects they have done with the products chosen to given an idea of how it would look installed in their home, office or building. ",
"After the customers pick the product that is right for them, the sales associate continues to oversee the process, making sure the delivery process goes smoothly in order to ensure a pleasant experience.",
"\n\nRosa Sugrañes founded Iberia Tiles in August 1979, and in 1986, the company opened their showroom at 4221 Ponce De Leon Blvd. ",
"in Coral Gables. ",
"Just 3 years later, Iberia Tiles moved to its present headquarters at 2975 NW 77th Ave. ",
"in Miami, while keeping the Ponce De Leon location, together yielding 80,000 square feet of total space. ",
"Over the ensuing 40 years, the company has been dedicated to providing the South Florida residential and commercial markets with design options for hard surface flooring. “",
"We have built a reputation of having the highest-quality finishes with endless design options relating to porcelain, stone, mosaics and slabs,” says Ferrando. “",
"After many years of hard work and making customer satisfaction one of our main priorities, we are one of the most recognized companies for tiles and stone in all of South Florida.” ",
"In addition to the huge selection of tile and stone, they also offer setting materials, profiles, faucets, bathroom furniture and more to their clientele, which includes builders, designers, architects and homeowners.",
"\n\nLooking toward the future, they plan to keep bringing attractive and innovative products to the South Florida market while continuing to grow by opening new stores and expanding distribution. “",
"We are currently renovating our main store in Miami, which will carry all of our products, and we are very proud of the exterior results so far,” he says. “",
"We will start the renovation of the interior this year.”",
"\n\nFerrando concludes: “Iberia Tiles has been around for 40 years for a reason,” he says. “",
"Our mission is to make our customers happy and we have a record of accomplishing that,” he says. “",
"We carry top-of-the-line products in the market at competitive prices. ",
"Whether you are a homeowner, architect, designer or builder, we are here to provide the best quality for all.”",
"\n\nIberia Tiles is located at 2975 NW 77th Ave. ",
"in Miami. ",
"Their Coral Gables office is located at 4221 Ponce De Leon Blvd. ",
"For more information, call 305.591.3880 (Miami) or 305.446.0222 (Coral Gables), or visit IberiaTiles.com.",
"\n\nTwo mega-boat shows in town. ",
"Perfect weather. ",
"It’s time to take the family and\nfriends out for a dinner cruise. ",
"Pay close attention to these yacht chef secrets to make things a little smoother out on the high seas."
] | {
"pile_set_name": "Pile-CC"
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0.011363636363636364,
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0.03076923076923077,
0.0380952380952381,
0,
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0
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[
"\nDonald Knuth: \"Wanted: A Name For High-Tech Grief\" - krs\nhttp://sunburn.stanford.edu/~knuth/news.html\n======\njsmcgd\n\"Microsoft\"\n\n------\nhenning\nhmm, gamers use \"QQ\" (due to the resemblance of tears coming from eyes), often\nin the context of \"less qq, more pew pew\" to communicate a lack of empathy.",
"\n\nWikipedia has an entry for the term \"computer rage\":\n<http://en.wikipedia.org/wiki/Computer_rage> , which seems to have a certain\namount of acceptance in the academic community, but it doesn't seem to have\nthe ability to catch on (not going to say the m-word, not going to say the\nm-word...) the way \"road rage\" or \"workaholic\" do.",
"\n\nNotice that discussing ways of _reducing_ this frustration are not part of the\ndiscussion.",
"\n\n------\ndfranke\nDupe: <http://news.ycombinator.com/item?id=79924>\n\n------\nalaskamiller\ntek-emo: depressed about technology.",
"\n\nbob was pretty tek-emo after his macbook battery exploded, his ipod hard drive\nfragged, his gmail accounts wiped, his facebook profile vandalized, and his\nWoW account stolen.",
"\n\n------\npasbesoin\nI'll raise the possibility of recycling the old \"e\" prefix, once more.",
"\n\ne-rage e-despair (e-spair?)",
"\n\nIt might even be applied in initially unanticipated ways. ",
"E.g. e-lag (a\ntakeoff of jet-lag): That tired, time-shifted feeling you get from 2 am\n\"global\" meetings, without the necessity of actually getting on a plane.",
"\n\nIt also can be taken to refer to things electronic, in general. ",
"Thus it might\nwell be retroactively applied to activities such as programming the VCR clock,\nand the like.",
"\n\nWhatever the phrase that sticks, an important component will be its easy\npronunciation. \"",
"Road rage\", \"jet-lag\". ",
"Simple and with preferred syllabic\nstructure. ",
"For more on that, google some of Theo Vennemann's (linguist) work\non optimal syllabic structures (I assume its out there somewhere).",
"\n\n~~~\njimbokun\nOf the ones I've read, I think e-rage has the best chance of actually catching\non.",
"\n\nYou should send it to Dr. Knuth.",
"\n\n------\ntsuru\ntech vex or tech tantrum\n\n------\njgrahamc\n\"tech strife\"\n\n~~~\nweeee\nYou can't say strife without mentioning Gonads... and Strife\n\n<http://www.albinoblacksheep.com/flash/weeee>\n\n------\nedu\niHate\n\n"
] | {
"pile_set_name": "HackerNews"
} | [
0.010033444816053512,
0.006006006006006006,
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[
"Introduction\n============\n\nErythropoietin (EPO), a well-known hematopoietic cytokine, is pleiotropic which exerts a distinctive neuroprotection effect, and plays a strong role in neuronal survival (Sirén et al. [",
"@b26]; Ghezzi and Brines [@b13]; Byts and Sirén [@b6]; Arcasoy [@b2]; Subiros et al. [",
"@b27]). ",
"In recent decades, there has been a growing interest among researchers worldwide to develop potential therapeutic strategies via the application of EPO in patients with neurological diseases, such as cerebral ischemia, traumatic brain injury, and neurodegenerative and neuroinflammatory diseases (Lewczuk et al. [",
"@b18]; Sirén et al. [",
"@b26]; Ghezzi and Brines [@b13]; Byts and Sirén [@b6]; Subiros et al. [",
"@b27]; Broxmeyer [@b5]). ",
"Although the short-term application of high-dose EPO seems to improve neuromuscular functions in patients with neurological diseases, excessive EPO contributes to high hematocrit systematically and the elevation of thrombotic risk in these patients (Sirén et al. [",
"@b26]; Vesey et al. [",
"@b29]; Kirkeby et al. [",
"@b15]; McPherson and Juul [@b20]; Meng et al. [",
"@b21]). ",
"In our study, we addressed a new biological material for neurological diseases based on EPO provided regionally at a nontoxic level; for instance, cell-based therapy.",
"\n\nStem cell therapy has been proposed as a potential candidate for treating neurological diseases by inducing pluripotent stem cells into differentiated neurons (Alvarez et al. [",
"@b1]; Yoo et al. [",
"@b34]); however, many unaddressed risks remain in this context. ",
"A high risk of tumorigenesis transformed from the transplantation of differentiated neurons remains an obstacle to the clinical usage of stem cell therapies (Shih et al. [",
"@b25]; Knoepfler [@b16]). ",
"To seek another approach for cell-based therapies, we suggested the differentiated fibroblasts as an alternative choice (Chen et al. [",
"@b8]).",
"\n\nHuman primary kidney cells can be enriched for EPO-producing cells by magnetic-bead sorting system. ",
"After administration of this subpopulation into a chronic renal injury rat model, renal function and renoprotective effects were markedly improved (Yamaleyeva et al. [",
"@b32]). ",
"One of our previous studies demonstrated that the implantation of 3T3 fibroblasts into the hippocampal striatum area of mice with intracerebral hemorrhage induces neurogenesis, reduces loss of brain tissue, and restores function (Chen et al. [",
"@b8]). ",
"The transplanted 3T3 fibroblasts survived and functioned well within 2 weeks after the transplantation, and appeared less tumorigenic (Chen et al. [",
"@b8]). ",
"Since the cell-based delivery of EPO to the damaged local brain area has not been demonstrated in the animal model of neurological disease, we considered to establish an EPO-overexpressing fibroblast cell line in our study as a material which might represent a short-term, high-dose, and regional therapeutic concept for future in vivo study on the treatment of neurological diseases.",
"\n\nTo test the bioactivities of secreted EPO, a cell model of neurodegeneration, PC12-INT-EGFP cells, which was established in our laboratory, was used in this study (Chien et al. [",
"@b10]). *",
"α*-internexin is a member of the family of neuronal intermediate filament (IF) proteins and coexists with neurofilament triplet proteins that are designated as NF-L, NF-M, and NF-H for low- (L), medium- (M), and high- (H) molecular-weight subunits (Yuan et al. [",
"@b36]). ",
"In the presence of overexpression of the *α*-internexin-enhanced green fluorescent protein fusion protein (*α*-INT-EGFP) in PC12 cells, PC12-INT-EGFP cells showed progressive neuronal death because of the abnormal accumulation of overexpressed *α*-internexin (Chien et al. [",
"@b10]; Lee et al. [",
"@b17]). ",
"Neuronal aggregation is a general characteristic found in many neurodegenerative diseases, such as neuronal intermediate filament inclusion disease (NIFID), amyotrophic lateral sclerosis (ALS), Alzheimer's diseases, Parkinson's disease, and Huntington's disease (Ross and Poirier [@b23]; Ching and Liem [@b11]; Perrot and Eyer [@b22]). ",
"Hence, we intended to test whether EPO secreted by EPO-overexpressing NIH/3T3 fibroblasts enhances the survival of degenerating PC12-INT-EGFP cells.",
"\n\nThe aims of our study were to establish an EPO-overexpressing NIH/3T3 fibroblast cell line and to identify possible neuroprotective effects of secreted EPO to provide a potential material for studies of cell-based therapy in animal models of neurological disorders.",
"\n\nMaterials and Methods\n=====================\n\nEPO-pCMS-EGFP plasmid construction\n----------------------------------\n\nThe clone with a full-length 579 bp mouse EPO cDNA was purchased from Sino Biological Inc. (Beijing, China). ",
"The coding region of mouse EPO was amplified by PCR using designed restriction enzyme sites: *EcoRI* at the 5′ end and *SalI* at the 3′ end. ",
"The primers used to clamp the mouse EPO cDNA were: (forward primer) *5′--GAA TTC ATG GGG GTG CCC GAA--3′* and (Reverse primer) *5′--GTC GAC TC ACC TGT CCC CTC T--3′*. ",
"The PCR-modified mouse EPO cDNA was subcloned into pCMS-EGFP (Clontech, Palo Alto, CA) to obtain the nonfusion coding sequence of EGFP. ",
"After confirmation by DNA sequencing, plasmids carrying a 100% correct sequence of the mouse EPO cDNA (RefSeq: NM_007942.2; <http://www.ncbi.nlm.nih.gov/nucleotide>, RRID: nlx_84100) were constructed and named EPO-pCMS-EGFP.",
"\n\nCell culture and differentiation\n--------------------------------\n\nThe NIH/3T3 cell line (ATCC® CRL-1658™) was cultured in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 1% nonessential amino acids (NEAAs), and 1× antibiotic/antimycotic solution (Invitrogen, Carlsbad, CA).",
"\n\nThe PC12-INT-EGFP cell line was cultured in DMEM supplemented with 7.5% heat-inactivated FBS, 7.5% heat-inactivated horse serum (Invitrogen), and 1× antibiotic/antimycotic solution (Invitrogen), and was maintained by 300 *μ*g/mL G418 sulfate (Millipore, Darmstadt, Germany). ",
"The PC12-INT-EGFP cell line was established and characterized well by Chien et al. ([",
"@b10]). ",
"Neuronal differentiation was induced using 100 ng/mL of nerve growth factor (NGF; R&D Systems, Minneapolis, MN) for 6 days before treatments with conditioned media.",
"\n\nCells were seeded on culture dishes (Corning, NY) and maintained in a 37°C humidified incubator with 5% CO~2~. The medium was replaced with fresh medium every 2 days.",
"\n\nPlasmid transfection and stable cell clone selection\n----------------------------------------------------\n\nNIH/3T3 cells (1 × 10^5^) were seeded on 35 mm culture dishes 1 day prior to plasmid transfection. ",
"Lipofectamine® LTX & PLUS™ reagents (Invitrogen) were used. ",
"NIH/3T3 cells were transfected with a plasmid mixture of 3 *μ*g of EPO-pCMS-EGFP and pDsRed-monomer-N1 or pCMS-EGFP and pDsRed-monomer-N1 (Clontech) separately at a ratio of 5:2. ",
"pDsRed-monomer-N1 with a kanamycin/neomycin resistance gene was cotransfected for G418 stable clone selection. ",
"Transfection procedure was in accordance with the instruction manual. ",
"Subsequently, cells were incubated in a humidified incubator with 5% CO~2~ at 37°C overnight, and changed to respective 3T3 growth medium. ",
"G418 sulfate (800 *μ*g/mL) was applied to the transfected cells for stable clone selection. ",
"After 14 days of G418 selection, surviving cell colonies with strong green fluorescence were picked under an inverted fluorescence microscope (DM IRME HC, Leica, Wetzlar, Germany). ",
"An EPO-3T3-EGFP stable cell clone and our experiment control, the 3T3-EGFP stable cell clone, were isolated for use in subsequent studies.",
"\n\nReverse transcription PCR (RT--PCR)\n-----------------------------------\n\nCells were harvested and rinsed twice with cold Dulbecco's Phosphate-Buffered Saline (DPBS). ",
"Total cellular RNA was extracted using the MaestroZol™ RNA PLUS Extraction Reagent (OmicsBio, Taipei City, Taiwan), according to the manufacturer's instructions. ",
"The ThermoScript™ RT--PCR System (Invitrogen) was used for cDNA synthesis, according to the manual provided by the manufacturer.",
"\n\nSemiquantitative PCR was performed using the SapphireAmp® Fast PCR Master Mix (TAKARA, Shiga, Japan). ",
"The forward primer used for detecting the expression of *EPO* was *5′--TTG CTA CTG ATT CCT CTG GGC--3′*, and the reverse primer was *5′--GTG AGT GTT CGG AGT GGA GC--3′*. ",
"The expression level of the glyceraldehyde-3-phosphaate dehydrogenase (*GAPDH*) gene was used as the internal control. ",
"The forward primer used for the detection of *GAPDH* was *5′--AAC TTT GGC ATT GTG GAA GG--3′*, and the reverse primer was *5′--ACA CAT TGG GGG TAG GAA CA--3′*. ",
"The PCR reaction was processed at 94°C for 1 min to denature the cDNA templates, followed by 45 amplification cycles (denaturation at 98°C for 5 sec, annealing at 57°C for EPO primers and 55°C for GAPDH primers for 5 sec, and extension at 72°C for 10 sec), and ended by a terminal extension at 72°C for 2 min. ",
"Subsequently, PCR products were analyzed by 1% agarose gel electrophoresis.",
"\n\nQuantitative real-time PCR (Q-PCR)\n----------------------------------\n\nQ-PCR was performed by using KAPA SYBR® FAST qPCR kit (KAPABiosystems, Wilmington, MA). ",
"Samples were run and detected on an Mx300P Real-time PCR system (Stratagene, La Jolla, CA) in a final reaction volume of 10 *μ*L. The thermocycling procedure was as follows: enzyme activation at 95°C for 3 min, 45 amplification cycles (denaturation at 95°C for 3 sec, annealing at 55°C for 20 sec, and extension at 72°C for 1 sec), and a final three-step dissociation (95°C for 1 min, 55°C for 30 sec, and 95°C for 30 sec). ",
"The expression level of *EPO* in each group was normalized to that of *GAPDH*. ",
"The following primers were used for Q-PCR: EPO, *5′--TTG CTA CTG ATT CCT CTG GGC--3′* and *5′--GTG AGT GTT CGG AGT GGA GC--3′*; and GAPDH, *5′--AAC TTT GGC ATT GTG GAA GG--3′*, and *5′--ACA CAT TGG GGG TAG GAA CA--3′*. ",
"The resulting data were further analyzed using a two-tailed *t*-test (paired) and were plotted using GraphPad Prism® 4.0 (GraphPad Software Inc., La Jolla, CA, <http://www.graphpad.com/>, RRID: rid_000081).",
"\n\nWestern blot analysis\n---------------------\n\nFor protein extraction, cells were harvested and rinsed twice with cold DPBS (Invitrogen). ",
"Cell pellets were homogenized in protein lysis buffer (Cell Signaling, Danvers, MA). ",
"Cell lysates were denatured at 97°C for 10 min in 1× sample buffer. ",
"For culture supernatants, 10 *μ*L out of a total of 10 mL of cultured medium was boiled with 1× sample buffer. ",
"All samples were stored at −20°C before analysis. ",
"Proteins (40 *μ*g/per lane) were loaded onto 12% SDS--PAGE. ",
"Proteins were transferred to a PVDF membrane. ",
"After blocking with 5% nonfat dry milk dissolved in TBS-T (0.1% Tween-20 in 1× TBS) for 40 min at room temperature, the membrane was hybridized with primary antibodies against EPO (1:200; Santa Cruz, Dallas, TX; Cat\\# sc-7956, RRID: AB_2098408), EGFP (1:2000; Millipore, Cat\\# MAB3580, RRID: AB_94936), and GAPDH (1:5000; Millipore, Cat\\# MAB374, RRID: AB_2107445) in the blocking buffer and incubated at 4°C overnight. ",
"After washing in TBS-T, the membrane was incubated with horseradish peroxidase-conjugated secondary antibodies diluted in TBS-T at room temperature for 1 h. The membrane was washed again and protein signals were developed using the SuperSignal West Femto Chemiluminescent Substrate (Thermo, Rockford, IL) and detected using a G:BOX/iChemi XL imager (Syngene, Cambridge, UK).",
"\n\nEnzyme-linked Immunosorbent Assay (ELISA)\n-----------------------------------------\n\nThe concentration of EPO in cell lysates (40 *μ*g, nondenatured) was also quantitated by ELISA. ",
"In addition, for the measurement of culture supernatants, 3 × 10^5^ 3T3, 3T3-EGFP, and EPO-3T3-EGFP cells were seeded on 60 mm dishes on Day 0. ",
"Culture supernatants were collected after 24, 48, and 72 h. Cell number was also counted. ",
"The culture supernatants collected were centrifuged at 1500 rpm, 4°C for 10 min to discard the cell debris and were stored at −80°C. ",
"The Mouse Erythropoietin Quantikine ELISA Kit (R&D Systems) was used to obtain quantitative data regarding the amount of both cell lysates and secreted EPO in culture supernatants by following the manual supplied by the manufacturer. ",
"After the reaction was terminated using Stop Solution, optic density was read at 450 nm on a microplate reader (Ultrospec ® 3100 pro; Amersham Bioscience Corp., Piscataway, NJ).",
"\n\nFunctional assays of EPO in conditioned media\n---------------------------------------------\n\nThe bioactivity of EPO secreted from the EPO-overexpressing NIH/3T3 cell line was examined in a cell model of neurodegeneration, PC12-INT-EGFP cells. ",
"3T3, 3T3-EGFP, and EPO-3T3-EGFP cells (1.6 × 10^6^ cells) were seeded in 10 cm dishes and cultured for 24 h. Culture supernatants were collected by sterile syringes and filtered through hydrophilic polyethersulfone membranes with a pore size of 0.22 *μ*m (Millipore) for subsequent functional assays. ",
"The concentration of secreted EPO in collected culture supernatants was also measured using the Mouse Erythropoietin Quantikine ELISA Kit (R&D Systems). ",
"After 6 days of NGF induction, PC12-INT-EGFP cells were supplemented with conditioned media (50% v/v), which combined half of the fresh medium for PC12 cells and half of the collected culture supernatants, as mentioned previously. ",
"Moreover, 10 IU/mL of recombinant human EPO (hrEPO; specific activity, 115,336 IU/mg P; Millipore) was applied as the positive control. ",
"PC12 cells treated with fresh medium alone were used as the vehicle group. ",
"A cell viability assay, 48 h live-cell imaging, and immunocytochemistry were performed on PC12-INT-EGFP cells for testing the bioactivity of the secreted EPO.",
"\n\nCell-viability assay: propidium iodide (PI)/Hoechst 33342 costaining\n--------------------------------------------------------------------\n\nPC12-INT-EGFP cells (5 × 10^3^ cells) were seeded in 4-well chamber slides (Millipore) coated with 50 *μ*g/mL poly-[d]{.smallcaps}-lysine. ",
"After 6 days of NGF induction, PC12-INT-EGFP cells were supplemented with conditioned media (50% v/v). ",
"Conditioned media were removed after 48 h of treatment. ",
"PC12-INT-EGFP cells were incubated in a mixture of the nuclear dyes Hoechst 33342 (1:3500; stock concentration, 10 *μ*g/mL; Invitrogen) and PI (1:200; stock concentration, 1 *μ*g/mL; Sigma-Aldrich, St. Louis, MO) diluted in fresh medium for PC12 cells for 40 min, followed by aspiration of the medium. ",
"Cells were washed in DPBS and fixed with 4% paraformaldehyde (PFA) for 15 min at room temperature. ",
"After washing with DPBS, specimens were mounted with Fluoro-Gel (Electron Microscopy Sciences, Hatfield, PA). ",
"Fluorescent images were acquired using a Leica DMR fluorescence microscope and a TCS SP5 confocal microscope (Leica).",
"\n\n### The cell-survival rate was calculated as follows\n\nData were analyzed statistically using one-way ANOVA and plotted using GraphPad Prism® 4.0 (GraphPad Software Corp.).",
"\n\n### Live-cell imaging via time-lapse microscopy\n\nPC12-INT-EGFP cells (5 × 10^4^ cells) were seeded in a 6-well plate. ",
"After 6 days of NGF induction, conditioned media (50% v/v) were used to supplement the cultures. ",
"Live-cell images of PC12-INT-EGFP cells with different treatments were recorded every 20 min for 48 h using the Real-Time Cultured Cell Monitoring system CCM-1.4Z (ASTEC Co. Ltd, Fukuoka, Japan).",
"\n\n### Immunocytochemistry\n\nPC12-INT-EGFP cells (2 × 10^3^ cells) were seeded on cover slips coated with 50 *μ*g/mL of poly-[d]{.smallcaps}-lysine in 24-well culture plates. ",
"After 6 days of NGF induction, conditioned media (50% v/v) were used to supplement cultures for 24 h. Cells were then fixed with 4% PFA for 15 min at room temperature and washed with PBS. ",
"After blocking in blocking buffer (3% FBS in PBS-T) for 30 min, cells were hybridized with primary antibodies against NF-M (1:100; Sigma-Aldrich, Cat\\# N5264, RRID: AB_477278), p-NF-M (1:100; Millipore, Cat\\# 05-774, RRID: AB_309985), and EGFP (1:200; Millipore, Cat\\# AB3080, RRID: AB_91337) in blocking buffer at 4°C overnight. ",
"After the samples were washed with PBS-T (0.1% Triton X-100 in PBS), cells were incubated with fluorescent-labeled secondary antibodies (1:200; anti-mouse IgG-rhodamine, Sigma-Aldrich, Cat\\# T5268, RRID: AB_261693 or anti-rabbit IgG-FITC, Sigma-Aldrich, Cat\\# F9006, RRID: AB_259787) and Hoechst 33342 (1:1000; stock concentration, 10 *μ*g/mL; Invitrogen) for 1 h, followed by washing with PBS-T. Finally, specimens were mounted on microscope slides with Fluoro-Gel (Electron Microscopy Sciences). ",
"Fluorescent images were acquired using a TCS SP5 confocal microscope (Leica).",
"\n\nResults\n=======\n\nCharacterization of EPO in the 3T3, 3T3-EGFP, and EPO-3T3-EGFP stable cell lines\n--------------------------------------------------------------------------------\n\nTo obtain a constitutively EPO-overexpressing cell clone, 800 *μ*g/mL of G418 was applied for 14 consecutive days for stable clone selection after the cotransfection of EPO-pCMS-EGFP and pDsRed-monomer-N1 into NIH/3T3 cells. ",
"The established EPO-3T3-EGFP stable clone, with strong green fluorescence, was observed under an inverted fluorescence microscope, and the experimental control, 3T3-EGFP stable cell clone, was also isolated for subsequent studies ([Fig. ",
"S1A](#sd6){ref-type=\"supplementary-material\"}). ",
"There was no significant difference in morphology and cell doubling time among the 3T3, 3T3-EGFP, and EPO-3T3-EGFP cell lines.",
"\n\nTo verify whether the transfected *EPO* gene was correctly overexpressed in EPO-3T3-EGFP cells, we examined the RNA level of EPO using both Q-PCR and RT--PCR analyses. ",
"The Q-PCR results revealed the relative levels of the EPO mRNA in each cell line (Fig.[1A](#fig01){ref-type=\"fig\"}). ",
"The expression level of *EPO* in the EPO-3T3-EGFP cell line was 4.27-fold higher than that observed in the 3T3 and 3T3-EGFP cell lines (*n* = 3, \\*\\**P *\\<* *0.05). ",
"RT--PCR also confirmed that the EPO-3T3-EGFP cell group expressed the transfected EPO cDNA (a 437 bp PCR product) at high levels (Fig.[1B](#fig01){ref-type=\"fig\"}).",
"\n\n{#fig01}\n\nNext, we determined the protein levels of overexpressed EPO by ELISA and western blotting, to verify the presence of EPO in nontransfected and transfected NIH/3T3 cells. ",
"An increase of cytosolic EPO was observed in the EPO-3T3-EGFP cell group, whereas endogenous EPO was scarcely detected in the 3T3 and 3T3-EGFP cell groups (Fig.[1C](#fig01){ref-type=\"fig\"} and [D](#fig01){ref-type=\"fig\"}). ",
"Our ELISA data showed a significant increase in cytosolic EPO (246 ± 11.07 pg/40 *μ*g of cell lysate, mean ± SD; paired *t*-test, \\*\\*\\**P *\\<* *0.001) compared with 3T3 cells (12.68 ± 10.06 pg/40 *μ*g of cell lysate) and 3T3-EGFP cells (15.31 ± 12.30 pg/40 *μ*g of cell lysate). ",
"Similar patterns were observed using immunocytochemistry staining ([Fig. ",
"S1B](#sd6){ref-type=\"supplementary-material\"}). ",
"In addition, extracellular EPO secretion from 3T3, 3T3-EGFP, and EPO-3T3-EGFP cells was analyzed by western blotting (Fig.[1D](#fig01){ref-type=\"fig\"}). ",
"Secreted EPO was detected only in the EPO-3T3-EGFP groups, whether the cells were cultured in the medium for NIH/3T3 cells or in the medium for PC12 cells.",
"\n\nTaken together, our results of the examination of *EPO* expression levels indicate that the RNA expression levels in the EPO-3T3-EGFP cell line were significantly higher than they were in the 3T3 and 3T3-EGFP cell lines. ",
"Increased cytosolic EPO and secreted EPO were observed in the EPO-overexpressing NIH/3T3 cell line, EPO-3T3-EGFP.",
"\n\nConcentration of secreted EPO in the culture supernatants from 3T3, 3T3-EGFP, and EPO-3T3-EGFP cells\n----------------------------------------------------------------------------------------------------\n\nTo quantify the amount of EPO secreted from 3T3, 3T3-EGFP, and EPO-3T3-EGFP cells, we collected their culture supernatants and performed ELISA. ",
"Cells (3 × 10^5^) were seeded on Day 0, and culture supernatants were collected for 3 consecutive days (24, 48, and 72 h). ",
"The statistical data presented in Table [@b1] showed that the level of EPO secreted from EPO-3T3-EGFP cells (4428.6 ± 156.3 pg/mL (mean ± SD) at 24 h; 11874.6 ± 724.1 pg/mL at 48 h; and 23888.8 ± 737.8 pg/mL at 72 h) was significantly higher than that secreted from 3T3 cells (undetectable at 24 and 48 h; 18.2 ± 31.5 pg/mL at 72 h) and 3T3-EGFP cells (undetectable at 24 h; 18.2 ± 31.5 pg/mL at 48 h; 34.4 ± 29.9 pg/mL at 72 h). ",
"There was no significant difference in cell doubling time among the groups.",
"\n\n###### \n\nQuantification of erythropoietin (EPO) secreted from the 3T3, 3T3-EGFP, and EPO-3T3-EGFP stable cell lines using an Enzyme-Linked Immunosorbent Assay (ELISA).",
"\n\n Number of hour(s) of EPO secretion (mean ± SD pg/mL, *n* = 3) \n -------------- --------------------------------------------------------------- ------------------------------------------------- -------------------------------------------------\n 3T3 --[1](#tf1-1){ref-type=\"table-fn\"} --[1](#tf1-1){ref-type=\"table-fn\"} 18.2 ± 31.5\n 3T3--EGFP --[1](#tf1-1){ref-type=\"table-fn\"} 18.2 ± 31.5 34.4 ± 29.9\n EPO-3T3-EGFP 4428.6[2](#tf1-2){ref-type=\"table-fn\"} ± 156.3 11874.6[2](#tf1-2){ref-type=\"table-fn\"} ± 724.1 23888.8[2](#tf1-2){ref-type=\"table-fn\"} ± 737.8\n\nEPO was undetectable in the culture supernatants.",
"\n\nHighly significant amount of secreted EPO was detected in the culture supernatants compared with the 3T3 and 3T3-EGFP cell groups (one-way ANOVA, *P *\\<* *0.001).",
"\n\nOur ELISA results indicated that EPO was secreted very rarely into the extracellular milieu from nontransfected NIH/3T3 cells and the experimental control group, 3T3-EGFP cells. ",
"However, in the case of the EPO-3T3-EGFP cell line, EPO was abundantly secreted into the extracellular milieu. ",
"This evidence suggests that the EPO overexpressed from EPO-3T3-EGFP cells may be functional extracellularly.",
"\n\nCell viability of PC12-INT-EGFP cells after conditioned media treatments for 48 h\n---------------------------------------------------------------------------------\n\nTo examine the bioactivity of the secreted EPO, we supplemented the *α*-internexin-overexpressing PC12 cell line, PC12-INT-EGFP cells, with conditioned media (50% v/v) on Day 6 after NGF induction. ",
"The level of secreted EPO was 5.40 ± 1.36 ng/mL (mean ± SD, *n* = 5) in the culture supernatants collected from EPO-3T3-EGFP cells and was undetectable in those collected from 3T3 and 3T3-EGFP cells, as assessed by ELISA. ",
"hrEPO (10 IU/mL) was also applied as the positive control. ",
"The functional bioactivity of secreted EPO was determined using a cell viability assay, 48 h live-cell imaging, and immunocytochemistry in PC12-INT-EGFP cells after conditioned media treatments.",
"\n\nAs PC12-INT-EGFP cells progressively underwent cell death after NGF induction (Chien et al. [",
"@b10]), we wanted to assess whether the neuronal survival rate was increased after supplementation with EPO. ",
"The cell viability assay for the survival of PC12-INT-EGFP cells was assessed using PI/Hoechst 33342 nuclear costaining after supplementation with 3T3 (Fig.[2A](#fig02){ref-type=\"fig\"}--[D](#fig02){ref-type=\"fig\"}), 3T3-EGFP (Fig.[2E](#fig02){ref-type=\"fig\"}--[H](#fig02){ref-type=\"fig\"}), and EPO-3T3-EGFP (Fig.[2I](#fig02){ref-type=\"fig\"}--[L](#fig02){ref-type=\"fig\"}) conditioned media and 10 IU/mL of hrEPO (Fig.[2M](#fig02){ref-type=\"fig\"}--[P](#fig02){ref-type=\"fig\"}) for 48 h; we also analyzed the vehicle group (Fig.[2Q](#fig02){ref-type=\"fig\"}--[T](#fig02){ref-type=\"fig\"}). ",
"The DIC images showed that, morphologically, dying PC12-INT-EGFP cells, which were double-labeled with PI and Hoechst 33342 appeared to be rather spherical (Fig.[2C](#fig02){ref-type=\"fig\"} and [D](#fig02){ref-type=\"fig\"}, arrowhead) compared with the surviving cells, which exhibited a flattened neuronal pattern (Fig.[2K](#fig02){ref-type=\"fig\"} and [L](#fig02){ref-type=\"fig\"}, arrow).",
"\n\n{#fig02}\n\nThe survival rate of PC12-INT-EGFP cells after different conditioned medium treatments was calculated for four repeated sets (*n* = 4), as shown in Fig.[2U](#fig02){ref-type=\"fig\"}. ",
"The survival rate of PC12-INT-EGFP cells supplemented with EPO-3T3-EGFP-conditioned medium (52.46 ± 3.34%) for 48 h was significantly increased compared with that of groups supplemented with 3T3 (31.49 ± 4.22%) and 3T3-EGFP (22.69 ± 5.79%) conditioned media, or with the vehicle (25.03 ± 3.88%). ",
"Supplementation with 10 IU/mL of hrEPO led to a significant increase in the survival rate of PC12-INT-EGFP cells (45.12 ± 8.88%) compared with the groups supplemented with 3T3 and 3T3-EGFP-conditioned media, or with the vehicle (one-way ANOVA, \\*\\**P *\\<* *0.01, \\*\\*\\**P *\\<* *0.001).",
"\n\nTherefore, the functional significance of secreted EPO was suggested by the increase in the survival of the PC12-INT-EGFP neuronal cells after treatment with EPO-3T3-EGFP conditioned medium for 48 h.\n\nLive-cell imaging of PC12-INT-EGFP cells after conditioned media treatments\n---------------------------------------------------------------------------\n\nTime-lapse microscopy images were acquired every 20 min for 48 h to examine morphological changes and the dynamic distribution of the overexpressed green fluorescent *α*-internexin-EGFP fusion protein (*α*-INT-EGFP) in PC12-INT-EGFP cells after supplementation with 3T3, 3T3-EGFP, and EPO-3T3-EGFP conditioned media (50% v/v) or with 10 IU/mL of hrEPO on day 6 after NGF induction. ",
"Real-time images were transformed into video (10 images/sec), as shown in the Supplementary Videos. ",
"We found that a fraction of aggregated *α*-INT-EGFP proteins in PC12-INT-EGFP cells were redistributed and disaggregated in the groups supplemented with EPO-3T3-EGFP-conditioned medium or with 10 IU/mL of hrEPO.",
"\n\nSubsequently, we collected and compared green fluorescence images, as well as bright-field images merged with green fluorescence images at 0, 24, and 48 h of PC12-INT-EGFP cells after supplementation with 3T3 ([Fig. ",
"S3A](#sd6){ref-type=\"supplementary-material\"}--[C](#sd6){ref-type=\"supplementary-material\"} and [S3a](#sd6){ref-type=\"supplementary-material\"}--[c](#sd6){ref-type=\"supplementary-material\"}), 3T3-EGFP ([Fig. ",
"S3D](#sd6){ref-type=\"supplementary-material\"}--[F](#sd6){ref-type=\"supplementary-material\"} and [S3d](#sd6){ref-type=\"supplementary-material\"}--[f](#sd6){ref-type=\"supplementary-material\"}), and EPO-3T3-EGFP ([Fig. ",
"S3G](#sd6){ref-type=\"supplementary-material\"}--[I](#sd6){ref-type=\"supplementary-material\"} and [S3g](#sd6){ref-type=\"supplementary-material\"}--[i](#sd6){ref-type=\"supplementary-material\"}) conditioned media, or with 10 IU/mL of hrEPO ([Fig. ",
"S3J](#sd6){ref-type=\"supplementary-material\"}--[L](#sd6){ref-type=\"supplementary-material\"} and [S3j](#sd6){ref-type=\"supplementary-material\"}--[l](#sd6){ref-type=\"supplementary-material\"}) as well as the vehicle ([Fig. ",
"S3M](#sd6){ref-type=\"supplementary-material\"}--[O](#sd6){ref-type=\"supplementary-material\"} and [S3m](#sd6){ref-type=\"supplementary-material\"}--[o](#sd6){ref-type=\"supplementary-material\"}). ",
"We observed that PC12-INT-EGFP cells treated with conditioned medium from EPO-3T3-EGFP cells had a healthier appearance compared with the other groups. ",
"Interestingly, some aggregated green fluorescent *α*-INT-EGFP in PC12-INT-EGFP cells supplemented with conditioned medium from EPO-3T3-EGFP cells exhibited dynamic patterns of disaggregation, which were not observed in the groups supplemented with conditioned media from 3T3 and 3T3-EGFP cells or with the vehicle. ",
"Moreover, the disaggregating *α*-INT-EGFP exhibited a rearranged distribution and was transported into neurites ([Fig. ",
"S3H](#sd6){ref-type=\"supplementary-material\"}, [h](#sd6){ref-type=\"supplementary-material\"}, [I](#sd6){ref-type=\"supplementary-material\"}, and [i](#sd6){ref-type=\"supplementary-material\"}, arrows). ",
"A few PC12-INT-EGFP cells supplemented with 10 IU/mL of hrEPO showed similar patterns of disaggregation ([Fig. ",
"S3L](#sd6){ref-type=\"supplementary-material\"} and [l](#sd6){ref-type=\"supplementary-material\"}, arrows).",
"\n\nDistribution patterns of NF-M, p-NF-M, and *α*-INT-EGFP in PC12-INT-EGFP cells at 24 h after conditioned media treatments\n-------------------------------------------------------------------------------------------------------------------------\n\nOur 48 h live-cell images might suggest that the EPO secreted from EPO-3T3-EGFP cells exhibited the bioactivity of rearranging and disaggregating the *α*-INT-EGFP overexpressed in PC12-INT-EGFP cells ([Fig. ",
"S3G](#sd6){ref-type=\"supplementary-material\"}--[I](#sd6){ref-type=\"supplementary-material\"} and [S3g](#sd6){ref-type=\"supplementary-material\"}--[i](#sd6){ref-type=\"supplementary-material\"}). ",
"Therefore, we wanted to investigate whether the secreted EPO also affected the distribution patterns of other IF proteins in PC12-INT-EGFP cells. ",
"Since *α*-internexin is highly related to NF-M axonal transportation and colocalizes with NF-M on a single neurofilament, as assessed by immunogold electron microscopy (Yuan et al. [",
"@b36]), we focused mainly on the distribution of NF-M and its phosphorylated type, p-NF-M, together with *α*-INT-EGFP, respectively, by immunocytochemical analysis in this study.",
"\n\nPC12-INT-EGFP cells were fixed and double immunostained with primary antibodies against NF-M or p-NF-M, together with *α*-INT-EGFP, respectively, at 24 h after supplementation with 3T3 (Figs.[3A](#fig03){ref-type=\"fig\"}--[C](#fig03){ref-type=\"fig\"}, [4A](#fig04){ref-type=\"fig\"}--[C](#fig04){ref-type=\"fig\"}), 3T3-EGFP (Figs.[3E](#fig03){ref-type=\"fig\"}--[G](#fig03){ref-type=\"fig\"}, [4E](#fig04){ref-type=\"fig\"}--[G](#fig04){ref-type=\"fig\"}), and EPO-3T3-EGFP (Figs.[3I](#fig03){ref-type=\"fig\"}--[K](#fig03){ref-type=\"fig\"}, [4I](#fig04){ref-type=\"fig\"}--[K](#fig04){ref-type=\"fig\"})-conditioned media, or with 10 IU/mL of hrEPO (Figs.[3M](#fig03){ref-type=\"fig\"}--[O](#fig03){ref-type=\"fig\"}, [4M](#fig04){ref-type=\"fig\"}--[O](#fig04){ref-type=\"fig\"}) or the vehicle (Figs.[3Q](#fig03){ref-type=\"fig\"}--[S](#fig03){ref-type=\"fig\"}, [4Q](#fig04){ref-type=\"fig\"}--[S](#fig04){ref-type=\"fig\"}). ",
"DIC images merged with Hoechst 33342 were also taken in each subgroup (Figs.[3D](#fig03){ref-type=\"fig\"}, [H](#fig03){ref-type=\"fig\"}, [L](#fig03){ref-type=\"fig\"}, [P](#fig03){ref-type=\"fig\"} and [T](#fig03){ref-type=\"fig\"}, [4D](#fig04){ref-type=\"fig\"}, [H](#fig04){ref-type=\"fig\"}, [L](#fig04){ref-type=\"fig\"}, [P](#fig04){ref-type=\"fig\"} and [T](#fig04){ref-type=\"fig\"}), to depict cellular morphology. ",
"We observed that, in the groups supplemented with 3T3 (Figs.[3A](#fig03){ref-type=\"fig\"} and [B](#fig03){ref-type=\"fig\"}, [4A](#fig04){ref-type=\"fig\"} and [B](#fig04){ref-type=\"fig\"}) and 3T3-EGFP (Figs.[3E](#fig03){ref-type=\"fig\"} and [F](#fig03){ref-type=\"fig\"}, [4E](#fig04){ref-type=\"fig\"} and [F](#fig04){ref-type=\"fig\"}) conditioned media, or with the vehicle (Figs.[3Q](#fig03){ref-type=\"fig\"} and [R](#fig03){ref-type=\"fig\"}, [4Q](#fig04){ref-type=\"fig\"} and [R](#fig04){ref-type=\"fig\"}), NF-M, p-NF-M, and *α*-INT-EGFP appeared to be aggregated and mainly located in the perikaryal region. ",
"The merged images indicated that a large proportion of aggregated NF-M, p-NF-M, and *α*-INT-EGFP were colocalized (Figs.[3C](#fig03){ref-type=\"fig\"}, [G](#fig03){ref-type=\"fig\"} and [S](#fig03){ref-type=\"fig\"}, [4C](#fig04){ref-type=\"fig\"}, [G](#fig04){ref-type=\"fig\"} and [S](#fig04){ref-type=\"fig\"}; arrowhead; yellow).",
"\n\n{#fig03}\n\n{#fig04}\n\nSurprisingly, we observed that NF-M (Fig.[3I](#fig03){ref-type=\"fig\"}; arrow), p-NF-M (Fig.[4I](#fig04){ref-type=\"fig\"}; arrow), and *α*-INT-EGFP (Figs.[3J](#fig03){ref-type=\"fig\"}, [4J](#fig04){ref-type=\"fig\"}; arrow) were transported into neurites and appeared to be less aggregated in the perikaryal region of PC12-INT-EGFP cells supplemented with EPO-3T3-EGFP conditioned medium and that the merged images showed high colocalization of either NF-M and *α*-INT-EGFP or p-NF-M and *α*-INT-EGFP (Figs.[3K](#fig03){ref-type=\"fig\"}, [4K](#fig04){ref-type=\"fig\"}; arrow; yellow). ",
"Similar distribution patterns were also found in PC12-INT-EGFP cells supplemented with 10 IU/mL of hrEPO (Figs.[3M](#fig03){ref-type=\"fig\"}--[O](#fig03){ref-type=\"fig\"}, [4M](#fig04){ref-type=\"fig\"}--[O](#fig04){ref-type=\"fig\"}; arrow), which were used as the positive control.",
"\n\nConclusively, rearranged and disaggregated patterns of NF-M, p-NF-M, and *α*-INT-EGFP, as assessed by immunocytochemical analysis in PC12-INT-EGFP cells, could be found in the groups supplemented with EPO-3T3-EGFP-conditioned medium and 10 IU/mL of hrEPO.",
"\n\nDiscussion\n==========\n\nNeurotrophins, such as NGF, brain-derived growth factor (BDNF), neurotrophin-3 (NT-3), NT-4, and EPO, are key regulators of the proliferation, maturation, and axonal regeneration of neurons (Tabira et al. [",
"@b28]; Bibel and Barde [@b4]; Chao et al. [",
"@b7]; Logan et al. [",
"@b19]). ",
"Studies have shown that 3T3 fibroblasts secrete NGF (Young et al. [",
"@b35]) and BDNF (Chen et al. [",
"@b8]). ",
"However, the production of EPO in 3T3 fibroblasts has not been demonstrated in previous studies. ",
"In our study, the characteristic examinations of NIH/3T3 fibroblast showed little expression level of EPO; nevertheless, EPO-3T3-EGFP cells exhibited a significantly high expression and secretion levels of EPO as demonstrated in Fig.[1](#fig01){ref-type=\"fig\"} and Table [@b1]. ",
"Therefore, we concluded that the expression of endogenous EPO in NIH/3T3 cells was below the threshold of detection. ",
"After the overexpression of EPO in NIH/3T3 cells, large amount of cytosolic EPO was secreted into the extracellular milieu.",
"\n\nhrEPO at 10 IU/mL has been proven to be sufficient for an optimal neuroprotective effect regarding neuronal survival in vitro (Sirén et al. [",
"@b26]; Wu et al. [",
"@b31]; Cho et al. [",
"@b12]). ",
"Hence, to examine and compare the bioactivity of the EPO secreted from EPO-3T3-EGFP cells, which was quantitated as 2.7 ng/mL in conditioned medium (50% v/v), 10 IU/mL of hrEPO (equal to 86.7 ng/mL of hrEPO) was also applied as a positive control in functional assays. ",
"Interestingly, although a 40-fold lower amount of secreted EPO from EPO-3T3-EGFP cells was present in cells treated with the conditioned medium compared with hrEPO, our results demonstrated the existence of similar neuroprotective effects on degenerating PC12-INT-EGFP cells after supplementation with either EPO-3T3-EGFP conditioned medium or 10 IU/mL of hrEPO. ",
"To further clarify the relationship of dosage and neuroprotective effectiveness of the EPO-3T3-EGFP conditioned medium compared with hrEPO, we applied 10 IU/mL of hrEPO as well as 0.25 IU/mL of hrEPO, which had the same amount of EPO as quantified in the EPO-3T3-EGFP conditioned medium, to the 3T3 conditioned medium. ",
"Our results showed that the significant difference could be observed between the groups supplemented with 0.25 IU/mL of hrEPO plus 3T3 conditioned medium and 10 IU/mL of hrEPO plus 3T3 conditioned medium; whereas no significant difference was found between the groups supplemented with 3T3 conditioned medium and 0.25 IU/mL of hrEPO plus 3T3 conditioned medium ([Fig. ",
"S2](#sd6){ref-type=\"supplementary-material\"}). ",
"Therefore, we could further confirm that the EPO-3T3-EGFP conditioned medium had the equivalent neuroprotective effectiveness as 10 IU/mL of hrEPO. ",
"Therefore, the cell dosage will be carefully tested before conducting the in vivo studies.",
"\n\nIn our study, the immunocytochemical patterns of NF-M showed that this protein was mainly located in the perikaryal region and appeared to be aggregated in the vehicle group or the groups supplemented with conditioned media from 3T3 and 3T3-EGFP cells. (",
"Fig.[3A](#fig03){ref-type=\"fig\"}, [E](#fig03){ref-type=\"fig\"} and [Q](#fig03){ref-type=\"fig\"}). ",
"Conversely, after supplementation with EPO, we found that NF-M was less aggregated in the perikaryal region and was transported into neurites (Fig.[3I](#fig03){ref-type=\"fig\"} and [M](#fig03){ref-type=\"fig\"}). ",
"As the role of nonphosphorylated NFs in axonal transportation has been well studied (Hoffman [@b14]; Chevalier-Larsen and Holzbaur [@b9]), we expected that the aberrant axonal transportation observed in PC12-INT-EGFP cells might be recovered after supplementation with EPO. ",
"Recently, it was reported that the motile phase of phosphorylated NFs not only processes the turnover of NFs but also mediates self-association to promote axonal outgrowth by cross-linked phosphorylated NFs (Barry et al. [",
"@b3]; Shea and Lee [@b24]). ",
"Therefore, phosphorylated NFs promote axonal outgrowth, whereas nonphosphorylated NFs mediate axonal transportation (Hoffman [@b14]; Barry et al. [",
"@b3]; Shea and Lee [@b24]). ",
"According to our immunostaining results, the distribution patterns of p-NF-M in PC12-INT-EGFP cells supplemented with EPO showed that the protein was mainly located in the processes (Fig.[4I](#fig04){ref-type=\"fig\"} and [M](#fig04){ref-type=\"fig\"}). ",
"In addition, previous studies have shown that neurotrophins are internalized from distal axons and transported retrogradely to the cell body, which is thought to be critical for cell survival (Ye et al. [",
"@b33]; Wagner et al. [",
"@b30]; Chevalier-Larsen and Holzbaur [@b9]). ",
"Retrograde transport is mediated by dynein, which binds directly to NF-M (Ye et al. [",
"@b33]; Chevalier-Larsen and Holzbaur [@b9]). ",
"Our immunocytochemistry results showed that NF-M and p-NF-M were transported into neurites and became less aggregated in the perikaryal region and indicated that the neuroprotective ability of EPO might overcome perikaryal aggregation, restore axonal transportation, reduce cellular toxicity, and, consequently, enhance neuronal survival (Fig.[2](#fig02){ref-type=\"fig\"}).",
"\n\nOur real-time cell imaging provided reliable and powerful information for tracing the distribution of fluorescent *α*-INT-EGFP in PC12-INT-EGFP cells after conditioned media treatments. ",
"We found progressive rearrangement and disaggregation of some *α*-INT-EGFP in the groups supplemented with the conditioned medium from EPO-3T3-EGFP cells or with 10 IU/mL of hrEPO ([Fig. ",
"S3](#sd6){ref-type=\"supplementary-material\"} and Supplementary Videos). ",
"The disaggregation ability of EPO has been investigated in ALS cell models overexpressing mutant SOD1 (Cu/Zn-binding superoxide dismutase) in NSC-34 cells (Cho et al. [",
"@b12]). ",
"However, the mechanism underlying the disaggregation effect of EPO on cytoskeletons remains unclear and should be investigated further in the future.",
"\n\nMore importantly, we established an EPO-overexpressing NIH/3T3 fibroblast cell line, EPO-3T3-EGFP, that produced an abundant amount of EPO and showed an effective neuroprotective effect of enhancing neuronal survival. ",
"Therefore, this EPO-overexpressing NIH/3T3 fibroblast cell line may represent a potential material for future studies of cell-based therapies for neurological diseases via the secretion of EPO on a short-term, high-dose, and regional basis.",
"\n\nThis work was supported by a grant to C.-L. Chien (NSC 100-2320-B-002-085) from the Ministry of Science and Technology, Taiwan. ",
"Facilities provided by grants from the Ministry of Education, Taiwan, to the Center for Genomic Medicine at the National Taiwan University are also acknowledged.",
"\n\nConflict of Interest\n====================\n\nThe authors confirm that there are no known conflicts of interest.",
"\n\nSupporting Information\n======================\n\n**Video S1.** ",
"Time-lapse_3T3 conditioned medium treatment.wmv.",
"\n\n**Video S2.** ",
"Time-lapse_3T3-EGFP conditioned medium treatment.wmv.",
"\n\n**Video S3.** ",
"Time-lapse\\_ EPO-3T3-EGFP conditioned medium treatment.wmv.",
"\n\n**Video S4.** ",
"Time-lapse\\_ positive control_hrEPO.wmv.",
"\n\n**Video S5.** ",
"Time-lapse\\_ vehicle.wmv.",
"\n\n**Figure S1.** ",
"Live-cell imaging and immunocytochemical staining of 3T3, 3T3-EGFP, and EPO-3T3-EGFP stable cell clones.",
"\n\n**Figure S2.** ",
"Cell-viability assay for cultured PC12-INT-EGFP cells after 3T3, 0.25 IU hrEPO + 3T3, 10 IU hrEPO + 3T3, and 3T3-EGFP conditioned media treatments for 48 h.\n\n**Figure S3.** ",
"48 h live-cell imaging of PC12-INT-EGFP cells after 3T3, 3T3-EGFP, and EPO-3T3-EGFP conditioned media treatments.",
"\n\n[^1]: **Funding Information** This work was supported by a grant to C.-L. Chien (NSC 100-2320-B-002-085) from the Ministry of Science and Technology, Taiwan. ",
"Facilities provided by grants from the Ministry of Education, Taiwan, to the Center for Genomic Medicine at the National Taiwan University are also acknowledged.",
"\n"
] | {
"pile_set_name": "PubMed Central"
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[
"Related literature {#sec1}\n====================\n\nFor background to the cardiotonic and anti-inflammatory properties of octahydroquinoline-3-carbonitrile derivatives, see: Behit & Baraka (2005[@bb3]); Girgis *et al.* (",
"2007[@bb7]). ",
"For a related structure, see: Asiri *et al.* (",
"2012[@bb2]). ",
"For additional conformational analysis, see: Cremer & Pople (1975[@bb5]).",
"\n\nExperimental {#sec2}\n==============\n\n {#sec2.1}\n\n### Crystal data {#sec2.1.1}\n\nC~17~H~17~BrN~2~O*M* *~r~* = 345.24Monoclinic,*a* = 11.1959 (10) Å*b* = 7.5902 (6) Å*c* = 18.3886 (12) Åβ = 100.453 (8)°*V* = 1536.7 (2) Å^3^*Z* = 4Mo *K*α radiationμ = 2.68 mm^−1^*T* = 100 K0.40 × 0.20 × 0.02 mm\n\n### Data collection {#sec2.1.2}\n\nAgilent SuperNova Dual diffractometer with an Atlas detectorAbsorption correction: multi-scan (*CrysAlis PRO*; Agilent, 2012[@bb1]) *T* ~min~ = 0.581, *T* ~max~ = 1.0009883 measured reflections3549 independent reflections2296 reflections with *I* \\> 2σ(*I*)*R* ~int~ = 0.052\n\n### Refinement {#sec2.1.3}\n\n*R*\\[*F* ^2^ \\> 2σ(*F* ^2^)\\] = 0.063*wR*(*F* ^2^) = 0.173*S* = 1.023549 reflections199 parameters22 restraintsH-atom parameters constrainedΔρ~max~ = 0.87 e Å^−3^Δρ~min~ = −0.44 e Å^−3^\n\n {#d5e490}\n\nData collection: *CrysAlis PRO* (Agilent, 2012[@bb1]); cell refinement: *CrysAlis PRO*; data reduction: *CrysAlis PRO*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb8]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb8]); molecular graphics: *ORTEP-3 for Windows* (Farrugia, 1997[@bb6]) and *DIAMOND* (Brandenburg, 2006[@bb4]); software used to prepare material for publication: *publCIF* (Westrip, 2010[@bb9]).",
"\n\nSupplementary Material\n======================\n\nCrystal structure: contains datablock(s) global, I. DOI: [10.1107/S1600536812029820/hb6875sup1.cif](http://dx.doi.org/10.1107/S1600536812029820/hb6875sup1.cif)\n\nStructure factors: contains datablock(s) I. DOI: [10.1107/S1600536812029820/hb6875Isup2.hkl](http://dx.doi.org/10.1107/S1600536812029820/hb6875Isup2.hkl)\n\nSupplementary material file. ",
"DOI: [10.1107/S1600536812029820/hb6875Isup3.cml](http://dx.doi.org/10.1107/S1600536812029820/hb6875Isup3.cml)\n\nAdditional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?hb6875&file=hb6875sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?hb6875sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?hb6875&checkcif=yes)\n\nSupplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [HB6875](http://scripts.iucr.org/cgi-bin/sendsup?hb6875)).",
"\n\nThe authors are grateful to King Abdulaziz University for providing the research facilities. ",
"The authors also thank the Ministry of Higher Education (Malaysia) for funding structural studies through the High-Impact Research scheme (UM.C/HIR/MOHE/SC/12).",
"\n\nComment\n=======\n\nIn continuation of our structural studies on octahydroquinoline-3-carbonitrile derivatives (Asiri *et al.*, ",
"2012), the crystal and molecular structure of the title compound, (I), was investigated. ",
"Interest in this class of compound stems from their demonstrated cardiotonic and anti-inflammatory properties (Behit & Baraka, 2005; Girgis *et al.*, ",
"2007).",
"\n\nIn (I), Fig. ",
"1, the N1-containing ring of the fused octahydroquinoline fused-ring system, adopts an envelope conformation with the C10 atom, carrying the phenyl ring, lying -0.531 (9)° out of the plane defined by the remaining five atoms \\[r.m.s. ",
"deviation = 0.0099 Å\\]. ",
"Owing to two conformations of equal weight, the assignment of conformation of the C~6~ ring is somewhat problematic but a conformational analysis indicates an intermediate conformation between screw-boat and half-chair (Cremer & Pople, 1975). ",
"The phenyl ring is almost orthogonal to the ring to which it is attached with the C9---C10---C12---C13 torsion angle being -101.3 (7)°.",
"\n\nThe most prominent interactions in the crystal packing is a pair of N---H···O hydrogen bonds between inversion related molecules leading to an eight-membered {···HNCO}~2~ synthon, Table 1. ",
"These are linked into a three-dimensional architecture by C---H···N, C---H···Br and C---H···π interactions, Fig. ",
"2 and Table 1.",
"\n\nExperimental {#experimental}\n============\n\nA mixture of the *p*-bromobenzaldehyde (1.4 g, 0.01 *M*), 2-methylcyclohexanone (1.2 g, 0.01 *M*), ethyl cyanoacetate (1.1 g, 0.01 *M*) and ammonium acetate (6.2 g, 0.0 8*M*) in absolute ethanol (50 ml) was refluxed for 6 h. The reaction mixture was allowed to cool, the formed precipitate was filtered, washed with water, dried and recrystallized from its ethanol solution as light yellow plates. *",
"M*.pt: 511--513 K. Yield: 78%.",
"\n\nRefinement {#refinement}\n==========\n\nCarbon-bound H-atoms were placed in calculated positions \\[C---H = 0.95--0.99 Å, *U*~iso~(H) = 1.2--1.5*U*~eq~(C)\\] and were included in the refinement in the riding model approximation. ",
"The N-bound H-atom was treated similarly with N---H = 0.88 Å and with *U*~iso~(H) = 1.2*U*~eq~(N). ",
"A part of the cyclohexene ring is disordered over two positions in an assumed 1:1 ratio. ",
"Pairs of 1,2-related distances were restrained to within 0.01 Å of each other. ",
"The anisotropic displacement parameters, restrained to be nearly isotropic, of the primed atoms were set to those of the unprimed ones. ",
"The amino H-atom is less than 2 Å from a methyl H-atom. ",
"As the methyl group was refined as a disordered methyl group, the short H1···H1d contact of 1.84 Å is an artifact.",
"\n\nFigures\n=======\n\n{#Fap1}\n\n{#Fap2}\n\nCrystal data {#tablewrapcrystaldatalong}\n============\n\n ------------------------- ---------------------------------------\n C~17~H~17~BrN~2~O *F*(000) = 704\n *M~r~* = 345.24 *D*~x~ = 1.492 Mg m^−3^\n Monoclinic, *P*2~1~/*c* Mo *K*α radiation, λ = 0.71073 Å\n Hall symbol: -P 2ybc Cell parameters from 2464 reflections\n *a* = 11.1959 (10) Å θ = 2.3--27.5°\n *b* = 7.5902 (6) Å µ = 2.68 mm^−1^\n *c* = 18.3886 (12) Å *T* = 100 K\n β = 100.453 (8)° Plate, light-yellow\n *V* = 1536.7 (2) Å^3^ 0.40 × 0.20 × 0.02 mm\n *Z* = 4 \n ------------------------- ---------------------------------------\n\nData collection {#tablewrapdatacollectionlong}\n===============\n\n ------------------------------------------------------------------- --------------------------------------\n Agilent SuperNova Dual diffractometer with an Atlas detector 3549 independent reflections\n Radiation source: SuperNova (Mo) X-ray Source 2296 reflections with *I* \\> 2σ(*I*)\n Mirror monochromator *R*~int~ = 0.052\n Detector resolution: 10.4041 pixels mm^-1^ θ~max~ = 27.6°, θ~min~ = 2.6°\n ω scan *h* = −14→9\n Absorption correction: multi-scan (*CrysAlis PRO*; Agilent, 2012) *k* = −9→9\n *T*~min~ = 0.581, *T*~max~ = 1.000 *l* = −22→23\n 9883 measured reflections \n ------------------------------------------------------------------- --------------------------------------\n\nRefinement {#tablewraprefinementdatalong}\n==========\n\n ------------------------------------- -------------------------------------------------------------------------------------------------\n Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods\n Least-squares matrix: full Secondary atom site location: difference Fourier map\n *R*\\[*F*^2^ \\> 2σ(*F*^2^)\\] = 0.063 Hydrogen site location: inferred from neighbouring sites\n *wR*(*F*^2^) = 0.173 H-atom parameters constrained\n *S* = 1.02 *w* = 1/\\[σ^2^(*F*~o~^2^) + (0.0744*P*)^2^ + 2.0179*P*\\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3\n 3549 reflections (Δ/σ)~max~ \\< 0.001\n 199 parameters Δρ~max~ = 0.87 e Å^−3^\n 22 restraints Δρ~min~ = −0.44 e Å^−3^\n ------------------------------------- -------------------------------------------------------------------------------------------------\n\nSpecial details {#specialdetails}\n===============\n\n -----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------\n Geometry. ",
"All e.s.d.\\'s (except the e.s.d. ",
"in the dihedral angle between two l.s. ",
"planes) are estimated using the full covariance matrix. ",
"The cell e.s.d.\\'s are taken into account individually in the estimation of e.s.d.\\'s in distances, angles and torsion angles; correlations between e.s.d.\\'s in cell parameters are only used when they are defined by crystal symmetry. ",
"An approximate (isotropic) treatment of cell e.s.d.\\'s is used for estimating e.s.d.\\'s involving l.s. ",
"planes.",
"\n Refinement. ",
"Refinement of *F*^2^ against ALL reflections. ",
"The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \\> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. ",
"and is not relevant to the choice of reflections for refinement. *",
"R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger.",
"\n -----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------\n\nFractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords}\n==================================================================================================\n\n ------ ------------- ------------- ------------- -------------------- ------------\n *x* *y* *z* *U*~iso~\\*/*U*~eq~ Occ. (",
"\\<1)\n Br1 0.06147 (5) 0.90018 (7) 0.92341 (3) 0.0586 (2) \n O1 0.4933 (5) 0.4661 (6) 0.5872 (2) 0.0912 (16) \n N1 0.4052 (4) 0.7076 (6) 0.5296 (2) 0.0576 (12) \n H1n 0.4373 0.6809 0.4907 0.069\\* \n N2 0.3645 (6) 0.3614 (6) 0.7319 (3) 0.0836 (18) \n C1 0.3778 (6) 0.9254 (7) 0.3984 (3) 0.0579 (14) \n H1A 0.3554 1.0180 0.3613 0.087\\* 0.50\n H1B 0.3492 0.8112 0.3771 0.087\\* 0.50\n H1C 0.4663 0.9223 0.4136 0.087\\* 0.50\n H1D 0.4252 0.8163 0.4067 0.087\\* 0.50\n H1E 0.4314 1.0231 0.3909 0.087\\* 0.50\n H1F 0.3143 0.9120 0.3544 0.087\\* 0.50\n C2 0.3211 (5) 0.9625 (7) 0.4635 (3) 0.0585 (14) \n C3 0.2661 (15) 1.1429 (16) 0.4681 (7) 0.061 (4) 0.50\n H3A 0.3222 1.2288 0.4516 0.073\\* 0.50\n H3B 0.1900 1.1461 0.4311 0.073\\* 0.50\n C4 0.2372 (13) 1.2098 (17) 0.5380 (6) 0.063 (3) 0.50\n H4A 0.3078 1.2763 0.5647 0.075\\* 0.50\n H4B 0.1679 1.2925 0.5268 0.075\\* 0.50\n C5 0.2067 (11) 1.0704 (13) 0.5856 (8) 0.055 (4) 0.50\n H5A 0.1212 1.0358 0.5676 0.066\\* 0.50\n H5B 0.2114 1.1197 0.6359 0.066\\* 0.50\n C3\\' 0.2305 (15) 1.1102 (18) 0.4484 (7) 0.061 (4) 0.50\n H3C 0.2712 1.2160 0.4330 0.073\\* 0.50\n H3D 0.1650 1.0762 0.4071 0.073\\* 0.50\n C4\\' 0.1773 (13) 1.1532 (17) 0.5133 (7) 0.063 (3) 0.50\n H4C 0.2227 1.2550 0.5382 0.075\\* 0.50\n H4D 0.0930 1.1935 0.4952 0.075\\* 0.50\n C5\\' 0.1727 (10) 1.0196 (15) 0.5692 (8) 0.055 (4) 0.50\n H5C 0.1035 0.9404 0.5508 0.066\\* 0.50\n H5D 0.1547 1.0790 0.6139 0.066\\* 0.50\n C6 0.2820 (6) 0.9091 (8) 0.5917 (3) 0.075 (2) \n H6 0.3575 0.9591 0.6222 0.090\\* 0.50\n H6\\' 0.3437 0.9871 0.6221 0.090\\* 0.50\n C7 0.3338 (5) 0.8612 (7) 0.5242 (3) 0.0543 (14) \n C8 0.4298 (6) 0.5976 (8) 0.5872 (3) 0.0675 (18) \n C9 0.3741 (6) 0.6431 (8) 0.6547 (3) 0.0667 (17) \n H9 0.4373 0.7148 0.6872 0.080\\* \n C10 0.2671 (5) 0.7576 (6) 0.6390 (2) 0.0457 (11) \n H10 0.2039 0.6833 0.6079 0.055\\* \n C11 0.3637 (5) 0.4810 (7) 0.6963 (2) 0.0522 (13) \n C12 0.2137 (4) 0.7995 (6) 0.7068 (2) 0.0423 (11) \n C13 0.1125 (6) 0.7135 (9) 0.7198 (3) 0.0698 (18) \n H13 0.0740 0.6294 0.6850 0.084\\* \n C14 0.0646 (5) 0.7472 (9) 0.7836 (3) 0.0704 (18) \n H14 −0.0070 0.6887 0.7914 0.085\\* \n C15 0.1213 (5) 0.8642 (6) 0.8342 (2) 0.0447 (11) \n C16 0.2224 (5) 0.9533 (7) 0.8224 (3) 0.0507 (12) \n H16 0.2602 1.0378 0.8573 0.061\\* \n C17 0.2689 (5) 0.9188 (6) 0.7589 (3) 0.0476 (12) \n H17 0.3401 0.9784 0.7511 0.057\\* \n ------ ------------- ------------- ------------- -------------------- ------------\n\nAtomic displacement parameters (Å^2^) {#tablewrapadps}\n=====================================\n\n ------ ------------ ------------ ------------ ------------ ------------ -------------\n *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^\n Br1 0.0719 (4) 0.0740 (4) 0.0378 (3) 0.0033 (3) 0.0312 (3) −0.0034 (2)\n O1 0.134 (4) 0.098 (3) 0.057 (2) 0.072 (3) 0.058 (3) 0.033 (2)\n N1 0.072 (3) 0.068 (3) 0.044 (2) 0.031 (2) 0.041 (2) 0.020 (2)\n N2 0.153 (6) 0.055 (3) 0.057 (3) 0.021 (3) 0.057 (3) 0.010 (2)\n C1 0.076 (4) 0.061 (3) 0.043 (3) −0.003 (3) 0.028 (3) 0.007 (2)\n C2 0.066 (4) 0.068 (3) 0.050 (3) 0.016 (3) 0.035 (3) 0.022 (3)\n C3 0.072 (8) 0.073 (5) 0.041 (6) 0.023 (5) 0.020 (5) 0.018 (4)\n C4 0.069 (7) 0.066 (6) 0.061 (6) 0.030 (5) 0.032 (5) 0.021 (4)\n C5 0.071 (6) 0.052 (6) 0.051 (6) 0.017 (5) 0.032 (5) 0.006 (5)\n C3\\' 0.072 (8) 0.073 (5) 0.041 (6) 0.023 (5) 0.020 (5) 0.018 (4)\n C4\\' 0.069 (7) 0.066 (6) 0.061 (6) 0.030 (5) 0.032 (5) 0.021 (4)\n C5\\' 0.071 (6) 0.052 (6) 0.051 (6) 0.017 (5) 0.032 (5) 0.006 (5)\n C6 0.090 (5) 0.090 (4) 0.062 (3) 0.047 (4) 0.058 (3) 0.040 (3)\n C7 0.060 (3) 0.067 (3) 0.045 (3) 0.024 (3) 0.035 (2) 0.017 (2)\n C8 0.085 (4) 0.077 (4) 0.051 (3) 0.042 (3) 0.041 (3) 0.019 (3)\n C9 0.096 (5) 0.066 (3) 0.050 (3) 0.028 (3) 0.043 (3) 0.017 (3)\n C10 0.064 (3) 0.044 (3) 0.034 (2) 0.004 (2) 0.023 (2) 0.000 (2)\n C11 0.090 (4) 0.044 (3) 0.031 (2) 0.009 (3) 0.032 (2) 0.000 (2)\n C12 0.057 (3) 0.043 (2) 0.032 (2) −0.001 (2) 0.021 (2) 0.0019 (19)\n C13 0.079 (4) 0.096 (4) 0.043 (3) −0.039 (4) 0.034 (3) −0.027 (3)\n C14 0.070 (4) 0.100 (5) 0.049 (3) −0.039 (3) 0.032 (3) −0.020 (3)\n C15 0.048 (3) 0.056 (3) 0.035 (2) 0.002 (2) 0.022 (2) −0.002 (2)\n C16 0.058 (3) 0.053 (3) 0.046 (3) −0.001 (2) 0.024 (2) −0.011 (2)\n C17 0.059 (3) 0.041 (2) 0.051 (3) −0.004 (2) 0.032 (2) −0.003 (2)\n ------ ------------ ------------ ------------ ------------ ------------ -------------\n\nGeometric parameters (Å, º) {#tablewrapgeomlong}\n===========================\n\n ------------------------- ------------- ----------------------- ------------\n Br1---C15 1.900 (4) C3\\'---H3D 0.9900\n O1---C8 1.225 (6) C4\\'---C5\\' 1.451 (10)\n N1---C8 1.336 (6) C4\\'---H4C 0.9900\n N1---C7 1.407 (6) C4\\'---H4D 0.9900\n N1---H1n 0.8800 C5\\'---C6 1.480 (9)\n N2---C11 1.118 (6) C5\\'---H5C 0.9900\n C1---C2 1.481 (7) C5\\'---H5D 0.9900\n C1---H1A 0.9800 C6---C10 1.469 (7)\n C1---H1B 0.9800 C6---C7 1.507 (7)\n C1---H1C 0.9800 C6---H6 1.0000\n C1---H1D 0.9800 C6---H6\\' 1.0000\n C1---H1E 0.9800 C8---C9 1.527 (7)\n C1---H1F 0.9800 C9---C11 1.465 (7)\n C2---C7 1.342 (7) C9---C10 1.465 (7)\n C2---C3\\' 1.503 (9) C9---H9 1.0000\n C2---C3 1.510 (9) C10---C12 1.511 (6)\n C3---C4 1.471 (10) C10---H10 1.0000\n C3---H3A 0.9900 C12---C13 1.366 (7)\n C3---H3B 0.9900 C12---C17 1.380 (7)\n C4---C5 1.454 (10) C13---C14 1.398 (7)\n C4---H4A 0.9900 C13---H13 0.9500\n C4---H4B 0.9900 C14---C15 1.358 (7)\n C5---C6 1.479 (9) C14---H14 0.9500\n C5---H5A 0.9900 C15---C16 1.369 (7)\n C5---H5B 0.9900 C16---C17 1.387 (6)\n C3\\'---C4\\' 1.464 (10) C16---H16 0.9500\n C3\\'---H3C 0.9900 C17---H17 0.9500\n \n C8---N1---C7 127.3 (4) H4C---C4\\'---H4D 107.0\n C8---N1---H1n 116.3 C4\\'---C5\\'---C6 117.4 (10)\n C7---N1---H1n 116.3 C4\\'---C5\\'---H5C 107.9\n C2---C1---H1A 109.5 C6---C5\\'---H5C 107.9\n C2---C1---H1B 109.5 C4\\'---C5\\'---H5D 107.9\n H1A---C1---H1B 109.5 C6---C5\\'---H5D 107.9\n C2---C1---H1C 109.5 H5C---C5\\'---H5D 107.2\n H1A---C1---H1C 109.5 C10---C6---C5\\' 115.6 (7)\n H1B---C1---H1C 109.5 C10---C6---C5 124.6 (6)\n C2---C1---H1D 109.5 C5\\'---C6---C5 22.9 (9)\n H1A---C1---H1D 141.1 C10---C6---C7 113.7 (5)\n H1B---C1---H1D 56.3 C5\\'---C6---C7 109.2 (7)\n H1C---C1---H1D 56.3 C5---C6---C7 115.9 (6)\n C2---C1---H1E 109.5 C10---C6---H6 98.1\n H1A---C1---H1E 56.3 C5\\'---C6---H6 120.9\n H1B---C1---H1E 141.1 C5---C6---H6 98.1\n H1C---C1---H1E 56.3 C7---C6---H6 98.1\n H1D---C1---H1E 109.5 C10---C6---H6\\' 105.9\n C2---C1---H1F 109.5 C5\\'---C6---H6\\' 105.9\n H1A---C1---H1F 56.3 C7---C6---H6\\' 105.9\n H1B---C1---H1F 56.3 C2---C7---N1 120.4 (4)\n H1C---C1---H1F 141.1 C2---C7---C6 123.3 (5)\n H1D---C1---H1F 109.5 N1---C7---C6 116.1 (4)\n H1E---C1---H1F 109.5 O1---C8---N1 123.1 (5)\n C7---C2---C1 124.6 (5) O1---C8---C9 120.4 (5)\n C7---C2---C3\\' 123.2 (7) N1---C8---C9 116.6 (4)\n C1---C2---C3\\' 111.5 (6) C11---C9---C10 117.5 (5)\n C7---C2---C3 117.1 (6) C11---C9---C8 108.5 (4)\n C1---C2---C3 117.2 (6) C10---C9---C8 114.4 (4)\n C4---C3---C2 121.3 (10) C11---C9---H9 105.0\n C4---C3---H3A 107.0 C10---C9---H9 105.0\n C2---C3---H3A 107.0 C8---C9---H9 105.0\n C4---C3---H3B 107.0 C9---C10---C6 113.8 (5)\n C2---C3---H3B 107.0 C9---C10---C12 113.2 (4)\n H3A---C3---H3B 106.7 C6---C10---C12 115.4 (4)\n C5---C4---C3 112.8 (13) C9---C10---H10 104.3\n C5---C4---H4A 109.0 C6---C10---H10 104.3\n C3---C4---H4A 109.0 C12---C10---H10 104.3\n C5---C4---H4B 109.0 N2---C11---C9 174.1 (7)\n C3---C4---H4B 109.0 C13---C12---C17 118.3 (4)\n H4A---C4---H4B 107.8 C13---C12---C10 120.6 (4)\n C4---C5---C6 117.1 (10) C17---C12---C10 121.1 (4)\n C4---C5---H5A 108.0 C12---C13---C14 121.0 (5)\n C6---C5---H5A 108.0 C12---C13---H13 119.5\n C4---C5---H5B 108.0 C14---C13---H13 119.5\n C6---C5---H5B 108.0 C15---C14---C13 119.5 (5)\n H5A---C5---H5B 107.3 C15---C14---H14 120.3\n C4\\'---C3\\'---C2 112.1 (9) C13---C14---H14 120.3\n C4\\'---C3\\'---H3C 109.2 C14---C15---C16 120.7 (4)\n C2---C3\\'---H3C 109.2 C14---C15---Br1 119.4 (4)\n C4\\'---C3\\'---H3D 109.2 C16---C15---Br1 119.8 (4)\n C2---C3\\'---H3D 109.2 C15---C16---C17 119.2 (5)\n H3C---C3\\'---H3D 107.9 C15---C16---H16 120.4\n C5\\'---C4\\'---C3\\' 119.5 (12) C17---C16---H16 120.4\n C5\\'---C4\\'---H4C 107.4 C12---C17---C16 121.3 (5)\n C3\\'---C4\\'---H4C 107.4 C12---C17---H17 119.4\n C5\\'---C4\\'---H4D 107.4 C16---C17---H17 119.4\n C3\\'---C4\\'---H4D 107.4 \n \n C7---C2---C3---C4 4.8 (19) C7---N1---C8---O1 −179.9 (7)\n C1---C2---C3---C4 −163.6 (12) C7---N1---C8---C9 0.2 (10)\n C3\\'---C2---C3---C4 117 (4) O1---C8---C9---C11 −24.4 (9)\n C2---C3---C4---C5 −30 (2) N1---C8---C9---C11 155.5 (6)\n C3---C4---C5---C6 42.1 (18) O1---C8---C9---C10 −157.8 (7)\n C7---C2---C3\\'---C4\\' 11.8 (19) N1---C8---C9---C10 22.1 (9)\n C1---C2---C3\\'---C4\\' −177.7 (11) C11---C9---C10---C6 −175.0 (5)\n C3---C2---C3\\'---C4\\' −67 (2) C8---C9---C10---C6 −46.0 (8)\n C2---C3\\'---C4\\'---C5\\' −25 (2) C11---C9---C10---C12 50.7 (7)\n C3\\'---C4\\'---C5\\'---C6 43 (2) C8---C9---C10---C12 179.7 (5)\n C4\\'---C5\\'---C6---C10 −170.4 (10) C5\\'---C6---C10---C9 174.9 (8)\n C4\\'---C5\\'---C6---C5 71 (2) C5---C6---C10---C9 −160.7 (9)\n C4\\'---C5\\'---C6---C7 −40.8 (15) C7---C6---C10---C9 47.5 (8)\n C4---C5---C6---C10 177.9 (10) C5\\'---C6---C10---C12 −51.8 (10)\n C4---C5---C6---C5\\' −109 (3) C5---C6---C10---C12 −27.4 (12)\n C4---C5---C6---C7 −30.9 (16) C7---C6---C10---C12 −179.2 (5)\n C1---C2---C7---N1 0.2 (10) C9---C10---C12---C13 −101.3 (7)\n C3\\'---C2---C7---N1 169.4 (10) C6---C10---C12---C13 125.1 (6)\n C3---C2---C7---N1 −167.4 (9) C9---C10---C12---C17 75.4 (6)\n C1---C2---C7---C6 175.6 (6) C6---C10---C12---C17 −58.2 (7)\n C3\\'---C2---C7---C6 −15.1 (13) C17---C12---C13---C14 1.1 (9)\n C3---C2---C7---C6 8.1 (12) C10---C12---C13---C14 177.9 (6)\n C8---N1---C7---C2 177.4 (6) C12---C13---C14---C15 −1.6 (10)\n C8---N1---C7---C6 1.7 (9) C13---C14---C15---C16 2.0 (9)\n C10---C6---C7---C2 158.9 (6) C13---C14---C15---Br1 −176.5 (5)\n C5\\'---C6---C7---C2 28.2 (11) C14---C15---C16---C17 −2.0 (8)\n C5---C6---C7---C2 4.5 (12) Br1---C15---C16---C17 176.6 (4)\n C10---C6---C7---N1 −25.4 (8) C13---C12---C17---C16 −1.0 (8)\n C5\\'---C6---C7---N1 −156.1 (7) C10---C12---C17---C16 −177.8 (4)\n C5---C6---C7---N1 −179.8 (8) C15---C16---C17---C12 1.4 (8)\n ------------------------- ------------- ----------------------- ------------\n\nHydrogen-bond geometry (Å, º) {#tablewraphbondslong}\n=============================\n\nCg1 is the centroid of the C12--C17 benzene ring.",
"\n\n ------------------------ --------- --------- ----------- ---------------\n *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A*\n N1---H1*n*···O1^i^ 0.88 2.08 2.921 (5) 161\n C1---H1*A*···N2^ii^ 0.98 2.57 3.442 (8) 148\n C13---H13···Br1^iii^ 0.95 2.86 3.811 (6) 174\n C1---H1*B*···*Cg*1^iv^ 0.98 2.78 3.590 (6) 141\n ------------------------ --------- --------- ----------- ---------------\n\nSymmetry codes: (i) −*x*+1, −*y*+1, −*z*+1; (ii) *x*, −*y*+3/2, *z*−1/2; (iii) −*x*, *y*−1/2, −*z*+3/2; (iv) *x*, −*y*+1/2, *z*−3/2.",
"\n\n###### Hydrogen-bond geometry (Å, °)\n\n*Cg*1 is the centroid of the C12--C17 benzene ring.",
"\n\n *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A*\n ---------------------- --------- ------- ----------- -------------\n N1---H1*n*⋯O1^i^ 0.88 2.08 2.921 (5) 161\n C1---H1*A*⋯N2^ii^ 0.98 2.57 3.442 (8) 148\n C13---H13⋯Br1^iii^ 0.95 2.86 3.811 (6) 174\n C1---H1*B*⋯*Cg*1^iv^ 0.98 2.78 3.590 (6) 141\n\nSymmetry codes: (i) ; (ii) ; (iii) ; (iv) .",
"\n\n[^1]: Additional correspondence author, e-mail: aasiri2\\@kau.edu.sa.",
"\n"
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[
"---\nabstract: 'Effects of the Dirac sea on the excitation energy of the giant monopole states are investigated in an analytic way within the $\\sigma-\\omega$ model. ",
"The excitation energy is determined by the relativistic Landau-Migdal parameters, $F_0$ and $F_1$. Their analytic expressions are derived in the relativistic random phase approximation(RRPA) without the Dirac sea, with the Pauli blocking terms and with the full Dirac sea. ",
"It is shown that in the RRPA based on the mean field approximation the Pauli blocking terms should be included in the configuration space, according to the relativistic Landau theory. ",
"In the renormalized RRPA, the incompressibility coefficient becomes negative, if N${\\bar{\\mathrm{N}}}$ excitations are neglected.'",
"\naddress:\n- |\n Department of Physics, Faculty of Science, Chiba University,\\\n Chiba 263-8522, Japan\n- 'Department of Applied Physics, Fukui University, Fukui 910-8507, Japan'\n- 'RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan'\nauthor:\n- Haruki Kurasawa\n- Toshio Suzuki\ntitle: Effects of the Dirac Sea on the Giant Monopole States\n---\n\nRelativistic model; Effects of the Dirac sea; Giant resonance states; Landau-Migdal parameters\n\nThe relativistic mean field approximation(RMFA) neglects the Dirac sea in the description of the nuclear ground state. ",
"Recently, however, it has been numerically shown that in the relativistic random phase approximation(RRPA) built on the RMFA, the monopole states cannot be well described without the Pauli blocking terms which express transitions between the Dirac sea and the occupied Fermi sea [@giai]. ",
"If the blocking terms are neglected, the excitation energies of the monopole states in the RRPA are much lower than those in the time-dependent relativistic mean field approximation [@ring].",
"\n\nThe purpose of the present paper is to show in an analytic way the role of the Dirac sea in the excitation energy of the monopole states. ",
"We will discuss the monopole states of nuclear matter in terms of the Landau-Migdal parameters using the $\\sigma-\\omega$ model. ",
"First, we will show that in the RRPA based on the RMFA, one should take into account the Pauli blocking terms in the configuration space. ",
"Second, the real effects of the Dirac sea will be discussed in the renormalized RRPA. ",
"It will be shown that N$\\bar{\\mathrm{N}}$ states yield essential effects on the excitation energy through the Landau-Migdal parameter, $F_0$.\n\nThe Landau-Migdal parameters, $F_0$ and $F_1$, are obtained by the second derivative of the total energy density with respect to the quasiparticle distribution. ",
"In the RMFA, they are given by [@mat; @bak] $$F_0 = {F_{\\mathrm{v}}}- \\frac{1 - {v_{\\mathrm{F}}}^2}{1 + {a_{\\mathrm{s}}}{F_{\\mathrm{s}}}}\n {F_{\\mathrm{s}}}, \\quad F_1 = -\\frac{{v_{\\mathrm{F}}}^2{F_{\\mathrm{v}}}}\n {1 + \\frac{1}{3}{v_{\\mathrm{F}}}^2{F_{\\mathrm{v}}}},\\label{par}$$ where we have defined $${F_{\\mathrm{s}}}= {N_{\\mathrm{F}}}\\left(\\frac{{g_{\\mathrm{s}}}}{{m_{\\mathrm{s}}}}\\right)^2,\\quad\n{F_{\\mathrm{v}}}= {N_{\\mathrm{F}}}\\left(\\frac{{g_{\\mathrm{v}}}}{{m_{\\mathrm{v}}}}\\right)^2,$$ $${N_{\\mathrm{F}}}= \\frac{2{p_{\\mathrm{F}}}{E_{\\mathrm{F}}}}{\\pi^2},\\quad\n{v_{\\mathrm{F}}}= \\frac{{p_{\\mathrm{F}}}}{{E_{\\mathrm{F}}}},\\quad\n{E_{\\mathrm{F}}}= ( {p_{\\mathrm{F}}}^2 + M^{*2})^{1/2}.$$ In the above equations, ${g_{\\mathrm{s}}}$ and ${g_{\\mathrm{v}}}$ stand for the Yukawa coupling constants, ${m_{\\mathrm{s}}}$ and ${m_{\\mathrm{v}}}$ the masses of the $\\sigma$- and $\\omega$-meson, respectively, and ${p_{\\mathrm{F}}}$ and $M^*$ denote the Fermi momentum and the effective nucleon mass. ",
"$ {N_{\\mathrm{F}}}$ and ${v_{\\mathrm{F}}}$ represent the relativistic density of states at the Fermi surface and the relativistic Fermi velocity. ",
"The factor, ${a_{\\mathrm{s}}}$, in $F_0$ of Eq.(\\[par\\]) will play an essential role in later discussions, which is given by $${a_{\\mathrm{s}}}{F_{\\mathrm{s}}}= \\frac{4}{(2\\pi)^3}\n \\left( \\frac{{g_{\\mathrm{s}}}}{{m_{\\mathrm{s}}}} \\right)^2\n \\int d^3p\\,\\frac{{\\mbox{\\boldmath{$p$}}}^2}{E_p^3}\\theta_p,\\quad\n E_p = ( {\\mbox{\\boldmath{$p$}}}^2 + M^{*2})^{1/2},\\label{pau}$$ where $\\theta_p$ denotes the step function, $\\theta({p_{\\mathrm{F}}}-\n|{\\mbox{\\boldmath{$p$}}}|)$.\n\nIn the relativistic model, the excitation energy of the monopole states is expressed as [@nks], $$E_{\\mathrm{M}}\n= \\left(\\frac{K}{\\epsilon_{\\mathrm{F}}\\langle r^2\\rangle}\\right)^{1/2},\n\\label{em}$$ where $\\epsilon_{\\mathrm{F}}$ denotes the Fermi energy and $\\langle\nr^2\\rangle$ the root mean square radius of the nucleus. ",
"The incompressibility coefficient, $K$, is expressed in terms of the above relativistic Landau-Migdal parameters, $$K = \\frac{3{p_{\\mathrm{F}}}^2}{\\epsilon_{\\mathrm{F}}}\n \\frac{1 + F_0}{1 + \\frac{1}{3}F_1}.\\label{com}$$ Since ${p_{\\mathrm{F}}}$ is determined by the nucleon density, and $\\epsilon_{\\mathrm{F}}$ is related to the nucleon binding energy, $E_{\\mathrm{B}}$, and the free nucleon mass, $M$, $$\\epsilon_{\\mathrm{F}} = E_{\\mathrm{B}} + M,\\label{fe}$$ the excitation energy of the monopole state is a function of $F_0$ and $F_1$.\n\nIn order to see the effects of the Pauli blocking terms on the monopole states, we derive the Landau-Migdal parameters according to the RRPA. ",
"We calculate the longitudinal RRPA correlation functions with and without the Pauli blocking terms. ",
"By comparing them with the correlation function of the Landau theory[@lan], we will obtain the expressions of the Landau-Migdal parameters in each approximation.",
"\n\nWhen following our previous papers [@bak; @ks], the mean field correlation function, ${\\Pi_{\\mathrm{H}}}$ [@bak; @ks], is given by the Fourier transform of the single-particle Green function, ${G_{\\mathrm{H}}}$, $${\\Pi_{\\mathrm{H}}}(A,B;k) = -\\frac{1}{2\\pi i}\\int d^4p\\,\n {\\mathrm{Tr}}[\\Gamma_A{G_{\\mathrm{H}}}(p+k)\\Gamma_B{G_{\\mathrm{H}}}(p)],\\label{cor}$$ where $k$ denotes the four-momentum, $(k_0,{\\mbox{\\boldmath{$k$}}})$, and $A$ and $B$ the Fourier transform of the external field expressed with the mean field, ${\\psi_{\\mathrm{H}}}({\\mbox{\\boldmath{$x$}}})$, $$A({\\mbox{\\boldmath{$k$}}}) = \\int d^3x \\exp(i{\\mbox{\\boldmath{$k$}}}\\cdot{\\mbox{\\boldmath{$x$}}})\n \\bar{\\psi}_{\\mathrm{H}}({\\mbox{\\boldmath{$x$}}})\\Gamma_A{\\psi_{\\mathrm{H}}}({\\mbox{\\boldmath{$x$}}}),\n \\label{ex}$$ $\\Gamma_A$ being some 4$\\times$4 matrices. ",
"The sum of the ring diagrams in the RRPA for the $\\sigma-\\omega$ model is described as [@bak; @ks], $$\\delta\\Pi_{\\mathrm{RPA}}(A, B;k)\n = \\frac{{\\chi_{\\mathrm{s}}}\\tilde{\\chi}_{\\mathrm{v}}}\n { {\\mathrm{det}} U_{\\mathrm{L}}}\n {\\Pi_{\\mathrm{H}}}(A,\\Lambda^a;k)(U_{\\mathrm{L}})_{ab}\n {\\Pi_{\\mathrm{H}}}(\\Lambda^b, B;k),\\label{ring}$$ where the contraction should be carried out with respect to the superfix and suffix, $a, b = -1, 0$, and $\\Lambda_{-1}$ and $\\Lambda_0$ are given by Eq.(\\[ex\\]) with $\\Gamma_A = 1$ and $\\gamma_0$, respectively. ",
"Moreover, ${\\chi_{\\mathrm{s}}}$ and $\\tilde{\\chi}_{\\mathrm{v}}$ represent, $${\\chi_{\\mathrm{s}}}= \\frac{1}{(2\\pi)^3}\n \\frac{{g_{\\mathrm{s}}}^2}{{m_{\\mathrm{s}}}^2 - k^2},\\quad \n \\tilde{\\chi}_{\\mathrm{v}} = \\frac{1}{(2\\pi)^3}\n \\frac{{g_{\\mathrm{v}}}^2}{{m_{\\mathrm{v}}}^2 - k^2}\\frac{k^2}{{\\mbox{\\boldmath{$k$}}}^2}.$$ The explicit form of the 2$\\times$2 matrix, $U_{\\mathrm{L}}$, in Eq.(\\[ring\\]) depends on whether or not the Pauli blocking terms are included in the mean field correlation functions as discussed below.",
"\n\nThe Green function, ${G_{\\mathrm{H}}}$, is given by the sum of those for a single-particle, hole and antinucleon, $${G_{\\mathrm{H}}}= G_{\\mathrm{p}}( 1 - \\theta_p) + {G_{\\mathrm{h}}}\\theta_p\n + {G_{\\bar{\\mathrm{N}}}}.$$ It is rewritten as a sum of the density-dependent and the Feynman part [@ks], $$\\begin{aligned}\n {G_{\\mathrm{H}}}= {G_{\\mathrm{D}}}+ {G_{\\mathrm{F}}},\\quad\n {G_{\\mathrm{D}}}= \\theta_p({G_{\\mathrm{h}}}- G_{\\mathrm{p}}),\\quad\n {G_{\\mathrm{F}}}= G_{\\mathrm{p}} + {G_{\\bar{\\mathrm{N}}}}.\\end{aligned}$$ Hence, ${\\Pi_{\\mathrm{H}}}$ is composed of the four terms like ${G_{\\mathrm{D}}}{G_{\\mathrm{D}}}$, ${G_{\\mathrm{D}}}{G_{\\mathrm{F}}}$, ${G_{\\mathrm{F}}}{G_{\\mathrm{D}}}$ and ${G_{\\mathrm{F}}}{G_{\\mathrm{F}}}$ [@ks]. ",
"In the RRPA based on the RMFA, the ${G_{\\mathrm{F}}}{G_{\\mathrm{F}}}$ term is neglected, which is divergent, while in the previous calculations [@bak], the ${G_{\\mathrm{D}}}{G_{\\mathrm{F}}}$ and ${G_{\\mathrm{F}}}{G_{\\mathrm{D}}}$ terms, which contain the Pauli blocking N$\\bar{\\mathrm{N}}$ excitations like $G_{\\mathrm{p}}\\theta_p{G_{\\bar{\\mathrm{N}}}}$, have been kept. ",
"Then we have obtained $$U_{\\mathrm{L}} = \\left(\n\\begin{array}{cc}\n{\\chi_{\\mathrm{s}}}( 1 - \\tilde{\\chi}_{\\mathrm{v}}{\\Pi_{\\mathrm{v}}}) &\n{\\chi_{\\mathrm{s}}}\\tilde{\\chi}_{\\mathrm{v}}\\Pi_{\\mathrm{sv}}\\\\\n{\\chi_{\\mathrm{s}}}\\tilde{\\chi}_{\\mathrm{v}}\\Pi_{\\mathrm{sv}} &\n\\tilde{\\chi}_{\\mathrm{v}}( 1 - {\\chi_{\\mathrm{s}}}{\\Pi_{\\mathrm{s}}})\n\\end{array}\\right),\n\\label{dfu}$$ where the mean field correlation functions are defined as $${\\Pi_{\\mathrm{s}}}= {\\Pi_{\\mathrm{H}}}(\\Lambda_{-1}, \\Lambda_{-1}; k),\\quad\n{\\Pi_{\\mathrm{v}}}= {\\Pi_{\\mathrm{H}}}(\\Lambda_0, \\Lambda_0;k),$$ $$\\Pi_{\\mathrm{sv}} = {\\Pi_{\\mathrm{H}}}(\\Lambda_{-1}, \\Lambda_0;k) = \\Pi_{\\rm\nH}(\\Lambda_0, \\Lambda_{-1};k).$$ The Landau prescription of the correlation functions is obtained at the limit $k \\rightarrow 0$. In this limit we have $${\\Pi_{\\mathrm{s}}}= (2\\pi)^3{N_{\\mathrm{F}}}\\{( 1 - {v_{\\mathrm{F}}}^2 )\\Phi(x)\n - {a_{\\mathrm{s}}}\\},\\label{s}$$ $${\\Pi_{\\mathrm{v}}}= (2\\pi)^3{N_{\\mathrm{F}}}\\Phi(x), \\ \\ \\ \n\\Pi_{\\mathrm{sv}} = (2\\pi)^3{N_{\\mathrm{F}}}( 1 - {v_{\\mathrm{F}}}^2 )^{1/2}\\Phi(x),\n\\label{v}$$ where $\\Phi(x)$ stands for the Lindhard function with $x = k_0/(|{\\mbox{\\boldmath{$k$}}}|{v_{\\mathrm{F}}})$ [@bak]. ",
"Using these equations, we obtain the generalized dielectric function from the factor of Eq.(\\[ring\\]) as $$\\begin{aligned}\n\\frac{1}{{\\chi_{\\mathrm{s}}}\\tilde{\\chi}_v}{\\mathrm{det}}U_{\\mathrm{L}}\n = ( 1 + {a_{\\mathrm{s}}}{F_{\\mathrm{s}}})\n \\left\\{ 1 + \\left( {F_{\\mathrm{v}}}- \\frac{1-v^2_{\\mathrm{F}}}{1+{a_{\\mathrm{s}}}{F_{\\mathrm{s}}}}\n {F_{\\mathrm{s}}}- {v_{\\mathrm{F}}}^2{F_{\\mathrm{v}}}x^2 \\right)\\Phi(x)\n\\right\\}.\\label{df}\\end{aligned}$$ In the Landau theory, Eq.(\\[df\\]) should be written as [@lan] $$\\frac{1}{{\\chi_{\\mathrm{s}}}\\tilde{\\chi}_{\\mathrm{v}}}\n {\\mathrm{det}}U_{\\mathrm{L}} =\nc\\left\\{ 1 + \\left( F_0 + \\frac{F_1}{1 + \\frac{1}{3}F_1}x^2\\right)\n \\Phi(x)\\right\\}.\\label{lan}$$ By comparing Eq.(\\[df\\]) with (\\[lan\\]), we obtain the Landau-Migdal parameters which are the same as in Eq.(\\[par\\]).",
"\n\nNext we investigate the role of the Pauli blocking terms in the Landau-Migdal parameters. ",
"We calculate the mean field correlation functions neglecting the Pauli blocking terms and taking the only particle-hole states. ",
"The calculation of the mean field correlation functions is a little different from the one in taking the Pauli blocking terms, since the correlation functions are not Lorentz covariant, and the continuity equation is provided in a different way, $$k_\\mu{\\Pi_{\\mathrm{H}}}(A, \\Lambda^\\mu;k) = \\langle [ \\Lambda_0({\\mbox{\\boldmath{$k$}}}),\nA^\\dagger({\\mbox{\\boldmath{$k$}}}) ] \\rangle,\\label{con}$$ where $\\Lambda^\\mu$ is given by replacing $\\Gamma_A$ with $\\gamma^\\mu$ in Eq.(\\[ex\\]), and the r.h.s. ",
"is related to the expectation value of the ground state as, $$\\langle \\ |[ \\Lambda_0({\\mbox{\\boldmath{$k$}}}), A^\\dagger({\\mbox{\\boldmath{$k'$}}}) ]|\\ \\rangle\n= \\delta( {\\mbox{\\boldmath{$k$}}} - {\\mbox{\\boldmath{$k'$}}} )\n\\langle [ \\Lambda_0({\\mbox{\\boldmath{$k$}}}), A^\\dagger({\\mbox{\\boldmath{$k'$}}})] \\rangle.$$ In including the Pauli blocking terms, the r.h.s. ",
"of Eq.(\\[con\\]) is always vanished, but in neglecting them, it is not for $\\Lambda_{1,2,3}$. Hence, the relationship between the correlation functions due to the time- and the longitudinal component of the $\\omega$-meson is written in the frame, ${\\mbox{\\boldmath{$k$}}} = ( |{\\mbox{\\boldmath{$k$}}}|, 0, 0 )$, as $${\\Pi_{\\mathrm{H}}}(\\Lambda_1, \\Lambda_1;k)\n = \\frac{k_0^2}{|{\\mbox{\\boldmath{$k$}}}|^2}{\\Pi_{\\mathrm{H}}}(\\Lambda_0, \\Lambda_0;k)\n - {a_{\\mathrm{v}}},\\label{tl}$$ where the additional term, ${a_{\\mathrm{v}}}$, comes from the r.h.s. ",
"of Eq.(\\[con\\]), $${a_{\\mathrm{v}}}= \\langle [ \\Lambda_0({\\mbox{\\boldmath{$k$}}}), \\Lambda^{1\\dagger}({\\mbox{\\boldmath{$k$}}})]\\rangle\n /|{\\mbox{\\boldmath{$k$}}}|.\\label{acon}$$ Because of this fact, the back flow effects due to the longitudinal $\\omega$-meson exchange on $\\delta\\Pi_{\\mathrm{RPA}}$ are not simply normalized as $\\tilde{\\chi}_{\\mathrm{v}}$, and $U_{\\mathrm{L}}$ in this case depends on ${a_{\\mathrm{v}}}$, $$U_{\\mathrm{L}}\n = \\left(\\begin{array}{cc}\n {\\chi_{\\mathrm{s}}}( 1 + {a_{\\mathrm{v}}}{\\chi_{\\mathrm{v}}}- \\hat{\\chi}_{\\mathrm{v}}{\\Pi_{\\mathrm{v}}}) &\n {\\chi_{\\mathrm{s}}}\\hat{\\chi}_{\\mathrm{v}}\n \\Pi_{\\mathrm{sv}}\\\\ {\\chi_{\\mathrm{s}}}\\hat{\\chi}_{\\mathrm{v}}\n \\Pi_{\\mathrm{sv}} &\n \\hat{\\chi}_{\\mathrm{v}}( 1 - {\\chi_{\\mathrm{s}}}{\\Pi_{\\mathrm{s}}})\n \\end{array}\n \\right)\\label{ddu},$$ where we have defined $${\\chi_{\\mathrm{v}}}= \\frac{1}{(2\\pi)^3}\n \\left( \\frac{{g_{\\mathrm{v}}}}{{m_{\\mathrm{v}}}}\\right)^2,\\quad \n\\hat{\\chi}_{\\mathrm{v}} = \\tilde{\\chi}_{\\mathrm{v}}\n- {a_{\\mathrm{v}}}{\\chi_{\\mathrm{v}}}^2.$$\n\nAt the limit, $k \\rightarrow 0$, ${\\chi_{\\mathrm{v}}}{a_{\\mathrm{v}}}$ becomes to be $$\\begin{aligned}\n{\\chi_{\\mathrm{v}}}{a_{\\mathrm{v}}}(k \\rightarrow 0)\n= -\\,4\\left(\\frac{{g_{\\mathrm{v}}}}{{m_{\\mathrm{s}}}}\\right)^2\n\\int \\frac{d^3p}{(2\\pi)^3}\\,\\frac{2{\\mbox{\\boldmath{$p$}}}^2/3 + M^{*2}}{E_p^3}\n\\theta_p\n= -\\frac{1}{3}{v_{\\mathrm{F}}}^2{F_{\\mathrm{v}}}.\\end{aligned}$$ Moreover, ${\\Pi_{\\mathrm{s}}}$ of the present case has not the term, ${a_{\\mathrm{s}}}$, in Eq.(\\[s\\]), while ${\\Pi_{\\mathrm{v}}}$ and $\\Pi_{\\mathrm{sv}}$ are the same as in Eq.(\\[v\\]). ",
"As a result the generalized dielectric function in this case is given by $$\\begin{aligned}\n& &\\frac{1}{{\\chi_{\\mathrm{s}}}\\hat{\\chi}_{\\mathrm{v}}}\n {\\mathrm{det}}U_{\\mathrm{L}} \\nonumber \\\\\n \\noalign{\\vskip4pt}\n&=& \\left( 1 - \\frac{{v_{\\mathrm{F}}}^2}{3}{F_{\\mathrm{v}}}\\right)\n \\left\\{ 1 + \\left( {F_{\\mathrm{v}}}- {F_{\\mathrm{s}}}( 1 - {v_{\\mathrm{F}}}^2)\n - \\frac{{v_{\\mathrm{F}}}^2{F_{\\mathrm{v}}}}\n {1 - \\frac{1}{3}{v_{\\mathrm{F}}}^2{F_{\\mathrm{v}}}}x^2\\right)\\Phi(x)\\right\\}.",
"\n \\label{dd}\\end{aligned}$$ Finally comparison of the above equation with Eq.(\\[lan\\]) provides us with the Landau-Migdal parameters in neglecting the Pauli blocking terms, $$F_0 = {F_{\\mathrm{v}}}- ( 1 - {v_{\\mathrm{F}}}^2){F_{\\mathrm{s}}}, \\quad\nF_1 = -{v_{\\mathrm{F}}}^2{F_{\\mathrm{v}}}.\\label{dpar}$$\n\nThe difference between Eqs.(\\[par\\]) and (\\[dpar\\]) is very clear. ",
"$F_0$ and $F_1$ in Eq.(\\[dpar\\]) have no denominator. ",
"In order to obtain the correct expressions of $F_0$ and $F_1$ within the RMFA, thus we need to include the Pauli blocking terms in the configuration space of the RRPA.",
"\n\nIn the Landau prescription, the denominators in Eq.(\\[par\\]) come from the self-consistent derivative of the effective mass and the baryon current with respect to the quasi-particle distribution, $n_i$ [@mat; @nks]. ",
"As to the effective mass in the RMFA, $$M^\\ast=M-\\left(\\frac{{g_{\\mathrm{s}}}}{{m_{\\mathrm{s}}}}\\right)^2\n \\frac{1}{V}\\sum_in_i\\frac{M^\\ast}{E_{p_i}},$$ we have $$\\frac{\\partial M^\\ast}{\\partial n_j}=\n-\\,\\frac{1}{V}\\left(\\frac{{g_{\\mathrm{s}}}}{{m_{\\mathrm{s}}}}\\right)^2\n\\frac{M^\\ast}{E_{p_j}}\n-\\left(\\frac{{g_{\\mathrm{s}}}}{{m_{\\mathrm{s}}}}\\right)^2\n \\frac{1}{V}\\sum_in_i\\frac{{\\mbox{\\boldmath{$p$}}}_i^2}{E^3_{p_i}}\n \\frac{\\partial M^\\ast}{\\partial n_j},\\label{mass}$$ $V$ being the nuclear volume. ",
"The coefficient of $\\partial M^\\ast/\\partial n_j$ in the r.h.s. ",
"yields ${a_{\\mathrm{s}}}{F_{\\mathrm{s}}}$ in the denominator of $F_0$, as seen in Eq.(\\[pau\\]). ",
"In the Green function formalism, the effective mass of the RMFA is written as $$M^\\ast=M+i\\left(\\frac{{g_{\\mathrm{s}}}}{{m_{\\mathrm{s}}}}\\right)^2\n \\int\\!\\frac{d^4p}{(2\\pi)^4}\\,{\\mathrm{Tr}}\\,{G_{\\mathrm{D}}}(p).$$ Hence the coefficient of $\\partial M^\\ast/\\partial n_j$ in Eq.(\\[mass\\]) is given by $${a_{\\mathrm{s}}}{F_{\\mathrm{s}}}=\n-i\\left(\\frac{{g_{\\mathrm{s}}}}{{m_{\\mathrm{s}}}}\\right)^2\n \\int\\!\\frac{d^4p}{(2\\pi)^4}\\,{\\mathrm{Tr}}\\left(\n \\frac{\\partial {G_{\\mathrm{D}}}(p)}{\\partial M^\\ast}\\right).$$ On the other hand, we have shown that $${a_{\\mathrm{s}}}{F_{\\mathrm{s}}}= - \\frac{1}{(2\\pi)^3}\n \\left(\\frac{{g_{\\mathrm{s}}}}{{m_{\\mathrm{s}}}}\\right)^2\n \\Pi_{\\mathrm{Pauli}}(k=0),$$ where $\\Pi_{\\mathrm{Pauli}}$ represents the Pauli blocking terms in Eq.(\\[cor\\]) for $\\Gamma_A = \\Gamma_B = 1$. Thus it is seen that in the Landau prescription of the RMFA, the derivative of ${G_{\\mathrm{D}}}$ includes implicitly the Pauli blocking terms. ",
"Indeed, we can prove that $$\\frac{\\partial {G_{\\mathrm{D}}}(p)}{\\partial M^\\ast}\n = {G_{\\mathrm{D}}}{G_{\\bar{\\mathrm{N}}}}+ {G_{\\bar{\\mathrm{N}}}}{G_{\\mathrm{D}}}+ {G_{\\mathrm{D}}}\\frac{M^*}{p_0}\\frac{\\partial}{\\partial p_0}.$$ If we integrate the r.h.s. ",
"over $p_0$, the Pauli blocking terms only remain.",
"\n\nThe same discussion is possible for the denominator of $F_1$. The self-consistent derivative of the current, ${\\mbox{\\boldmath{$j$}}}$, as to the quasi-particle distribution provides [@mat], $$\\frac{\\partial {\\mbox{\\boldmath{$j$}}}}{\\partial n_j}\n = \\frac{1}{V}\\frac{{\\mbox{\\boldmath{$p$}}}_j}{E_{p_j}}\n- \\frac{1}{3}{v_{\\mathrm{F}}}^2{F_{\\mathrm{v}}}\\frac{\\partial {\\mbox{\\boldmath{$j$}}}}{\\partial n_j}.\\label{mfc}$$ The coefficient of the second term yields the denominator of $F_1$. Using the Green function, the current of the RMFA is written as, $${\\mbox{\\boldmath{$\\Sigma$}}} = \\left(\\frac{{g_{\\mathrm{v}}}}{{m_{\\mathrm{v}}}}\\right)^2{\\mbox{\\boldmath{$j$}}}\n= -\\,i \\left(\\frac{{g_{\\mathrm{v}}}}{{m_{\\mathrm{v}}}}\\right)^2\\int\n\\frac{d^4p}{(2\\pi)^4}\\,{\\mathrm{Tr}}({\\mbox{\\boldmath{$\\gamma$}}}{G_{\\mathrm{D}}}(p')),\\quad\n{\\mbox{\\boldmath{$p$}}}' = {\\mbox{\\boldmath{$p$}}} - {\\mbox{\\boldmath{$\\Sigma$}}}.$$ Hence, the coefficient of the second term in Eq.(\\[mfc\\]) is given by $$-\\,\\frac{1}{3}{v_{\\mathrm{F}}}^2{F_{\\mathrm{v}}}\\delta_{ij}\n= -\\,i\\left(\\frac{{g_{\\mathrm{v}}}}{{m_{\\mathrm{v}}}}\\right)^2\n\\int\\frac{d^4p}{(2\\pi)^4}\\,{\\mathrm{Tr}}\n\\left.",
"\n \\left( \\gamma^j \\frac{\\partial {G_{\\mathrm{D}}}(p')}{\\partial {\\Sigma}^i}\n \\right)\\right|_{{\\mbox{\\boldmath{$\\Sigma$}}}=0}.$$ We can show that the above derivative of ${G_{\\mathrm{D}}}$ required in the RMFA is expressed by using the Pauli blocking terms as $$\\frac{\\partial {G_{\\mathrm{D}}}}{\\partial {\\Sigma}^i}\n = {G_{\\mathrm{D}}}\\gamma_i{G_{\\bar{\\mathrm{N}}}}+ {G_{\\bar{\\mathrm{N}}}}\\gamma_i{G_{\\mathrm{D}}}- {G_{\\mathrm{D}}}\\frac{p'^i}{E_{p'}}\\frac{\\partial}{\\partial p_0}.$$\n\nLet us explore the effects of the Pauli blocking terms in more detail. ",
"The Pauli blocking terms reduce always the contribution of the $\\sigma$-meson to $F_0$ through the factor ${a_{\\mathrm{s}}}$ in Eq.(\\[par\\]), since ${a_{\\mathrm{s}}}$ is positive, as seen in Eq.(\\[pau\\]). ",
"On the other hand, the contribution of the $\\omega$-meson to $F_0$ is not affected. ",
"Therefore, the value of $F_0$ becomes always smaller, and the incompressibility, $K$, is reduced according to Eq.(\\[com\\]), when the Pauli blocking terms are neglected. ",
"On the contrary, the absolute value of $F_1$ in Eq.(\\[dpar\\]), which has no denominator, becomes always larger, compared with the correct one in Eq.(\\[par\\]), so that $K$ is enhanced in neglecting the Pauli blocking terms.",
"\n\nWe calculate the values of $F_0$, $F_1$ and $K$ using the following parameters [@hs] as an example, $$M = 939,\\quad {m_{\\mathrm{s}}}= 520,\\quad {m_{\\mathrm{v}}}= 783\n \\ \\ ({\\mathrm{MeV}}),$$ $${g_{\\mathrm{s}}}^2 = 109.626,\\quad {g_{\\mathrm{v}}}^2 = 190.431,$$ which reproduce the nucleon binding energy, $E_{\\mathrm{B}} = -15.75$ MeV at ${p_{\\mathrm{F}}}= 1.30$ fm$^{-1}$. In this case, we have $M^* = 0.541M$, ${v_{\\mathrm{F}}}= 0.451$ and ${a_{\\mathrm{s}}}= 9.07\\times10^{-3}$. These values provide us with $$F_0 = 0.569, \\quad F_1 = -1.151, \\quad K = 544 \\ {\\mathrm{MeV}}$$ in taking the Pauli blocking terms, and $$F_0 = -0.368, \\quad F_1 = -1.866, \\quad K = 357 \\ {\\mathrm{MeV}}$$ in neglecting the Pauli blocking terms. ",
"Thus both Landau-Migdal parameters are strongly affected by the Pauli blocking terms, and, in particular, $F_0$ changes its sign. ",
"Consequently, the value of $K$ is fairly reduced in neglecting the Pauli blocking terms. ",
"In $^{208}$Pb, the reduction amounts to about 2.7 MeV for the present parameters. ",
"This fact may be observed in ref. [",
"@giai] by numerical calculations.",
"\n\nNow real effects of the Dirac sea should be explored with the fully renormalized RRPA, where the ${G_{\\mathrm{F}}}{G_{\\mathrm{F}}}$ term is also calculated in the Hartree correlation functions. ",
"Then, the Pauli exclusion principle in both the Fermi sea and the Dirac sea is correctly taken into account. ",
"Such calculations based on the renormalized Hartree approximation(RHA) have been done by the present authors in ref. [",
"@dks]. ",
"For complete discussions, we quote those results here. ",
"The Landau-Migdal parameters in this case are given by $$F_0 = F_\\omega - \\alpha_{\\mathrm{ren}} {F_{\\mathrm{s}}},\\quad\nF_1 = -\\frac{{v_{\\mathrm{F}}}^2F_\\omega}{1 + \\frac{1}{3}{v_{\\mathrm{F}}}^2F_\\omega},\n\\label{rpar}$$ where we have used the abbreviations: $$F_\\omega = {N_{\\mathrm{F}}}\\left(\\frac{{g_{\\mathrm{v}}}}{m_0}\\right)^2,\\quad\n \\alpha_{\\mathrm{ren}}\n = \\frac{1 - {v_{\\mathrm{F}}}^2}{1 + {a_{\\mathrm{s}}}{F_{\\mathrm{s}}}+ a_{\\mathrm{D}}}.",
"\n \\label{dir}$$ Formally the above equation is similar to Eq.(\\[par\\]), but the mass of the $\\omega$-meson is replaced by the bare mass, $m_0$, in $F_\\omega$ and the Dirac sea yields an additional effect, $a_{\\mathrm{D}}$ in $\\alpha_{\\mathrm{ren}}$ [@dks].",
"\n\nAs to $F_1$, essentially there is no additional effects from the Dirac sea. ",
"The renormalized correlation function from the ${G_{\\mathrm{F}}}{G_{\\mathrm{F}}}$ term due to the $\\omega$-meson exchange disappears at the limit $k \\rightarrow 0$ and has no contribution to $F_1$. Replacement of ${m_{\\mathrm{v}}}$ by $m_0$ comes from the fact that the $\\omega$-meson propagator is written in terms of the bare mass[@dks]. ",
"The value of $F_1$, however, depends on those of the Yukawa coupling constants used in the RHA. ",
"In order to reproduce the nucleon binding energy and the Fermi momentum mentioned before[@dks], the RHA requires ${g_{\\mathrm{s}}}^2\n= 66.117$ and ${g_{\\mathrm{v}}}^2 = 79.927$. These values give $M^* =\n0.7306M$ and $m_0 = 691.171$ MeV, so that we obtain $F_1 = -0.620$.\n\nOn the other hand, $F_0$ is strongly affected by the Dirac sea through $a_{\\mathrm{D}}$ in Eq.(\\[dir\\]). ",
"In using ${v_{\\mathrm{F}}}$ = 0.3502 of the present RHA, its value is much larger than that of ${a_{\\mathrm{s}}}{F_{\\mathrm{s}}}$, $$a_{\\mathrm{D}} = 0.405, \\quad {a_{\\mathrm{s}}}{F_{\\mathrm{s}}}= 0.0296.$$ This Dirac sea effects reduce strongly the contribution of the $\\sigma$-meson to $F_0$ through $\\alpha_{\\mathrm{ren}}$, and we have $$F_0 = 0.676.$$ If $a_{\\mathrm{D}}$ were neglected, then the value of $F_0$ would be $ -1.56$, which means $K < 0$. This fact reflects that $\\bar{{\\mathrm{N}}}$-degrees of freedom play an important role to stabilize the nucleus in the RHA.",
"\n\nFinally we give two comments. ",
"First, since the restoring force of the giant quadrupole states comes mainly from the distortion of the kinetic energy density, its excitation energy depends on $F_1$[@nks], $$E_{\\mathrm{Q}}\n= \\left( \\frac{6{p_{\\mathrm{F}}}^2}{5\\epsilon_{\\mathrm{F}}^2\\langle\nr^2 \\rangle}\\frac{1}{1 + \\frac{1}{3}F_1} \\right)^{1/2}.",
"\n\\label{eq}$$ Thus, the Pauli blocking terms affect also the excitation energy of the quadrupole states in the RRPA based on th RMFA. ",
"Moreover, the Pauli blocking terms should be taken into account in the description of the center of mass motion, which requires the correct $F_1$ [@nks]. ",
"This fact has been observed in arguments on the spurious state of RRPA by Dawson and Furnstahl [@fur]. ",
"In the same way the Pauli blocking terms are necessary for discussions of the nuclear current or magnetic moments [@pv]. ",
"The isovector dipole states depend on $F_1$ and $F'_1$, which also require the Pauli blocking terms. ",
"The detail will be published in a separate paper.",
"\n\nSecond, we note that Eqs.(\\[em\\]), (\\[com\\]) and (\\[eq\\]) are formally the same as those in nonrelativistic models, except for $\\epsilon_{\\mathrm{F}}$ in their denominators [@nks]. ",
"In nonrelativistic models, it is replaced by the nucleon mass, $M$. However, they are related to each other as Eq.(\\[fe\\]) through the nucleon binding energy which is negligible compared with the nucleon mass. ",
"Thus the relativistic correction to the excitation energies of the monopole and quadrupole states is less than 1% for $E_{\\mathrm{B}} = -15.75$ MeV, if the values of the Landau-Migdal parameters in relativistic models are the same as in nonrelativistic ones.",
"\n\nIn conclusion, in the relativistic random phase approximation(RRPA) based on the relativistic mean field approximation, the Pauli blocking terms should be taken into account for consistent descriptions of the Landau-Migdal parameters. ",
"The real effects of the Dirac sea on the excitation energy of the monopole states are studied in the RRPA built on the renormalized Hartree approximation. ",
"Then the nucleon-antinucleon states affect strongly the excitation energy of the monopole states through the Landau-Migdal parameter, $F_0$. The incompressibility coefficient becomes negative, if antinucleon-degrees of freedom are neglected. ",
"The Landau-Migdal parameter, $F_1$, is not affected formally by the renormalization.",
"\n\nThe authors would like to thank Professor Nguyen Van Giai and Professor P. Ring for useful discussions.",
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"\n"
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"I[NTRODUCTION]{.smallcaps} {#sec1-1}\n==========================\n\nMenopause is a crucial event in a woman\\'s life as she witnesses several physical and psychological changes during the transition. ",
"One such important change is the increase in body weight and an alteration in fat distribution increasing the risk of menopausal symptoms and metabolic disorders. ",
"The severity of menopausal symptoms is higher among obese women as compared to nonobese women, and clinically significant weight loss results in marked improvement of these symptoms, especially hot flashes, mood disorders, and sleep disturbances.\\[[@ref1]\\] However, achieving clinically significant weight loss is far more challenging in perimenopausal women due to several factors. ",
"This review aims to understand the association between menopause and obesity and its impact on women in perimenopausal age group. ",
"Besides, we have suggested a weight management module for its management.",
"\n\nB[URDEN OF]{.smallcaps} O[BESITY IN]{.smallcaps} M[ENOPAUSAL]{.smallcaps} W[OMEN]{.smallcaps} {#sec1-2}\n=============================================================================================\n\nThe problem of obesity is rising at an alarming rate, with disproportionately higher prevalence in female than male counterparts. ",
"This trend can largely be attributed to differences in age-specific reproductive cycles (pregnancy, lactation, and menopause) in women. ",
"A pooled analysis of international studies on menopausal obesity reports that almost 39% women undergoing menopausal transition are either overweight or obese.\\[[@ref2]\\] In the Indian context, the proportion of overweight/obese women increases from 4% at younger age to 34% at middle and older age.\\[[@ref3]\\] This steep increase in the prevalence of obesity in middle-aged women coincides with the initiation of the menopausal transition.",
"\n\nNearly, 401 million perimenopausal women in our country will be predisposed to the risk of menopausal obesity by 2026.\\[[@ref4]\\] Obese women at this stage are exposed to the dual burden of menopausal symptoms and metabolic complications of obesity for the rest of their life.\\[[@ref5]\\] Weight gain at this stage can be partly attributed to the lack of awareness among middle-aged women toward their health-related issues as they prioritize the wellness of their family members over their own. ",
"This neglect impedes the initiation of any weight loss intervention by them, further aggravating the problem of weight gain. ",
"The massive proportions of menopausal women and the affected number of life years due to obesity and its consequences make it an issue of public health concern.",
"\n\nP[ATHOPHYSIOLOGY:]{.smallcaps} M[ECHANISM OF]{.smallcaps} M[ENOPAUSAL]{.smallcaps} O[BESITY]{.smallcaps} {#sec1-3}\n========================================================================================================\n\nThe mechanism of the development of obesity in menopausal women is outlined in [Figure 1](#F1){ref-type=\"fig\"}. ",
"The continuous depletion of the follicular ovarian pool during menopausal transition lowers estrogen production with a relative increase in androgen levels. ",
"This hormonal imbalance alters energy homeostasis by regulating hunger and satiety signals.\\[[@ref6]\\] Estrogen inhibits the action of hunger signals, preventing events of excessive calorie consumption. ",
"It is postulated that during the menopausal transition because of fluctuating estrogen levels, its effectiveness to modulate hunger hormones is reduced.\\[[@ref7]\\] Menopausal women experience more intense hunger signals encouraging increased food intake which promotes weight gain.",
"\n\n{#F1}\n\nThe hormonal imbalance during menopause also promotes the higher accumulation of fat in the abdominal region. ",
"Low estrogen levels along with high androgen levels lead to redistribution of fat present in the gluteal and femoral regions to abdominal regions of the body, favoring abdominal obesity.\\[[@ref8]\\] Besides, higher abdominal obesity is an independent risk factor for future metabolic complications.\\[[@ref9]\\]\n\nMenopausal obesity is primarily driven by hormonal imbalance and its effect on energy balance. ",
"Some other crucial factors, such as unhealthy eating behavior, sedentary lifestyle, and secondary causes (hypothyroidism, cushing syndrome, and medication) might also account for the differences in personal weight gain trajectories among these women.",
"\n\nR[ISK]{.smallcaps} F[ACTORS OF]{.smallcaps} M[ENOPAUSAL]{.smallcaps} O[BESITY]{.smallcaps} {#sec1-4}\n==========================================================================================\n\nObesity in menopausal women is a result of several modifiable and nonmodifiable factors. ",
"Nonmodifiable factors comprise of physiological factors, whereas psychosocial and lifestyle-related behaviors are categorized as modifiable risk factors, as depicted in [Table 1](#T1){ref-type=\"table\"}.\\[[@ref10]\\] Physiological risk factors such as chronological aging, slower basal metabolic rate (BMR), hormonal fluctuations, and the presence of metabolic disorders affect the pace of weight gain. ",
"Hormonal fluctuations experienced during the transition are strongly associated with psychological distress.\\[[@ref11]\\] Women generally deal with distress by indulging in unhealthy eating behavior. ",
"Excessive caloric intake coupled with an overall sedentary lifestyle is conventionally associated with weight gain in menopausal women. ",
"The key factors driving the prevalence of obesity in menopausal women are briefly discussed below:\n\n###### \n\nEtiological factors in menopausal obesity\n\n -------------------------------------------------------------------------------------------------------------------------------------------------------------------\n Physiological factors Hormonal factor Lifestyle-related factors Psychological distress\n ----------------------------------------------- ------------------- ---------------------------------------------------------------------- ------------------------\n Aging\\ Hypoestrogenemia\\ Excessive caloric intake\\ Depression\\\n Decrease in BMR\\ Hyperandrogenemia Low dietary fiber intake\\ Anxiety\\\n Decrease in lean mass\\ Excessive SSB intake\\ Mood disorder\\\n Secondary causes (hypothyroidism, PCOS etc.)\\ Processed and convenience food (primarily energy-dense) consumption\\ Irritability\\\n Musculoskeletal disorders Skipping meal\\ Emotional eating\n Large portion size\\ \n Vitamin D deficiency\\ \n Low physical activity\\ \n Sedentary behavior\\ \n Irregular sleep\\ \n Smoking and alcohol intake \n\n -------------------------------------------------------------------------------------------------------------------------------------------------------------------\n\nBMR: Basal Metabolic rate, PCOS: Polycystic ovary syndrome, SSB: Sugar-sweetened beverages\n\nPhysiological factors {#sec2-1}\n---------------------\n\nChronological aging is a competing risk factor for weight gain in middle-aged women. ",
"On an average, a weight gain of half kilogram per year is generally observed in this group.\\[[@ref12]\\] Moreover, weight gain coexists with a decline in lean mass. ",
"The proportion of lean mass is positively associated with BMR, a component of energy expenditure. ",
"Slow metabolic rate in menopausal women decreases their capacity to effectively burn calories promoting a positive calorie balance.\\[[@ref13]\\] Other physiological causes such as hypothyroidism, polycystic ovary syndrome, and musculoskeletal disorders can act as primary reasons for weight gain in menopausal women.",
"\n\nPsychological factors {#sec2-2}\n---------------------\n\nMenopausal women report a high prevalence of negative emotional state (depression, stress, anxiety, tension, and mood disorder), sleep disturbances, and sexual problems during the period of transition.\\[[@ref14]\\] Psychological distress commonly stems from body image issues. ",
"Women presenting with issues related to either body image and/or psychology report more episodes of emotional eating to combat distress.\\[[@ref15]\\] Emotional eating or overeating is strongly associated with weight gain, as well as difficulties in self-regulation during weight loss attempts.\\[[@ref16]\\]\n\nLifestyle related factors {#sec2-3}\n-------------------------\n\nPositive energy balance and poor quality of the diet are drivers of weight gain in middle-aged women. ",
"A \"westernised\" diet pattern, including HFSS (high fat, sugar, and salt) products and low dietary fiber intake is positively associated with weight gain during the menopausal transition.\\[[@ref17]\\] Higher consumption of processed, fried, or convenience food due to its easy availability is also identified as a prime reason for higher body mass index (BMI).\\[[@ref18]\\]\n\nThe higher preference for convenience food is also inversely proportional to time spent in home-cooked meals by these women. ",
"The lack of home-cooked meals impacts meal regularity, promoting the intake of large and/or energy-dense portions. ",
"The unhealthy eating behavior coupled with physical inactivity, irregular sleep patterns, smoking cessation, and excessive alcohol consumption leads to weight gain in this group of women.",
"\n\nA progressive reduction in physical activity is observed with aging, especially in females. ",
"The preference for sedentary behavior in middle-aged women might be due to diminished muscle strength that limits their functional ability to perform daily activities.\\[[@ref19]\\] The limited-time spent in daily chores and physical activity is compensated by involvement in sedentary behaviors such as watching television, reading, and talking. ",
"More than half (64.7%) of Indian women follow this sedentary lifestyle.\\[[@ref18]\\] Besides, these women rarely adjust their caloric intake according to decreased daily activity, making them gain weight.",
"\n\nThe complex interplay of various determinants and associated symptoms enhances the risk of noncommunicable comorbidities, functional disability, and distress in menopausal women impacting the quality of their life.",
"\n\nO[BESITY IN]{.smallcaps} M[ENOPAUSE AND]{.smallcaps} I[TS]{.smallcaps} I[MPLICATIONS]{.smallcaps} {#sec1-5}\n=================================================================================================\n\nOverweight and obese menopausal women are at a greater risk of associated metabolic and cardiovascular complications, osteoporosis, and cancers.\\[[@ref20]\\] The risk of metabolic complications is compounded by abdominal fat distribution. ",
"Intra-abdominal fat around the viscera acts as metabolically active tissue, producing inflammatory markers (e.g., interleukin \\[IL\\]-1, IL-6, leptin, and tumor necrosis factor-α) which regulate the metabolic function.\\[[@ref21]\\] Besides, studies suggest that higher abdominal fat is positively correlated with hypertension, insulin resistance, and pro-atherogenic lipid profile, which are well-established risk factors for cardiovascular diseases.\\[[@ref22]\\]\n\nMajority of women during menopause also complain about bone-related issues such as joint and back pain, knee-related issues, osteoporosis, and fractures. ",
"In most of these cases, the degenerative changes in the bone are driven by a marked decrease in circulating estrogen levels. ",
"The depletion in the levels of estrogen enhances bone resorption without a corresponding rise in bone deposition rate.\\[[@ref23]\\] The amount of bone resorbed is greater than the amount of bone deposited, leading to a net bone loss, presenting as low bone density and quality. ",
"The reduction in bone strength predisposes menopausal women to bone-related issues, especially osteoporosis, exposing them to a high risk of fractures.\\[[@ref24]\\]\n\nAt later, premenopausal stage, higher BMI is an independent risk factor for breast, endometrium, and uterine cancers. ",
"Obese menopausal women have a long-standing exposure to estrogen due to its continuous production by adipose tissues. ",
"The unopposed exposure to estrogen is responsible for high cancer risk in these women.\\[[@ref25]\\] Higher adiposity also poses as an independent risk factor for systemic complications such as chronic kidney failure, chronic liver disease, obstructive sleep apnea, pulmonary distress, and sexual dysfunction than their healthy counterparts.\\[[@ref21]\\]\n\nThe harmful effect of obesity at midlife goes beyond body image issues, impacting the overall health of these women. ",
"Successful management of obesity is known to help in the management of obesity and its related complications, promoting healthy aging.",
"\n\nC[HALLENGES IN THE]{.smallcaps} M[ANAGEMENT OF]{.smallcaps} M[ENOPAUSAL]{.smallcaps} O[BESITY]{.smallcaps} {#sec1-6}\n==========================================================================================================\n\nThe management of obesity in menopausal women is a great challenge. ",
"Current weight management interventions result in modest weight loss outcomes, which are poorly sustained in the long term. ",
"This can be attributed to a number of barriers that undermine the efficacy of weight-loss strategies producing insignificant weight loss. ",
"Some of these factors include specific physiological state, underlying metabolic condition or psychological distress, behavioral issues (low self-esteem, low self-efficacy), obesogenic environment, and lack of social support.\\[[@ref26]\\] Most of these barriers are commonly present at menopausal stage making weight management even more challenging.",
"\n\nMenopausal women encounter more barriers during weight loss attempts than the general adult population. ",
"These challenges are specific to their physiological stage. ",
"The menopausal stage favors adiposity and might coexist with a number of metabolic comorbidities, functional disability, and body image issues. ",
"The presence of menopausal symptoms may also impede successful compliance with weight loss advice. ",
"Failure to lose and maintain weight enhances psychological distress, which acts as cues for unhealthy eating behavior and noncompliance to the given weight loss regime favoring further weight gain.",
"\n\nWeight gain has a bidirectional relationship with vasomotor symptoms, metabolic, and functional comorbidities. ",
"The clustering of a number of complications might affect the healthy aging and quality of life of these women. ",
"These complications can primarily be addressed by successful management of obesity in menopausal women. ",
"A comprehensive weight management module addressing women-centric barriers should be devised for achievement of successful weight loss outcomes.",
"\n\nM[ANAGEMENT OF]{.smallcaps} O[BESITY]{.smallcaps} {#sec1-7}\n=================================================\n\nThe management of obesity is a stepwise intensification of pharmacological and nonpharmacological approaches. ",
"Grade I obesity is managed by nonpharmacological approaches such as the introduction of a low-calorie diet and increased physical activity. ",
"Pharmacological therapy is recommended for patients unable to achieve weight loss goals through these measures. ",
"The indications for grade II and grade III obesity include a combination of patient-specific pharmacological and surgical recommendations.\\[[@ref27]\\] These recommendations have to be patient-specific considering the physiology, stage of transition, symptom severity, and the presence of metabolic complications. ",
"The weight management advice specific to perimenopausal women is given below:\n\nDietary recommendations {#sec2-4}\n-----------------------\n\nDietary management is based on the introduction of caloric deficit while improving the overall quality of diet. ",
"A calorie deficit is achieved by reducing 500--750 kcal from current caloric intake taking due account of caloric expenditure, baseline BMI, and the presence of associated comorbidities.\\[[@ref28]\\] In general, an intake of 1200--1000 kcal is suggested in clinical practice. ",
"The proportion of protein (20%--25%), fat (\\<30%), and carbohydrates (40%--50%) with respect to total calories is calculated accordingly.\\[[@ref29]\\] The recommended diet should be high in fiber as the antioxidants, especially from fruits and vegetables decrease the oxidative stress that affects the number and quality of ovarian follicles.\\[[@ref30]\\] Women should have daily intake of at least 2 litres of water. ",
"Limitations on salt, sugar, and processed foods should be observed. ",
"These women should incorporate corrective eating behavior such as 5--6 small and frequent meals, limited portion size, balanced meals, healthy snacking, and control over emotional eating episodes.\\[[@ref31]\\] Some specific suggestions for menopausal women are as follows:\n\nIncorporate foods rich in calcium such as milk and milk products, nuts and seeds, beans, green leafy vegetables for the maintenance of bone health. ",
"The intake of red meat, carbonated beverages, and certain foods high in phytates should be avoided as it hinders calcium absorption.",
"Iron-rich food (whole cereal and pulses, lean meat, egg, spinach, nuts, and seeds) for heavy menstrual bleeding and magnesium (green leafy vegetables, nuts and seeds, legumes) should be consumed for relieving menopausal symptoms such as hot flushes, insomnia, palpitations, and irritability.",
"Food rich in phytoestrogen, especially soybean, helps in alleviating menopausal symptoms and promotes musculoskeletal and bone health.",
"Both peri and postmenopausal women are vulnerable to Vitamin D deficiency. ",
"Proper screening and supplementation should be provided.",
"Spicy food, alcohol, and caffeine should be avoided for relief from hot flashes.",
"\n\nThe studies have shown inconsistent results on the effectiveness of incorporating soy products, calcium supplementation, and lifelong fish consumption in relieving menopausal symptoms.\\[[@ref32]\\]\n\nRecommendations for physical activity {#sec2-5}\n-------------------------------------\n\nPhysical activity helps to achieve negative calorie balance and relieves vasomotor symptoms. ",
"Menopausal women are generally advised 150 min/week of moderate-intensity physical activity such as aerobic exercise (walking, jogging, swimming, and cycling) coupled with household activities. ",
"The incorporation of resistance training exercises (2--3 times/week) helps to maintain bone and muscle mass. ",
"A combination of aerobics, resistance training, and balance exercises is the most effective in managing weight, vasomotor symptom severity, and psychological distress in these women.\\[[@ref33]\\] Walking and aerobics have protective effect on vasomotor symptoms. ",
"Practicing yoga helps to relieve hot flashes and improves the quality of sleep in menopausal women.\\[[@ref34]\\]\n\nThe physical activity regime has to be progressive and individualized according to patient\\'s needs. ",
"Steps to a progressive activity regime incorporating recommended activities for menopausal women are given below:\n\nStep I {#sec2-6}\n------\n\nAging makes the body less flexible. ",
"Start with warm-up exercises such as full body stretches, walking for 10 min on the treadmill, suryanamaskar, etc. ",
"Warming up helps to prepare the body for exercise by gradually increasing physical activity, joint mobility, and stretching.",
"\n\nStep II {#sec2-7}\n-------\n\nAerobic exercises help to burn calories and provide cardiometabolic benefits to older women. ",
"Aerobic exercise can be initiated by walking for a short duration at a comfortable pace. ",
"A progressive increase in aerobic exercises by incorporating dancing, cycling, jogging, running, and swimming can be done as the regime progresses.",
"\n\nStep III {#sec2-8}\n--------\n\nShort bouts of resistance exercise and strength training can also be incorporated using resistance bands, weight resistance, or utilizing one\\'s own body weight. ",
"It is recommended that these exercises can be incorporated on every alternate day focusing on the abdomen, arms, legs, shoulders, and hips.\\[[@ref35]\\] These exercises help to maintain muscle mass and bone density in menopausal women.",
"\n\nStep IV {#sec2-9}\n-------\n\nPracticing yoga and stretches help to maintain flexibility in older age women to perform daily chores. ",
"These light intensity exercise do not spike the vasomotor symptoms and help to ease the psychological symptoms.\\[[@ref36]\\]\n\nStep V {#sec2-10}\n------\n\nBalance exercises help in postural and gait control to prevent falls in menopausal women. ",
"Practices such as tai chi, pilates, and some functional exercises Can help to maintain balance\\[[@ref37]\\]\n\nStep VI {#sec2-11}\n-------\n\nThe exercise session should conclude with cooling down exercises such as walking a few minutes and muscle relaxing postures and stretches which will ease the pain.",
"\n\nRegular exercise has both short-term and long-term benefits in menopausal women. ",
"Short term benefits include the management of menopausal symptoms, psychological distress, weight issues, immobility, and injuries.\\[[@ref35]\\] Long-term physical activity helps in improvement of chronic disorders such as mood disorders, dementia, chronic pain, diabetes, strokes, and cardiovascular episodes reducing mortality and enhancing overall quality of life.\\[[@ref38][@ref39]\\]\n\nBehavioral therapy {#sec2-12}\n------------------\n\nBehavioral therapy is a set of strategies, which includes goal setting, problem-solving, emotional eating, stimulus control, and relapse prevention.\\[[@ref40]\\] These strategies aim to improve patient\\'s compliance with the recommended dietary and exercise regimens. ",
"The compliance to lifestyle modification advice by menopausal women is influenced by the associated psychological distress. ",
"Psychological issues induce unhealthy behaviors and reduce self-regulation during weight loss attempts, which can be better addressed by progressive sessions based on behavioral strategies.",
"\n\nIt is imperative to initiate the sessions after assessing the patient\\'s readiness to change their existing dietary and activity behavior and set patient-specific weight loss targets. ",
"An initial understanding of woman\\'s knowledge, attitude, and practices regarding obesity can also help in recommending patient-specific advice.\\[[@ref41]\\] Second, the identification of primary behaviors associated with weight gain should be done prior to counseling about the required behavioral modification techniques. ",
"This helps to modify, incorporate, and sustain behaviors that would lead to weight loss. ",
"For example, a sedentary patient can be advised to complete \"10,000 steps per day,\" \"walking for 30--40 min to and from work or for household chores,\" etc. ",
"Finally, the patient has to be advised self-monitoring techniques such as to maintain dietary and activity logs to assess the compliance and its associated facilitators and barriers. ",
"Patient\\'s compliance can also be assessed with the help of questionnaire, which can highlight the barriers that limits adherence to the given dietary and activity advice.\\[[@ref42]\\] The barriers and facilitators can be addressed in the following sessions for sustenance of positive behaviors to produce clinically significant weight loss.\\[[@ref43]\\]\n\nPharmacological management {#sec2-13}\n--------------------------\n\nHormone replacement therapy (HRT) is the administration of estradiol with progesterone to supplement for estrogen deficiency at menopause.\\[[@ref44]\\] The prescription of HRT is an effective strategy for overall management of vasomotor symptoms, bone health, and cognitive functioning, especially at postmenopausal stage.\\[[@ref45]\\] There is contradicting literature on the effect of HRT on the weight status, with studies supporting and refuting its role in weight loss. ",
"A number of studies have highlighted the role of HRT in the reduction of abdominal obesity, insulin resistance, and associated cardiovascular risk.\\[[@ref46]\\] The effectiveness of HRT depends on a number of factors such as estrogen dose, combination with progesterone, duration, time of initiation, and route of administration.\\[[@ref47]\\] The discussion regarding the role of HRT on the body fat accumulation and distribution and its role in metabolic risk prevention requires more research and its discussion is beyond the scope of this review.",
"\n\n[Table 2](#T2){ref-type=\"table\"} depicts the weight management module for menopausal women. ",
"The module consists of pharmacological and nonpharmacological components of obesity management, customized for menopausal women. ",
"These components address eating and activity behavior and underlying psychological factors specific for the achievement of desirable weight loss outcomes. ",
"This weight management module can be used by obstetricians and gynecologists in their regular clinical practice for an effective management of patients presenting with menopausal obesity.",
"\n\n###### \n\nWomen centric weight management module\n\n Women centric weight management module\n -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------\n Step I: Assessment\n Clinical and lifestyle history: Elicit clinical history of risk factors of obesity and its related comorbidities, psychological distress, and severity of menopausal symptoms. ",
"Lifestyle-related factors leading to weight gain should be highlighted\n Anthropometric measurement: Height, weight, body mass index, waist circumference, and bioelectric impedance (if available) should be measured\n Biochemical assessment: Biological factors such as lipid profile, HbA1c, kidney function test, liver function test, blood pressure, thyroid-stimulating hormone and fasting blood glucose. ",
"Further laboratory test can be initiated for patient-specific indications\n Dietary and physical activity assessment: Assess current caloric intake and overall physical activity status\n Step II: Prescription: Medical, dietary, and activity advice\n Medical prescription: Prescribe the required medication on indication of metabolic or adverse menopausal symptoms\n HRT is recommended in adverse menopausal symptoms\n Low-dose HRT - 0.3 mg CEE/1 mg estradiol and MPA 1.5 mg\n Nonoral route - Patches, gel, vaginal cream, and implants or tibolone\n Dietary advice\n Balanced hypocaloric diet (deficit 500 kcal), rich in Fe, Ca, and phytoestrogen\n Incorporate 5 servings of fruits and vegetables and high fiber (nuts, oilseeds, whole cereal, and pulses)\n Small and frequent meals with optimum portion size\n Limit processed foods rich in fat (saturated and cholesterol) food, sugar, and salt intake\n Physical activity\n Activity plan of 150 min/week as a combination of aerobics, strength training, balance, and flexibility should be planned\n Advice to maintain overall active status: Walk-in office, take stairs, commute via public transport, walk the dog, etc.",
"\n Behavioral advice\n Use strategies like self-monitoring (food and activity log), goal setting (5%-10% weight loss), eating behavior (EatWell Plate, Food label reading), problem solving (discuss maladaptive eating behavior) and stimulus control (use distraction to avoid excessive eating)\n Some menopausal symptoms such as hot flashes, mood swings, insomnia and irritability can be managed by lifestyle modification techniques. ",
"The incorporation of these advices also helps to maintain heart and bone health\n Step III: Follow-up\n Essential to re-enforce advices, track progress, and manage challenges in weight loss process\n\nMPA: Medroxyprogesterone acetate, CEE: Conjugate equine estrogen, HRT: Hormone replacement therapy, HbA1c: Hemoglobin A1c\n\nFinancial support and sponsorship {#sec2-14}\n---------------------------------\n\nNil.",
"\n\nConflicts of interest {#sec2-15}\n---------------------\n\nThere are no conflicts of interest.",
"\n"
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"Failure of transcutaneous electrical nerve stimulation and indomethacin to reduce opiate requirement following cholecystectomy.",
"\nThis randomized study examined the effect of transcutaneous electrical nerve stimulation (TENS) and indomethacin on postoperative opiate requirement in 60 patients after cholecystectomy. ",
"An open intravenous bolus of 25 mg of indomethacin followed by an infusion of 5 mg in 1 h, alone or combined with either low or high frequency TENS, was administered during the study period of 16 h. An intravenous bolus of either 5 mg of oxycodone or 0.15 mg of buprenorphine was administered double blindly for postoperative pain relief. ",
"The number of doses of buprenorphine given (3, 9) differed (P = 0.01) from the number of doses of oxycodone given (5, 4). ",
"Neither indomethacin nor TENS reduced the postoperative opiate requirement."
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"“It is regrettable that the Government has ducked the opportunity for substantial reform of the regressive and arcane TV licence fee. ",
"It remains a throwback to an era when there was a single TV channel and the only way to watch it was via an unwieldy box in your living room. ",
"With the technology now in place for people to subscribe to their choice of thousands of competing channels and watch them wherever they happen to be, the time has surely come to explore a new, fairer funding model fit for the 21st century.”",
"\n\nOn the announcement regarding publication of salaries within the BBC, he continued:\n\n\"Licence fee payers deserve to know how their money is being spent and so only revealing the salaries of those earning more than an eye-watering £450,000 just doesn’t cut the mustard. ",
"Other public bodies are rightly obliged to reveal far greater detail about all those on six-figure salaries and the Government has offered no justification for allowing the BBC to escape that scrutiny. ",
"By failing to promote proper transparency in this area, ministers are letting down all of us who are forced to stump up the cash to fund these pay deals.\"",
"\n\nTPA spokesmen are available for live and pre-recorded broadcast interviews via 07795 084 113 (no texts)"
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"Daedalus\n\nIOHK, a blockchain research and development company, announced its highly-engineered digital wallet Daedalus has been integrated with Ethereum Classic’s (ETC) command line client Mantis. ",
"Through the integration, Daedalus, which supports Cardano’s cryptocurrency Ada, a top five cryptocurrency by market cap, ..."
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"\n92 Md. App. ",
"179 (1992)\n607 A.2d 103\nROBERT BOWIE JOHNSON, JR., ",
"ET AL.",
"\nv.\nCHESTER M. WRIGHT, ET AL.",
"\nNo. ",
"1317, September Term, 1991.",
"\nCourt of Special Appeals of Maryland.",
"\nMay 28, 1992.",
"\nWilliam M. Ferris (Krause & Ferris, on the brief), Annapolis, for appellants.",
"\nMichael J. Budow (Anne K. Howard and Budow & Noble, on the brief), Bethesda, for appellee, Taylor.",
"\nDavid A. Simison, Millersville, for other appellees.",
"\nArgued before ALPERT, BLOOM and CATHELL, JJ.",
"\nBLOOM, Judge.",
"\nRobert Bowie Johnson, his wife, Nancy Griggs Johnson, and their two daughters, Lisa Ann and Nancy Beth Johnson, appeal from a judgment entered by the Circuit Court for Anne Arundel County in favor of appellees, First United Pentecostal Church of Annapolis, Maryland, Inc., Chester M. Wright, Alice Wright, Susan Richards, David Shaffer, David Huston, Daryl Savage, Robert Schlissler, Fred D. Bishop, and Owen Taylor. ",
"We must dismiss the appeal because it was not filed timely.",
"\nThe action originated with a pro se complaint, 28 pages (and 53 numbered paragraphs) in length, purporting to assert, against appellees and two persons who were never served, claims for defamation and invasion of privacy. ",
"Upon motion, the circuit court dismissed the complaint with leave to file an amended complaint that would conform to the Maryland Rules of Procedure. ",
"Appellants retained counsel, who filed an amended complaint alleging defamation, invasion of privacy, and \"interference.\" ",
"The count for \"interference\" was dropped by appellants. ",
"Appellee Chester M. Wright filed a counterclaim for defamation. ",
"Appellees' motion to dismiss was granted and, with leave of court, appellants filed a second amended complaint, which purported or attempted to assert claims for defamation, invasion of privacy, and conspiracy. ",
"Upon motion by appellees, the court dismissed that complaint by order dated 10 January 1991.",
"\nOn 21 January 1991, appellant Robert Bowie Johnson Jr., acting pro se, filed a motion to reverse the dismissal order of 10 January. ",
"On 12 February, seven of the appellees filed a motion, pursuant to Md. Rule 1-341, for attorneys' fees. ",
"The court denied both the motion to revise the order of dismissal and the motion for attorneys' fees, but granted leave to appellees to refile the motion for fees within 30 days.",
"\nAppellants, again pro se, filed a notice of appeal to this Court. ",
"We dismissed that appeal, pursuant to Maryland Rule 8-602; since the counterclaim of Chester M. Wright was still pending, there was no final judgment. ",
"Rule 2-602. ",
"In the meantime, seven of the appellees had filed a new motion for counsel fees.",
"\nOur mandate dismissing the first appeal was issued 17 June 1991. ",
"Thereafter, on 12 July 1991, the circuit court conducted a hearing on the counsel fee motion. ",
"At that hearing, the court dismissed Chester Wright's counterclaim. ",
"On 16 July 1991, the court issued an order denying appellees' motion for attorneys' fees.",
"\nThis appeal from the dismissal of their second amended complaint was filed on 14 August 1991, more than 30 days after the court dismissed the counterclaim but less than 30 days after the court denied appellees' motion for attorneys' fees.",
"\n\nMotion to Dismiss\nAppellees have included in their briefs a motion to dismiss the appeal pursuant to Md. Rule 8-603(c). ",
"They contend that appellants' second appeal to this Court was not filed within 30 days after entry of the judgment as required by Md. Rule 8-202(a).",
"\nWhen the circuit court dismissed appellee Chester M. Wright's counterclaim on 12 July 1991, that order of dismissal constituted a final appealable judgment in the litigation between the parties, even though the circuit court had not yet disposed of appellees' motion for attorneys' fees.",
"\nAlthough the precise issue raised by appellees' motion to dismiss the appeal has never been directly addressed by this Court, we held in Larche v. Car Wholesalers, Inc., 80 Md. App. ",
"322, 328, 562 A.2d 1305 (1989), \"that a claim for attorneys' fees under § 2310(d)(2) of the Magnuson-Moss Act is collateral to the principal action so that an appeal will lie from a final judgment on the underlying claim despite the pendency of a decision on the attorney's fees claim.\" ",
"This is so even though the Magnuson-Moss Act provides that a prevailing consumer may recover costs and attorneys' fees as part of the judgment. ",
"The Court of Appeals, in Md.-Nat'l Capitol Park and Planning Comm'n v. Crawford, 307 Md. 1, 38-39, 511 A.2d 1079 (1986), held that although a claim for attorneys' fees under 42 U.S.C. § 1983 is an integral part of the § 1983 remedy, it is nonetheless viewed as being collateral to the § 1983 action. ",
"We hold, therefore, that appellees' claim for attorneys' fees under Md. Rule 1-341 was collateral to the action between the parties. ",
"There was a final appealable judgment on 12 July 1991, when the circuit court dismissed the counterclaim of appellee Chester M. Wright. ",
"This appeal, noted on 14 August 1991, was not filed within 30 days after entry of the final judgment, as required by Md. Rule 8-202(a). ",
"The pendency of the collateral motion for attorneys' fees did not stay or enlarge the time for taking an appeal from the judgment. ",
"If an appeal is not filed within the time limits prescribed, \"the appellate court acquires no jurisdiction and the appeal must be dismissed.\" ",
"Houghton v. County Comm'rs of Kent Co., 305 Md. 407, 413, 504 A.2d 1145 (1986).",
"\nAPPEAL DISMISSED.",
"\nCOSTS TO BE PAID BY APPELLANTS.",
"\n"
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"require('../../modules/es6.reflect.delete-property');\nmodule.exports = require('../../modules/$.core').Reflect.deleteProperty;"
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"pile_set_name": "Github"
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[
"G protein-coupled receptor 101 mRNA expression in supraoptic and paraventricular nuclei in rat hypothalamus is altered by pregnancy and lactation.",
"\nIn a previous study performed in mouse models of energetic challenge, there was evidence to suggest that the orphan G protein-coupled receptor GPCR101 may have a role in the regulation of energy balance. ",
"To further investigate this possibility, we utilised in situ hybridisation to determine the effect of energetic challenges experienced by pregnant and lactating rats on GPCR101 mRNA expression. ",
"In the rat hypothalamus, GPCR101 mRNA expression was detected in a number of hypothalamic nuclei. ",
"During pregnancy and lactation, GPCR101 mRNA level remained unchanged in most nuclei, but had increased in the supraoptic nucleus by the end of pregnancy and remained elevated during lactation. ",
"GPCR101 mRNA expression showed a similar pattern of expression in the rostral ventromedial parvocellular subdivision of the paraventricular nucleus. ",
"A common feature of these two nuclei is the production of the peptide oxytocin. ",
"Dual in situ hybridisation revealed GPCR101 and oxytocin mRNA co-expression in neurons of these two nuclei. ",
"In the supraoptic nucleus, in situ hybridisation revealed that the temporal regulation of oxytocin and GPCR101 mRNA expression were similar. ",
"In the paraventricular nucleus, although temporal changes in oxytocin mRNA expression were similar to GPCR101, the spatial expression of the two mRNA species was different; in contrast to GPCR101, oxytocin mRNA expression changed in both parvo- and magnocellular neurons during lactation. ",
"In conclusion, increased GPCR101 mRNA expression in supraoptic and paraventricular nuclei from late pregnancy to late lactation may reflect the functional importance of this receptor in the regulation of neurons of these nuclei during this period."
] | {
"pile_set_name": "PubMed Abstracts"
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[
"Article content continued\n\nThe five were caught at the airport in Sydney and sentenced to prison there.",
"\n\nHe said he previously made a similar — but successful — trip, picking up luggage in Las Vegas with cocaine glued into the lining, and delivering it undetected. ",
"He tried to back out but he feared for his safety from others in the drug networks, court heard, so he pressed ahead with a delivery.",
"\n\nEven knowing the fear and pressure of making the trip, he still went on to recruit others to courier the bricks of high-grade cocaine for the unnamed organization.",
"\n\nDan Kirby, Pastukhov’s lawyer, said his client was just a broker in the larger drug network and only made arrangements for a few friends who volunteered to go.",
"\n\n“He was clearly nowhere near the top” of the ring’s hierarchy, Kirby said. ",
"If some of the drug mules felt threatened, he said, it was not by Pastukhov, whom he described as a non-violent person.",
"\n\nThe education I’ve had as a result of having to rebuild from scratch was almost worth going through the scandal, and I’m ultimately better off for it\n\nAt the time, Pastukhov was the high-profile music editor for Vice Canada, a popular, youth-oriented media outlet. ",
"Prior to Pastukhov’s arrest, the National Post detailed allegations from six additional people in Canada, primarily young journalists working at Vice, who said Pastukhov unsuccessfully tried to recruit them as couriers. ",
"He has not been charged in relation to those claims.",
"\n\nAs a first-time offender with excellent prospects for rehabilitation who pleaded guilty, Pastukhov deserves a sentence in the six to eight year range, Kirby said.",
"\n\nFaiyaz Alibhai, prosecutor with the Anti-Organized Crime Team of the Public Prosecution Service of Canada, said Pastukhov’s account was a self-serving version of events."
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[
"A touch of Zen: post-translational regulation of the Leishmania stress response.",
"\nAcross bacterial, archaeal and eukaryotic kingdoms, heat shock proteins (HSPs) are defined as a class of highly conserved chaperone proteins that are rapidly induced in response to temperature increase through dedicated heat shock transcription factors. ",
"While this transcriptional response governs cellular adaptation of fungal, plant and animal cells to thermic shock and other forms of stress, early-branching eukaryotes of the kinetoplastid order, including trypanosomatid parasites, lack classical mechanisms of transcriptional regulation and show largely constitutive expression of HSPs, thus raising important questions on the function of HSPs in the absence of stress and the regulation of their chaperone activity in response to environmental adversity. ",
"Understanding parasite-specific mechanisms of stress-response regulation is especially relevant for protozoan parasites of the genus Leishmania that are adapted for survival inside highly toxic phagolysosomes of host macrophages causing the various immuno-pathologies of leishmaniasis. ",
"Here we review recent advances on the function and regulation of chaperone activities in these kinetoplastid pathogens and propose a new model for stress-response regulation through a reciprocal regulatory relationship between stress kinases and chaperones that may be relevant for parasite-adaptive differentiation and infectivity."
] | {
"pile_set_name": "PubMed Abstracts"
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[
"Q:\n\nGridPanel CheckboxSelectionModel - Somar seleção (ext.net)\n\nComo eu posso somar uma coluna em particular q esta selecionada, via java-script?",
"\nEstou utilizando ext.net.",
"\n <script>\n var sumCheck= function () {\n var resultSum;\n\n /* todo loop selectedrows\n resultSum += column(field_value); */;\n\n alert(resultSum);\n };\n </script>\n\n <ext:GridPanel runat=\"server\" ID=\"grid1\" Height=\"250px\" Frame=\"true\" StoreID=\"dsGrid1\">\n <ColumnModel runat=\"server\">\n <Columns>\n <ext:NumberColumn runat=\"server\" DataIndex=\"field_value\" Format=\",0.00\" Align=\"Right\"/> \n </Columns>\n </ColumnModel>\n <SelectionModel>\n <ext:CheckboxSelectionModel runat=\"server\" Mode=\"Multi\">\n <Listeners>\n <SelectionChange Fn=\"sumCheck()\" />\n </Listeners> \n </ext:CheckboxSelectionModel>\n </SelectionModel> \n</ext:GridPanel>\n\nObrigado a quem puder me ajudar.",
"\n\nA:\n\nConsegui resolver com ajuda do stack em ingles, segue um exemplo com a soluçao para ajudar quem tiver a mesma duvida:\n<%@ Page Language=\"C#\" %>\n\n<%@ Register Assembly=\"Ext.",
"Net\" Namespace=\"Ext.",
"Net\" TagPrefix=\"ext\" %>\n<script runat=\"server\">\n protected void Page_Load(object sender, EventArgs e)\n {\n if (!",
"X.IsAjaxRequest)\n {\n this.",
"Store2.DataSource = new object[]\n {\n new object[] { 'A', 20 },\n new object[] { 'B', 52 },\n new object[] { 'C', 36 }\n };\n this.",
"Store2.DataBind();\n\n }\n }\n</script>\n<!",
"DOCTYPE html PUBLIC \"-//W3C//DTD XHTML 1.0 Transitional//EN\" \n \"http://www.w3.org/TR/xhtml1/DTD/xhtml1-transitional.dtd\">\n<html xmlns=\"http://www.w3.org/1999/xhtml\">\n<head runat=\"server\">\n <title>Ext.",
"NET Example</title>\n</head>\n<body>\n <form runat=\"server\">\n <ext:ResourceManager runat=\"server\" />\n\n <ext:GridPanel runat=\"server\">\n <Store>\n <ext:Store ID=\"Store2\" runat=\"server\">\n <Model>\n <ext:Model runat=\"server\" AutoDataBind=\"true\">\n <Fields>\n <ext:ModelField Name=\"product\" />\n <ext:ModelField Name=\"price\" />\n </Fields>\n </ext:Model>\n </Model>\n\n <Reader>\n <ext:ArrayReader />\n </Reader>\n </ext:Store>\n </Store>\n <ColumnModel runat=\"server\">\n <Columns>\n <ext:Column runat=\"server\" Header=\"Product\" DataIndex=\"product\" Flex=\"1\" />\n <ext:Column runat=\"server\" Header=\"Price ($)\" DataIndex=\"price\" Flex=\"1\" />\n </Columns>\n </ColumnModel>\n <SelectionModel>\n <ext:CheckboxSelectionModel runat=\"server\" Mode=\"Multi\">\n <Listeners>\n <SelectionChange Handler=\"var total = 0;\n var grid = this;\n var selected = grid.getSelection();;\n Ext.",
"Array.forEach(selected, function (rec) {\n total += rec.get('price');\n });\n alert(total);\n \" />\n </Listeners>\n </ext:CheckboxSelectionModel>\n </SelectionModel>\n\n </ext:GridPanel>\n\n </form>\n</body>\n</html>\n\n"
] | {
"pile_set_name": "StackExchange"
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0.002028397565922921,
0.002398081534772182
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[
"---\nlayout: base\ntitle: 'Statistics of Polarity in UD_Komi_Permyak-UH'\nudver: '2'\n---\n\n## Treebank Statistics: UD_Komi_Permyak-UH: Features: `Polarity`\n\nThis feature is universal.",
"\nIt occurs with 1 different values: `Neg`.",
"\n\n13 tokens (2%) have a non-empty value of `Polarity`.",
"\n7 types (2%) occur at least once with a non-empty value of `Polarity`.",
"\n1 lemmas (0%) occur at least once with a non-empty value of `Polarity`.",
"\nThe feature is used with 1 part-of-speech tags: <tt><a href=\"koi_uh-pos-AUX.html\">AUX</a></tt> (13; 2% instances).",
"\n\n### `AUX`\n\n13 <tt><a href=\"koi_uh-pos-AUX.html\">AUX</a></tt> tokens (54% of all `AUX` tokens) have a non-empty value of `Polarity`.",
"\n\nThe most frequent other feature values with which `AUX` and `Polarity` co-occurred: <tt><a href=\"koi_uh-feat-Connegative.html\">Connegative</a></tt><tt>=EMPTY</tt> (13; 100%), <tt><a href=\"koi_uh-feat-Mood.html\">Mood</a></tt><tt>=Ind</tt> (11; 85%), <tt><a href=\"koi_uh-feat-Person.html\">Person</a></tt><tt>=3</tt> (8; 62%), <tt><a href=\"koi_uh-feat-Tense.html\">Tense</a></tt><tt>=Past</tt> (8; 62%), <tt><a href=\"koi_uh-feat-Number.html\">Number</a></tt><tt>=Sing</tt> (7; 54%).",
"\n\n`AUX` tokens may have the following values of `Polarity`:\n\n* `Neg` (13; 100% of non-empty `Polarity`): <em>эз, эг, оз, озӧ, ог, эд</em>\n* `EMPTY` (11): <em>вермы, Вӧлі, бы, верман, вӧв, коліс, не, овлӧ, овны, позь</em>\n\n"
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"pile_set_name": "Github"
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[
"Search engines have become popular tools to identify and locate specific information on the Internet. ",
"A search engine is a computer program that, when queried for information, retrieves either related information or pointers to the location of related information, or both, by evaluating content stored in its search database.",
"\nA key metric in evaluating the performance of search engines is relevance of the search results. ",
"Search engine developers are always striving to deliver search results that are relevant to the search query being processed. ",
"Consistent with this goal, there have been attempts to rank search results based on a number of different factors. ",
"One of the more popular ways to rank search results involves analyzing the location and frequency of keywords on a web page. ",
"Another frequently used technique is analyzing how web pages link to each other. ",
"A web page gets a ranking boost based on the number of other web pages that are linked to it. ",
"Click-through rates of search results are analyzed in some search engines. ",
"The general rule is: the higher the click-through rate, the higher the ranking."
] | {
"pile_set_name": "USPTO Backgrounds"
} | [
0,
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[
"'Your doctor has clearly been trying to kill you all along':"
] | {
"pile_set_name": "OpenWebText2"
} | [
0
] | 0 | 5 |
[
"A total of 319 Police support staff yesterday stormed the Ministry of Finance and Economic Development in protest with pla-cards demanding the payment of their backlog salaries to a tune of three billion and thirty-six million eight hundred and eighty thousand leones.",
"\n\nThey claimed that the Ministry of Finance owe them 56 months backlog salaries starting from July 2011 to February 2016 and had vehemently refused to honour the payment of their wages and allowance, rent and transport for no good reasons.",
"\n\nChief Steward of the Police Support Staff (PSS), Moses F. Anthony alleged that they have made numerous effort in making sure that the payment process is finalized by going through the various procedures.",
"\n\n“Labour Ministry together with the Sierra Leone Labour Congress reached an agreement with Parliament and the law makers had authorized the ministry of Finance to pay us, but all of our efforts in coming and going had proved abortive.” ",
"he claimed.",
"\n\nHe said they are still performing their labour service in supporting the Sierra Leone Police (SLP), such as cleaning and other chores.",
"\n\nHe noted that the Ministry of Finance has absolutely no right to hold on to their monies. ",
"He added: “We went to State House this morning and the President instructed Honourable Nurudeen Sankoh-Yilla who spoke to us and promise to settle it. ",
"But we are here to register our disappointment over the constant delay by the Ministry,” he stated.",
"\n\nIn a letter written by the Ministry of Labour and Social Security copied to the President, The Inspector General of Police, The Commissioner of Labour, The President Labour Congress among others, confirmed the claims made they workers.",
"\n\nAnthony disclosed that many of his colleagues had died and retired without acquiring their backlog salaries as a result of the delay on the part of finance.",
"\n\nHe noted that the monies were legitimately giving to them by government, adding that the Police must help them in securing their monies. “",
"Finance must pay us. ",
"We have work for the money and it belong to all of us here” he insisted.",
"\n\nWhen the Head of the Police media, ASP Brima Kamara was contacted for his comment, he admitted that they were Police support Staff working for them.",
"\n\nThe Public Relation Officer in the Ministry of Finance and Economic Development, Sayoh Kamara in reaction said he cannot comment because he has no knowledge about the issue even though he was at the scene."
] | {
"pile_set_name": "Pile-CC"
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"/**\n * @name Test for try catches\n */\n\nimport csharp\n\nfrom Method m, TryStmt s, SpecificCatchClause c, LocalVariable v\nwhere\n s.getEnclosingCallable() = m and\n m.getName() = \"MainTryThrow\" and\n s.getCatchClause(0) = c and\n c.getVariable() = v and\n v.getName() = \"e\" and\n v.getType().getName() = \"Exception\"\nselect c, c.getCaughtExceptionType().toString()\n"
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"pile_set_name": "Github"
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[
"Q:\n\nMade changes to previous release, now need to incorporate latest release into current branch (Git)\n\nUPDATED Sorry for this lame question, but I need some guidance: I have an iPad app I'm making major changes to on branch 3.2.0. ",
" I received notification that the previous version 3.1.0 had a bug, so I switched to an existing branch (3.1.0) from 3.2.0, made the changes, created a new branch (3.1.1) and committed it (local and remote). ",
" This is what it looks like now:\n\nNow, I need to incorporate the changes made to 3.1.1 into 3.2.0 without farkeling anything up in 3.2.0. ",
" I've read about merging and rebasing, but not sure which to use.",
"\nHow do I do that from within XCode 6.1?",
"\nUPDATE #2 So I did the 'git checkout 3.2.0' and the 'git cherry-pick 3.1.1' and this is what happened:\n\niMac-2:salonbook rolfmarsh$ git checkout 3.2.0\n 2014-12-22 14:11:23.988 xcodebuild[21886:13545655] [MT] PluginLoading: Required plug-in compatibility UUID C4A681B0-4A26-480E-93EC-1218098B9AA0 for plug-in at path '~/Library/Application Support/Developer/Shared/Xcode/Plug-ins/Alcatraz.xcplugin' not present in DVTPlugInCompatibilityUUIDs\n Already on '3.2.0'\n iMac-2:salonbook rolfmarsh$ git cherry-pick 3.1.1\n warning: Cannot merge binary files: ja.lproj/MainStoryboard.strings (HEAD vs. 012c66e... GR - 1.3.1)\n warning: Cannot merge binary files: it.lproj/MainStoryboard.strings (HEAD vs. 012c66e... GR - 1.3.1)\n warning: Cannot merge binary files: fr.lproj/MainStoryboard.strings (HEAD vs. 012c66e... GR - 1.3.1)\n warning: Cannot merge binary files: es.lproj/MainStoryboard.strings (HEAD vs. 012c66e... GR - 1.3.1)\n warning: Cannot merge binary files: en.lproj/MainStoryboard.strings (HEAD vs. 012c66e... GR - 1.3.1)\n warning: Cannot merge binary files: de.lproj/MainStoryboard.strings (HEAD vs. 012c66e... GR - 1.3.1)\n error: could not apply 012c66e... GR - 1.3.1\n hint: after resolving the conflicts, mark the corrected paths\n hint: with 'git add ' or 'git rm '\n hint: and commit the result with 'git commit'\n\nNow what do I do? ",
" (I was afraid of something like this!) :-{",
"\n\nA:\n\nYou need to cherry-pick the commit with the fix.",
"\ngit checkout 3.2.0\ngit cherry-pick 3.1.1\n\nUnlike a merge, this will take the patch only from the specified commit, not the entire history since the two branches have diverged.",
"\nBut how to do it from within Xcode? ",
"Ain't got no clue. ",
"Search Google for Xcode git cherry-pick. ",
"Except that in the 1st 2 hits it's git add -p what they call cherry picking. ",
"I'm at a loss here. ",
"Just use the command line. ",
"It's easy.",
"\nUpon conflicts, git status shows the conflicting files as both modified. ",
"Edit them, git add them and then git commit. ",
"Git remembers that this commit should finish the cherry-pick.",
"\nYou practice of creating releases with branches is dangerous. ",
"That's what tags are for. ",
"Branches move with each commit on them. ",
"Tags stay.",
"\n\n"
] | {
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"The Best Paint Colors to Complement Brass Fixtures\n\nBrass and other metallics are versatile and give you a lot of choices in color selection. ",
"You'll want to look at the items and materials around your fixtures as well and think about how other aspects of the room (such as floors or carpet, drapes, and furniture) will fit in before you make a final decision.",
"\n\ncredit:\nHemera Technologies/AbleStock.com/Getty Images\n\nSelecting the Color\n\nSeek to harmonize your paint colors first with surrounding colors, unless the brass elements are large or you wish to highlight them. ",
"Match the brass fixture with a metallic paint for an exotic look. ",
"Many easy-to-use metallics are now available at high-quality paint stores and home improvement centers. ",
"Stick with a yellow-gold to match the brass color rather than a silver metallic—the yellow-gold will work better in most cases.",
"\n\nDeep reds and crimsons are classic colors that will go well with the warmth of brass. ",
"Intense oranges and yellows can be too close to the brass color and may clash, so they're best avoided (except in small doses).",
"\n\nOffsetting brass with a complement in the mauve or purple range can create a dynamic effect, but ensure that colors like these don't adversely impact the color of the rest of the room before taking this route. ",
"Use warm wood colors and neutrals, which provide a harmonious base for brass, and bring attention to the fixtures to make them stand out.",
"\n\nUsing more-neutral colors will also make it easier to harmonize with the other colors in the area. ",
"Darker browns will go with the brass to lend a feeling of warmth. ",
"Be careful not to go too dark, or the room could become cavelike. ",
"Always remember that a color will be more intense on the wall than it looks in the store or on a swatch.",
"\n\nSelect a lighter color to make it easier to match existing elements; however, in this case the brass fixtures may be less prominent, so find a balance if you want to highlight the brass. ",
"White goes with everything, but it doesn't have a lot of decorative punch, and it won't show the brass to its best advantage. ",
"Blues and greens are also available options, but are often cooler colors that may combat the brass. ",
"Select with care and lean toward colors in this range of the spectrum that have a mixture of gray."
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"Guyer\n\nGuyer is a surname. ",
"Notable people with the surname include:\n\n Brandon Guyer (born 1986), American professional baseball outfielder\n Cindy Guyer, American model and actress\n Denis Guyer (born 1966), American politician\n Gino Guyer (born 1983), American professional ice hockey centre\n Gordon Guyer (born 1926), president of Michigan State University from 1992 to 1993\n Jane I. Guyer, George Armstrong Kelly Professor in the Department of Anthropology at The Johns Hopkins University\n Michael F. Guyer (1874–1959), American cytologist and zoologist\n Lux Guyer (1894–1955), Swiss architect\n Paul Guyer, Jonathan Nelson Professor of Philosophy at Brown University\n Reyn Guyer (born 1935), American inventor\n Tennyson Guyer (1913–1981), member of the United States House of Representatives\n Thad McIntosh Guyer (born 1950), American civil rights lawyer\n U. S. Guyer (1868–1943), U.S. Representative from Kansas"
] | {
"pile_set_name": "Wikipedia (en)"
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"ATF: Most guns at Mexican crime scenes traced to US\n\nMore than 68 percent of the weapons recovered at Mexican crime scenes over a five-year period were traced to U.S. manufacturers or U.S. dealers who import firearms, according to statistics of the Bureau of Alcohol, Tobacco, Firearms and Explosives.",
"\n\nBetween 2007 and 2011, Mexican law enforcement submitted 99,691requests to the ATF for tracing, and 68,161 of those firearms were determined to come from U.S. makers or were legally imported into the United States by federally licensed firearms dealers.",
"\n\nThe ATF said it was unable to determine the source of the rest of the firearms because of missing information about the guns themselves, where they came from and how they got into Mexico.",
"\n\nbattles over turf in several areas of Mexico, including in Juárez, where firearms were used in most of estimated 11,000 homicides that police reported between 2007 and the end of November.",
"\n\nThis is a breakdown of total firearms recovered in Mexico and traced by ATF, and the number of weapons of unknown origin:\n\n2011: 20,335, U.S.; 14,504, unknown.",
"\n\n2010: 8,338, U.S.; 6,404, unknown.",
"\n\n2009: 21,555, U.S.; 14,376, unknown.",
"\n\n2008: 32,111, U.S.; 21,035, unknown.",
"\n\n2007: 17,352, U.S.; 11,842, unknown.",
"\n\nThe “ATF Mexico” report does not include information on which, or if any, of the reported firearm recoveries were traced to the agency’s Operation Fast and Furious, in which federal agentsallowed guns purchased by straw buyers in the U.S. to be smuggled into Mexico in an attempt to identify and arrest high-level arms traffickers.",
"\n\nMore than 1,000 of the 2,000 weapons connected to the Phoenix-based operation are unaccounted for, according to U.S. lawmakers, who investigated the botched ATF operation that began in late 2009.",
"\n\nThe ATF shut down Fast and Furious after Border Patrol Agent Brian Terry was fatally shot Dec. 14, 2010, in Arizona near the Mexican border. ",
"A rifle connected to the ATF operation was found in the vicinity of Terry’s body.",
"\n\nSome of the weapons attributed to Operation Fast and Furious were smuggled across the border through El Paso, and they were found by Mexican law enforcement officers at crime scenes in Juárez and other places in the state of Chihuahua.",
"\n\nRecently, new allegations threaten the ATF with another scandal, prompting a U.S. senator to request an investigation.",
"\n\nU.S. Sen. Charles Grassley, who had initiated an investigation into Fast and Furious, said in a Dec. 19 letter to Department of Justice Inspector General Michael Horowitz that a former ATF official assigned to Phoenix might have purchased a gun that Mexican officials allegedly found at the scene of a November shootout between drug cartel operatives and Mexican soldiers in Sinaloa, Mexico.",
"\n\nGrassley’s letter said the area of the shootout reported by Mexican officials appears to coincide with a firefight that killed several people in the same area.",
"\n\n“The gunfight claimed five lives, including a member of the Mexican military and a Sinaloa beauty queen, Maria Susana Flores Gamez,” Grassley’s letter said. ",
"His letter also said that the weapon allegedly obtained by the ATF official was purchased Jan. 7, 2010, but Grassley had no information on how it ended up in Mexico.",
"\n\n“This information’s implications and its ability to undermine public confidence in the integrity of ATF operations cannot be overstated,” Grassley’s letter said. “",
"Your (Horowitz’s) office needs to work swiftly. ",
"There must be a thorough, independent, and public explanation of these circumstances as quickly as possible.”",
"\n\nNo one was available for comment late Wednesday at the ATF offices in Phoenix and Washington, D.C.\n\nThe ATF also reported statistics for firearm recoveries and tracings in the United States, including Texas.",
"\n\nBetween Jan. 1, 2011, and Dec. 31, 2011, the ATF traced 15,058 firearm recoveries to Texas. ",
"The ATF said most of the tracings are for weapons found by U.S. law enforcement officers at crime scenes in Texas and in other states, but traced back to Texas sources.",
"\n\nThe top three recovery cities in Texas were Houston, with 3,034 firearm recoveries; Dallas, with 2,463; and Corpus Christi, with 502. ",
"ATF figures for El Paso recoveries were not available.",
"\n\n“We use the ATF’s tracing resources to investigate gun ownership, periodically, on a case-by-case basis,” said Mike Baranyay, a detective with the El Paso Police Department. “",
"Our investigators can also check whether a weapon is stolen through the NCIC (National Crime Information Center) system.”"
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[
"Seven people have been injured after a man wielding an axe attacked commuters at the main railway station in Dusseldorf.",
"\n\nGerman police said a man was arrested after the incident at 9pm on Thursday.",
"\n\n\"A person, probably armed with an axe, attacked people at random,\" they said in a statement.",
"\n\nImage: Police on the main concourse of Dusseldorf railway station\n\nEarlier reports said two attackers had been arrested, but police said this was not the case.",
"\n\nThree of those who were hurt had suffered serious injuries, and eyewitnesses reported seeing people lying on the ground injured.",
"\n\n\nThe suspected attacker was arrested after jumping off an overpass near the station, police said.",
"\n\nImage: The station was closed following the incident\n\nThe 36-year-old man, who was described as being from \"the former Yugoslavia\" and living in the nearby city of Wuppertal, suffered serious injuries and is being treated in hospital.",
"\n\nAn axe was recovered from the scene and officers were searching the area in and around the station, which was closed.",
"\n\nGermany has been on a heightened terror alert after a hijacked lorry ploughed into a Christmas market in Berlin, killing 12 people, last year. ",
"Islamic State claimed responsibility."
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"Dichelopa fulvistrigata\n\nDichelopa fulvistrigata is a species of moth of the family Tortricidae. ",
"It is found on Tahiti.",
"\n\nReferences\n\nCategory:Moths described in 1928\nCategory:Dichelopa"
] | {
"pile_set_name": "Wikipedia (en)"
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"within Modelica.",
"Magnetic.",
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"ElectricSheet;\nrecord M330_50A \"M330-50A (1.0809) @ 50Hz\"\n extends FluxTubes.",
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"BaseData(\n mu_i=500,\n B_myMax=0.7,\n c_a=24000,\n c_b=9.38,\n n=9.6);\n annotation (Documentation(info=\"<html>\n<p>\nPlease refer to the description of the enclosing package <a href=\\\"modelica://Modelica.",
"Magnetic.",
"FluxTubes.",
"Material.",
"SoftMagnetic\\\">SoftMagnetic</a> for a description of all soft magnetic material characteristics of this package.",
"\n</p>\n<p>\nSample: complete core after machining and packet assembling<br>\n</p>\n</html>\"));\nend M330_50A;\n"
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"A probabilistic functional atlas of the VIM nucleus constructed from pre-, intra- and postoperative electrophysiological and neuroimaging data acquired during the surgical treatment of Parkinson's disease patients.",
"\nWe have previously introduced a concept of a probabilistic functional atlas (PFA) to overcome limitations of the current electronic stereotactic brain atlases: anatomical nature, spatial sparseness, inconsistency and lack of population information. ",
"The PFA for the STN has already been developed. ",
"This work addresses construction of the PFA for the ventrointermediate nucleus (PFA-VIM). ",
"The PFA-VIM is constructed from pre-, intra- and postoperative electrophysiological and neuroimaging data acquired during the surgical treatment of Parkinson's disease patients. ",
"The data contain the positions of the chronically implanted electrodes and their best contacts. ",
"For each patient, the intercommissural distance, height of the thalamus and width of the third ventricle were measured. ",
"An algorithm was developed to convert these data into the PFA-VIM, and to present them on axial, coronal and sagittal planes and in 3-D. The PFA-VIM gives a spatial distribution of the best contacts, and its probability is proportional to best contact concentration in a given location. ",
"The region with the highest probability corresponds to the best target. ",
"The PFA-VIM is calculated with 0.25-mm3 resolution from 107 best contacts in two situations: with and without lateral compensation against the width of the third ventricle. ",
"For the PFA-VIM compensated laterally, the anterior, lateral and dorsal coordinates of the mean value are (in mm) 6.24, 13.83, 1.68 for the left VIM and 6.54, -13.84, 2.10 for the right VIM. ",
"The coordinates of the mean value of the highest probability region along with the highest number of the best contacts (P) are: 6.25, 14.25, 1.75, P = 16, for the left VIM, and 6.0, -14.0, 1.00, P = 18, for the right VIM. ",
"The coordinate system origin is at the posterior commissure. ",
"For the PFA-VIM not compensated laterally, the coordinates of the mean value are 6.24, 13.99, 1.68 for the left VIM and 6.53, -14.13, 2.10 for the right VIM. ",
"The coordinates of the mean value of the highest probability region along with the highest number of the best contacts are 5.58, 13.67, 1.33, P = 14, for the left VIM, and 6.36, -14.03, 1.11, P = 17, for the right VIM. ",
"The PFA-VIM atlas overcomes several limitations of the current anatomical atlases and can improve targeting of thalamotomies and thalamic stimulations. ",
"It is dynamic and can easily be extended with new cases."
] | {
"pile_set_name": "PubMed Abstracts"
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[
"INTRODUCTION {#sec1-1}\n============\n\nThis review emphasizes the traditional uses and clinical potential of *Calendula* species. ",
"The review is intended to attract the attention of natural product researchers throughout the world to focus on the unexplored potential of the *Calendula* species. ",
"This genus needs to be investigated systematically so that potential species can be exploited as therapeutic agents.",
"\n\nThe review has been compiled using references from major databases such as Chemical Abstracts, Medicinal and Aromatic Plant Abstracts, PubMed, King\\'s American Dispensatory, Henriette\\'s Herbal Homepage, Duke\\'s Phytochemical and Ethnobotany. ",
"The available information on *Calendula* has been divided into six sections, i.e., ethnopharmacology, morphology and microscopy, phytoconstituents, pharmacological reports, clinical studies and toxicology.",
"\n\nTHE GENUS CALENDULA {#sec1-2}\n===================\n\nThe genus *Calendula* (*Asteraceae*) includes approximately 25 *herbaceous* annual or perennial species, most common being *Calendula officinalis* Linn., *",
"Calendula arvensis* Linn., *",
"Calendula suffruticosa* Vahl., *",
"Calendula stellata* Cav., *",
"Calendula alata* Rech., *",
"Calendula tripterocarpa* Rupr.\\[[@ref1]\\] The genus is native to the Mediterranean countries.\\[[@ref2]\\]\n\nEthnopharmacology {#sec2-1}\n-----------------\n\n### Traditional uses {#sec3-1}\n\n*C. alata* Rech.f., ",
"aerial parts are used for the treatment of kidney stones and gall stones.\\[[@ref3]\\]\n\n*C. arvensis* Linn. (",
"Field marigold) has been used as disinfectant, antispasmodic and diuretic.\\[[@ref4]\\] In Italian folk medicine, the plant is used as anti-inflammatory, anticancer and antipyretic agent.\\[[@ref5]\\] In Spain, the leaves are considered sudorific. ",
"Traditionally, it is used as an emmenagogue, diaphoretic and sedative.\\[[@ref6]\\] It is known to have wound healing properties and crushed leaves are topically applied on wounds.\\[[@ref7]\\] The decoction of the flower heads has been used for treating burns.\\[[@ref8]\\]\n\n*C. officinalis* Linn. (",
"Pot marigold) has been traditionally used in the treatment of inflammations of internal organs, gastrointestinal ulcers and dysmenorrhea and as a diuretic and diaphoretic in convulsions. ",
"It is also used for inflammations of the oral and pharyngeal mucosa, wounds and burns.\\[[@ref9]\\] *Calendula* is a cleansing and detoxifying herb and the infusion treat chronic infections.\\[[@ref10]\\] The dried flower heads have been used for their antipyretic, anti-tumor and cicatrizing effects.\\[[@ref11]\\] Topical application of infusion of flowers is used as antifungal and antiseptic in wounds, marks, freckles, sprain and conjunctivitis.\\[[@ref12]\\] *Calendula* tea is used as eyewashes, gargles, diaper rashes and other inflammatory conditions of the skin and mucous membranes.\\[[@ref13]\\] Mother tincture of *C. officinalis* is used in homoeopathy for the treatment of mental tension and insomnia.\\[[@ref14]\\]\n\nMedicinal properties of *C. officinalis* have been mentioned in Ayurvedic and Unani system of medicine indicating that leaves and flowers are antipyretic, anti-inflammatory, antiepileptic and antimicrobial.\\[[@ref15]\\] In traditional and homoeopathic medicine, *C. officinalis* has been used for poor eyesight, menstrual irregularities, varicose veins, hemorrhoids and duodenal ulcers.\\[[@ref16]\\] In the middle ages, *Calendula* flowers were used for liver obstructions, snake bites and to strengthen the heart. ",
"It was used in the 18^th^ century as a remedy for headache, jaundice and red eyes. ",
"The plant was employed in the civil war to treat wounds and as a remedy for measles, smallpox and jaundice.\\[[@ref17]\\]\n\nDecoction and infusion of *Calendula persica* C.A. Mey aerial parts are employed for the treatment of kidney stones.\\[[@ref3]\\]\n\nAlternative and complementary medicinal uses {#sec2-2}\n--------------------------------------------\n\nAmong the various species of the genus *Calendula*, *C. officinalis* is the only one, which is extensively used clinically throughout the world. ",
"The plant is listed in German Commission E, European Scientific Co-operative on Phytotherapy, British Herbal Pharmacopoeia, World Health Organization monographs for wound healing and anti-inflammatory actions.\\[[@ref18]\\] *C. officinalis* preparations are used in various complementary and alternative medicine systems mainly for burns, cuts, rashes, dermatitis and varicosis.\\[[@ref19]\\] It is also included as part of treatment for dry skin, bee stings and foot ulcers.\\[[@ref20]\\] The essential oil of the plant is used for soothing central nervous system and as a wound healer.\\[[@ref21]\\]\n\n*C. officinalis* preparations currently in use include carophyllenic ointment (containing carotenoids extracted from the flowers) and pot marigold tincture. ",
"It is one of the constituents of proprietary homoeopathic medicine Traumeel^®^, used for treating the symptoms associated with acute musculoskeletal injuries including pain and swelling.\\[[@ref22]\\] Otikon otic solution and naturopathic herbal extract ear drops solution, ear drop formulations of naturopathic origin containing *Calendula* flowers, have been reported to be effective for the management of otalgia associated with acute otitis media in children.\\[[@ref23][@ref24]\\]\n\nMorphology and microscopy {#sec2-3}\n-------------------------\n\n*C. arvensis* Linn. ",
"is an annual herb, not generally exceeding 15 cm in height. ",
"Leaves lance-shaped; stem slender, hairy; inflorescence single flower head up to 4 cm wide with bright yellow to yellow-orange ray florets around a center of yellow disc florets.\\[[@ref25][@ref26]\\]\n\n*C. officinalis* Linn. ",
"\\[[Figure 1](#F1){ref-type=\"fig\"}\\] is an annual or biennial plant attaining height of 30-60 cm. ",
"Leaves lower spatulate, 10-20 cm long and 1-4 cm wide; higher oblong and mucronate, 4-7 cm long; stem angular, hairy and solid; flower heads bright yellow to orange; marginal flowers in cultivated plants multi-seriate, corolla oblong spatulate, 15-25 mm long and 3 mm wide; corolla of disc flowers rounded, at the top tridentate, 1.5-2.5 cm long and 4-7 mm in diameter with 5 mm long tubular florets.\\[[@ref27][@ref28]\\]\n\n{#F1}\n\nThe powdered *C. officinalis* is yellowish brown with a characteristic, aromatic odor and a slightly bitter taste; comprises fragments of the corolla, anomocytic stomata in the apical region of outer epidermis, covering and glandular trichomes, elongated sclerenchymatous cells, pollen grains, fragments of the walls of the ovaries containing brown pigment, fragments of stigma, fragments of the fibrous layer of the others.\\[[@ref29][@ref30]\\]\n\n*C. stellata* Cav., ",
"is a small, attractive annual growing to a height of 30 cm or more. ",
"Leaves oval or oblong, somewhat pointed, wavy-toothed;\\[[@ref31]\\] stems scabrous; achenes outer five with membranous toothed margins, the five inner ones \"boat-shaped\" and smooth on the back, the rest angular and muricated on the back.\\[[@ref32]\\]\n\n*C. suffruticosa* Vahl., ",
"is a perennial plant reaching a height between 20 cm and 40 cm. ",
"Leaves lance-shaped, slightly toothed, covered with short sticky hairs; stem young one first erected, later begin to hang and spread to the soil; flowers bright yellow, each measuring about 2.5 cm in diameter.\\[[@ref31][@ref33]\\]\n\nPhytoconstituents {#sec2-4}\n-----------------\n\nFour species of *Calendula* have been investigated phytochemically. [",
"Table 1](#T1){ref-type=\"table\"} summarizes the phytoconstituents of different species of *Calendula*. [",
"Figure 2](#F2){ref-type=\"fig\"} represents chemical structures of some phytoconstituents reported from the genus *Calendula*.",
"\n\n###### \n\nPhytoconstituents of different species of *Calendula*\n\n![](",
"PRev-7-179-g002)\n\n{#F2}\n\nPharmacological reports {#sec2-5}\n-----------------------\n\nThe available literature reveals that amongst 12-20 species of *Calendula*, only three species, i.e., *C. officinalis, C. arvensis* and *C. suffruticosa* have been evaluated for their pharmacological activities.",
"\n\nTincture of *C. arvensis* was active against *Staphylococcus aureus* at concentrations of 10 mg/ml or 25 mg/ml.\\[[@ref56]\\] Sesquiterpene glycosides from *C. arvensis* were able to inhibit vesicular stomatitis virus infection.\\[[@ref57]\\] A saponin containing fraction from the aerial parts of *C. arvensis* had hemolytic activity *in vitro* and anti-inflammatory activity against carrageenan induced paw edema in rats.\\[[@ref58]\\] Saponins showed antimutagenic activity against benzo (a) pyrene 1 μg and mutagenic urine concentrate from a smoker (SU) 5 μL with a dose-response relationship.\\[[@ref59]\\]\n\nPreparations of *C. officinalis* are mainly applied in the form of infusions, tinctures and ointments as a wound healing remedy for inflammations of the skin, mucous membranes, for poorly healing wounds, bruises, boils and rashes, e.g., pharyngitis and leg ulcers.\\[[@ref27]\\] In the mixed lymphocyte reaction, 70% ethanol extract showed stimulatory effects at 0.1-10 μg/ml, followed by inhibition at higher concentrations.\\[[@ref60]\\] Phagocytosis of human granulocytes was stimulated by polysaccharides isolated from aqueous extract of *Calendula* flowers.\\[[@ref61]\\] Extracts of *Calendula* flowers of differing polarities exhibited anti-oxidative effects on liposomal lipid peroxidation induced by Fe^2^ + and ascorbic acid.\\[[@ref62][@ref63]\\] Isorhamnetin 3-glycosides from *Calendula* flowers inhibited lipoxygenase from rat lung cytosol at a concentration of 1.5 × 10^-5^ M.\\[[@ref64]\\] In a test system based on porcine buccal membranes, strong concentration dependent adhesive processes were observed with a low viscosity polysaccharide enriched extract (98% carbohydrates) of *Calendula* flowers. ",
"These findings suggested that the polysaccharides may contribute to therapeutic effects in the treatment of irritated mucosa.\\[[@ref65]\\] A triterpene enriched fraction given orally to mice inoculated with Ehrlich mouse carcinoma prevented the development of ascites and increased survival time compared to control.\\[[@ref66]\\] Triterpenes such as faradiol and taraxasterol inhibit experimental tumor promotion and are therefore considered as inhibitors of tumor growth.\\[[@ref67]\\] A saponin rich fraction administered orally at 50 mg/kg body weight to hyperlipemic rats reduced the serum lipid level.\\[[@ref68][@ref69]\\] The aqueous alcohol extract of *C. officinalis* showed central nervous system inhibitory effect with marked overall sedative activity as well as hypotensive effect.\\[[@ref70]\\] The alcohol extract of flowers of *C. officinalis* possesses anti-HIV properties.\\[[@ref71]\\] A cream containing *calendula* extract has been reported to be effective in dextran and burn edemas as well as in acute lymphedema in rats. ",
"Activity against lymphedema was primarily attributed to enhancement of macrophage proteolytic activity.\\[[@ref72]\\] The essential oil of the flowers inhibited the growth *in vitro* of *Bacillus subtilis*, *Escherichia coli*, *S. aureus*, *Pseudomonas aeruginosa* and *Candida albicans*.\\[[@ref73]\\] Acetone, ethanol or water extracts inhibited the growth *in vitro* of the fungus Neurospora crass.\\[[@ref74]\\] A flavonoid fraction isolated from the flowers inhibited the *in vitro* growth of *S. aureus*, *Sarcina lutea*, *E. coli*, *Klebsiella pneumonia* and *Candida monosa*.\\[[@ref75]\\] The 50% ethanol extract of the plant showed spermicidal activity in rats at 2% concentration.\\[[@ref76]\\]\n\n*C. suffruticosa* inhibited pathogenic micro-organisms, especially *Pseudomonas syringae*, *Pseudomonas fluorescens*, *Xanthomonas campestris*, *Agrobacterium tumefaciens*.\\[[@ref77]\\]\n\nClinical studies {#sec2-6}\n----------------\n\nIn a randomized, open controlled study, the effects of three ointments were compared after topical treatment of patients with 2^nd^ or 3^rd^ degree burns for 17 days: *Calendula* flower ointment (prepared by digestion in vaseline) (*n* = 53) or vaseline only (*n* = 50) or a proteolytic ointment (*n* = 53). ",
"The success rates were considered to be 37/53 for *Calendula* flower ointment, 27/50 for vaseline and 35/53 for the proteolytic ointment.\\[[@ref78]\\] In an open uncontrolled pilot study, 30 patients with burns or scalds were treated 3 times/day for up to 14 days with a hydrogel containing 10% of a hydro-ethanol extract. ",
"The symptoms reddening, swelling, blistering, pain, soreness and heat sensitivity were scored before, during and at the end of treatment. ",
"Total score and individual scores for each symptom improved.\\[[@ref79]\\] In women with surgical wounds, local application of a mixture containing 70% oily extract of *Hypericum perforatum* and 30% oily extract of *C. arvensis* improved the rate of healing, compared with controls.\\[[@ref53]\\] Phase III randomized single blinded trial of *C. officinalis* compared with trolamine for the prevention of acute dermatitis during irradiation for breast cancer was conducted. ",
"Patients who had been operated on for breast cancer and who were to receive post-operative radiation therapy were randomly allocated to application of either *Calendula* ointment containing 20% of fresh *Calendula* aerial parts in petroleum jelly (126 patients) or trolamine (128 patients) on the irradiated fields after each session. ",
"The primary end point was the occurrence of acute dermatitis of grade 2 or higher. ",
"Secondary end points were the occurrence of pain, the quantity of the topical agent used and the patient satisfaction. ",
"The occurrence of acute dermatitis of grade 2 or higher was significantly lower (41% vs. 63%; *P* \\< 0.001) with the use of *Calendula* than with trolamine. ",
"Moreover, patients receiving *Calendula* had less frequent interruption of radiotherapy and significantly reduced radiation-induced pain.\\[[@ref80]\\] Clinical examination of an ointment with *C. officinalis* extract was carried out in 34 patients with venous leg ulcer. ",
"A total of 21 patients with 33 venous ulcers were treated with ointment, applied twice a day for 3 weeks. ",
"Control group that consisted of 13 patients with 22 venous ulcers were treated with saline solution dressings, applied to ulcers for 3 weeks. ",
"In the experimental group, the total surface of all the ulcers at the beginning of the therapy was 67,544 mm^2^. After the 3^rd^ week, the total surface of all the ulcers was 39,373 mm^2^ (a decrease of 41.71%). ",
"In seven patients, complete epithelialization was achieved. ",
"In the control group, the total surface of all ulcers at the beginning of the therapy was 69,722 mm^2^. After the 3^rd^ week, the total surface of all ulcers was 58,743 mm^2^ (a decrease of 14.52%). ",
"In four patients, complete epithelialization was achieved. ",
"There was a statistically significant acceleration of wound healing in the experimental group (*P* \\< 0.05), suggesting the positive effects of the ointment with marigold extract on venous ulcer epithelialization.\\[[@ref81]\\]\n\nToxicology {#sec2-7}\n----------\n\nAlthough rare, skin contact with *Calendula* preparations may result in an allergic reaction to the herb. ",
"Sensitization to *Calendula* and allergic contact reactions have been reported.\\[[@ref82][@ref83]\\] There have also been incidents of anaphylactic shock after gargling with an infusion of *Calendula*.\\[[@ref84]\\]\n\nCONCLUSION {#sec1-3}\n==========\n\nAbout 12-20 species of the genus *Calendula* have been reported in various floras. ",
"Among these, most of the ethnopharmacological reports are available on *C. officinalis* and *C. arvensis*. ",
"Further, only four species of *Calendula* have been partially investigated for their phytoconstituents. ",
"A close scrutiny of literature on *Calendula* reveals that three species have been investigated pharmacologically. ",
"Pharmacological studies reveal that *C. officinalis* exhibits antibacterial, antiviral, anti-inflammatory, anti-tumor and antioxidant properties; *C. arvensis* possesses antibacterial, anti-inflammatory, antimutagenic and hemolytic activities; and *C. suffruticosa* exhibits antimicrobial activity. *",
"C. officinalis* has been included in number of herbal formulations, which are in clinical use for the treatment of various ailments like central nervous system disorders. ",
"Keeping in view the ethnopharmacology, phytochemical and pharmacological reports, low toxicity and frequency of use, *C. officinalis* seems to hold great potential for in depth investigation for various biological activities. ",
"Few preliminary pharmacological reports support medicinal potential of some *Calendula* species. ",
"These species need to be investigated systematically with a view to establish their varied pharmacological activities and mode of actions.",
"\n\n**Source of Support:** Financial assistance has been provided by UGC\n\n**Conflict of Interest:** None declared\n"
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"Q:\n\nLength extension attack SHA-1 message division with padding problem?",
"\n\nI'm was reading this example for length extension attack given here \nlink\nWhen working out, how the extended block length be divisible by 512 (SHA block size).",
"\nI'm assuming following:-\n\nIn SHA, the size of the blocks is 512 bit. ",
" \nThe last block must contain:the rest of data in message (mod 512).",
"\nsome filling (padding)\nthe last 64 bits as length\n\nIn example given in link shared above, this is what extended msg looks like \nhttp://example.com/downloadfile=report.pdf%80%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%A8/../../../../../../../etc/passwd&mac=ee40aa8ec0cfafb7e2ec4de20943b673968857a5\nExample 1\nCalculating \nA more precise of asking is that,\nmessage =10 bytes = 80 bits\nsecret key = 11 bytes= 88 bits\n168 mod 512= 160 bits= 21 bytes\n64 - 21= 43 \npadding +message length= 464+552 =1016 bits\nadding /../../../../../../../etc/passwd 32 x 8= 256 bits\nAdding it to A8/= 424\n\nHow I make sense If I add the missing padding which is 256 mod 512 =256=32 bytes \n\n64-32 = 32 x8= 256 bits\n\nExample 2\ncount=10&lat=37.351&user_id=1&long=-119.827&waffle=eggo\\x80\\x00\\x00\n \\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\n \\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\n \\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\\x00\n \\x00\\x00\\x02\\x28&waffle=liege\nGoing on by logic\n\nmessage =55 bytes = 440 bits\nsecret key = 14 bytes= 112 bits\nlength encoding = 552\n552 mod 512= 40 bits= 5 bytes\n64 - 5= 59 bytes\nIf you check the padding its 58 bytes not 59 . ",
"Can you tell why?",
"\npadding +message length= 472+552 =1024 bits\nadding extra &waffle=liege 13 x 8= 104 \nadding to existing message length(552) + 104= 656\nHow I make sense If I add the missing padding which is 656 mod 512 =144 \n= 18 bytes\n64 - 18= 46 x 8 = 368 bits\n104 + 368 (message length and padding)\n\nA:\n\nOK, lets go through this step by step:\n\nthe message size of http://example.com/downloadfile=report.pdf is 10 bytes, as only the filename (report.pdf) is hashed according to the article;\nthe key size is usually known and was explicitly set in the article to 11 bytes, not 15 (11 bytes is a bit short for a key size, by the way);\nso the length of the message is 10 + 11 = 21 bytes, or 168 bits and A8 is indeed 168;\nto the padding + length encoding needs to be 64 - 21 = 43 bytes, lets check that:\n%80%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%00%A8\nyep, that seems to be correct.",
"\n\nNote that 64 bytes is 512 bits for the block size and that e.g. %80 is the encoding of a single byte with value 80h, so you need to count the characters and then divide by 3.",
"\nSo I'm not sure how you got your input values for the message size and key size, but they are way off. ",
"So you would not end up with the right values, regardless of the correctness of your formulas.",
"\n\n"
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"Q:\n\nExtract depth map from a 3D anaglyph image\n\nSuppose we have a generic red/cyan 3D anaglyph photo. ",
"How can it be processed so a depth map is extracted?",
"\n\nA:\n\nAn anaglyph is just a superposition of a left-eye and right-eye image, using different colours for each.",
"\nAssuming you can use the colour components to extract the original greyscale left and right images, the problem is no different to any stereo vision problem. ",
"You need to determine the epipolar geometry, perform rectification on one of the images, then create a disparity map to derive relative depth information.",
"\n\n"
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"Records everything on video. ",
"In the doggy style, in the missionary position and in the pose of a rider. ",
"The first time sucks a dick of his boyfriend.",
"\n\nPublished by TenderBabesManager"
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"\n(2007)\nYanisse ADRIAN-SILVA, Plaintiff,\nv.\nMANLEY BERENSON MONTEHIEDRA MANAGEMENT, et al., ",
"Defendants.",
"\nCivil. ",
"No. ",
"03-1890(FAB).",
"\nUnited States District Court, D. Puerto Rico.",
"\nSeptember 13, 2007.",
"\n\nMEMORANDUM AND ORDER\nFRANCISCO A. BESOSA, District Judge.",
"\nFederal Rule of Civil Procedure 60(b)(6), provides that the Court may relieve a party from a final order for any reason justifying relief from the operation of the judgment. ",
"To prevail, the party seeking the relief must establish that there are extraordinary circumstances that warrant, it. ",
"United States v. Bans, 834 F.2d 1114, 1123 (1st Cir.1987).",
"\nDistrict courts enjoy considerable discretion in deciding motions brought under Rule 60(b). ",
"As such, the ruling of the trial court upon such motion will be set aside only upon a clear showing of abuse of discretion. ",
"U.S. v. Berenguer, 821 F.2d 19, 20 (1st Cir.1987); Lepore v. Vidockler, 792 F.2d 272, 274 (1st Cir.1986); Pagan v. American Airlines, Inc., 534 F.2d 990, 993 (1st Cir.1976); 11 Wright & Miller, Federal Practice and Procedure: Civil § 2872, at 157 and 261.",
"\nOn May 9, 2007, this case was dismissed after the parties reached a settlement and filed a stipulation of dismissal. (",
"Docket No. ",
"379) The Court entered judgment dismissing the case.",
"\nOn August 31, 2007, plaintiff moved to vacate the judgment and for a new trial. (",
"Docket No. ",
"382) Plaintiff requests that the Court vacate its judgment and reinstate the matter for trial \"at the earliest available date\". ",
"The gist of plaintiff's argument is that the defendants breached their obligations under the settlement agreement. ",
"Specifically, she claims that the defendants agreed to cooperate with her to \"minimize any potential tax impact of the settlement\" and that they agreed the settlement would not have tax consequences if it was structured. ",
"Now, she further argues, defendants' position is that \"they will only pay Plaintiff if she gets a letter from the Puerto Rico Treasury Department (\"PRTD\") stating that the amount is not subject to retention or which amount is subject to retention ...\". ",
"Id., p. 8. ",
"In addition, defendants insist that 100% of the settlement is taxable as emotional damages and wish not to work \"in good faith toward the allocation of the settlement proceeds to physical damages\" (Docket No. ",
"382, p. 8, 9) (emphasis added) In her opinion, this situation constitutes an extraordinary circumstance under Rule 60(b)(6) for the court to set aside the judgment, because the \"breach\" by defendants results in a 20% reduction of plaintiff's anticipated recovery. (",
"Docket No. ",
"382, p. 5)\nDefendants opposed plaintiff's request. (",
"Docket No. ",
"384) In essence, they claim that they have never refused to honor the settlement. ",
"They claim, however, that pursuant to the Puerto Rico Internal Revenue Code, it is the PRTD which determines the nature and tax treatment of any settlement payment. ",
"Consequently, they cannot make any payments without withholding the potential tax debt, unless there is an administrative determination from the PRTD of what part of the settlement constitutes taxable income subject to withholding.[1] In addition, they argue that any claims that plaintiff may have regarding whether to allocate the entire settlement to physical or emotional damages for tax purposes, should be also submitted to the PRTD. (",
"Docket No. ",
"384, p. 4) The Court agrees.",
"\nIt is clear that the manner in which a settlement should be structured for tax purposes does not constitute an extraordinary circumstance, as required by Rule 60, which could cause the court to vacate the judgment. ",
"It is not for the Court to make a determination on the tax withholding requirement. ",
"Such a determination is within the exclusive jurisdiction of the PRTD. ",
"Accordingly, Plaintiff's Motion to Vacate Judgment and Set New Trial Date is DENIED. ",
"Plaintiff should proceed to initiate an administrative proceeding with the PRTD regarding the taxable nature of the settlement pursuant to PRTD's Administrative Determinations 07-01 and 05-02.",
"\nDefendants' Motion Submitting Correct Version (Docket No. ",
"384) is hereby GRANTED. ",
"Docket No. ",
"383 is STRICKEN FROM THE RECORD.",
"\nIT IS SO ORDERED.",
"\nNOTES\n[1] Advisory Letter No. ",
"99-01 (Procedure for the request and issuance of Rulings and Administrative Determination Letters) outlines a procedure by which any taxpayer who wishes to identify the nature of the indemnity payment can do so by requesting an administrative determination. ",
"Pursuant to Section II, Part A of the Advisory Letter No. ",
"99-01 \"the ruling will be issued only on prospective transactions [sic] and on completed transactions [sic]\", (emphasis added)\n"
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"Each issue will focus on a new character from the upcoming movie!",
"\n\nMy Little Pony: The Movie in theaters in October!",
"\n\n\n\nTentative Release Date: June 28th, 2017\n\nLights! ",
"Camera! ",
"Stardom! ",
"It's almost here folks!will hit theaters this October and IDW is going to be paving the way with a four issue prequel mini-series!Obviously there was a ton of questions about the series when the trade paperback collecting the series was posted on Amazon. ",
"Well, it looks like the answers to at least some of those questions are contained after the break!I hope you're all ready, for the road tostarts here!Ted Anderson (w) • Andy Price (a & mc) • Heather Breckel (c) • Tony Fleecs (sc) • Kaori Matsuo (ric)This fall, My Little Pony: The Movie hits theaters, and this prequel mini-series is your first look at the fantastic adventure to come! ",
"Danger looms over Equestria as a new villain debuts!FC • 32 pages • $3.99"
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"An analog-to-digital converter (ADC) is a device that converts continuous analog signals to discrete digital numbers. ",
"Generally, an ADC samples an input signal at a predetermined sampling rate calculated using the Nyquist-Shannon Sampling Theorem. ",
"Under that theorem, perfect reconstruction of a continuous time signal can be obtained if the sampling rate is greater than twice the highest frequency of the signal. ",
"Sampling at twice the highest frequency may, however, not be possible, especially for wideband signals or the resolution (effective number of bits) obtained at this rate may not be sufficient. ",
"A wideband signal can be defined as a signal operating at a wide range of frequencies, e.g., above 1 GHz. ",
"For these reasons, previously known ADCs may be inadequate to handle wideband applications in, for example, electronic warfare, radar, cognitive radio, signals intelligence, telecommunications, and signal sampling in space. ",
"Moreover, previously known ADCs rely on high-speed, high-power electronics that can be cumbersome, power-hungry, and expensive."
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"Expressed sequence tags from Amoebophrya sp. ",
"infecting Karlodinium veneficum: comparing host and parasite sequences.",
"\nParasitic dinoflagellates of the genus Amoebophrya play important roles in the ecology of estuaries and open ocean environments. ",
"Little is known of the cell and molecular biology of Amoebophrya, but the genus is intermediate on phylogenetic trees between apicomplexans and typical dinophycean dinoflagellates. ",
"Here, we constructed four cDNA libraries, from different stages after infecting the host, Karlodinium veneficum, with Amoebophrya sp. ",
"These libraries were used to generate 898 expressed sequence tags (ESTs), with sequences attributed to either the host or parasite, based on AT bias, codon usage, and occurrence during infection. ",
"Overall, 209 sequences were attributable to the parasite and 685 to the host. ",
"The 50 putative parasite sequences with good protein matches in GenBank were used to find the same protein from host ESTs. ",
"For 26 genes, both host and parasite sequences were identified, of which 20 encoded ribosomal proteins. ",
"PCR for seven predicted parasite and two host genes were used to confirm attributions. ",
"The most common host and parasite ESTs were compared to see if multiple gene copies were present. ",
"The host plastocyanin gene had multiple sequence variants, but parasite rps27a contained only one polymorphism, likely due to an amplification error. ",
"Amplification, cloning, and sequencing of five parasite protein-coding genes suggested that the parasite has a single sequence for each gene, but three host genes were found to have multiple variants. ",
"The genome of Amoebophrya sp. ",
"infecting K. veneficum appears to have an organization more similar to other eukaryotes than to the tandem gene arrangements found in dinoflagellates."
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"Evolutionary Relationships among Boulengerella Species (Ctenoluciidae, Characiformes): Genomic Organization of Repetitive DNAs and Highly Conserved Karyotypes.",
"\nCtenoluciidae is a Neotropical freshwater fish family whose representatives are known as bicudas. ",
"The genus Boulengerella contains 5 species, and 4 of them (B. cuvieri, B. lateristriga, B. lucius, and B. maculata) were cytogenetically analyzed in the present study by conventional and molecular procedures. ",
"All 4 species have a very similar karyotype, with 2n = 36 chromosomes (14 metacentrics + 16 submetacentrics + 6 subtelocentrics; FN = 72). ",
"However, the heterochromatin distribution pattern is species-specific. ",
"In all 4 species, the nucleolus organizer region is located in pair 18, as also confirmed by cytogenetic mapping of 18S rDNA. ",
"In turn, 5S rRNA genes are present in 2 chromosome pairs: in pair 1 of all 4 species, and in pair 10 of B. lateristriga, B. maculata, and B. cuvieri, but in pair 4 of B. lucius. ",
"The telomeric probe highlighted terminal regions in all chromosomes, as well as an interstitial centromeric sequence in pair 3 of the 3 first-mentioned species. ",
"Notably, a conspicuous heteromorphic secondary constriction in chromosomes 18 was found only in the males of the 3 species, rendering one of the homologs much larger than the other one. ",
"This feature, associated with a large 18S rDNA block and accumulation of telomeric sequences, suggests the presence of an XX/XY sex chromosome system in the analyzed Boulengerella species."
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"Hmmm, so Mayor Pete says South Bend is a “welcoming city” that doesn’t task police with enforcing federal immigration law. ",
"He also seems to recognize that cops enforcing immigration law terrorizes immigrant communities. ",
"He even goes to pains to say the city’s not full yet. ",
"So why not just answer “yes”?",
"\n\nAdvertisement"
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"Traumatic Anterior Cerebral Artery Pseudoaneurysmal Epistaxis.",
"\nPseudoaneurysmal epistaxis is a rare but emergent condition. ",
"We report a case of traumatic anterior cerebral artery pseudoaneurysmal epistaxis and review the published literature. ",
"A 49-year-old man sustained severe head trauma. ",
"He was diagnosed with multiple skull bone fractures, left subdural hematoma, subarachnoid hemorrhage, pneumocephalus, and right frontal hematoma. ",
"Subdural hematoma evacuation was done at a local hospital. ",
"In the following months, he experienced repeated epistaxis that required nasal packing to stop the bleeding. ",
"Digital subtraction angiography showed an anterior cerebral artery pseudoaneurysm protruding into the posterior ethmoid sinus. ",
"Embolization of the aneurysm was performed with microcoils, and the parent artery was occluded by thrombosis. ",
"The patient presented 1 month later with another epistaxis episode. ",
"Digital subtraction angiography showed recanalization of the parent artery and recurrence of the aneurysm. ",
"The parent artery was occluded for the second time with coils and Onyx embolic agent. ",
"Pseudoaneurysmal epistaxis is rare, and this is the first report of an anterior cerebral artery pseudoaneurysm that manifested with epistaxis. ",
"Endovascular intervention has become the first choice of treatment for this disease. ",
"The high recurrence rate is the main disadvantage of endovascular intervention. ",
"Aneurysm trapping with bypass surgery is another treatment option."
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"Q:\n\nWhere does Polymer 2 CLI store variants?",
"\n\nWhen you have a Polymer 2 bower.json with dependency variants and run polymer install --variants, where does it store the variant dependent components?",
"\n\nA:\n\nThe variants are stored in the same parent directory of the default bower_components/. For example, given variants named \"variant-1\" and \"variant-2\", the resulting directory structure of the command is:\nbower-variant-1.json\nbower-variant-2.json\nbower.json\nbower_components/\nbower_components-variant-1/\nbower_components-variant-2/\n\nYou can find an example test fixture for the polymer install --variants command in polymer-cli source. ",
"Run the command in that directory to see the result described above.",
"\n\n"
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"Mexican police have found a stolen truck that was carrying dangerous radioactive material the UN said could provide an ingredient for a \"dirty bomb,\" a government official has said.",
"\n\nThe truck was found on Wednesday close to where it was stolen outside Mexico City, said the official, but could not confirm whether the cargo was aboard.",
"\n\nThe truck was stolen on Monday while it was taking the radioactive material cobalt-60 from a hospital in the northern city of Tijuana to a radioactive waste-storage centre, Mexican officials and the UN agency said earlier.",
"\n\nThe vehicle was seized when the driver stopped at a gas station in the town of Temascalapa, 35km northeast of Mexico City.",
"\n\nMardonio Jimenez, from National Nuclear Security commission has told Al Jazeera the container was found open and that whoever opened it has been exposed to lethal doses of radiation and will require immediate medical attention.",
"\n\nAuthorities are looking into clinics in the area.",
"\n\nThe army has sealed the area while authorities implement a procedure to retrieve the open container.",
"\n\nMexican officials say the thieves were most likely common criminals unaware of the truck's radioactive cargo.",
"\n\nTruck hijacking is common in Mexico and the theft occurred in the State of Mexico, which is not a drug cartel stronghold.",
"\n\n\"Our suspicion is that they had no idea what they had stolen. ",
"This is a area where robberies are common,\" Fernando Hidalgo, spokesman for the Hidalgo state prosecutor, said earlier.",
"\n\nDirty bomb\n\n\n\nApart from peaceful medical and industrial applications, experts say, cobalt-60 can also be used in a dirty bomb in which conventional explosives disperse radiation from a radioactive source.",
"\n\nThe International Atomic Energy Agency, which has stepped up calls on member states to tighten security to prevent nuclear and radioactive materials from falling into the wrong hands, made no mention of any such risk in its statement on Wednesday.",
"\n\nThe IAEA also did not give details on how much radioactive material was in the vehicle when it was seized.",
"\n\nCobalt-60 is used in the treatment of cancer."
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"Q:\n\nHas Hawking Radiation Ever Been Observed?",
"\n\nI know Hawking Radiation has firm theoretical footing, but has a signal ever actually been observed? ",
"What observational research is being done to attempt to see this effect? ",
"Is it simply too tall an order (i.e. - too far away, too weak of a signal, etc..)? ",
"\n\nA:\n\nAccording to this MIT Technology Review \"First Observation of Hawking Radiation\" and an associated article \"Hawking radiation from ultrashort laser pulse filaments\" where the authors have simulated Hawking radiation in the laboratory, using ultrashort laser pulse filaments.",
"\nSo, in part answer to your question, yes Hawking Radiation is believed to have been observed, but in a laboratory environment.",
"\nAccording to \"Observing Hawking radiation in Bose-Einstein condensates\nvia correlation measurements\" (Fabbri, 2012), direct observation of the Hawking radiation is (in their word): hopeless.",
"\nHowever, once again simulations are possible:\n\nHawking effect, which depends only on kinematical properties of wave propagation\n in the presence of horizons, is present also in nongravitational contexts,\n for instance in stationary fluids undergoing supersonic flow.",
"\n\nFrom these articles, it would seem that direct observations of Hawking radiation is not feasible currently; however, we are able to produce analogues of the phenomena in the laboratory.",
"\n\n"
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"6\nSolve -862 = -312*o + 555 + 767 for o.\n7\nSolve -41*l - 183 - 123 = -60 for l.\n-6\nSolve 123*d = -281*d + 3358 - 9822 for d.\n-16\nSolve 259 - 154 = -58*y - 243 for y.\n-6\nSolve -t + 102 - 113 = 0 for t.\n-11\nSolve 0 = -28*d - 6410 + 6466 for d.\n2\nSolve -10*k + 128 + 182 = 190 for k.\n12\nSolve 28*g + 63 = 69*g - 224 for g.\n7\nSolve 607 - 49 = 31*k for k.\n18\nSolve 5465*z = 2733*z + 2746*z - 112 for z.\n8\nSolve 16*s + 459 = 46*s - 381 for s.\n28\nSolve -f - 7*f - 90 = -2*f for f.\n-15\nSolve -925*l - 934*l + 152 = -1851*l for l.\n19\nSolve -174*y + 315 - 5709 = 0 for y.\n-31\nSolve 269 = -145*u + 740 + 689 for u.\n8\nSolve 512 + 94 = 53*y + 76 for y.\n10\nSolve 58*c - 577 = -924 - 987 for c.\n-23\nSolve -17*a - 31*a - 79*a + 254 = 0 for a.\n2\nSolve -104*g - 431 = -156 + 557 for g.\n-8\nSolve 16*l + 14*l = 45 + 285 for l.\n11\nSolve 149*x + 1142*x - 48802 = -586*x for x.\n26\nSolve -266*g + 464 = 32 - 1962 for g.\n9\nSolve -34*a - a = -5*a - 1020 for a.\n34\nSolve -12*c + 747917 - 747521 = 0 for c.\n33\nSolve 0 = -118*t + 178 + 1314 + 986 for t.\n21\nSolve 1273*t = 1304*t - 62 for t.\n2\nSolve -32*b + 101*b - 566 = -2153 for b.\n-23\nSolve 500*c + 4893 = -6607 for c.\n-23\nSolve -16945 + 16993 = 4*d for d.\n12\nSolve 6490 = 33*x + 6985 for x.\n-15\nSolve -222*f - 700 = -362*f for f.\n5\nSolve 0 = 48*y + 200 + 159 - 1127 for y.\n16\nSolve 176*z + 194 - 2306 = 0 for z.\n12\nSolve -58*x - 2970 = 25*x + 52*x for x.\n-22\nSolve 236 = 80*q - 4 for q.\n3\nSolve 3*q - 36*q = -72*q + 117 for q.\n3\nSolve -284*u + 1334 = -2358 for u.\n13\nSolve -113*p + 214*p - 900 = 151*p for p.\n-18\nSolve 24329 = -25*p + 23479 for p.\n-34\nSolve 99*u = 42*u - 798 for u.\n-14\nSolve 814*w + 5165 = -2975 for w.\n-10\nSolve -116*u + 100*u - 4 = 44 for u.\n-3\nSolve 0 = -176*j + 38*j + 966 for j.\n7\nSolve -168*o + 9*o + 179 = 974 for o.\n-5\nSolve -3653 - 640 = -1219*b + 1696*b for b.\n-9\nSolve 9045 = 28*t + 4537 + 4396 for t.\n4\nSolve -524*b - 8 = -528*b for b.\n2\nSolve 165 = 13*m + 126 for m.\n3\nSolve -875*z = -852*z - 322 for z.\n14\nSolve -45*o - 99 = -18 - 801 for o.\n16\nSolve -6*a = -10*a - 0*a - 24 for a.\n-6\nSolve -19 = -0*m - 14*m + 135 for m.\n11\nSolve -100*m + 42*m = -50*m - 224 for m.\n28\nSolve 6103 = -87*o + 5146 for o.\n-11\nSolve -58*c - 42*c + 115 = -77*c for c.\n5\nSolve 29*i + 44 = -72 for i.\n-4\nSolve 0 = 2164*s - 2125*s - 351 for s.\n9\nSolve 195 = -61*i + 1171 for i.\n16\nSolve 8*q - 2*q = -6*q for q.\n0\nSolve 251*x + 621 = 182*x for x.\n-9\nSolve -864*q - 684*q = 6192 for q.\n-4\nSolve -73*t + 5*t + 476 = 0 for t.\n7\nSolve g - 2*g + 10 - 16 = 0 for g.\n-6\nSolve -304 = 130278*g - 130294*g for g.\n19\nSolve -3113*y = -3167*y - 378 for y.\n-7\nSolve -45*v + 6*v + 341 = -8*v for v.\n11\nSolve -1687*t + 1693*t + 36 = 0 for t.\n-6\nSolve -74*x + 236 + 46 = -532 for x.\n11\nSolve -3 - 22 = 35*s + 10 for s.\n-1\nSolve -2264*n + 2330*n = -726 for n.\n-11\nSolve -97*x - 119*x = -234*x + 324 for x.\n18\nSolve 585 = -3*m - 62*m for m.\n-9\nSolve 7593 - 7636 = 43*b for b.\n-1\nSolve -80 + 65 = -17*p + 155 for p.\n10\nSolve 0 = 11*m - 660221 + 660243 for m.\n-2\nSolve -768 = 21*v + 75*v for v.\n-8\nSolve -34*r + 488 - 152 = -72 for r.\n12\nSolve 5553*k - 62 - 66 = 5561*k for k.\n-16\nSolve 3*r = 2*r - 63 + 68 for r.\n5\nSolve -16*r = -16*r + 12*r + 168 for r.\n-14\nSolve 31*d = 275*d + 4148 for d.\n-17\nSolve -896*o + 899*o = -69 for o.\n-23\nSolve 245*c = -263*c - 2911 - 2677 for c.\n-11\nSolve 1461549*x + 136 = 1461515*x for x.\n-4\nSolve 0*o - o - 2 = -3*o for o.\n1\nSolve -4659*q - 12 = 4660*q - 9320*q for q.\n12\nSolve 175*d = 54*d + 242 for d.\n2\nSolve -22*g + 102514 = 102580 for g.\n-3\nSolve -158*p + 72*p + 126*p = -480 for p.\n-12\nSolve 8*r + 310914 - 311114 = 0 for r.\n25\nSolve 0*g + 257 = 11*g + 103 for g.\n14\nSolve -188 = i + 2*i - 212 for i.\n8\nSolve 20*l - 530 + 103 + 227 = 0 for l.\n10\nSolve -4*h - 21 = -0*h - 25*h for h.\n1\nSolve 0 = -35*d - 3127 + 3407 for d.\n8\nSolve -7*p + 755 = 5*p + 139*p for p.\n5\nSolve 4*l + 137*l + l - 1704 = 0 for l.\n12\nSolve -4187 + 862 = -230*s + 585 for s.\n17\nSolve 0 = -1847*k + 1793*k - 594 for k.\n-11\nSolve 0 = -30*m + 16 + 3 + 71 for m.\n3\nSolve 0 = -178*i + 189*i - 132 for i.\n12\nSolve 29*m - 386 = -560 for m.\n-6\nSolve 0 = -12*f + 191 + 1 for f.\n16\nSolve -9*s - 5977 + 2979 + 2755 = 0 for s.\n-27\nSolve 11093 = 61*u + 11154 for u.\n-1\nSolve -119*k - 110*k - 34*k = 1315 for k.\n-5\nSolve -6*w - 14214 + 14238 = 0 for w.\n4\nSolve -312*f + 416*f = -816*f - 16560 for f.\n-18\nSolve -330*t - 282 - 3766 = 2552 for t.\n-20\nSolve -18*h - 275 = -0*h - 41 for h.\n-13\nSolve 230*s + 7860 = -220*s - 74*s for s.\n-15\nSolve -1535*f - 3553 = -34253 for f.\n20\nSolve 3*k + 5049 = -294*k for k.\n-17\nSolve -1364 = 373*u - 311*u for u.\n-22\nSolve -86*c + 2722 = 228 for c.\n29\nSolve -20 = -79*b - 968 for b.\n-12\nSolve -510*s = -609*s - 297 for s.\n-3\nSolve -2*r = 120*r + 122 for r.\n-1\nSolve -21*b = 11*b - 416 for b.\n13\nSolve 1528*d = -6344 - 1296 for d.\n-5\nSolve 276*j + 82 = 101*j - 2018 for j.\n-12\nSolve 228*s + 28*s - 107 - 1685 = 0 for s.\n7\nSolve -73 - 176 + 24 = 45*y for y.\n-5\nSolve -694*l - 16700 = -1432 for l.\n-22\nSolve 103*x - 6027 = -4276 for x.\n17\nSolve -227*n - 221 - 969 = -57*n for n.\n-7\nSolve 54*c = -182*c + 236 for c.\n1\nSolve 0 = -2105836*g + 2105809*g + 243 for g.\n9\nSolve 98*h = -74*h - 2236 for h.\n-13\nSolve 11*y - 3*y - 10 = 94 for y.\n13\nSolve 25*y - 17*y - 630 = -34*y for y.\n15\nSolve -10*f - 5*f - 36 = 24 for f.\n-4\nSolve 0 = -45*j - 10*j - 416 - 354 for j.\n-14\nSolve 34*a - 534 = -252 + 432 for a.\n21\nSolve 71*z - 390 = 95 + 83 for z.\n8\nSolve 279*l - 600*l + 1053 = -282*l for l.\n27\nSolve -b - 2*b - 64 + 97 = 0 for b.\n11\nSolve 230*h - 1907 = -6277 for h.\n-19\nSolve 33 = 214*i + 33 for i.\n0\nSolve 110*v + 91*v + 1904 = -37*v for v.\n-8\nSolve -411*m + 31 = -398*m + 44 for m.\n-1\nSolve 722 - 252 = 94*s for s.\n5\nSolve 0 = 12297*h - 12300*h - 42 for h.\n-14\nSolve 48046*r = 48036*r - 80 for r.\n-8\nSolve 2232*c - 280 = 2204*c for c.\n10\nSolve 0 = -118*j - 281 + 45 for j.\n-2\nSolve -138*w - 40*w = 3738 for w.\n-21\nSolve 0 = 75*r - 42*r - 107*r + 2368 for r.\n32\nSolve 58*q = -1807 + 473 for q.\n-23\nSolve 31*p - 6*p - 153 = -26*p for p.\n3\nSolve 418*c - 279 = -1115 for c.\n-2\nSolve -235*s - 267*s - 163*s = 4655 for s.\n-7\nSolve y - 18 = -8 - 6 for y.\n4\nSolve -50 = -1087*g + 1137*g for g.\n-1\nSolve 0 = -86*o - 23*o + 71*o - 456 for o.\n-12\nSolve -83*l + 1325 = 80 for l.\n15\nSolve -54*d - 50*d = -113*d - 9 for d.\n-1\nSolve 655 = 154*k + 1733 for k.\n-7\nSolve 0 = -14*a + 94 + 234 - 48 for a.\n20\nSolve 0 = -438*r + 485*r + 564 for r.\n-12\nSolve 0*i - 3*i = -2*i - 5 for i.\n5\nSolve -2653 + 2828 = 25*a for a.\n7\nSolve 28960 = -12*a + 28864 for a.\n-8\nSolve 214*i - 399 = -137 - 1974 for i.\n-8\nSolve -30*s + 706*s = 15548 for s.\n23\nSolve -64*u + 174 + 906 = -712 for u.\n28\nSolve 756 = -14023*m + 13939*m for m.\n-9\nSolve d - 156 = 27*d + 78 for d.\n-9\nSolve 2600*q = 2611*q + 231 for q.\n-21\nSolve -9*d + 162*d - 182 + 29 = 0 for d.\n1\nSolve 86*h + 83*h - 161*h = -24 for h.\n-3\nSolve 117*g - 357 = 85*g + 59 for g.\n13\nSolve -261*x - 1200 = -181*x for x.\n-15\nSolve -63*l - 7 = -62*l - 4 for l.\n-3\nSolve -9*z - 3 - 62 = -4*z for z.\n-13\nSolve 235*o - 3140 = 25*o - 830 for o.\n11\nSolve -322*h + 3913 = -1970 + 2019 for h.\n12\nSolve 44*c - 41 + 56 = -29 for c.\n-1\nSolve -7*d = -35 + 35 for d.\n0\nSolve -385 - 182 = -1065*p + 1086*p for p.\n-27\nSolve 154*n + 4045 = 965 for n.\n-20\nSolve -9*r - 312 = -12*r + 27*r for r.\n-13\nSolve -7*z - 240 = -219 for z.\n-3\nSolve -48*k - 143*k + 1458 = -29*k for k.\n9\nSolve 0 = -287*p - 450*p + 6633 for p.\n9\nSolve -8*q - 209 = -44*q + 259 for q.\n13\nSolve -5*w = -252 + 187 for w.\n13\nSolve -66 = -2049*a + 2055*a for a.\n-11\nSolve -140*m - 284 = -41 + 177 for m.\n-3\nSolve -12*u = 101*u - 268 - 410 for u.\n6\nSolve -350*p - 1029 = 721 for p.\n-5\nSolve 4 + 152 = -31*n - 247 for n.\n-13\nSolve 14 = -98563*l + 98577*l for l.\n1\nSolve 0 = 12*i + 72 - 130 - 50 for i.\n9\nSolve -4 = -112*v + 42*v + 2866 for v.\n41\nSolve 48653 - 48568 = 17*u for u.\n5\nSolve 21 = 9*n - 5 - 10 for n.\n4\nSolve -122*f + 42136 = 39696 for f.\n20\nSolve -5*g = -5*g + 33*g - 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"The first one doesn't do much for me... I like the wind patterns in the third, but my preference is for the middle one, which I see as 'penguin meets seal' in a somewhat watercolour fashion (similar to Morten Solberg's work).",
"\n\nMike.",
"\n\nLogged\n\nIf your mind is attuned to beauty, you find beauty in everything.~ Jean Cooke ~"
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"1169\n\nYear 1169 (MCLXIX) was a common year starting on Wednesday (link will display the full calendar) of the Julian calendar.",
"\n\nEvents \nBy Area\n\nAfrica\n Nur ad-Din, atabeg of Aleppo, invades Egypt, and on March 26 names his nephew Saladin sultan as well as vizier of Cairo.",
"\n\nEurope\n January – Henry II of England and Louis VII of France sign a peace treaty which includes the betrothal of their respective heirs, twelve-year-old Richard I of England and nine-year-old Alys, Countess of the Vexin.",
"\n February 4 – 1169 Sicily earthquake: An earthquake with an estimated magnitude of around 7 strikes the eastern coast of Sicily, causing an estimated 15,000 deaths.",
"\n May 1 – The Norman invasion of Ireland begins. ",
"Among those arriving is Cambro-Norman knight (and vassal of Henry II of England) Richard de Clare, who has made an alliance with exiled Irish chief Diarmait Mac Murchada to help him regain the throne of Leinster. ",
"This begins the period of Anglo-Norman dominance of Ireland. ",
"\n Siege of Badajoz by Gerald the Fearless: The adventurer receives the support of King Afonso I of Portugal. ",
"The Almohad caliph, Abu Yaqub Yusuf, manages to broker an alliance with King Ferdinand II of León against Afonso. ",
"The allies manage to besiege the Portuguese in Badajoz, and to finally take both the king and Gerald prisoners.",
"\n During the Swedish power struggle, Boleslaw is killed, but his brother Kol continues as king of Östergötland until 1173, in opposition to King Knut Eriksson of Sweden.",
"\n The appointed Bishop of Estonia, Fulco, becomes the first known Christian missionary to visit Estonia.",
"\n Prince Andrey Bogolyubsky of Vladimir-Suzdal sacks Kiev and makes Vladimir the capital of Kievan Rus'.",
"\n\nBy topic\n\nArts\n Eleanor of Aquitaine leaves the English court of Henry II, to establish her own court in Poitiers. ",
" It will become known as a center of courtly love.",
"\n\nBirths \n September 10 – Alexius II Comnenus, Byzantine Emperor (d. 1183)\n\nDeaths \n January 2 – Bertrand de Blanchefort, sixth Grand Master of the Knights Templar (b. c. 1109)\n February 4 – John of Ajello, Bishop of Catania \n July 9 – Guido of Ravenna, Italian cartographer, entomologist and historian\n Stephen du Perche, chancellor of Sicily and archbishop of Palermo\n Boleslaw Sverkerson, king of Östergötland (Sweden) since 1167\n\nReferences"
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"That’s an achievement Chicago should strive to match and exceed. ",
"Ordinary people can help with adopting safe practices. ",
"Such as: Don’t talk or text on your smartphone when you’re driving — or when you’re walking across a street. ",
"Drive within the speed limit and don’t blow through red lights. ",
"In short, keep the safety of yourself and everyone else foremost in your mind, whether you’re behind the wheel or on foot. ",
"That is the surest way to prevent accidents."
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"Maximizing Customer Revenue With Analytics\n\nBy Tim Connell\n\nThe key to an effective customer experience is to know your customer and individualize your interactions to best fit their needs and situation. ",
"Doing so allows you to maximize revenue per customer. ",
"With a small customer base, this can be done in person and based on ongoing relationships. ",
"With a larger customer base, it gets much more difficult. ",
"You may need to customize interactions with customers you’ve never met in person, and likely will never meet. ",
"This is where analytics, especially predictive analytics, comes into play.",
"\n\nPaying Attention to the Present\n\nAnalytic tools can help you segment your customer base, identifying groups of customers that are more similar to each other than to other customers. ",
"Analyzing the buying patterns of those groups gives you models that can help to predict the likely purchases of new customers. ",
"All you need to know is which group the new customer is most like.",
"\n\nSimilarly, you can look at the pattern of product purchases (sometimes called market basket analysis) to see what pairs of items are often purchased together. ",
"When you see interest in or purchase of one side of the pair you can recommend the other.",
"\n\nThe more data you have and the more analytic tools you apply, the more individualized you can be. ",
"Combining customer grouping and item analysis gives you different item pairings for different groups. ",
"Adding in sales channels and other additional data helps refine these predictions even more.",
"\n\nLearning From the Past\n\nPredictive analytics are built on the idea that past behavior is the best predictor of future behavior. ",
"These tools mine past data to find patterns that will help predict future behavior. ",
"Sometimes these patterns are obvious (past purchasers of Coke products are likely to continue to purchase Coke products). ",
"Other times these patterns make no logical sense (people who use a particular deodorant are more likely to purchase Pepsi products). ",
"But logical sense isn’t really the goal here. ",
"What is important is the pattern and its ability to predict future behavior.",
"\n\nIn most situations, predictive tools are ‘trained’ using historical data. ",
"This historical data is run through an algorithm, which is then told what the ‘correct’ answer is for each record. ",
"The algorithm then identifies patterns in the data that best predict these ‘correct’ answers. ",
"When given new data, the algorithm looks for these same patterns and returns a likelihood based on the best match.",
"\n\nFinding the Best Approach\n\nPoint-and-click analytical tools that can generate moderately good predictions are increasingly available to non-technical users. ",
"Some of these tools even use predictive models to help you build your own. ",
"However, there are a lot of ways to build a bad or mediocre model, and fewer ways to build one that really works. ",
"Accurate predictions involve a level of knowledge about data and statistics that may require the help of an experienced expert.",
"\n\nAvoiding the Pitfalls\n\nThe biggest pitfall to watch out for is ‘overfitting’. ",
"An overfitted model is one that relies on patterns in the training data (used in development) that don’t exist in the real-world data. ",
"Experienced modelers follow a defined methodology and bring a number of statistical concepts and tests to bear to help reduce the likelihood of overfitting.",
"\n\nThe old saying “Garbage In, Garbage Out” also applies. ",
"Predictive analytics tools are highly dependent on the quality of the data they use. ",
"Predictive algorithms will find whatever patterns exist in a data set, even if those patterns are based on inaccurate, mis-entered, missing, or otherwise invalid data. ",
"As a result, the quality of the underlying data set has an enormous impact on the accuracy and efficacy of the resulting tool.",
"\n\nFurther, it is very important to ensure that the data consumed by a predictive algorithm exists prior to when the prediction needs to be made. ",
"This may seem obvious, but you’d be surprised how often this is missed. ",
"Because we use historical data to create predictive models, it is possible to build a model that relies on data that is not entered or available until after the prediction needs to be made. ",
"Such models will look great in development and testing but will fail spectacularly in the field because you are asking the algorithm to make predictions using data that doesn’t exist yet.",
"\n\nEffective but Always in Flux\n\nPredictive analytics are not 100% accurate, and never will be. ",
"Ultimately, they just tell us when something has a higher likelihood of happening. ",
"A big part of implementing a predictive tool is determining what to do when it is correct and how to handle when it is incorrect. ",
"For example, an online retailer wouldn’t automatically add something to a customer’s cart just because the algorithm said they are more likely to purchase it. ",
"They would, however, add it to a “you might also like…” screen that makes it easier for the customer to add it themselves.",
"\n\nSimilarly, predictive analytics is not a “one-and-done” effort. ",
"The context and data patterns that models rely on is subject to change over time, especially as new products are offered, new markets are entered, and customers churn. ",
"Models should be evaluated regularly to ensure predictive accuracy and should updated if they don’t meet established standards.",
"\n\nAbout RedMane\n\nRedMane provides software solutions and systems integration services that address complex, real-world challenges in human services, healthcare, and the commercial sector. ",
"We are a problem-solving company. ",
"Technology is just one of our tools.",
"\n\nTo speak with a RedMane expert about your needs, email info@redmane.com or call 773-331-0001 today.",
"\n\nAbout Tim Connell\n\nTim Connell is a data scientist and solution architect at RedMane Technology. ",
"He’s been performing data analysis and implementing solutions for over 25 years. ",
"Tim’s work spans commercial firms and the public sector. ",
"He holds a Ph.D. from the University of Wisconsin.",
"\n\nRedMane’s delivery has been great! ",
"I expected a lot and the RedMane team listened, asked the right questions and jumped in with both feet."
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"Q:\n\nHow to detect if OS X is in dark mode?",
"\n\nMy cocoa app has to change its behaviour when run in the new OS X \"dark mode\".",
"\nIs there a way to detect if OS X style is set to this mode?",
"\n\nA:\n\nDon't think there's a cocoa way of detecting it yet, however you can use defaults read to check whether or not OSX is in dark mode.",
"\ndefaults read -g AppleInterfaceStyle\n\nEither returns Dark (dark mode) or returns domain pair does not exist.",
"\nEDIT:\nAs Ken Thomases said you can access .GlobalPreferences via NSUserDefaults, so \nNSString *osxMode = [[NSUserDefaults standardUserDefaults] stringForKey:@\"AppleInterfaceStyle\"];\n\nIf osxMode is nil then it isn't in dark mode, but if osxMode is @\"Dark\" then it is in dark mode.",
"\n\nA:\n\nSwift 2 -> String (\"Dark\", \"Light\")\nlet appearance = NSUserDefaults.standardUserDefaults().stringForKey(\"AppleInterfaceStyle\") ?? \"",
"Light\"\n\nSwift 3 -> Enum (Dark, Light)\nenum InterfaceStyle : String {\n case Dark, Light\n\n init() {\n let type = UserDefaults.standard.string(forKey: \"AppleInterfaceStyle\") ?? \"",
"Light\"\n self = InterfaceStyle(rawValue: type)!",
"\n }\n}\n\nlet currentStyle = InterfaceStyle()\n\nA:\n\nYou can detect this using NSAppearanceCustomization method effectiveAppearance, by checking for darkAqua.",
"\nSwift 4 example:\nextension NSView {\n var isDarkMode: Bool {\n if #available(OSX 10.14, *) {\n if effectiveAppearance.name == .darkAqua {\n return true\n }\n }\n return false\n }\n}\n\n"
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"Emerald Empress\n\nThe Emerald Empress is a fictional character in DC Comics. ",
"A supervillainess that is an enemy of the Legion of Super-Heroes and a member of the Fatal Five, she was created by Jim Shooter and Curt Swan, and first appeared in Adventure Comics #352 (January 1967).",
"\n\nFictional character biography\n\nOrigins \nSarya of the planet Venegar (referred to simply as 'the Empress') was recruited by Superboy and the Legion to combat the menace of the Sun-Eater. ",
"Once the Sun-Eater was defeated, she joined the Fatal Five with Tharok, Validus, Mano and the Persuader.",
"\n\nThe Empress had no innate super-powers; rather, she employed a powerful mystical item called the Emerald Eye of Ekron, an approximately 2' diameter sphere that obeyed her mental commands. ",
"The Eye could fly and emit blasts of energy, and allowed the Empress to fly as well as survive in space. ",
"The Eye's residual energy also gave her, on at least one occasion, super-strength. ",
"It caused her to grow to gigantic stature during one battle. ",
"The Eye could also reform itself if shattered.",
"\n\nThe Eye is an item of immense power; it defeated Superboy directly more than once, though it seemed to have more trouble with Mon-El, perhaps because he was immune to green Kryptonite and its blasts may have contained elements of it. ",
"Despite this, for unknown reasons, the Eye does not like green Kryptonite, and being exposed to a chunk of it has made the Eye flee on more than one occasion (leaving the Empress behind temporarily).",
"\n\nThe Emerald Empress died when Legionnaire Sensor Girl used her powers of illusion to mask Sarya's presence from the Emerald Eye of Ekron. ",
"As the Empress' body quickly withered and decomposed, she expressed relief to be free from the Eye's control, indicating both that their symbiotic relationship was unwilling and that the Empress was far older than she appeared.",
"\n\nCera Kesh & Ingria Olav \nCera Kesh first appeared as the Emerald Empress in Legionnaires #2. ",
"Slightly overweight and with poor skin, she was also telekinetic and sought to join the Legion through their open audition program. ",
"Mocked by Legion member Inferno (for whom she harbored an infatuation) for her appearance, Kesh fled in embarrassment and anger, and was found by the Emerald Eye. ",
"Transformed by it into an idealized version of herself, and with all the powers of the Eye boosting her own, she succumbed to the Eye's influence and turned to a life of crime with the other members of the Fatal Five. ",
"At the same time, Leland McCauley found a second Emerald Eye, with which he hoped to turn Ingria Olav into the new Emerald Empress. ",
"Instead, Cera killed her and gained the power of both Eyes. ",
"She was not seen again, as the timeline she was a part of ended shortly thereafter.",
"\n\nGarryn Bek & L.E.G.I.O.N.\nThe Emerald Eye also appeared in L.E.G.I.O.N., where it was controlled by, or controlled, the L.E.G.I.O.N.naires Garryn Bek and Marij'n Bek. ",
"Under its influence, the two would kill innocent people.",
"\n\nEmpress \nAfter the Zero Hour event and the subsequent reboot of the Legion's continuity, a character simply called the 'Empress' appeared, unconnected to the Emerald Eye of Ekron (which appeared separately later). ",
"Although she had no powers, she was as dangerous as the rest of the Fatal Five, being a sadistic murderess who had taught herself how to kill any known lifeform.",
"\n\nThe Eye itself was in possession of the supervillain Scavenger, but was discovered by Shrinking Violet, who fell under its control. ",
"With the Legion's help, Violet managed to break the Eye's hold on her, but not before she had sent half the team into the past and attracted the attention of the ancient sorcerer Mordru.",
"\n\nEventually, the Eye came into the hands of the Empress. ",
"The Empress seemed to have broken the Eye's will, leaving her unequivocally in control.",
"\n\nThis version of the Legion is still in continuity, but now established as taking place on a parallel world, which means that this Eye is not the same as the one the original Legion encountered, but the Eye of an alternate universe.",
"\n\n52\nIn the present, the Emerald Eye has appeared in the pages of 52, in the possession of Lobo, and in The Brave and The Bold back in the hands of the Emerald Empress.",
"\n\nLobo, unable or unwilling to use its powers, kept the item in a small chest under his supervision. ",
"When Starfire used the Eye to save the population of Sector 3500 from a swarm of strange creatures, Lobo revealed that he knew something more on the origins of the Eye. ",
"An Emerald Head of Ekron also existed and was searching for its lost eyeball. ",
"Ekron is apparently a member of the Green Lantern Corps, but has been driven insane by the destruction of the Space Sector under his protection by Lady Styx. ",
"The Emerald Eye itself is later revealed as a precursor of the technology that later led to the power ring worn by all Green Lanterns, with less functionality but nevertheless a formidable weapon.",
"\n\nFinal Crisis and beyond\nEmerald Empress (possibly Cera Kesh), alongside the other Fatal Five members, was among the supervillains in Superboy-Prime's Legion of Super-Villains.",
"\n\nIn Legion of Super-Heroes Annual 1 (2011), the Eye finds a new Empress on the planet of Orando. ",
"This young girl fights Shrinking Violet, Light Lass, Sun Boy, Sensor Girl and Gates of the Legion before being defeated by Violet. ",
"The girl was released from the Eye's control, but the Eye itself managed to flee the planet.",
"\n\nDC Rebirth\nThe Emerald Empress appears as one of Max Lord's supervillains in Justice League vs. Suicide Squad. ",
"It is revealed that she was part of the first Suicide Squad, along with Lobo, Johnny Sorrow, Rustam and Doctor Polaris.",
"\n\nEmerald Eye of Ekron\nAccording to the year-spanning maxiseries \"52\" (2006), the Eye was once a real eye for the cosmic entity called \"Ekron\". ",
"But, somehow Emerald Empress got the Eye and got it to work for her. ",
"In the 52 weekly series, Lobo kept the eye in a box while watching it. ",
"Soon Starfire used it to stop villains from destroying an entire Space Sector. ",
"Lobo revealed that the Eye was part of the Emerald Head of Ekron, that was a member of the Green Lantern Corps, until driven insane by his space sector being destroyed. ",
"The Eye was an early prototype for the power rings.",
"\n\nHowever, when the Eye was reintroduced in the Legion Annual of 2011, none of this was acknowledged. ",
"Rather, Ekron was referred to as a world where the Eye had once been worshipped as a god.",
"\n\nThe 52 explanation also neglects any existence of the Eye wielded by Garryn Bek of L.E.G.I.O.N. in the 21st century.",
"\n\nPowers and abilities\nThe Emerald Empress has no innate superpowers of her own, but wields the Emerald Eye of Ekron. ",
"Her connection to the object gives her direct access to its immense mystical power, which she employs in a variety of ways. ",
"\n\nThe object itself flies in the air and is virtually indestructible. ",
"Her command over the Eye gives her the ability to fly and survive in the vacuum of space, generate protective force fields around herself, project blasts strong enough to hurt Superboy, create energy constructs, hypnotize others, and teleport. ",
"It has also given her superhuman strength on more than one occasion, and even made herself grow to giant size. ",
"In a recent appearance, the Eye gave the Empress the power to cast illusions or alter reality, rebuilding the planet of Orando into a medieval-like society as she envisioned it. ",
"It can also see through every spectrum and wavelength, reform itself if it shatters, enhance any innate powers that its current user has, and keep the Empress young and beautiful.",
"\n\nReception\nEmerald Empress was ranked 38th in Comics Buyer's Guide's \"100 Sexiest Women in Comics\" list.",
"\n\nIn other media\n\nTelevision\n The Cara Kesh version of Emerald Empress has appeared in the episode \"Far From Home\" of Justice League Unlimited, voiced by Joanne Whalley. ",
"In that episode, the Eye's power proved to be stronger than a Green Lantern Power Ring.",
"\n The Sarya version of Emerald Empress is the leader of the Fatal Five in the Legion of Super Heroes animated series, voiced by Jennifer Hale in season one and Tara Strong from then on. ",
"As in the comics, the Emerald Eye of Ekron is the source of her mystic powers. ",
"Some clues to this version's relationship with the Eye can be observed in the first-season finale \"Sundown\". ",
"She had been separated from it for some time during her imprisonment and hugged it when it was returned to her, suffered no physical effects when Shrinking Violet damaged its circuitry from within once the Fatal Five betrayed the Legion, nor when Matter-Eater Lad took a bite out of it in the season two premiere. ",
"Though its destruction has left her powerless, biting into it damaged Matter-Eater Lad's mind, leaving him in a near-comatose state for most of the season.",
"\n Though not appearing in Batman: The Brave and the Bold, the Emerald Empress is referenced in \"The Super-Batman of Planet X\". ",
"Batman mentions to Green Arrow that the space pirates they are chasing are stealing the Emerald Eye of Ekron.",
"\n\nFilm\n A version of Emerald Empress made a cameo appearance with the other villains in Justice League: The New Frontier.",
"\n A version of Emerald Empress appears in the 2019 DC Universe Original Movie Justice League vs. the Fatal Five, voiced by Sumalee Montano. ",
"In this version, she is Mano's lover. ",
"She and Validus were sent back into the 21st century to be imprisoned on Oa since the Green Lanterns no longer existed in the 31st century to hold dangerous criminals like them. ",
"She is freed by Mano, revealing her plan to steal the power of the Green Lantern battery and send her Eye into the sun to destroy it, and Earth with it, preventing the Legion of Superheroes from being formed.",
"\n\nReferences\n\nExternal links\nEmerald Eye at Cosmic Teams Obscure Characters Index.",
"\n\nCategory:Characters created by Curt Swan\nCategory:Characters created by Jim Shooter\nCategory:Comics characters introduced in 1967\nCategory:DC Comics supervillains\nCategory:Extraterrestrial supervillains\nCategory:Female characters in comics\nCategory:Female supervillains\nCategory:Fictional emperors and empresses"
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"\n#\n# Translators:\n# Alex Gaynor <alex.gaynor@gmail.com>, 2012\n# Jannis Leidel <jannis@leidel.info>, 2011\n# Meir Kriheli <mkriheli@gmail.com>, 2012-2013\nmsgid \"\"\nmsgstr \"\"\n\"Project-Id-Version: django-core\\n\"\n\"Report-Msgid-Bugs-To: \\n\"\n\"POT-Creation-Date: 2013-08-16 15:07+0200\\n\"\n\"PO-Revision-Date: 2013-11-02 12:33+0000\\n\"\n\"Last-Translator: Meir Kriheli <mkriheli@gmail.com>\\n\"\n\"Language-Team: Hebrew (http://www.transifex.com/projects/p/django/language/\"\n\"he/)\\n\"\n\"MIME-Version: 1.0\\n\"\n\"Content-Type: text/plain; charset=UTF-8\\n\"\n\"Content-Transfer-Encoding: 8bit\\n\"\n\"Language: he\\n\"\n\"Plural-Forms: nplurals=2; plural=(n !",
"= 1);\\n\"\n\n#: templates/formtools/wizard/wizard_form.html:15\nmsgid \"first step\"\nmsgstr \"צעד ראשון\"\n\n#: templates/formtools/wizard/wizard_form.html:16\nmsgid \"prev step\"\nmsgstr \"צעד אחרון\"\n\n#: templates/formtools/wizard/wizard_form.html:18\nmsgid \"submit\"\nmsgstr \"שלח\"\n\n#: wizard/views.py:275\nmsgid \"ManagementForm data is missing or has been tampered.\"",
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"Introduction {#S1}\n============\n\nTissue-resident and monocyte-derived macrophages are innate immune cells that play a key role in normal tissue homeostasis, presentation of foreign and self antigens following infection or injury, pathogen clearance, and resolution of inflammation and wound healing. ",
"Depending on the microenvironment, macrophages can be programed to adopt a variety of proinflammatory, regulatory, resolving, and immunosuppressive activation phenotypes, particularly *in vivo*. ",
"These activation states exist as a complex continuum of overlapping phenotypes; however, macrophage subsets with distinct functions have been defined ([@B1]). ",
"Macrophages are considered M1-polarized when stimulated by IFN-γ or Toll-like receptor (TLR) ligands, such as lipopolysaccharide (LPS), to express inducible nitric oxide synthase (iNOS; Nos2) and produce nitric oxide (NO). ",
"NOS enzymes metabolize [l]{.smallcaps}-arginine to citrulline and NO. ",
"NO is a short-lived gaseous messenger with physiological and pathological effects. ",
"Nanomolar concentrations of NO, generated by endothelial NOS and neuronal NOS, are important for maintaining homeostasis, regulating vasodilation, and for the aggregation, recruitment, and adhesion of platelets to the vascular endothelium. ",
"iNOS generates micromolar levels of NO that modulates various pathophysiological processes and is important for killing intracellular pathogens ([@B2]).",
"\n\nIn contrast, M2-polarized macrophages result following stimulation of cells with a variety of stimuli, including type 2 cytokines such as interleukin (IL)-4 or IL-13. ",
"M2-polarized macrophages express a distinct [l]{.smallcaps}-arginine-metabolizing enzyme, arginase 1 (Arg1), which hydrolyzes [l]{.smallcaps}-arginine to [l]{.smallcaps}-ornithine and urea. [",
"l]{.smallcaps}-Ornithine can be further metabolized to polyamines, which participate in a variety of fundamental cellular functions (e.g., proliferation, cell membrane transport), and [l]{.smallcaps}-proline, which is an essential component of collagen. ",
"In addition to playing important roles in defense against extracellular parasites and tissue repair, Arg1 expression and activity in myeloid cells have emerged as a major regulator of innate and adaptive immune responses ([@B3]). ",
"Other M2-like suppressive or anti-inflammatory macrophages include myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). ",
"MDSCs are considered to be an immature population of myeloid cells, including both monocyte-like (GR-1/Ly-6C^+^) and neutrophil-like (GR-1/Ly-6G^+^) populations, associated with tumors or infections that suppress proinflammatory responses ([@B4], [@B5]). ",
"Depending on the context, MDSCs have been shown to mediate their suppressive activity via NO- and/or Arg1-dependent mechanisms. ",
"Importantly, macrophages are not permanently programed, but are considered \"plastic\" -- that is, macrophages have been shown to change activation phenotypes depending on the local environment.",
"\n\nAlthough the M1/iNOS and M2/Arg1 division is generally appropriate, Arg1 can be induced in M1-like macrophages under certain conditions. ",
"Thus, due to the spectrum of activation states for macrophages, a framework for macrophage-activation nomenclature was recently suggested ([@B6]). ",
"In an attempt to avoid confusion in this review, we focused on the specific effects of the [l]{.smallcaps}-arginine metabolizing enzymes iNOS or Arg1 on the pathogenesis of viral infections, noting other activation markers where appropriate.",
"\n\nIncreasing evidence suggests that myeloid cell programing, iNOS, and Arg1 contribute to the pathogenesis of numerous virus infections, suggesting that therapies that target these cells and pathways may be beneficial for the treatment of some virus diseases. ",
"In this review, we highlight recent studies of viral infections where myeloid cell polarization -- resulting in expression of iNOS or Arg1 -- contribute to viral control or the development of chronic virus infection and mediate the resolution of tissue damage or cause immunopathology.",
"\n\nNO Production Can be Beneficial during Virus Infection {#S2}\n======================================================\n\nNO has antimicrobial activity against a number of bacteria, parasites, and fungi ([@B7], [@B8]). ",
"Additionally, NO has been shown to have direct antiviral effects *in vitro* and/or *in vivo* against several viruses, including DNA viruses such as herpes simplex virus type-1 (HSV-1), ectromelia virus (EV), and vaccinia virus (VV) ([@B9], [@B10]), as well as some RNA viruses such as vesicular stomatitis virus (VSV) ([@B11]), Japanese encephalitis virus (JEV) ([@B12]), dengue virus (DENV) ([@B13]), and coxsackievirus (Table [1](#T1){ref-type=\"table\"}) ([@B14]--[@B17]). ",
"There are several advantages of using NO as an antiviral agent. ",
"For instance, unlike complement and antibody, NO can readily pass through cellular membranes into neighboring cells as well as some viruses. ",
"Additionally, NO is likely to act on a variety of both viral and virally exploited cellular targets, inhibiting viral replication as well as limiting the capacity of viruses to develop resistance. ",
"Lastly, the effect of NO is independent of immune recognition of the infected cell, in contrast to that of antiviral lymphocytes, which could be important in virus-infected cells where expression of MHC class I molecules may be downregulated and in some virally infected tissues such as the brain where expression of MHC class I and II molecules is limited.",
"\n\n###### \n\n**Differential roles for the [l]{.smallcaps}-arginine-hydrolyzing enzymes iNOS and Argl in virus-induced diseases**.",
"\n\n iNOS/NO Reference Arg1 Reference\n ------------------------- -------------------------------- ----------------------------------------------------------------- --------------------------------- -------------------------------- ------------------------------------------------------------------- -------------------\n **Beneficial for host** **Antiviral** Ectromelia virus (EV) ([@B9], [@B10], [@B18]) **Tissue repair/regeneration** Respiratory syncytial virus (RSV) ([@B19]--[@B21])\n Herpes simplex virus-1 (HSV-1) ([@B9], [@B10], [@B22]--[@B26]) Influenza ([@B27])\n Cytomegalovirus (CMV)[^a^](#tfn1){ref-type=\"table-fn\"} ([@B28], [@B29]) Coxsackievirus B3 (CVB3)[^d^](#tfn4){ref-type=\"table-fn\"} ([@B30], [@B31])\n Vaccinia virus (VV) ([@B9], [@B10], [@B32]) \n Marek's disease virus (MDV)[^b^](#tfn2){ref-type=\"table-fn\"} ([@B33] --[@B35]) \n Hepatitis B virus (HBV) ([@B36]) \n Vesicular stomatitis virus (VSV) ([@B11]) \n Japanese encephalitis virus (JEV) ([@B12]) \n Dengue virus (DENV) ([@B13], [@B37]--[@B41]) \n West Nile virus (WNV) ([@B42]) \n Sindbis virus (SINV) ([@B43]) \n Reovirus (T3A strain) ([@B44]) \n Coxsackievirus B3 and B4 (CVB3, CVB4) ([@B14]--[@B17], [@B91]) \n **Detrimental to host** **Immunopathologic** Influenza ([@B45]--[@B55]) **Immunopathologic** SARS-CoV ([@B56], [@B57])\n HSV-1 ([@B58]--[@B60]) Murine γ-herpesvirus-68 (MHV-68)[^e^](#tfn5){ref-type=\"table-fn\"} ([@B61] --[@B63])\n Feline immunodeficiency virus ([@B64], [@B65]) \n **Promotes viral persistence** Cytomegalovirus (CMV)[^c^](#tfn3){ref-type=\"table-fn\"} ([@B66]) **Promotes viral persistence** LCMV clone 13 ([@B67])\n rJ2.2 strain of mouse hepatitis virus (neurotropic coronavirus) ([@B68]) Ross River virus (RRV), chikungunya virus (CHIKV) ([@B69])\n Marek's disease virus (MDV)[^f^](#tfn6){ref-type=\"table-fn\"} ([@B35])\n Lymphocytic choriomeningitis virus (LCMV) clone 13 ([@B70]) Hepatitis C virus (HCV) ([@B71])\n Human immunodeficiency virus (HIV) ([@B72]--[@B77])\n Hepatitis B virus (HBV) ([@B78]--[@B80])\n Influenza ([@B81], [@B82])\n Human papillomavirus (HPV)[^g^](#tfn7){ref-type=\"table-fn\"} ([@B83])\n\n*^a^HCMV, *in vitro*; MCMV, in 129/Sv/Ev x C57BL/6 F1 mice*.",
"\n\n*^b^For resistant chickens*.",
"\n\n*^c^MCMV, in BALB/c mice*.",
"\n\n*^d^In female BALB/c mice*.",
"\n\n*^e^In *Ifngr*^ −/−^ mice*.",
"\n\n*^f^For susceptible chickens*.",
"\n\n*^g^Mouse model of HPV-induced cancer*.",
"\n\nIn initial studies *in vitro*, inhibition of EV, VV, and HSV-1 replication in mouse RAW 264.7 macrophages and in primary mouse macrophages following IFN-γ treatment was shown to be largely dependent on NO production ([@B9], [@B10]). ",
"Additionally, pharmacologic inhibition of NOS or genetic deletion of *Nos2* resulted in increased viral titers and mortality following EV infection in mice ([@B9], [@B18]). ",
"Moreover, NO affects several events in the late stages of the life cycle of VV, including viral DNA replication, viral protein synthesis, and virion maturation *in vitro* ([@B32]). ",
"These studies provided some of the first evidence that macrophage-produced NO has direct antiviral effects.",
"\n\nIn addition to inhibiting HSV-1 replication *in vitro*, macrophage-derived NO has been shown to have anti-HSV properties *in vivo*. ",
"In a mouse model of HSV-1-mediated corneal disease, iNOS was highly induced in the trigeminal ganglion (TG) of HSV-1-infected mice, and its expression was markedly reduced in mice depleted of macrophages ([@B22]). ",
"Depletion of macrophages prior to HSV-1 infection resulted in markedly reduced iNOS expression and higher viral loads in the TG of infected mice ([@B22], [@B23]), suggesting that macrophages were the main source of iNOS expression in the affected tissues following HSV-1 infection and that NO had important anti-HSV-1 properties *in vivo*. ",
"Consistent with these data, inhibition of NOS activity resulted in increased viral loads in the TG ([@B22]). ",
"Additional studies showed that F4/80^+^GR-1^+^ inflammatory monocytes were recruited to the eye via an IFN-α-driven CCL2 gradient and restricted HSV-1 replication in that tissue via NO production ([@B24]). ",
"It was further shown that NO production by F4/80^+^ macrophages in the brains of HSV-1-infected mice blocked viral replication in a partially TLR2- and TLR9-dependent mechanism ([@B25]). ",
"Finally, following footpad inoculation, HSV-1-infected *Nos2*^−/−^ mice displayed a delayed clearance of virus from the dorsal root ganglia (DRG) and exhibited an increase in the frequency of virus reactivation in DRG ([@B26]).",
"\n\nThe reactivity of NO and its higher oxides and nitrosothiol products ([@B84]) makes it likely that a variety of molecular targets are involved in its antiviral action. ",
"It has been shown that NO can inhibit ribonucleotide reductase ([@B85], [@B86]), a rate-limiting enzyme in DNA synthesis, and NO can lead to the deamination of mammalian and bacterial DNA ([@B87], [@B88]), which may be important antiviral mechanisms. ",
"Indeed, HSV-1 encodes its own ribonucleotide reductase and although it is not required for HSV-1 replication *in vitro*, it is necessary under conditions where the intracellular pool of deoxynucleotides is limited ([@B89], [@B90]). ",
"Thus, by inactivating this cellular and/or viral enzyme, NO may halt virus replication by directly inhibiting viral DNA synthesis.",
"\n\nIn addition to HSV-1, treatment of primary human cells with an NO donor following infection with human cytomegalovirus (HCMV), a beta-herpesvirus, resulted in a significant reduction of early and late viral protein expression ([@B28]). ",
"Consistent with these *in vitro* data, *Nos2*^−/−^ mice (129/Sv/Ev x C57BL/6 F1) exhibited increased viral titers and mortality following infection with murine CMV (MCMV; Smith VR194 strain) ([@B29]).",
"\n\nNitric oxide has also been shown to have antiviral properties on a chicken herpesvirus, Marek's disease virus (MDV), which can cause T cell lymphomas in chickens: Addition of NO-generating compounds inhibited viral replication in chicken fibroblasts ([@B33]). ",
"Additionally, the treatment of chickens with an inhibitor of iNOS increased the level of MDV replication *in vivo* ([@B34]). ",
"Further studies demonstrated that NO production was limited to chickens that were genetically resistant to tumor development following MDV infection or to chickens that were vaccinated before being inoculated with MDV ([@B35]). ",
"Thus, NO appeared to be produced in both types of resistance to tumor development in Marek's disease, either acquired after vaccination or genetic. ",
"Together, these findings suggest a role of NO in the protective immune mechanisms against Marek's disease, possibly through its activity on viral replication.",
"\n\nFinally, studies with HBV, a hepadnavirus associated with acute and chronic hepatitis, demonstrated that HBV replicated to higher levels in the livers of HBV-transgenic *Nos2*^−/−^ mice than control transgenic mice, and transgenic *Nos2*^−/−^ mice had increased liver disease ([@B36]). ",
"It was further demonstrated that NO production by mononuclear cells, most likely macrophages, in the liver mediated most of the antiviral activity resulting from IFN-γ production by virus-specific T cells ([@B36]), suggesting an antiviral role for macrophage-derived NO following HBV infection in mice.",
"\n\nIn addition to DNA viruses, macrophage-derived NO also exerts antiviral effects against a number of RNA viruses. ",
"Inhibition of JEV, a mosquito-transmitted flavivirus that causes encephalitis in humans, in IFN-γ-activated RAW 264.7 macrophages *in vitro* correlated with NO production, and IFN-γ-activated RAW 264.7 macrophage-mediated inhibition of JEV replication in murine neuroblastoma N18 cells was NO-dependent ([@B12]). ",
"Moreover, inhibition of NOS activity led to increased mortality in JEV-infected mice ([@B12]).",
"\n\nIn terms of its mechanism of action, NO was found to inhibit JEV RNA synthesis, viral protein accumulation, and virus release from infected cells *in vitro* ([@B12]). ",
"These data suggest that NO may be directly or indirectly inhibiting viral enzymes and/or other cellular components required for viral replication, and this may subsequently block viral protein synthesis. ",
"Additionally, NO may interfere with the release and/or maturation of virions.",
"\n\nMonocyte/macrophage-derived NO may also block replication of DENV, another mosquito-transmitted flavivirus. ",
"Infection with DENV resulted in increased levels of NO in patients with dengue fever, the classic form of the disease ([@B37]). ",
"Additionally, iNOS expression was induced in CD14^+^ monocytes from a subset of acutely infected individuals ([@B13]). ",
"It was further shown that *ex vivo* infection of human monocytes with DENV-1 resulted in increased iNOS expression, and inhibition of iNOS activity led to increased DENV antigen detection in these cells ([@B13]). ",
"Moreover, treatment of C6/36 mosquito cells with an NO donor resulted in reduced DENV-positive cells ([@B13]). ",
"These data suggest that DENV replication is susceptible to NO-mediated inhibition. ",
"Consistent with this, *Nos2*^−/−^ mice were shown to be more susceptible to DENV infection, resulting in more severe disease and increased lethality in mouse models of DENV-2 and DENV-3 infection ([@B38], [@B39]). ",
"It was further demonstrated that, following DENV infection *in vivo*, IL-12 and IL-18 induced IFN-γ production, resulting in iNOS expression and NO production, which contributed to viral control ([@B38], [@B39]).",
"\n\nIn addition to monocyte/macrophage-derived NO, a recent study demonstrated that platelets isolated from patients with dengue fever had increased [l]{.smallcaps}-arginine transport and increased NO production compared to platelets from healthy controls ([@B40]). ",
"However, NO has anti-aggregatory properties, and Mendes-Ribeiro et al. ([",
"@B40]) found that dengue patients exhibited decreased collagen-induced platelet aggregation, consistent with the vascular leak and hemorrhagic manifestations of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), thus establishing an association between reduced platelet aggregation, enhancement of the [l]{.smallcaps}-arginine--NO pathway, and DHF/DSS ([@B41]).",
"\n\nIn contrast, Getts and colleagues showed that experimentally abrogating NO activity during West Nile virus (WNV) encephalitis, a related flavivirus, in NO-competent mice at a specific, relatively late time point prolonged survival of infected mice, while pharmacological inactivation throughout disease did not ([@B42]). ",
"Combined, these data suggest that although during DENV infection IFN-γ-induced NO production has a role in antiviral defense, it is likely that dysregulation of the IL-12/18--IFN-γ--NO axis leads to immune-mediated damage in certain flavivirus infections. ",
"Along these lines, it has also been shown that treatment of mice with a NOS inhibitor increased mortality rates following Sindbis virus (SINV) infection ([@B43]), suggesting a protective role for NO during this particular CNS infection. ",
"However, SINV replication in the brain was unaffected. ",
"Furthermore, treatment of neuroblastoma cells with NO donors had little effect on SINV replication but increased cell viability ([@B43]). ",
"These data suggest that NO protects mice from fatal SINV-induced encephalitis by a distinct mechanism that does not directly involve the inhibition of virus growth but rather may enhance survival of the infected neuron until the immune response can control virus replication.",
"\n\nNitric oxide also plays an antiviral role during CNS infection with reovirus. ",
"Infection of neonatal mice with the prototypic neurotropic reovirus strain (T3A) induced iNOS expression in brain areas demonstrating reovirus antigen expression and associated virus-induced injury ([@B44]). ",
"Reovirus also induced iNOS expression following *in vitro* infection of primary neuronal and glial cultures. ",
"Reovirus was shown to infect a subpopulation of microglial cells *in vitro* ([@B44]), suggesting that direct virus interaction may induce iNOS in this specialized population of macrophages. ",
"Treatment of neuronal cultures with an NO donor inhibited viral replication whereas a NOS inhibitor increased viral growth ([@B44]), suggesting iNOS has the potential to exert antiviral activity *in vivo*.",
"\n\nFinally, coxsackievirus infection has been shown to induce expression of iNOS in macrophages infiltrating the hearts of infected mice ([@B17]). ",
"Treatment of WT mice with a NOS inhibitor and infection of *Nos2*^−/−^ mice resulted in more severe coxsackievirus-induced pancreatitis and myocarditis, elevated viral loads in tissues, and decreased survival compared to WT mice following coxsackievirus B3 (CVB3) infection ([@B14], [@B15], [@B17]). ",
"Similarly, *Nos2*^−/−^ mice infected with coxsackievirus B4 exhibited decreased survival and delayed viral clearance compared to WT mice ([@B16]). ",
"These data suggest an antiviral effect of NO against coxsackievirus infection. ",
"Consistent with this, it was demonstrated that NO inhibits the 2A and 3C proteinases of CVB3 *in vitro* ([@B91]). ",
"Additionally, CVB3-infected outbred mice showed significantly reduced signs of myocarditis after treatment with NO donors ([@B91]).",
"\n\nNO Production Can be Detrimental to Host {#S3}\n========================================\n\nMyeloid cell production of NO can be immunopathologic during virus infections {#S3-1}\n-----------------------------------------------------------------------------\n\nDespite its protective capacity during some viral infections, NO can also contribute to immunopathology. ",
"The pathological effects of NO are likely due, at least in part, to oxidative damage caused by the interaction of NO with oxygen radicals such as the superoxide anion radical $\\left( O_{2}^{-} \\right)$ and hydrogen peroxide (H~2~O~2~).",
"\n\nFor example, although addition of an NO donor to virus-infected MDCK cells reduced influenza A and B viral burden *in vitro* ([@B45]), treatment of mice with inhaled NO (iNO) did not decrease the viral load of influenza A (mouse-adapted H1N1 strain)-infected mice; in fact, prophylactic treatment with iNO resulted in enhanced weight loss and decreased survival following infection ([@B46]), suggesting a pathogenic role for NO. ",
"Consistent with this, chickens, which show a high level of mortality and associated pathology following avian influenza infection, had higher levels of iNOS expression in the lungs compared with H5N1 influenza-infected ducks, which show relatively minor symptoms following influenza infection ([@B47]). ",
"Additionally, Akaike and colleagues ([@B48]) found evidence of the production of peroxynitrite, which is generated through the reaction of NO and O~2~^--^, in the lungs of influenza A (mouse-adapted H2N2 strain)-infected mice. ",
"Moreover, inhibition of NOS resulted in enhanced survival and decreased pneumonia, but not decreased viral loads, in influenza-infected mice ([@B48], [@B49]), suggesting that NO was contributing to pathogenesis rather than having direct antiviral effects. *",
"Nos2*^−/−^ mice also survived a lethal dose of influenza A virus (PR/8/34 strain) infection with little histopathologic evidence of pneumonitis; however, in these studies no infectious virus was detected in *Nos2*^−/−^ mice at day 6 after infection ([@B49]). ",
"The enhanced viral control in *Nos2*^−/−^ mice was shown to require the activity of IFN-γ ([@B51]), with *Nos2*^−/−^ mice also producing increased virus-specific IgG2a antibody titers ([@B50]). ",
"Additionally, genetic deletion of *Nos2* or pharmacologic inhibition of NOS enhanced survival of mice inoculated with the highly pathogenic (non-mouse-adapted) 1918 influenza virus strain, although mice exhibited similar viral loads to control mice in lung tissue at the peak of viral replication ([@B51]). ",
"Influenza infection *in vitro* was shown to induce apoptosis, and a reduction in influenza-mediated apoptosis was noted in cells treated with a NOS inhibitor ([@B52]). ",
"Similarly, fewer apoptotic cells were found in the lungs of influenza-infected *Nos2*^−/−^ mice, suggesting that NO mediates cell death following influenza infection ([@B52]). ",
"The cellular source of iNOS/NO following influenza infection in mice was shown to be CCR2^+^ inflammatory monocytes that accumulate in the lungs: CCR2^−/−^ mice survived a lethal challenge of influenza infection (PR/8/34 strain) and had significantly reduced accumulation of iNOS-expressing macrophages in the lung, with no associated increase in viral titers or dissemination ([@B53]).",
"\n\nIt was also recently shown that a subset of monocyte-derived dendritic cells (DCs), described as TNF-α/iNOS-producing DCs (tipDCs), accumulate in greater numbers during the course of lethal versus sublethal influenza infections, suggesting a pathogenic role for this subpopulation of myeloid cells ([@B54]). ",
"Interestingly, though, Aldridge et al. ([",
"@B54]) found that the tipDCs also stimulated a local, protective CD8^+^ T cell response in the virus-infected respiratory tract, indicating both protective and pathogenic roles for these cells in influenza infection. ",
"It was further shown that partially compromising tipDC recruitment via treatment with pioglitazone, a synthetic agonist of the peroxisome proliferator-activated receptor-γ (PPAR-γ), was protective against lethal influenza challenge ([@B54]). ",
"Pioglitazone treatment led to a reduction in the levels of CCL2 (MCP-1) and MCP-3 in the BAL fluid of influenza-infected mice ([@B54]). ",
"Pioglitazone has also been shown to reduce the production of a wide range of proinflammatory molecules, including iNOS ([@B55]), providing further evidence for the importance of NO production by monocyte-derived cells in the pathogenesis of influenza infection.",
"\n\nPharmacologic inhibition of NOS using [l]{.smallcaps}-NMMA also decreased pneumonitis and increased survival following intranasal infection of CBA/J mice with HSV-1, despite a 17-fold increase in viral titers in the lung at day 3 after inoculation ([@B58]). ",
"In contrast, treatment of BALB/c mice with a different NOS inhibitor \\[aminoguanidine (AG), administered intranasally\\] resulted in enhanced pneumonitis, viral titers, and mortality following infection with a different strain of HSV-1 ([@B59]). ",
"Thus, the precise role of NO in HSV-1 pneumonitis remains to be determined. ",
"NO and other ROS/RNS were also shown to be pathogenic in the brains of mice with herpes encephalitis: iNOS was induced in CD11b^+^ resident microglia following intranasal infection with HSV-1, and oxidative and nitrative damage was found in the brains of infected animals ([@B60]).",
"\n\nA common neurological complication of HIV infection in the developed world is sensory neuronal injury accompanied by inflammation, which is clinically manifested as disabling pain and gait instability. ",
"Feline immunodeficiency virus (FIV) infection of cats, which causes similar neuroinflammation together with immunosuppression in cats, resulted in induction of iNOS and STAT-1, which were predominantly produced by macrophages, in DRG ([@B64]). ",
"Additionally, inhibition of NOS resulted in reduced nitrotyrosine and prevented neuronal injury in FIV-infected DRG cultures *in vitro* ([@B64]). ",
"These data suggest that lentivirus infection contributes to axonal and neuronal injury through a mechanism involving M1 macrophage immune activation mediated by STAT-1 and iNOS activation. ",
"In addition to these studies, infection of mice with the retrovirus LP-BM5, which causes profound immunodeficiency, induces CD11b^+^GR-1^+^Ly-6C^+^ MDSC-like cells that inhibit both T- and B-cell responses in an iNOS/NO-dependent but arginase-independent fashion ([@B65]). ",
"This study identified an important -- and only recently appreciated -- role for iNOS-expressing myeloid cell-mediated suppression of B cell responses in retrovirus infection.",
"\n\nMyeloid cell production of NO can inhibit viral clearance {#S3-2}\n---------------------------------------------------------\n\nThe oxidative effects of NO have also been shown to inhibit immune cells, particularly T cells. ",
"This phenomenon has been appreciated for a number of years in the context of tumors ([@B92]), where myeloid suppressor cells can inhibit the anti-tumor T cell response via the effects of NO in addition to other mechanisms ([@B2], [@B4]). ",
"In a similar manner, it has been shown that NO can inhibit the antiviral immune response.",
"\n\nMCMV clearance from BALB/c mice is predominantly CD8^+^ T cell-mediated. ",
"A recent report showed that MCMV infection in BALB/c mice induced CD11b^+^Ly-6C^hi^ inflammatory monocyte recruitment from the bone marrow to infected tissues that was dependent on CCR2 signaling ([@B66]). ",
"This recruitment was shown to inhibit antigen-specific CD8^+^ T cell activation, expansion, and cytotoxic activity via NO production, thus facilitating viral persistence ([@B66]).",
"\n\nIn a similar fashion, NO may contribute to a defective immune response following infection of mice with an attenuated neurotropic coronavirus (rJ2.2 strain of mouse hepatitis virus). ",
"rJ2.2-infected WT mice exhibited mild acute encephalitis, followed by a non-lethal, chronic demyelinating disease ([@B68]). ",
"In marked contrast, rJ2.2 infection of mice that transgenically express CCL2 in the brain (CCL2 Tg) ineffectively cleared virus and rapidly succumbed to the infection ([@B68]). ",
"CCL2 Tg mice mounted a dysregulated immune response, characterized by increased accumulation of iNOS-expressing macrophages and microglia as well as regulatory T cells, but decreased Arg1 expression ([@B68]). ",
"These data suggest that persistent CCL2 overexpression establishes and sustains an immunological milieu that may predispose mice to a defective immune response to a typically minimally virulent virus.",
"\n\nArginase Activity Can be Beneficial for Tissue Repair Following Virus Infection {#S4}\n===============================================================================\n\nArginase activity is important for wound healing and tissue regeneration through the production of polyamines and proline ([@B2]). ",
"In the context of some viral infections, arginase activity and M2 macrophage activation have been shown to be beneficial for tissue repair following virus-induced damage. ",
"For instance, resolution of severe respiratory syncytial virus (RSV)-induced bronchiolitis in mice is mediated by M2 macrophages that counteract cyclooxygenase (COX)-2-induced lung pathology ([@B19], [@B20]). ",
"Arg1 was induced in the lungs of RSV-infected mice, and its induction was shown to be IL-4Rα-dependent ([@B19]). ",
"Additionally, WT macrophages adoptively transferred into RSV-infected IL-4Rα^−/−^ mice restored the M2 phenotype in the lungs and decreased lung pathology ([@B19]). ",
"It was further shown that the lipoxogenase pathway was important for M2 macrophage activation and lung resolution following RSV infection ([@B20]). ",
"Most recently it was demonstrated that treating mice with agents that sustain Arg1 expression (e.g., IL-4/anti-IL-4 immune complexes) limited RSV-induced lung pathology ([@B21]).",
"\n\nConsistent with a pathogenic role for iNOS/NO following influenza infection (described above), it was recently shown that the presence of airway bacteria polarize alveolar macrophages into a M2 phenotype, thus limiting influenza-mediated lethal lung inflammation. ",
"Wang and colleagues ([@B27]) demonstrated that priming with *Staphylococcus aureus*, which commonly colonizes the upper respiratory mucosa, attenuated influenza-mediated lung injury via TLR2 signaling that recruited peripheral CCR2^+^CD11b^+^ monocytes into the alveoli ([@B27]). ",
"These monocytes polarized alveolar macrophages into a M2 phenotype characterized by high Arg1 as well as Ym1, FIZZ1, and IL-10 expression ([@B27]). ",
"It was further shown that *S. aureus*-primed M2 alveolar macrophages inhibited inflammatory cell recruitment to the lung, including neutrophils, NK cells, and CD8 T cells ([@B27]). *",
"S. aureus*-primed M2 alveolar macrophages also expressed higher levels of the inhibitory ligand PD-L1 ([@B27]), suggesting that expression of a combination of anti-inflammatory cytokines and inhibitory ligands could be the mechanisms by which *S. aureus*-primed M2 alveolar macrophages limit influenza-mediated lung inflammation.",
"\n\nAs discussed above, coxsackievirus B3 (CVB3) infection causes myocarditis in human beings as well as in male BALB/c mice. ",
"Although female mice do not develop severe myocarditis, both male and female mice have comparable numbers of infiltrating macrophages and viral titers in the heart following CVB3 infection ([@B30]). ",
"The macrophages infiltrating the heart in male mice were skewed toward a M1 phenotype characterized by high expression of iNOS ([@B17]) as well as M1-associated cytokines such as IFN-γ and IL-12 ([@B30]). ",
"Additionally, inhibition of NOS resulted in increased viral titers and higher mortality in CVB3-infected mice ([@B17]), consistent with an antiviral role for NO during CVB3 infection (see above). ",
"However, in contrast to male mice, the heart-infiltrating macrophages in female mice were skewed toward a M2 phenotype characterized by high expression of Arg1 as well as IL-4 and IL-10 ([@B30]). ",
"Moreover, adoptive transfer of *ex vivo*-programed M1 macrophages significantly increased myocarditis in both male and female mice. ",
"Strikingly, transfer of M2-programed macrophages into susceptible male mice alleviated myocardial inflammation by modulating the local cytokine profile from a M1 to M2 phenotype and promoting peripheral regulatory T cell (Treg) differentiation ([@B30]). ",
"Using different variants of CVB3, one that caused myocarditis in C57BL/6 mice and one that did not, it was additionally shown that the myocarditic variant induced a M1 macrophage phenotype ([@B31]). ",
"In contrast, the amyocarditic variant induced a M2 macrophage phenotype, which was also associated with the activation of NKT cells that promoted a Treg response ([@B31]). ",
"The ability of NKT cells to suppress myocarditis was shown by adoptive transfer of purified NKT cells into NKT knockout (Jα18 knockout) mice infected with the myocarditic CVB3 variant, which inhibited cardiac inflammation and increased Treg response ([@B31]). ",
"Cardiac virus titers were equivalent in all mouse strains indicating that NKT cells did not participate in control of virus infection ([@B31]). ",
"Thus, although NO appears to have antiviral properties against CVB3, these data indicate an important role for Arg1-expressing M2 macrophages in controlling CVB3-induced myocarditis.",
"\n\nArginase Activity Can Promote Viral Persistence and/or Exacerbated Immunopathology {#S5}\n==================================================================================\n\nArginase activity can inhibit viral clearance {#S5-3}\n---------------------------------------------\n\nAs a consequence of their co-evolution with their hosts, viruses have developed numerous strategies to evade the host immune system and ensure their own replication and survival. ",
"Recent studies have identified a new evasion strategy for viruses: exploitation of the host's anti-inflammatory, wound repair response to promote chronic infection.",
"\n\nTwo strains of LCMV -- Armstrong (Arm) and clone 13 (C13) -- have been studied for decades as models for acute and chronic infections ([@B93]). ",
"Infection of mice with the Arm strain leads to a robust CD8^+^ T cell response that rapidly clears the virus ([@B94]), whereas infection with C13 results in T cells with impaired functionality, enabling the virus to persist ([@B95]). ",
"It was recently demonstrated that C13 infection led to an enhanced and sustained expansion of cells that resembled MDSCs ([@B70]). ",
"These suppressive myeloid cells inhibited T cell proliferation *ex vivo* via an iNOS/NO-dependent but Arg1-independent mechanism. ",
"Another study, however, found that Arg1-expressing immunoregulatory antigen presenting cells induced during C13 infection suppressed T cell responses ([@B67]). ",
"Most recently, it was demonstrated that T cell responses were improved -- resulting in clearance of the normally chronic C13 infection -- when either myeloid cells or T cells lacked IL-10 production ([@B96]). ",
"Overall, these data demonstrate the importance of iNOS/Arg1-expressing myeloid cells in viral persistence.",
"\n\nSimilar to LCMV C13 infection, it was recently demonstrated that infection of mice with the arthritogenic alphaviruses Ross River virus (RRV) and chikungunya virus (CHIKV) resulted in the induction of Arg1 in macrophages in the infected and inflamed musculoskeletal tissues ([@B69]). ",
"It was further shown that genetic deletion of myeloid cell *Arg1* resulted in enhanced viral control in inflamed muscle tissue and reduced tissue pathology following RRV infection in mice ([@B69]), suggesting an important role for Arg1-expressing macrophages in the persistence of these chronic viruses.",
"\n\nInfection of mice with Theiler's murine encephalomyelitis virus (TMEV) results in persistent virus infection in the CNS, which contributes to the development of a demyelinating disease that has similarities with multiple sclerosis. ",
"Bowen and Olson ([@B97]) showed that CD11b^+^Ly-6C^+^ cells infiltrated the CNS following infection and were the dominant cell type during the innate immune response. ",
"Depletion of the CD11b^+^Ly-6C^+^ cells via administration of an anti-GR-1 Ab resulted in reduced development of demyelinating disease and enhanced virus-specific CD4^+^ and CD8^+^ T cell responses ([@B97]). ",
"Additionally, TMEV-infected, anti-GR-1 Ab-treated mice had decreased myelin-specific CD4^+^ T cell responses compared to control Ab-treated mice during the demyelinating disease at a later time post-infection ([@B97]). ",
"Although the expression of Arg1 was not investigated in this study, TMEV-infected mice had elevated expression of IL-10 in the brain and spinal cord ([@B97]), suggesting a role for this cytokine in the suppression of antiviral T cell responses, potentially through the effects of Arg1.",
"\n\nInterestingly, a role for the modulation of arginine metabolism in viral control versus persistence along with associated disease has recently been demonstrated for the tumor-inducing, chicken-specific herpesvirus MDV. ",
"We mentioned above that MDV was vulnerable to the antiviral properties of NO, with iNOS being induced in genetically resistant chickens and in vaccinated chickens ([@B35]). ",
"In contrast, MDV induced strong macrophage arginase activity in cell extracts from adherent monocytes from genetically susceptible chickens, but not in chickens that were resistant to Marek's disease, either genetically or acquired after vaccination ([@B35]). ",
"Together, these data suggest that in the case of Marek's disease, the state of resistance versus sensitivity to disease was correlated with a reciprocal balance of NOS versus arginase activities in macrophages.",
"\n\nThis phenomenon of Arg1-mediated T cell suppression has also been recognized in human viral infections. ",
"Arg1 mRNA and protein levels were elevated in HCV-infected liver cell lines *in vitro* and in HCV-infected liver samples compared with paired hepatocellular carcinoma samples from the same patients or with uninfected liver tissues ([@B71]). ",
"Additionally, the number of MDSCs in chronic HCV patients correlated with levels of plasma HCV-RNA ([@B98]). ",
"Cai et al. ([",
"@B98]) also found that MDSCs from patients with chronic HCV infection suppressed T cell function via an Arg1-dependent mechanism. ",
"An additional study found that more PBMCs from chronic HCV patients expressed the phenotypic markers of MDSCs than PBMCs from healthy controls, and these cells expressed increased levels of p47^phox^, a component of the NADPH oxidase complex ([@B99]), suggesting a role for ROS in MDSC-mediated suppression. ",
"Consistent with this, CD33^+^ mononuclear cells co-cultured with HCV-infected hepatocytes or HCV core protein suppressed T cell proliferation in a ROS-dependent manner ([@B99]). ",
"Overall, these data suggest that multiple mechanisms -- including arginine metabolism and ROS -- may be at play in myeloid cell-mediated suppression of anti-HCV T cell responses.",
"\n\nIt has been suggested that prolonged immune activation during chronic virus infections, such as HCV and HIV, provides an environment that drives viral replication and disease progression ([@B100], [@B101]). ",
"Moreover, immune activation can drive an anti-inflammatory response to limit immunopathology, which can be characterized by the presence of M2-like macrophages. ",
"Indeed, similar to HCV infection, a role for arginase and M2-polarized MDSC-like cells has been identified in the suppression of antiviral T cell responses following HIV infection. ",
"Individuals with detectable HIV-1 infection showed an increase in the frequency of CD163^+^CD16^+^CD14^+^ monocytes, which are thought to be precursors of M2 macrophages, when compared to seronegative or HIV-1-infected persons with undetectable viral loads, and monocyte frequency correlated positively with HIV-1 viremia and negatively with CD4^+^ T cell counts (in patients with counts \\<450 cells/μl) ([@B72]). ",
"Furthermore, Qin and colleagues ([@B73]) observed elevated levels of MDSCs, defined as HLA-DR^−/low^ CD11b^+^CD33^+/high^CD14^+^CD15^−^cells, in the peripheral blood of HIV-1-seropositive subjects compared with healthy controls, and these MDSCs suppressed T cell responses in an Arg1-dependent manner. ",
"Moreover, PBMCs from HIV-seropositive patients exhibited increased levels of arginase activity ([@B73]). ",
"Cloke and colleagues ([@B74]) found that increased arginase activity correlated with lower CD4^+^ T cell counts, and this association was abrogated following antiretroviral treatment ([@B75]). ",
"Additionally, exposure of PBMCs to HIV gp120 expanded T cell-suppressive MDSCs *in vitro* ([@B76]). ",
"These data point to a direct role for arginase-expressing MDSC-like cells in the suppression of anti-HIV T cell responses. ",
"Consistent with that, individuals co-infected with HIV and *Leishmania* parasites had increased arginase activity in PBMCs and plasma compared with *Leishmania*-only infected individuals, even though *Leishmania* infection alone results in increased arginase activity ([@B77]). ",
"In addition, the parasite load in the spleen was significantly higher in co-infected patients ([@B77]). ",
"The arginase-expressing cells were identified as low-density granulocytes ([@B77]). ",
"These results suggest that increased arginase might contribute to the poor immune responses and disease outcome characteristic of patients with *Leishmania* and HIV co-infection.",
"\n\nHepatitis B virus (HBV) infection is another common chronic viral infection, with estimates as high as 350 million chronically infected humans ([@B102]). ",
"Bility and colleagues ([@B78]) recently developed a humanized mouse model with both a human immune system and human liver cells, named the A2/NSG-hu HSC/Hep humanized mouse model, to study the pathogenesis of HBV infection. ",
"Following HBV infection, the mice developed persistent HBV infection as well as chronic hepatitis and liver fibrosis ([@B78]). ",
"The liver disease was associated with a high level of infiltrating human macrophages with a M2-like activation phenotype ([@B78]). ",
"Similarly, M2-like macrophage accumulation was seen in chronic HBV-infected patients, and M2-like macrophage induction in the liver was associated with accelerated liver fibrosis and necrosis in patients with acute HBV-induced liver failure ([@B78]), suggesting a role for M2 macrophages in persistent HBV infection. ",
"Additionally, patients with acute HBV infection had increased serum levels of arginase, and this serum inhibited IFN-γ production by CD8^+^ T cells ([@B79]). ",
"Das et al. ([",
"@B80]) also found decreased [l]{.smallcaps}-arginine levels in the circulation of chronic HBV patients with marked liver inflammation (\\>100 ALT) and increased arginase activity in liver extracts taken directly *ex vivo* from patients with chronic HBV compared with those from patients with other types of liver pathology ([@B80]). ",
"They further showed that CD8^+^ T cells from chronic HBV patients, regardless of their antigen specificity, exhibited less IL-2 but not IFN-γ or TNF-α production and impaired proliferation following TCR-dependent stimulation, indicating an aberrant antiviral T cell response in chronic HBV infection ([@B80]). ",
"In the A2/NSG-hu HSC/Hep humanized mouse model, HBV-infected mice had impaired liver T cell responses, and M2 macrophages were associated with T cells in the liver ([@B78]). ",
"Expression of the TCR signaling molecule CD3ζ was reduced in both peripheral and intrahepatic CD8^+^ T cells from chronic HBV patients; similarly, CD28 was also downregulated on CD8^+^ T cells from high viral load HBV patients ([@B80]). ",
"Downregulation of the CD3ζ molecule has previously been shown to occur in the arginine-depleted tumor microenvironment. ",
"Consistent with this, *in vitro* transfection of CD3ζ and CD28 restored IL-2 production and supplementation of [l]{.smallcaps}-arginine partially restored CD3ζ expression and T cell proliferation ([@B80]). ",
"These data suggest a role for arginase activity and arginine depletion in the impairment of anti-HBV T cells functions.",
"\n\nIn the absence of iNKT cells, influenza A (PR/8 strain) infection was shown to induce the expansion of CD11b^+^GR-1^+^ MDSCs in the lungs of mice, which suppressed influenza-specific T cell and antibody responses through the activity of both arginase and NOS, resulting in higher viral titers and increased mortality ([@B81]). ",
"Adoptive transfer of iNKT cells reversed this phenotype; mice had an increased survival rate, reduced viral titers, and increased virus-specific immune responses, suggesting a novel immunomodulatory role for iNKT cells during influenza virus infection ([@B81]). ",
"Moreover, these authors identified that influenza infection in humans induced the expansion of CD11b^+^ myeloid cells with suppressive activity that could be reduced by iNKT cell activation or the inhibition of arginase and NOS activity. ",
"Similarly, it was recently shown that highly pathogenic H5N1 and H1N1 influenza virus infection induced the accumulation of CD11b^+^GR-1^+^ cells and the expression of Arg1 in the lungs ([@B82]), further supporting a role for M2-polarized MDSC-like cells in promoting viral persistence and immunopathology.",
"\n\nHelminth infection induces the expression of type 2 cytokines and is associated with M2 macrophage activation, as determined by Arg1, FIZZ1, and Ym1 expression. ",
"Indeed, Osborne and colleagues ([@B83]) found that Arg1, FIZZ1, and Ym1 were highly induced in the ileum of mice infected with the helminth *Trichinella spiralis* (Ts). ",
"Interestingly, they further showed that co-infection of mice with Ts and murine norovirus (MNV) resulted in decreased frequencies and numbers of MNV-specific CD8^+^ and CD4^+^ T cells within the small intestine and spleen as well as decreased polyfunctionality of these T cells, compared to Ts-only infected mice ([@B83]). ",
"Additionally, the defective T cell responses were associated with increased viral loads in the double-infected mice compared to the mono-infected controls ([@B83]), suggesting that Ts-elicited M2-activated macrophages inhibited the antiviral T cell response to MNV. ",
"Lastly, neutralization of Ym1, a chitinase-like molecule, in co-infected mice partially restored antiviral immunity and was associated with enhanced control of viral replication ([@B83]). ",
"These data point to a new mechanism by which Arg1-expressing macrophages inhibit antiviral responses.",
"\n\nCumulatively, these data are reminiscent of macrophages found in tumors (e.g., MDSCs, TAMs) that have been shown to suppress anti-tumor T cell responses via a variety of NO- and/or Arg1-dependent mechanisms ([@B4], [@B5]). ",
"Indeed, in a mouse model of human papillomavirus (HPV)-induced cancer, Arg1-expressing CD11b^+^F4/80^+^ macrophages infiltrated the tumors and inhibited T cell responses, including virus-specific T cells, by suppressing T cell proliferation and promoting a regulatory phenotype ([@B103]). ",
"Moreover, depletion of the tumor-infiltrating macrophages resulted in reduced tumor growth and increased tumor infiltration by virus-specific CD8^+^ T cells ([@B103]). ",
"Thus, increasing evidence points to a direct role for arginase-expressing M2-polarized cells in the suppression of antiviral T cell responses and the persistence of a variety of important pathogenic viruses. ",
"In addition to the actions of iNOS and Arg1, MDSC-like cells can employ other mechanisms to promote chronic viral infections, which were recently reviewed by Goh and colleagues ([@B104]).",
"\n\nM2 macrophage activation can promote immunopathology {#S5-4}\n----------------------------------------------------\n\nIn contrast to some parasitic infections where M2 macrophages limit Th2 cell-mediated immunopathology, M2-polarized macrophages have been shown to promote immunopathology in some viral infections. ",
"For example, it was recently demonstrated that SARS-CoV infection of mice induced suppressive alveolar macrophages that inhibited the induction of antiviral T cell responses, a phenotype that was reversed by the adoptive transfer of activated bone marrow-derived DCs into mice prior to virus infection ([@B56]). ",
"Additionally, SARS-CoV-infected mice lacking hematopoietic STAT-1 expression were shown to have greater weight loss and lung pathology, and this was associated with the activation of M2 macrophages ([@B57]). ",
"To further test the role of M2 macrophages in enhanced pathogenesis following SARS-CoV infection, the authors generated STAT-1/STAT-6 double knockout mice due to the established role for STAT-6 in driving M2 macrophage activation in response to IL-4/IL-13 stimulation. ",
"STAT-1/STAT-6 double knockout mice, which reversed the upregulation of M2 macrophages observed in STAT-1-deficient mice, had reduced lung disease and prefibrotic lesions ([@B57]). ",
"These data support the notion that M2 macrophages contribute to SARS-CoV pathogenesis.",
"\n\nIn another example, mice deficient in the IFN-γR exhibit more severe disease following infection with murine gamma-herpesvirus-68 (MHV-68), including interstitial and intra-alveolar fibrosis that is reminiscent of idiopathic pulmonary fibrosis (IPF) in human beings. ",
"In this model, alveolar macrophages were recruited to the lungs of MHV-68-infected IFN-γR^−/−^ mice, were associated with areas of fibrosis, and exhibited a M2-polarized phenotype characterized by the expression of FIZZ1, Ym1, and Arg1 ([@B61]). ",
"Additionally, lung tissue from patients with IPF showed increased expression of Arg1 in alveolar macrophages compared with normal lung ([@B61]). ",
"These results suggest that virus-induced upregulation of Arg1 could be mediating lung fibrogenesis. ",
"MHV-68 infection in IFN-γR^−/−^ mice also resulted in fibrosis in lymphoid tissues such as the spleen, which is a site of latent MHV-68 infection, and the liver ([@B62], [@B63]). ",
"Similar to the lung, MHV-68 infection in the absence of IFN-γR signaling induced a M2 macrophage response in the spleen, characterized by high Arg1 expression along with FIZZ1 and M2/Th2 cytokines such as IL-13, resulting in fibrotic disease in the spleen ([@B105]). ",
"Moreover, depletion of T cells prevented MHV-68-mediated fibrosis in IFN-γR^−/−^ mice ([@B62]), suggesting that M2 macrophages were further driving Th2 activation to possibly create a M2/Th2 cytokine-induced cycle, resulting in the exaggerated pathology. ",
"In contrast to IFN-γR^−/−^ mice, iNOS was induced in the spleen of MHV-68-infected WT mice ([@B105]), indicating an important role for IFN-γ in inducing a M1-associated immune response to control gamma-herpesvirus infection and limiting Arg1-mediated immunopathology.",
"\n\nConclusion {#S6}\n==========\n\nMacrophages and other myeloid cells have marked phenotypic heterogeneity, as a result of distinct cellular differentiation programs, distribution in tissues, and responsiveness to various endogenous and exogenous stimuli. ",
"Indeed, macrophages have well-established roles in development, tissue homeostasis, coordinating the adaptive immune response and inflammation, as well as directing tissue resolution and repair following damage -- processes that are often modulated via the actions of the arginine-hydrolyzing enzymes Nos2 and Arg1. ",
"We have highlighted a number of viral infections in which these enzymes have a beneficial effect: NO has antiviral properties against a variety of viruses, and arginase activity can mediate tissue repair and regeneration following a viral insult (Table [1](#T1){ref-type=\"table\"}). ",
"However, NO production can also result in immunopathology in some virus infections, and the suppressive functions of Arg1-expressing macrophages can promote immunopathology. ",
"Additionally, some viruses have exploited the immune-suppressive properties of iNOS- and/or Arg1-expressing macrophages to evade the immune response, particularly the antiviral T cell response, resulting in chronic viral infections.",
"\n\nClearly, iNOS- and/or Arg1-mediated responses are important in many viral infections. ",
"Thus, there is the potential to develop the means to selectively stimulate or inhibit either M1 or M2 responses to mediate viral clearance or repair tissue damage. ",
"Due to the overlap in immunosuppressive mechanisms of iNOS- and/or Arg1-expressing suppressor cells, therapeutic strategies under development to limit the immunosuppressive effects of myeloid cells in cancer may be beneficial in treating persistent/chronic virus infections. ",
"However, as described above, iNOS and Arg1 activity can be both beneficial and detrimental during certain viral infections. ",
"Therefore, further research is needed to define the molecular and tissue-specific mechanism(s) by which iNOS and Arg1 influence the clearance of viral pathogens as well as the injury and repair of tissues. ",
"In addition, a better understanding of the pathways regulating macrophage polarization (specifically iNOS and/or Arg1 induction and activity), macrophage trafficking, and the precise effects of iNOS and Arg1 activity on other immune cells following different virus infections will inform the development of therapeutics that target critical effector molecules to promote viral control and limit immunopathology.",
"\n\nConflict of Interest Statement {#S7}\n==============================\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.",
"\n\nWork in Dr. Morrison's laboratory is supported by NIH-NIAID grants U19 AI109680 and R01 AI108725. ",
"Kristina S. Burrack was supported by NIH-NIAID training grant T32 AI052066.",
"\n\n[^1]: Edited by: Charles Dudley Mills, BioMedical Consultants, USA\n\n[^2]: Reviewed by: Masaaki Murakami, Hokkaido University, Japan; Mayda Gursel, Middle East Technical University, Turkey\n\n[^3]: This article was submitted to Antigen Presenting Cell Biology, a section of the journal Frontiers in Immunology.",
"\n"
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"Caricature Artist Entertainment\n\nServing Miami-Dade, Broward, and Palm Beach Counties\n\nPlanning a party or special event?",
"\n\nKeep your guests laughing from the moment they arrive! ",
"Caricatures are a great way to introduce everybody and give them something to talk about. ",
"People of all ages love to watch funny drawings of their friends and family appear before their eyes! ",
"Plus, when the party is over, they will leave with a unique gift and an experience they will always remember!"
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"Q:\n\nHow to set application independent parameters like server addedress in android\n\nI need a solution for the really common but important issue that i am thinking of.",
"\nI have created application in which i have hard coded my server address in /res/values/strings.xml file. ",
"Suppose if my server address changes run-time due to some reasons, then i have to make changes in the file and then i have to recompile it.",
"\nSo is there any way that i put my server address out of my application.. So we do not have to recomplie the application. ",
"Instead of it, it will read new server address from out side and resume its normal work...\nAny type of related suggestions,links,blogs appreciated..\n\nA:\n\nI got the answer by reading this blog. ",
"\nWhich says you should use shard preferences with the activity extending PreferenceActivity.",
"\nHere you can set your server address and all the dynamic stuff that will change by the time. ",
"So that you will not have to recompile the apk. ",
"Just change the settings in shared preferences. ",
"\nRead this important bog that all app developer wants to know it.. \n\n"
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"The iPhone's dead, long live the Windows Phone. ",
"That must be the genius proclamation that incited Microsoft to celebrate Windows Phone 7 reaching RTM status with the incomprehensible procession you see above. ",
"An elaborate parade, replete with hearses and black capes, was organized last week to denote the passing of the BlackBerry and iPhone into the land of unwanted gadgets. ",
"We'd say this is done in poor taste, but we don't enjoy stating the obvious. ",
"We will, however, enjoy the fallout from this poorly judged stunt. ",
"See our favorite image after the break and lots more at the source.: ",
"Apparently the team also engaged in a Thriller dance . ",
"Words are failing us, so just hop on past the break and mash play."
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[
"Charlotte Court / former Asylum for\n\nthe Deaf and Dumb\n\nCharlotte Court, just by the Bricklayers Arms roundabout on the Old Kent Road, is an apartment building converted from the former London County Council School for the Deaf. ",
"It was built in 1886 on the site of the Asylum for the Deaf and Dumb, one of the earliest institutions for the education of deaf children. ",
"The Asylum for the Deaf and Dumb had been built in 1807-09 and founded by the Rev John Townsend of Jamaica Road Chapel, Bermondsey and the Rev Henry Cox Mason, curate of Bermondsey, and Henry Thornton, MP for Southwark. ",
"The names of the first two founders are commemorated in the names of the streets close by.",
"\n\nThe Asylum’s first home was in Grange Road, Bermondsey, which opened in 1792 when Rev. Townsend became familiar with the difficulty of a deaf child within his parish who was sent by his parents to the privately run Thomas Braidwood’s Academy for the Deaf in Edinburgh. ",
"He was struck by the boy’s keen intellect and agreed with the boy’s mother, Mrs Creasey, there was a need for a charitable institution in London for the education of the deaf. ",
"With the support of Mason and Thornton, he opened the Asylum at a time when the educational needs of the deaf were largely ignored. ",
"When the school opened there were six pupils whose number increased twice yearly as more pupils were selected by the Committee of Governors of the Asylum. ",
"Candidates were between the ages of six and twelve years of age and of “sound mind”.",
"\n\nYet the numbers on the waiting list still kept growing and it was only possible to admit half of the candidates. ",
"It was clear larger premises were required and Rev. Thornton launched a subscription for a new building. ",
"The patronage of the Duke of Gloucester was gained and he laid the foundation stone of the new building in 1807. ",
"The building was completed two years later and able to accommodate 200 pupils. ",
"The scope of the education received was to evolve from the teaching of religious instruction and a basic educational groundwork through to equipping pupils with a means by which to earn their living independently upon completion of their education. ",
"To this end, pupils received training in trades such as mechanics and design, and in some cases apprenticeships were paid for.",
"\n\nJoseph Watson, nephew of Thomas Braidwood, was engaged as a teacher in the Asylum’s early days and became its head teacher. ",
"He was unwavering in his belief that deaf and dumb pupils should be treated the same as those who were able to hear. “",
"Persons born deaf are, in fact, neither depressed below, nor raised above, the general scale of human nature, as\n\nregards their dispositions and powers, either of body or mind.” ",
"He also believed that teaching sign-language which, while facilitating communication between the deaf, increased isolation. ",
"He believed that lip-reading which used the same language common throughout the country, was to be encouraged and would aid integration.",
"\n\nIn 1875 a new school was opened in Margate where the older pupils went to be educated and, when the old asylum was demolished in 1886, the younger pupils were sent there temporarily whilst the new school was being built. ",
"At this time, a London Board School, called the Townsend Street School and still thriving, was also built on land to the rear which had previously been the Asylum’s garden. ",
"In 1902, the younger pupils were moved permanently to the school in Margate which was subsequently named the Royal School for the Deaf. ",
"It closed in 2015.",
"\n\nThe Old Kent Road school was sold to the London School Board and came under the authority of the London County Council two years later. ",
"A school for physically handicapped children was opened on the ground floor and a smaller school for deaf children on the second floor. ",
"The school survived until 1968 when a new school opened in Grove House in Elmcourt Road, Norwood which closed in 2002.",
"\n\nPlanning permission for the building in Old Kent Road for a change of use from school to residential was granted in 1994 and the building subsequently converted."
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[
"Q:\n\nprinting the number of times a element occurs in a file using regex\n\nI have a long data similar to below \n 16:24:59 0 0 0\n 16:24:59 0 1 0\n 16:25:00 0 1 0\n 16:25:00 0 1 0\n 16:25:00 0 2 0\n 16:25:00 0 2 0\n 16:25:00 1 0 1\n 16:25:01 0 0 0\n 16:25:01 0 0 0\n 16:25:01 0 0 0\n 16:25:01 0 0 0\n 16:25:01 4 9 4\n 16:25:02 0 0 0\n 16:25:02 0 0 0\n 16:25:02 0 0 0\n 16:25:02 0 1 0\n 16:25:02 1 9 1\n 16:25:02 2 0 2\n\nI wish to have a output where it prints the element in column 1, and the number of times it occurs. ",
"Below is what I expect. ",
"How can I do this?",
"\n 16:24:59 2\n 16:25:00 5\n 16:25:01 5\n 16:25:02 6\n\nHow can I replace the above to\n t1 2\n t2 5\n t3 5\n t4 6\n .",
"\n .",
"\n tn 9 \n\nA:\n\nIt's pretty straight forward using awk\nawk '{count[$1]++} END{ for ( i in count) print i, count[i]}'\n\nTest\n$ awk '{count[$1]++} END{ for ( i in count) print i, count[i]}' input\n16:24:59 2\n16:25:00 5\n16:25:01 5\n16:25:02 6\n\nWhat it does?",
"\n\ncount[$1]++ creates an associative array indexed by the first field.",
"\nEND Action performed at the end of input file.",
"\nfor ( i in count) print i, count[i] Iterate through the array count and print the values\n\n"
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