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An acidic sphingomyelinase Type C activity from Mycobacterium tuberculosis
Actividad de una esfingomielinasa ácida tipo C producida por Mycobacterium tuberculosis
Jorge Castro-Garzaa, Francisco González-Salazara,b, Frederick D. Quinnc, Russell K. Karlsc, Laura Hermila De La Garza-Salinasd, Francisco J. Guzmán-de la Garzae, Javier Vargas-Villarreala,
Corresponding author
jvargas147@yahoo.com.mx

Corresponding author.
a Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social, Monterrey, N.L., México
b Departamento de Ciencias Básicas, División de Ciencias de la Salud, Universidad de Monterrey, San Pedro Garza García, N.L., México
c Department of Infectious Diseases, University of Georgia, Athens, GA, USA
d Coordinación de Planeación y Enlace Institucional, Instituto Mexicano Del Seguro Social, Delegación Nuevo León, Monterrey, N.L., México
e Unidad de Investigación Epidemiológica y en Servicios de Salud, Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social, Monterrey, N.L., México
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Products from SMase C are ceramide and phosphorylcholine while SMase D degrades sphingomyelin to phosphoryl ceramide and choline<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">11&#44;19</span></a>&#46; Furthermore&#44; SMases are classified by their optimum pH activity and localization into &#40;a&#41; acid SMase &#40;A-SMase&#41;&#44; &#40;b&#41; secretory Zn<span class="elsevierStyleSup">2&#43;</span>-dependent SMase &#40;A-sSMase&#41;&#44; &#40;c&#41; neutral Mg<span class="elsevierStyleSup">2&#43;</span>-dependent SMase &#40;N-SMase&#41;&#44; &#40;d&#41; neutral Mg<span class="elsevierStyleSup">2&#43;</span>-independent SMase &#40;N-iSMase&#41;&#44; &#40;e&#41; alkaline SMase&#44; and &#40;f&#41; bacterial SMase-phospholipase C<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">5</span></a>&#46; Several species of bacteria&#44; viruses&#44; and even parasites infect host cells by exploiting either the A-SMase or the N-SMase-ceramide system&#44; or both<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">3&#44;6&#44;14</span></a>&#46; Alternatively&#44; it has been shown that cellular stress produces plasma secretion of A-SMases resulting in the formation of membrane-embedded&#44; ceramide-enriched lipid rafts and the reorganization of receptor complexes leading to signaling events and regulation of a cellular phenotype that protect mice in a sepsis model<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">9</span></a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Moreover&#44; several pathogenic bacteria produce SMases with direct activity on target host cells&#46; These virulence factors include <span class="elsevierStyleItalic">Clostridium perfringens</span> alpha-toxin&#44; possessing phospholipase C-SMase and biological activities causing hemolysis&#44; dermonecrosis and potentially death of the host<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">20</span></a>&#46; Inhibition of <span class="elsevierStyleItalic">Bacillus cereus</span> SMase prevented mortality in mice<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">15</span></a>&#46; Phospholipase C&#47;SMase from the opportunistic pathogen <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span> has hemolytic activity and is selectively cytotoxic to mammalian endothelial cells<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">23</span></a>&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Staphylococcus aureus</span> invades non-professional phagocytes&#44; eventually resides in acidified phago-endosomes and subsequently escapes from this compartment due to a synergistic activity of the cytolytic peptide&#44; staphylococcal &#948;-toxin and the SMase &#946;-toxin<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">4</span></a>&#46; A similar effect has been reported for the <span class="elsevierStyleItalic">C&#46; perfringens</span> SMase activity<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">25</span></a>&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">We previously reported the identification of alkaline&#44; neutral&#44; and acidic SMase activities from <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span><a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">26</span></a>&#46; In the present study&#44; we report a novel acidic mycobacterial Zn<span class="elsevierStyleSup">2&#43;</span>-dependent SMase activity&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Mycobacterial whole cell extracts</span><p id="par0030" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">M&#46; tuberculosis</span> strains H37Rv and CDC1551 were grown in Middlebroook 7H9 medium supplemented with OADC for 10 days at 37<span class="elsevierStyleHsp" style=""></span>&#176;C&#46; Cultures were harvested by centrifugation at 3000<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">g</span> for 15<span class="elsevierStyleHsp" style=""></span>min&#46; An approximate mass of 800<span class="elsevierStyleHsp" style=""></span>mg &#40;wet weight&#41; in 1<span class="elsevierStyleHsp" style=""></span>ml of PBS plus 0&#46;5<span class="elsevierStyleHsp" style=""></span>&#37; Triton X100 was gamma-irradiated for 48<span class="elsevierStyleHsp" style=""></span>h in a Gammacell 3000 equipment &#40;Elan&#44; Nordion International Inc&#44; Kanata&#44; Ontario&#44; Canada&#41;&#46; The gamma-irradiated bacteria were washed twice with PBS and resuspended in 1<span class="elsevierStyleHsp" style=""></span>ml of sodium acetate-buffer solution 100<span class="elsevierStyleHsp" style=""></span>mM pH 5&#46;5 &#40;ABS&#41; with 0&#46;5<span class="elsevierStyleHsp" style=""></span>&#37; Triton X-100 &#40;Sigma Chemical Co&#46;&#44; St&#46; Louis&#44; MO&#41; and Boehringer Manheim complete EDTA-free protease inhibitor cocktail &#40;cat&#46; No&#46; 1836-170&#41;&#46; Bacterial suspensions were disrupted with the Fast Prep System &#40;MP Biomedicals&#44; Santa Ana&#44; CA&#41; by applying 5 cycles of 1<span class="elsevierStyleHsp" style=""></span>min at setting 6&#44; with 2<span class="elsevierStyleHsp" style=""></span>min resting on ice in between runs&#46; The whole cell extracts were centrifuged twice at 16<span class="elsevierStyleHsp" style=""></span>000<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">g</span> for 8<span class="elsevierStyleHsp" style=""></span>min at room temperature&#44; to remove intact bacterial cells&#46; The preparations were divided into 200<span class="elsevierStyleHsp" style=""></span>&#956;l aliquots and stored at &#8722;70<span class="elsevierStyleHsp" style=""></span>&#176;C until used&#46; Protein quantification was done by the method proposed by Lowry et al&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">13</span></a>&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Sphingomyelinase activity</span><p id="par0035" class="elsevierStylePara elsevierViewall">The measurement of SMase was based on the method described by Vargas-Villarreal <span class="elsevierStyleItalic">et al</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">26</span></a>&#44; with minor modifications&#46; The mycobacterial whole cell extracts were the sources of enzymes for all the described experiments&#46; In brief&#44; 2&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;Ci of &#91;N-methyl-<span class="elsevierStyleSup">14</span>C&#93;-sphingomyelin &#40;47<span class="elsevierStyleHsp" style=""></span>mCi&#47;mmol&#59; PerkinElmer Life and Analytical Science&#44; Boston&#44; MA&#41; was mixed with 200<span class="elsevierStyleHsp" style=""></span>mM sodium acetate &#40;pH 5&#46;5&#41;&#44; 2<span class="elsevierStyleHsp" style=""></span>mM Zn<span class="elsevierStyleSup">2&#43;</span>&#44; 4<span class="elsevierStyleHsp" style=""></span>&#37; Triton X-100 and 0&#46;3<span class="elsevierStyleHsp" style=""></span>mM sphingomyelin&#46; The mixtures were sonicated in an Ultratip Labsonic System &#40;Lab-Line Instrument Inc&#46;&#44; Melrose Park IL&#41;&#44; applying one pulse of 40<span class="elsevierStyleHsp" style=""></span>W&#47;min&#46; The assays were performed by mixing 10<span class="elsevierStyleHsp" style=""></span>&#956;l of the substrate preparation with 10<span class="elsevierStyleHsp" style=""></span>&#956;l of whole cell extract suspension of <span class="elsevierStyleItalic">M&#46; tuberculosis</span> strain H37Rv or CDC-1551 containing 0&#8211;2<span class="elsevierStyleHsp" style=""></span>&#956;g of total protein&#46; The mixture was vortexed for 10<span class="elsevierStyleHsp" style=""></span>sec and incubated at 37<span class="elsevierStyleHsp" style=""></span>&#176;C for 60<span class="elsevierStyleHsp" style=""></span>min&#46; The reaction was stopped by adding 25<span class="elsevierStyleHsp" style=""></span>&#956;l of 1<span class="elsevierStyleHsp" style=""></span>mg&#47;ml sphingomyelin&#44; 1<span class="elsevierStyleHsp" style=""></span>mg&#47;ml phosphorylcholine and 1<span class="elsevierStyleHsp" style=""></span>mg&#47;ml choline &#40;Sigma Chemical Co&#46;&#44; St&#46; Louis&#44; MO&#41; in 5<span class="elsevierStyleHsp" style=""></span>&#37; trichloroacetic acid in n-butanol&#46; Non-digested sphingomyelin was separated from the SMase hydrolysis products &#40;phosphorylcholine and choline&#41; by thin-layer chromatography &#40;TLC&#41;&#46; The assay mixtures were applied &#40;45<span class="elsevierStyleHsp" style=""></span>&#956;l&#41; on 10<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>cm silica-gel plates &#40;0&#46;25-mm thickness&#44; 60-mesh&#59; Merck&#44; Germany&#41;&#46; The plates were placed in a TLC tank containing chloroform&#58;methanol&#58;water &#40;65&#58;25&#58;4&#44; v&#47;v&#41; as a mobile phase&#46; The tank was loaded 15<span class="elsevierStyleHsp" style=""></span>min before starting each chromatographic run with the mobile phase-vapors to saturate the internal atmosphere&#46; The spots corresponding to choline and phosphorylcholine &#40;origin&#41;&#44; and sphingomyelin &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleInf">f</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;29&#41; were developed by exposing the TLC plates to iodine vapors<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">21</span></a>&#46; To identify &#91;<span class="elsevierStyleSup">14</span>C&#93;-sphingomyelin&#44; &#91;<span class="elsevierStyleSup">14</span>C&#93;-phosphorylcholine and &#91;<span class="elsevierStyleSup">14</span>C&#93;-choline spots&#44; their respective relative migration coefficients &#40;<span class="elsevierStyleItalic">R</span><span class="elsevierStyleInf">f</span>&#41; were compared with those of their corresponding non-radioactive standards &#40;Sigma Chemical Co&#46;&#44; St&#46; Louis&#44; Mo&#46;&#41; obtained in the same run&#46; The two spots corresponding to &#91;<span class="elsevierStyleSup">14</span>C&#93;-sphingomyelin&#44; and &#91;<span class="elsevierStyleSup">14</span>C&#93;-phosphorylcholine and &#91;<span class="elsevierStyleSup">14</span>C&#93;-choline mixed were scraped from the TLC silica gel plates and placed into plastic vials containing 5<span class="elsevierStyleHsp" style=""></span>ml scintillation liquid &#40;BCS&#44; Biodegradable Counting Scintillation&#59; Amersham International Corporation&#44; Buckinghamshire&#44; England&#41;&#46; Radioactivity in each vial was determined with a 1600 Tri-Carb liquid scintillation spectrometer &#40;Packard Instrument Company&#44; Inc&#46;&#44; Downers Grove&#44; IL&#41;&#46; The device was adjusted to work with unquenched samples at 96<span class="elsevierStyleHsp" style=""></span>&#37; efficiency&#46; One unit of SMase activity was defined as 1<span class="elsevierStyleHsp" style=""></span>pmole of &#91;<span class="elsevierStyleSup">14</span>C&#93;-sphingomyelin hydrolyzed &#40;equivalent to picomoles of &#91;<span class="elsevierStyleSup">14</span>C&#93;-phosphorylcholine plus &#91;<span class="elsevierStyleSup">14</span>C&#93;-choline released&#41; in 1<span class="elsevierStyleHsp" style=""></span>h of incubation&#46; The specific activity was given as the number of units of SMase activity per mg of total mycobacterial proteins&#46; The classification of the SMase type was determined as described previously<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">26</span></a>&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Effect of incubation time&#44; dose&#44; pH and cations on sphingomyelinase activity</span><p id="par0040" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Time</span>&#58; The rate of hydrolysis of sphingomyelin was determined at various time points over 60<span class="elsevierStyleHsp" style=""></span>min by mixing 10<span class="elsevierStyleHsp" style=""></span>&#956;l of whole mycobacterial extracts &#40;containing 2<span class="elsevierStyleHsp" style=""></span>&#956;g of total proteins&#41; with 2&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;Ci &#91;N-methyl-<span class="elsevierStyleSup">14</span>C&#93;-sphingomyelin &#40;final concentration 1<span class="elsevierStyleHsp" style=""></span>mg&#47;ml&#41; dissolved in 20<span class="elsevierStyleHsp" style=""></span>&#956;l of 200<span class="elsevierStyleHsp" style=""></span>mM sodium acetate buffer &#40;pH 5&#46;5&#41;&#44; 1<span class="elsevierStyleHsp" style=""></span>mM Zn<span class="elsevierStyleSup">2&#43;</span>&#44; and 0&#46;2<span class="elsevierStyleHsp" style=""></span>&#37; Triton X-100&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Dose</span>&#58; Variable amounts of protein from whole cell extracts from strains H37Rv and CDC1551 were assayed by mixing 10<span class="elsevierStyleHsp" style=""></span>&#956;l of whole mycobacterial extracts &#40;containing various concentrations of protein between 0 and 2<span class="elsevierStyleHsp" style=""></span>&#956;g&#41; with 2&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;Ci &#91;N-methyl-<span class="elsevierStyleSup">14</span>C&#93;-sphingomyelin &#40;final concentration 1<span class="elsevierStyleHsp" style=""></span>mg&#47;ml&#41; dissolved in 20<span class="elsevierStyleHsp" style=""></span>&#956;l of 200<span class="elsevierStyleHsp" style=""></span>mM sodium acetate buffer &#40;pH 5&#46;5&#41;&#44; 1<span class="elsevierStyleHsp" style=""></span>mM Zn<span class="elsevierStyleSup">2&#43;</span>&#44; and 0&#46;2<span class="elsevierStyleHsp" style=""></span>&#37; Triton X-100 at 37<span class="elsevierStyleHsp" style=""></span>&#176;C&#44; for 1<span class="elsevierStyleHsp" style=""></span>h at pH 5&#46;5&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">pH</span>&#58; pH values were adjusted with appropriate proportions of sodium acetate &#40;pH 3&#8211;6&#41; or Trizma-Base &#40;pH 7&#8211;10&#41; buffers to mycobacterial extracts containing 2<span class="elsevierStyleHsp" style=""></span>&#956;g of total protein and incubated for 1<span class="elsevierStyleHsp" style=""></span>h at 37<span class="elsevierStyleHsp" style=""></span>&#176;C prior to running the standard assay as described above&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Cations</span>&#58; Each metal cation was assayed separately&#46; Assay mixtures with 1 or 10<span class="elsevierStyleHsp" style=""></span>mM MgCl<span class="elsevierStyleInf">2</span>&#44; CaCl<span class="elsevierStyleInf">2</span>&#44; ZnSO<span class="elsevierStyleInf">4</span>&#44; HgCl<span class="elsevierStyleInf">2</span>&#44; MnCl<span class="elsevierStyleInf">2</span>&#44; or CoCl<span class="elsevierStyleInf">2</span>&#44; or with 1 or 10<span class="elsevierStyleHsp" style=""></span>mM of chelating agent EDTA &#40;Sigma Chemical Co&#46;&#44; St&#46; Louis&#44; MO&#41; were incubated for 1<span class="elsevierStyleHsp" style=""></span>h at 37<span class="elsevierStyleHsp" style=""></span>&#176;C to run the standard assay as described above&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Statistics</span><p id="par0055" class="elsevierStylePara elsevierViewall">All the experiments were performed by triplicate &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#41;&#46; Slopes of the effect of incubation time and dose of mycobacterial extracts were calculated by linear regression&#46; Statistical significance was determined using ANOVA&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Results</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Dependence of mycobacterial sphingomyelinase on incubation time and dose of extracts</span><p id="par0060" class="elsevierStylePara elsevierViewall">The SMase activity of both H37Rv and CDC1551 strains increased linearly between 0 and 60<span class="elsevierStyleHsp" style=""></span>min of incubation &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;99&#41;&#46; After 60<span class="elsevierStyleHsp" style=""></span>min of incubation 37&#46;89<span class="elsevierStyleHsp" style=""></span>pmol and 16&#46;1<span class="elsevierStyleHsp" style=""></span>pmol of &#91;<span class="elsevierStyleSup">14</span>C&#93;-phosphorylcholine were recovered from chromatography plates of H37Rv and CDC1551&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">The amount of &#91;<span class="elsevierStyleSup">14</span>C&#93;-phosphorylcholine released from &#91;<span class="elsevierStyleSup">14</span>C&#93;-sphingomyelin also increased linearly as a function of extract dose of both strains &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;99&#41;&#46; After 60<span class="elsevierStyleHsp" style=""></span>min incubation with 2<span class="elsevierStyleHsp" style=""></span>&#956;g of total protein extract 37&#46;94<span class="elsevierStyleHsp" style=""></span>pmol and 17&#46;65<span class="elsevierStyleHsp" style=""></span>pmol of &#91;<span class="elsevierStyleSup">14</span>C&#93;-phosphorylcholine were recovered from strains H37Rv and CDC1551&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Those values corresponded to a specific SMase activity of 37&#46;9<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span><span class="elsevierStyleHsp" style=""></span>U&#47;mg&#47;h for H37Rv&#44; which was 2&#46;15 times higher &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; than that of CDC1551 &#40;17&#46;6<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span><span class="elsevierStyleHsp" style=""></span>U&#47;mg&#47;h&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Dependence on pH</span><p id="par0070" class="elsevierStylePara elsevierViewall">Assayed extracts from both strains produced one primary peak of SMase activity at pH 5&#46;5&#44; which corresponds to the maximum specific activity&#46; The peak from strain H37Rv extracts was almost three times higher than that of strain CDC1551 &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Effect of divalent cations</span><p id="par0075" class="elsevierStylePara elsevierViewall">The SMase activity detected in whole cell extracts with no extra reagents added was defined as the basal activity equivalent to 100<span class="elsevierStyleHsp" style=""></span>&#37;&#46; Subsequently&#44; the activity was stimulated at different rates by 1 and 10<span class="elsevierStyleHsp" style=""></span>mM concentration of cations Co<span class="elsevierStyleSup">2&#43;</span>&#44; Mn<span class="elsevierStyleSup">2&#43;</span>&#44; Zn<span class="elsevierStyleSup">2&#43;</span>&#44; and Mg<span class="elsevierStyleSup">2&#43;</span> or inhibited by Hg<span class="elsevierStyleSup">2&#43;</span> and Ca<span class="elsevierStyleSup">2&#43;</span>&#46; As expected&#44; chelating agent EDTA resulted in the greatest inhibition&#58; 96&#8211;99<span class="elsevierStyleHsp" style=""></span>&#37; for strain H37Rv and 75&#8211;77<span class="elsevierStyleHsp" style=""></span>&#37; for CDC1551&#46; Results are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Discussion</span><p id="par0080" class="elsevierStylePara elsevierViewall">Sphingomyelinases &#40;SMases&#41; are enzymes produced by mammalian cells&#59; their main activity is considered to occur during digestive processes&#46; However&#44; these enzymes and the products derived from the hydrolysis of the substrate sphingomyelin are involved in many other cell regulating functions such as cell growth&#44; differentiation&#44; cell migration&#44; adhesion&#44; inflammation and apoptosis<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">2&#44;22&#44;24</span></a>&#46; A more recent interest in the enzymes has been in their protective roles against pathogens by inhibiting invasion&#44; regulating cytokine responses and inducing apoptosis in infected host cells<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">7</span></a>&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Pathogens also produce SMases and they may act as virulence factors as demonstrated with <span class="elsevierStyleItalic">C&#46; perfringens</span><a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">20</span></a>&#44; <span class="elsevierStyleItalic">B&#46; cereus</span><a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">15</span></a>&#44; <span class="elsevierStyleItalic">P&#46; aeruginosa</span><a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">23</span></a>&#44; <span class="elsevierStyleItalic">Listeria spp&#46;</span><a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">17</span></a> and <span class="elsevierStyleItalic">S&#46; aureus</span><a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">4</span></a>&#46; Previously&#44; we reported the identification of acidic&#44; alkaline and neutral SMases activities in <span class="elsevierStyleItalic">M&#46; tuberculosis</span>&#46; In that report&#44; neutral SMase had the highest activity and was stimulated by Mg<span class="elsevierStyleSup">2&#43;</span>&#44; Mn<span class="elsevierStyleSup">2&#43;</span> and Co<span class="elsevierStyleSup">2&#43;</span> while acidic and alkaline SMase activities remained uncharacterized<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">26</span></a>&#46; Therefore&#44; in this study&#44; <span class="elsevierStyleItalic">M&#46; tuberculosis</span> acidic SMase activity is further characterized&#46; Maximal SMase activity occurs in a pH range from 5 to 6&#44; with optimal activity at pH at 5&#46;5 &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; The assay for cation-induced SMase activity at pH 5&#46;5 resulted in elevated activities by Co<span class="elsevierStyleSup">2&#43;</span>&#44; Mn<span class="elsevierStyleSup">2&#43;</span>&#44; Zn<span class="elsevierStyleSup">2&#43;</span>&#44; and to a lesser extent Mg<span class="elsevierStyleSup">2&#43;</span> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Zn<span class="elsevierStyleSup">2&#43;</span>-inducible activity was not previously reported for <span class="elsevierStyleItalic">M&#46; tuberculosis</span>&#46; Thus&#44; it can be classified as Zn<span class="elsevierStyleSup">2&#43;</span>-dependent acidic SMase activity&#46; By comparing its biochemical characteristics with other SMases&#44; it may correspond to a secretory acidic SMase&#46; In mammalian hosts&#44; this type of SMase regulates immune response<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">10</span></a>&#46; In this instance&#44; the presence of exogenous SMase produced by <span class="elsevierStyleItalic">M&#46; tuberculosis</span> during infection may interfere with the normal host inflammatory response thus allowing for the establishment of infection and the development of disease&#46; Recently&#44; Roca and Ramakrishnan<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">18</span></a> observed that the chemical blockade of host acid SMase activity prevents TNF-induced macrophage programmed necroptosis and mycobacterial release from the cell&#46; Thus&#44; <span class="elsevierStyleItalic">M&#46; tuberculosis</span> acidic SMase may aid in macrophage escape through the induction of necroptosis by its enzymatic product ceramide&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Presently&#44; <span class="elsevierStyleItalic">M&#46; tuberculosis</span> genome annotation in Tuberculist predicts that the protein products from genes <span class="elsevierStyleItalic">plcA</span> &#40;<span class="elsevierStyleItalic">Rv2351c</span>&#41;&#44; <span class="elsevierStyleItalic">plcB</span> &#40;<span class="elsevierStyleItalic">Rv2350c</span>&#41;&#44; <span class="elsevierStyleItalic">plcC</span> &#40;<span class="elsevierStyleItalic">Rv2349c</span>&#41;&#44; and <span class="elsevierStyleItalic">plcD</span> &#40;<span class="elsevierStyleItalic">Rv1755c</span>&#44; reported as a fragment&#41; have phospholipase and SMase activities and they are noted as virulence factors implicated in the pathogenesis of <span class="elsevierStyleItalic">M&#46; tuberculosis</span> at the level of intracellular survival by the alteration of cell signaling events or by direct cytotoxicity<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">12&#44;16</span></a>&#46; Several bacterial phospholipases possess both phospholipase and SMase activities&#59; an example is the alpha-toxin from the pathogen <span class="elsevierStyleItalic">C&#46; perfringens</span><a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">20</span></a>&#46; The activity we have identified in this study may correspond to <span class="elsevierStyleItalic">M&#46; tuberculosis</span> phospholipase C expressed from gene <span class="elsevierStyleItalic">plcC</span> &#40;<span class="elsevierStyleItalic">Rv2349c</span>&#41; because the proteins from the <span class="elsevierStyleItalic">plcA</span> and <span class="elsevierStyleItalic">plcB</span> genes are membrane-associated phospholipases C&#46; Furthermore&#44; another report where <span class="elsevierStyleItalic">M&#46; smegmatis</span> was used as an expression system of four <span class="elsevierStyleItalic">M&#46; tuberculosis plc</span> genes supports this idea&#59; <span class="elsevierStyleItalic">plcC</span> product was found to be the most active of the four recombinant PLCs under acidic conditions<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">1</span></a>&#46; However&#44; a novel <span class="elsevierStyleItalic">M&#46; tuberculosis</span> enzyme with SMase activity cannot be ruled out&#46; More research work is needed to make this determination&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Sphingomyelinases &#40;SMases&#41; and their hydrolysis products &#40;ceramide and phosphorylcholine&#41; are regulators of a multitude of cellular processes&#46; Several pathogens produce SMases as virulence factors&#46; In the present study&#44; we report a novel acidic mycobacterial Zn<span class="elsevierStyleSup">2&#43;</span>-dependent SMase activity&#46; The relevance of this enzyme in tuberculosis pathogenesis remains to be elucidated&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Ethical disclosures</span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Protection of human and animal subjects</span><p id="par0100" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this investigation&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Confidentiality of data</span><p id="par0105" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appears in this article&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Right to privacy and informed consent</span><p id="par0110" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appears in this article&#46;</p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conflict of interest</span><p id="par0115" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "titulo" => "Materials and methods"
          "secciones" => array:4 [
            0 => array:2 [
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              "titulo" => "Mycobacterial whole cell extracts"
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              "titulo" => "Sphingomyelinase activity"
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              "titulo" => "Effect of incubation time&#44; dose&#44; pH and cations on sphingomyelinase activity"
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              "titulo" => "Statistics"
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          "titulo" => "Results"
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              "titulo" => "Dependence of mycobacterial sphingomyelinase on incubation time and dose of extracts"
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              "titulo" => "Dependence on pH"
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              "titulo" => "Effect of divalent cations"
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              "titulo" => "Confidentiality of data"
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          "titulo" => "Conflict of interest"
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        10 => array:2 [
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          "titulo" => "Acknowledgements"
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          "titulo" => "References"
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    "fechaRecibido" => "2015-08-07"
    "fechaAceptado" => "2016-01-15"
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            1 => "Tuberculosis"
            2 => "Sphingomyelinase"
            3 => "Virulence factors"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Sphingomyelinases &#40;SMases&#41; catalyze the hydrolysis of sphingomyelin to ceramide and phosphorylcholine&#46; Sphingolipids are recognized as diverse and dynamic regulators of a multitude of cellular processes mediating cell cycle control&#44; differentiation&#44; stress response&#44; cell migration&#44; adhesion&#44; and apoptosis&#46; Bacterial SMases are virulence factors for several species of pathogens&#46; Whole cell extracts of <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> strains H37Rv and CDC1551 were assayed using &#91;N-methyl-<span class="elsevierStyleSup">14</span>C&#93;-sphingomyelin as substrate&#46; Acidic Zn<span class="elsevierStyleSup">2&#43;</span>-dependent SMase activity was identified in both strains&#46; Peak SMase activity was observed at pH 5&#46;5&#46; Interestingly&#44; overall SMase activity levels from CDC1551 extracts are approximately 1&#47;3 of those of H37Rv&#46; The presence of exogenous SMase produced by <span class="elsevierStyleItalic">M&#46; tuberculosis</span> during infection may interfere with the normal host inflammatory response thus allowing the establishment of infection and disease development&#46; This Type C activity is different from previously identified <span class="elsevierStyleItalic">M&#46; tuberculosis</span> SMases&#46; Defining the biochemical characteristics of <span class="elsevierStyleItalic">M&#46; tuberculosis</span> SMases helps to elucidate the roles that these enzymes play during infection and disease&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Las esfingomielinasas &#40;SMasas&#41; catalizan la hidr&#243;lisis de esfingomielina a ceramida y fosforilcolina&#46; Los esfingol&#237;pidos son reconocidos como reguladores diversos y din&#225;micos de una multitud de procesos celulares que median en el control del ciclo celular&#44; la diferenciaci&#243;n&#44; la respuesta al estr&#233;s&#44; la migraci&#243;n celular&#44; la adhesi&#243;n y la apoptosis&#46; Las esfingomielinasas bacterianas son factores de virulencia reconocidos en varias especies de pat&#243;genos&#46; En este trabajo se analizaron los extractos de c&#233;lulas enteras de las cepas de <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> H37Rv y CDC1551 utilizando &#91;N-metil-<span class="elsevierStyleSup">14</span>C&#93;-esfingomielina como sustrato&#46; Se identific&#243; actividad de SMasa-&#225;cida dependiente de zinc en ambas cepas&#46; La actividad m&#225;xima se observ&#243; a pH 5&#46;5&#46; Curiosamente&#44; los niveles de actividad de SMasa generados a partir de extractos de la cepa CDC1551 son aproximadamente un tercio de los de la cepa H37Rv&#46; La presencia de una SMasa ex&#243;gena producida por <span class="elsevierStyleItalic">M&#46; tuberculosis</span> durante la infecci&#243;n puede interferir con la respuesta inflamatoria del hu&#233;sped&#44; permitiendo as&#237; el establecimiento de la infecci&#243;n y el desarrollo de la enfermedad&#46; Esta actividad tipo C es distinta de las actividades previamente reportadas para <span class="elsevierStyleItalic">M&#46; tuberculosis</span>&#46; Definir las caracter&#237;sticas bioqu&#237;micas de las esfingomielinasas de <span class="elsevierStyleItalic">M&#46; tuberculosis</span> ayudar&#225; a dilucidar el papel que desempe&#241;an estas enzimas durante la infecci&#243;n y la enfermedad&#46;</p></span>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Time-course of mycobacterial SMase activity&#46; Mycobacterial cell fractions &#40;2<span class="elsevierStyleHsp" style=""></span>&#956;g of total protein&#41; were tested for SMase activity at incubation time points between 0 and 60<span class="elsevierStyleHsp" style=""></span>min&#46; Symbols represent the mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SE of &#91;<span class="elsevierStyleSup">14</span>C&#93;-phosphorylcholine released by <span class="elsevierStyleItalic">M&#46; tuberculosis</span> whole cell extracts of strains H37Rv &#40;&#9675;&#41; or CDC1551 &#40;&#9679;&#41; in three independent experiments performed in triplicate&#46;</p>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Dose-dependence of <span class="elsevierStyleItalic">M&#46; tuberculosis</span> SMase activity&#46; Mycobacterial cell fractions containing 0&#8211;2<span class="elsevierStyleHsp" style=""></span>&#956;g of protein per assay were tested&#46; Symbols represent the mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SE of &#91;<span class="elsevierStyleSup">14</span>C&#93;-phosphorylcholine released &#91;in pmol&#93; by <span class="elsevierStyleItalic">M&#46; tuberculosis</span> whole cell extracts of strains H37Rv &#40;&#9675;&#41; or CDC1551 &#40;&#9679;&#41;&#46; All assays were performed at pH 5&#46;5 with 1<span class="elsevierStyleHsp" style=""></span>h incubation&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Effect of pH on mycobacterial SMase activity&#46; Mycobacterial cell fractions containing 2<span class="elsevierStyleHsp" style=""></span>&#956;g of proteins were tested at different pH levels &#40;range 3&#8211;9&#41;&#46; Symbols represent the means<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SE of SMase specific activity of <span class="elsevierStyleItalic">M&#46; tuberculosis</span> whole cell extracts of strains H37Rv &#40;&#9675;&#41; or CDC1551 &#40;&#9679;&#41;&#46;</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="4" align="center" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> strain</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="2" align="center" valign="top" style="border-bottom: 2px solid black">H37Rv</td><td class="td" title="table-entry  " colspan="2" align="center" valign="top" style="border-bottom: 2px solid black">CDC-1551</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="4" align="center" valign="top" style="border-bottom: 2px solid black">Concentration &#40;mM&#41;</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " colspan="4" align="center" valign="top" style="border-bottom: 2px solid black">Normalized specific SMase activity</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;00&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;00&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;00&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">EDTA&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;29&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;74&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">MnCl<span class="elsevierStyleInf">2</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;88&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;75&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;01&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CoCl<span class="elsevierStyleInf">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;05&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CaCl<span class="elsevierStyleInf">2</span>&nbsp;\t\t\t\t\t\t\n
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