We have recently reported that two typical G s -coupled receptors, the  2 -adrenergic receptor a... more We have recently reported that two typical G s -coupled receptors, the  2 -adrenergic receptor and the receptor for prostaglandin E 1 , stimulate phospholipase C-⑀ (PLC-⑀) and increase intracellular Ca 2؉ concentration ([Ca 2؉ ] i ) in HEK-293 cells and N1E-115 neuroblastoma cells, respectively, by a pathway involving Epac1, a cAMP-activated and Rap-specific guanine nucleotide exchange factor (GEF), and the GTPase Rap2B. Here we have demonstrated that these G s -coupled receptors use this pathway to activate H-Ras and the extracellular signal-regulated kinases 1 and 2 (ERK1/2). Specifically, agonist activation of the receptors resulted in activation of H-Ras and ERK1/2. The latter action was suppressed by dominant negative H-Ras, but not Rap1A. The receptor actions were independent of protein kinase A but fully mimicked by an Epac-specific cAMP analog as well as by a constitutively active Rap2B mutant. On the other hand, a cAMP-binding-deficient Epac1 mutant, the Rap GTPase-activating proteinII, and a dominant negative Rap2B mutant suppressed receptor-and Epac-mediated activation of H-Ras and ERK1/2. Finally, we have demonstrated that activation of H-Ras and ERK1/2 requires the lipase activity of PLC-⑀ and the subsequent [Ca 2؉ ] i increase, suggesting that H-Ras activation is mediated by a Ca 2؉ -activated GEF. In line with this hypothesis, receptor-mediated activation of H-Ras and ERK1/2 was strongly enhanced by expression of RasGRP1, a Ca 2؉regulated Ras-GEF. Collectively, our data indicated that G s -coupled receptors can activate H-Ras and subsequently the mitogen-activated protein kinases ERK1/2 by a Ca 2؉ -activated Ras-GEF, possibly RasGRP1, mediated by cAMP-activated Epac proteins, which then lead via Rap2B and PLC-⑀ stimulation to [Ca 2؉ ] i increase.
The membrane phospholipid, phosphatidylinositol 4,5-bisphosphate (PIP(2)), plays a critical role ... more The membrane phospholipid, phosphatidylinositol 4,5-bisphosphate (PIP(2)), plays a critical role in various, apparently very different cellular processes. As precursor for second messengers generated by phospholipase C isoforms and class I phosphoinositide 3-kinases, PIP(2) is indispensable for cellular signaling by membrane receptors. In addition, PIP(2) directly affects the localization and activity of many cellular proteins via specific interaction with unique phosphoinositide-binding domains and thereby regulates actin cytoskeletal dynamics, vesicle trafficking, ion channel activity, gene expression and cell survival. The activity and subcellular localization of phosphatidylinositol 4-phosphate 5-kinase (PIP5K) isoforms, which catalyze the formation of PIP(2), are actively regulated by membrane receptors, by phosphorylation and by small GTPases of the Rho and ARF families. Spatially and temporally organized regulation of PIP(2) synthesis by PIP5K enables dynamic and versatile PIP(2) signaling and represents an important link in the execution of cellular tasks by Rho and ARF GTPases.
An integrated packaging system is developed for the multilayer laminate gas-phase microreactor di... more An integrated packaging system is developed for the multilayer laminate gas-phase microreactor die whose design and fabrication was described in Part 1 of this series. A commercial plastic socket used for integrated circuit testing was adapted so the reactor chip could be easily installed while maintaining consistent alignment with all electrical contacts. A heated fluidics interface was developed that connects the nonmetallic feed and product gas ports on the microreactor chip to metal tubing. Thermal experiments and 3-D finite-element heat transfer simulations of the combined socket-fluidics assembly showed that the plastic reactor socket could be safely operated up to 250°C. Other tests showed that the microreactor heaters were capable of achieving membrane temperatures in excess of 600°C.
2011 IEEE International Conference on Microwaves, Communications, Antennas and Electronic Systems (COMCAS 2011), 2011
An 15th order bandpass delta-sigma modulator for class-S power amplifiers is presented. The modul... more An 15th order bandpass delta-sigma modulator for class-S power amplifiers is presented. The modulator is based on a third order low pass prototype which is designed to meet the requirements for signal-to-noise ratio (SNR) of major mobile communication standards in a bandwidth of around 30 MHz. The transform z−1 → z−5 leads to a repetition of the low pass notch in the noise transfer function (NTF) at frequencies f = n/5fs, n = 1, 2, 3, 4, 5, &. Apart from sinc filtering due to rectangular output pulses the NTF shape is equal in all frequency bands. The two lower frequency bands at f = 1/5fs, 2/5 fs are independent from each other and can be used for concurrent transmission in the 450 MHz and 900 MHz band. The paper investigates the modulator with respect to the signal to noise ratio, the stability and the coding efficiency versus input amplitudes of tones in both frequency bands.
Latency-active promoter 2 (LAP 2) is a TATA-less promoter in herpes simplex virus type 1 (HSV-1) ... more Latency-active promoter 2 (LAP 2) is a TATA-less promoter in herpes simplex virus type 1 (HSV-1) that can express genes during viral latency. Four regions of LAP2 are protected from DNase I digestion in vitro by either HeLa cell nuclear extracts or purified Sp1. Transient gene expression assays of LAP2 substitution mutants demonstrate that two of the regions protected by Sp1 and three other regions protected by nuclear extract are important for promoter function. The mutation causing the most significant reduction in expression alters a stretch of 23 thymidine residues (T 23 ) that binds a protein with several properties common to high-mobilitygroup (HMG) proteins. The T 23 binding activity is heat stable, can be inhibited by poly(dA-dT) ⅐ poly(dA-dT), and is inhibited by minor-groove-binding drugs. Antiserum directed against HMG I(Y) blocked the formation of one of the DNA-protein complexes on the T 23 oligonucleotide, suggesting that a protein antigenically related to HMG I(Y) binds to LAP2 in vitro. Direct evidence of HMG I(Y) involvement in LAP2 function is provided by the findings that recombinant HMG I(Y) protein facilitates Sp1 binding to LAP2 in mobility shift assays and that antisense HMG I(Y) RNA specifically inhibits LAP2 function in vivo. These results suggest that DNA structure may be an important determinant of the activity of a promoter that is capable of escaping the global shutoff of transcription that occurs during viral latency. * Corresponding author. 5393 on April 27, 2016 by guest http://mcb.asm.org/ Downloaded from LAP2 and that HMG I(Y) antisense RNA specifically inhibits LAP2 promoter function in vivo.
Journal of the American Academy of Child and Adolescent Psychiatry, Jan 8, 2002
To measure specific neurophysiological attention deficits in children with hyperkinetic disorders... more To measure specific neurophysiological attention deficits in children with hyperkinetic disorders (HD; the ICD-10 diagnosis for severe and pervasive attention-deficit/hyperactivity disorder [ADHD]). In a multicenter sample of 148 children with HD and control children aged 8 to 14 years, event-related potential maps were recorded during a cued continuous performance test (A-X/O-X). Maps to cues (requiring attention but no response) and distractors and performance were tested for differences between age- and sex-matched HD and control groups (n = 57 each), as well as between clinics (n = 5). The N1, P3a, and P3b maps revealed reliable attention effects, with larger amplitudes after cues than after distractors, and only minor differences across clinics. Children with HD missed more targets, made more false alarms, and had larger N1 followed by smaller P3b amplitudes after cues than did controls. Cue-P3b amplitude correlated with detecting subsequent targets. Cue-P3b tomography indicated posterior sources that were attenuated in children with HD. Brain mapping indicates that children with HD attend to cues (preceding potential targets) with increased initial orienting (N1) followed by insufficient resource allocation (P3b). These multiple, condition-specific attention deficits in HD within 300 msec extend previous results on ADHD and underline the importance of high temporal resolution in mapping severe attention deficits.
We demonstrate the design, fabrication, and operation of microfluidic chemical reactors for the s... more We demonstrate the design, fabrication, and operation of microfluidic chemical reactors for the synthesis of colloidal silica particles. Two reactor configurations are examined: laminar flow reactors and segmented flow reactors. We analyze particle sizes and size distributions and examine their change with varying linear flow velocity and mean residence time. Laminar flow reactors are affected by axial dispersion at high linear velocities, thus leading to wide particle size distributions under these conditions. Gas is used to create a segmented flow, consisting liquid plugs separated by inert gas bubbles. The internal recirculation created in the liquid plugs generates mixing, which eliminates the axial dispersion effects associated with laminar flow reactors and produces a narrow size distribution of silica nanoparticles.
Stimulation of phospholipase C (PLC) by G q -coupled receptors such as the M 3 muscarinic acetylc... more Stimulation of phospholipase C (PLC) by G q -coupled receptors such as the M 3 muscarinic acetylcholine receptor (mAChR) is caused by direct activation of PLC- enzymes by G␣ q proteins. We have recently shown that G s -coupled receptors can stimulate PLC-⑀, apparently via formation of cyclic AMP and activation of the Rasrelated GTPase Rap2B. Here we report that PLC stimulation by the M 3 mAChR expressed in HEK-293 cells also involves, in part, similar mechanisms. M 3 mAChR-mediated PLC stimulation and [Ca 2؉ ] i increase were reduced by 2,5-dideoxyadenosine (dd-Ado), a direct adenylyl cyclase inhibitor. On the other hand, overexpression of G␣ s or Epac1, a cyclic AMP-regulated guanine nucleotide exchange factor for Rap GTPases, enhanced M 3 mAChR-mediated PLC stimulation. Inactivation of Rasrelated GTPases with clostridial toxins suppressed the M 3 mAChR responses. The inhibitory toxin effects were mimicked by expression of inactive Rap2B, but not of other inactive GTPases (Rac1, Ras, RalA, Rap1A, and Rap2A). Activation of the M 3 mAChR induced GTP loading of Rap2B, an effect strongly enhanced by overexpression of G␣ s and inhibited by dd-Ado. Overexpression of PLC-⑀ and PLC-1, but not PLC-␥1 or PLC-␦1, enhanced M 3 mAChR-mediated PLC stimulation and [Ca 2؉ ] i increase. In contrast, expression of a catalytically inactive PLC-⑀ mutant reduced PLC stimulation by the M 3 mAChR and abrogated the potentiating effect of G␣ s . In conclusion, our findings suggest that PLC stimulation by the M 3 mAChR is a composite action of PLC-1 stimulation by G␣ q and stimulation of PLC-⑀ apparently mediated by G s -dependent cyclic AMP formation and subsequent activation of Rap2B.
Makromolekulare Chemie Macromolecular Symposia, Oct 1, 1991
We have developed a highly sensitive, multi-angle, static light scattering (TRSLS = time resolved... more We have developed a highly sensitive, multi-angle, static light scattering (TRSLS = time resolved static light scattering) instrument, which measures the angular dependent Rayleigh scattering intensity of solutions simultaneously at 38 angles within approximately one second. It is thus suitable as a quick and easy to use static light scattering device for routine polymer and colloid characterization. The time resolution allows the kinetics of many systems to be investigated down to a second time scale, such as polymerization kinetics of linear, branched and crosslinked polymer structures, thermoreversible gelation, growth of colloidal particles, structural changes in micellar systems, etc.
This work presents the design, fabrication, and testing of an integrated mixer/valve and a method... more This work presents the design, fabrication, and testing of an integrated mixer/valve and a method for determining its mixing performance. The method correlates the mixing time to a quantitatively measurable observable. We present modeling and experimental results using this method.
We recently reported that activation of the highly efficient phospholipase C (PLC) stimulatory m3... more We recently reported that activation of the highly efficient phospholipase C (PLC) stimulatory m3 muscarinic acetylcholine receptor (mAChR) can induce a long-lasting G i -mediated heterologous potentiation of PLC stimulation in human embryonic kidney (HEK) 293 cells, which was accompanied by an increased cellular level of the PLC substrate phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P 2 ]. Here, we examined whether such a potentiated PLC response is also induced by the rather poorly PLC stimulatory m2 mAChR and the endogenously expressed purinergic and lysophosphatidic acid receptors. Pretreatment of m2 mAChR-expressing HEK 293 cells for 2 min with carbachol, followed by agonist washout and measurement of PLC activity Ն40 min later, caused a long-lasting (up to ϳ90 min) heterologous potentiation of receptor-and G protein-mediated PLC stimulation. A similar heterologous po-This work was supported by the Deutsche Forschungsgemeinschaft and the IFORES program of the Universitä tsklinikum Essen.
We have recently reported that two typical G s -coupled receptors, the  2 -adrenergic receptor a... more We have recently reported that two typical G s -coupled receptors, the  2 -adrenergic receptor and the receptor for prostaglandin E 1 , stimulate phospholipase C-⑀ (PLC-⑀) and increase intracellular Ca 2؉ concentration ([Ca 2؉ ] i ) in HEK-293 cells and N1E-115 neuroblastoma cells, respectively, by a pathway involving Epac1, a cAMP-activated and Rap-specific guanine nucleotide exchange factor (GEF), and the GTPase Rap2B. Here we have demonstrated that these G s -coupled receptors use this pathway to activate H-Ras and the extracellular signal-regulated kinases 1 and 2 (ERK1/2). Specifically, agonist activation of the receptors resulted in activation of H-Ras and ERK1/2. The latter action was suppressed by dominant negative H-Ras, but not Rap1A. The receptor actions were independent of protein kinase A but fully mimicked by an Epac-specific cAMP analog as well as by a constitutively active Rap2B mutant. On the other hand, a cAMP-binding-deficient Epac1 mutant, the Rap GTPase-activating proteinII, and a dominant negative Rap2B mutant suppressed receptor-and Epac-mediated activation of H-Ras and ERK1/2. Finally, we have demonstrated that activation of H-Ras and ERK1/2 requires the lipase activity of PLC-⑀ and the subsequent [Ca 2؉ ] i increase, suggesting that H-Ras activation is mediated by a Ca 2؉ -activated GEF. In line with this hypothesis, receptor-mediated activation of H-Ras and ERK1/2 was strongly enhanced by expression of RasGRP1, a Ca 2؉regulated Ras-GEF. Collectively, our data indicated that G s -coupled receptors can activate H-Ras and subsequently the mitogen-activated protein kinases ERK1/2 by a Ca 2؉ -activated Ras-GEF, possibly RasGRP1, mediated by cAMP-activated Epac proteins, which then lead via Rap2B and PLC-⑀ stimulation to [Ca 2؉ ] i increase.
The membrane phospholipid, phosphatidylinositol 4,5-bisphosphate (PIP(2)), plays a critical role ... more The membrane phospholipid, phosphatidylinositol 4,5-bisphosphate (PIP(2)), plays a critical role in various, apparently very different cellular processes. As precursor for second messengers generated by phospholipase C isoforms and class I phosphoinositide 3-kinases, PIP(2) is indispensable for cellular signaling by membrane receptors. In addition, PIP(2) directly affects the localization and activity of many cellular proteins via specific interaction with unique phosphoinositide-binding domains and thereby regulates actin cytoskeletal dynamics, vesicle trafficking, ion channel activity, gene expression and cell survival. The activity and subcellular localization of phosphatidylinositol 4-phosphate 5-kinase (PIP5K) isoforms, which catalyze the formation of PIP(2), are actively regulated by membrane receptors, by phosphorylation and by small GTPases of the Rho and ARF families. Spatially and temporally organized regulation of PIP(2) synthesis by PIP5K enables dynamic and versatile PIP(2) signaling and represents an important link in the execution of cellular tasks by Rho and ARF GTPases.
An integrated packaging system is developed for the multilayer laminate gas-phase microreactor di... more An integrated packaging system is developed for the multilayer laminate gas-phase microreactor die whose design and fabrication was described in Part 1 of this series. A commercial plastic socket used for integrated circuit testing was adapted so the reactor chip could be easily installed while maintaining consistent alignment with all electrical contacts. A heated fluidics interface was developed that connects the nonmetallic feed and product gas ports on the microreactor chip to metal tubing. Thermal experiments and 3-D finite-element heat transfer simulations of the combined socket-fluidics assembly showed that the plastic reactor socket could be safely operated up to 250°C. Other tests showed that the microreactor heaters were capable of achieving membrane temperatures in excess of 600°C.
2011 IEEE International Conference on Microwaves, Communications, Antennas and Electronic Systems (COMCAS 2011), 2011
An 15th order bandpass delta-sigma modulator for class-S power amplifiers is presented. The modul... more An 15th order bandpass delta-sigma modulator for class-S power amplifiers is presented. The modulator is based on a third order low pass prototype which is designed to meet the requirements for signal-to-noise ratio (SNR) of major mobile communication standards in a bandwidth of around 30 MHz. The transform z−1 → z−5 leads to a repetition of the low pass notch in the noise transfer function (NTF) at frequencies f = n/5fs, n = 1, 2, 3, 4, 5, &. Apart from sinc filtering due to rectangular output pulses the NTF shape is equal in all frequency bands. The two lower frequency bands at f = 1/5fs, 2/5 fs are independent from each other and can be used for concurrent transmission in the 450 MHz and 900 MHz band. The paper investigates the modulator with respect to the signal to noise ratio, the stability and the coding efficiency versus input amplitudes of tones in both frequency bands.
Latency-active promoter 2 (LAP 2) is a TATA-less promoter in herpes simplex virus type 1 (HSV-1) ... more Latency-active promoter 2 (LAP 2) is a TATA-less promoter in herpes simplex virus type 1 (HSV-1) that can express genes during viral latency. Four regions of LAP2 are protected from DNase I digestion in vitro by either HeLa cell nuclear extracts or purified Sp1. Transient gene expression assays of LAP2 substitution mutants demonstrate that two of the regions protected by Sp1 and three other regions protected by nuclear extract are important for promoter function. The mutation causing the most significant reduction in expression alters a stretch of 23 thymidine residues (T 23 ) that binds a protein with several properties common to high-mobilitygroup (HMG) proteins. The T 23 binding activity is heat stable, can be inhibited by poly(dA-dT) ⅐ poly(dA-dT), and is inhibited by minor-groove-binding drugs. Antiserum directed against HMG I(Y) blocked the formation of one of the DNA-protein complexes on the T 23 oligonucleotide, suggesting that a protein antigenically related to HMG I(Y) binds to LAP2 in vitro. Direct evidence of HMG I(Y) involvement in LAP2 function is provided by the findings that recombinant HMG I(Y) protein facilitates Sp1 binding to LAP2 in mobility shift assays and that antisense HMG I(Y) RNA specifically inhibits LAP2 function in vivo. These results suggest that DNA structure may be an important determinant of the activity of a promoter that is capable of escaping the global shutoff of transcription that occurs during viral latency. * Corresponding author. 5393 on April 27, 2016 by guest http://mcb.asm.org/ Downloaded from LAP2 and that HMG I(Y) antisense RNA specifically inhibits LAP2 promoter function in vivo.
Journal of the American Academy of Child and Adolescent Psychiatry, Jan 8, 2002
To measure specific neurophysiological attention deficits in children with hyperkinetic disorders... more To measure specific neurophysiological attention deficits in children with hyperkinetic disorders (HD; the ICD-10 diagnosis for severe and pervasive attention-deficit/hyperactivity disorder [ADHD]). In a multicenter sample of 148 children with HD and control children aged 8 to 14 years, event-related potential maps were recorded during a cued continuous performance test (A-X/O-X). Maps to cues (requiring attention but no response) and distractors and performance were tested for differences between age- and sex-matched HD and control groups (n = 57 each), as well as between clinics (n = 5). The N1, P3a, and P3b maps revealed reliable attention effects, with larger amplitudes after cues than after distractors, and only minor differences across clinics. Children with HD missed more targets, made more false alarms, and had larger N1 followed by smaller P3b amplitudes after cues than did controls. Cue-P3b amplitude correlated with detecting subsequent targets. Cue-P3b tomography indicated posterior sources that were attenuated in children with HD. Brain mapping indicates that children with HD attend to cues (preceding potential targets) with increased initial orienting (N1) followed by insufficient resource allocation (P3b). These multiple, condition-specific attention deficits in HD within 300 msec extend previous results on ADHD and underline the importance of high temporal resolution in mapping severe attention deficits.
We demonstrate the design, fabrication, and operation of microfluidic chemical reactors for the s... more We demonstrate the design, fabrication, and operation of microfluidic chemical reactors for the synthesis of colloidal silica particles. Two reactor configurations are examined: laminar flow reactors and segmented flow reactors. We analyze particle sizes and size distributions and examine their change with varying linear flow velocity and mean residence time. Laminar flow reactors are affected by axial dispersion at high linear velocities, thus leading to wide particle size distributions under these conditions. Gas is used to create a segmented flow, consisting liquid plugs separated by inert gas bubbles. The internal recirculation created in the liquid plugs generates mixing, which eliminates the axial dispersion effects associated with laminar flow reactors and produces a narrow size distribution of silica nanoparticles.
Stimulation of phospholipase C (PLC) by G q -coupled receptors such as the M 3 muscarinic acetylc... more Stimulation of phospholipase C (PLC) by G q -coupled receptors such as the M 3 muscarinic acetylcholine receptor (mAChR) is caused by direct activation of PLC- enzymes by G␣ q proteins. We have recently shown that G s -coupled receptors can stimulate PLC-⑀, apparently via formation of cyclic AMP and activation of the Rasrelated GTPase Rap2B. Here we report that PLC stimulation by the M 3 mAChR expressed in HEK-293 cells also involves, in part, similar mechanisms. M 3 mAChR-mediated PLC stimulation and [Ca 2؉ ] i increase were reduced by 2,5-dideoxyadenosine (dd-Ado), a direct adenylyl cyclase inhibitor. On the other hand, overexpression of G␣ s or Epac1, a cyclic AMP-regulated guanine nucleotide exchange factor for Rap GTPases, enhanced M 3 mAChR-mediated PLC stimulation. Inactivation of Rasrelated GTPases with clostridial toxins suppressed the M 3 mAChR responses. The inhibitory toxin effects were mimicked by expression of inactive Rap2B, but not of other inactive GTPases (Rac1, Ras, RalA, Rap1A, and Rap2A). Activation of the M 3 mAChR induced GTP loading of Rap2B, an effect strongly enhanced by overexpression of G␣ s and inhibited by dd-Ado. Overexpression of PLC-⑀ and PLC-1, but not PLC-␥1 or PLC-␦1, enhanced M 3 mAChR-mediated PLC stimulation and [Ca 2؉ ] i increase. In contrast, expression of a catalytically inactive PLC-⑀ mutant reduced PLC stimulation by the M 3 mAChR and abrogated the potentiating effect of G␣ s . In conclusion, our findings suggest that PLC stimulation by the M 3 mAChR is a composite action of PLC-1 stimulation by G␣ q and stimulation of PLC-⑀ apparently mediated by G s -dependent cyclic AMP formation and subsequent activation of Rap2B.
Makromolekulare Chemie Macromolecular Symposia, Oct 1, 1991
We have developed a highly sensitive, multi-angle, static light scattering (TRSLS = time resolved... more We have developed a highly sensitive, multi-angle, static light scattering (TRSLS = time resolved static light scattering) instrument, which measures the angular dependent Rayleigh scattering intensity of solutions simultaneously at 38 angles within approximately one second. It is thus suitable as a quick and easy to use static light scattering device for routine polymer and colloid characterization. The time resolution allows the kinetics of many systems to be investigated down to a second time scale, such as polymerization kinetics of linear, branched and crosslinked polymer structures, thermoreversible gelation, growth of colloidal particles, structural changes in micellar systems, etc.
This work presents the design, fabrication, and testing of an integrated mixer/valve and a method... more This work presents the design, fabrication, and testing of an integrated mixer/valve and a method for determining its mixing performance. The method correlates the mixing time to a quantitatively measurable observable. We present modeling and experimental results using this method.
We recently reported that activation of the highly efficient phospholipase C (PLC) stimulatory m3... more We recently reported that activation of the highly efficient phospholipase C (PLC) stimulatory m3 muscarinic acetylcholine receptor (mAChR) can induce a long-lasting G i -mediated heterologous potentiation of PLC stimulation in human embryonic kidney (HEK) 293 cells, which was accompanied by an increased cellular level of the PLC substrate phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P 2 ]. Here, we examined whether such a potentiated PLC response is also induced by the rather poorly PLC stimulatory m2 mAChR and the endogenously expressed purinergic and lysophosphatidic acid receptors. Pretreatment of m2 mAChR-expressing HEK 293 cells for 2 min with carbachol, followed by agonist washout and measurement of PLC activity Ն40 min later, caused a long-lasting (up to ϳ90 min) heterologous potentiation of receptor-and G protein-mediated PLC stimulation. A similar heterologous po-This work was supported by the Deutsche Forschungsgemeinschaft and the IFORES program of the Universitä tsklinikum Essen.
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