Abstract 1172: Neointima Formation is Dependent on p38α Mitogen-Activated Protein Kinase

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Brandon M Proctor ◽  
Anthony J Muslin
Keyword(s):  
P38 Mapk ◽  
Carotid Arteries ◽  
Thymidine Incorporation ◽  
Fold Increase ◽  
Arterial Injury ◽  
Mitogen Activated Protein Kinase ◽  
Neointima Formation ◽  
Mapk Activity ◽  
Mitogen Activated Protein ◽  
P38α Mapk

Neointima formation frequently occurs after arterial injury and is responsible for substantial human morbidity. We previously demonstrated that the intracellular linker protein Grb2 is required for neointima formation, and that Grb2 regulates p38α mitogen-activated protein kinase (MAPK) activation in vascular smooth muscle cells (SMCs). In this work, the role of p38α MAPK in neointima formation was examined. In vitro experiments showed that pharmacological inhibition of p38 MAPK activity in cultured SMCs blocked platelet-derived growth factor (PDGF)-stimulated DNA replication and cell proliferation. Specifically, in control SMCs, overnight stimulation with PDGF induced an 11.8-fold increase in thymidine incorporation and a 1.9 fold increase in cell number. However, inhibition of p38 MAPK activity reduced PDGF-induced thymidine incorporation to 2.8-fold (P = 0.0006) and completely blocked PDGF-stimulated cell proliferation (P = 0.0001). Also, p38 MAPK activity was required for PDGF-induced inactivation of the retinoblastoma tumor suppressor protein, Rb, and induction of mini-chromosome maintenance protein-6 (MCM6), a fundamental regulator of DNA replication. Next, compound transgenic mice were generated with doxycycline (Dox)-inducible, SMC-specific expression of a dominant-negative form of p38α MAPK (SMC-DN-p38α ). Dox induced robust expression of DN-p38α mRNA and protein in the aorta and carotid arteries of compound transgenic mice, and inactivation of native, arterial p38 MAPK. SMC-DN-p38α and single transgenic, control mice were subjected to carotid injury by use of an epoxy resin-beaded probe. After 21 days, control mice developed robust neointima formation that frequently resulted in an occlusive lesion with a mean neointima/media ratio of 2.62 (N = 8). In contrast, SMC-DN-p38α mice were resistant to the development of neointima. Specifically, neointima/media ratio was reduced to 0.63 for SMC-DN-p38α mice (N = 12; P = 0.045). In addition, compared to control mice, injured carotid arteries of SMC-DN-p38α mice showed defective p38 MAPK activation in SMCs of the tunica media. Our results demonstrate that vascular SMC p38α MAPK is required for neointima formation after arterial injury.

272. Signalling pathways involved in mouse GDF9 and BMP15 stimulated thymidine uptake by rat granulosa cells

2008 ◽  
Vol 20 (9) ◽  
pp. 72
Author(s):  
K. L. Reader ◽  
C. J. McIntosh ◽  
J. L. Juengel
Keyword(s):  
P38 Mapk ◽  
Granulosa Cells ◽  
Molecular Mechanisms ◽  
Thymidine Incorporation ◽  
Fold Increase ◽  
Fertility Control ◽  
Mitogen Activated Protein Kinase ◽  
Thymidine Uptake ◽  
Cooperative Effects ◽  
Mitogen Activated Protein

The oocyte-secreted factors growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are essential for ovarian follicular growth and development. Understanding the molecular mechanisms of these factors could assist with the development of future products for fertility control. Thymidine uptake by rat granulosa cells is stimulated cooperatively by GDF9 and BMP15. Inhibitors of the activin receptor-like kinase (ALK) 4,5,7 and the nuclear factor kappaB (NFKB) second messenger pathways block ovine GDF9 and BMP15 stimulated thymidine incorporation. The ALK 4,5,7 receptor pathway is known to be essential for the cooperative effects of mouse (m)GDF9 and mBMP15 on thymidine incorporation but the role of other pathways has yet to be determined, which was the focus of this study. Inhibitors of NFKB (Sn50; 10µg/mL), ALK 2,3,6 receptor (Dorsomorphin; 1µM), p38 mitogen-activated protein kinase (p38 MAPK; SB239063; 5 µM) and c-Jun-N-terminal kinase (JNK; TAT-TI-JIP153–163; 5 µM) pathways were each cultured with recombinant mGDF9 (25 ng/mL) and mBMP15 (6 ng/mL) in a rat granulosa cell [3H]-thymidine bioassay. The p38 MAPK inhibitor caused partial inhibition of thymidine uptake but this appeared to be non-specific as a similar level of suppression was observed in the control cultures. Neither the ALK 2,3,6 receptor nor the NFKB pathway inhibitors had any effect on mGDF9 and mBMP15 stimulated thymidine uptake. The JNK inhibitor showed a 1.7-fold increase in stimulation above the mGDF9 and mBMP15 effect (P < 0.01) but a similar stimulation was also observed in some controls. This differs from the results observed with ovine GDF9 and BMP15 where thymidine uptake was completely blocked by the NFKB inhibitor and the JNK inhibitor had no effect. In conclusion, the molecular mechanisms of GDF9 and BMP15 function are dependent on the species of origin of the growth factor and therefore caution is needed when extrapolating findings from one species to another.

Adaphostin promotes caffeine-evoked autocrine Fas-mediated death pathway activation in Bcr/Abl-positive leukaemia cells

2011 ◽  
Vol 439 (3) ◽  
pp. 453-470 ◽  
Author(s):  
Wen-Hsin Liu ◽  
Long-Sen Chang
Keyword(s):  
P38 Mapk ◽  
K562 Cells ◽  
Mitogen Activated Protein Kinase ◽  
Pathway Activation ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
P38α Mapk ◽  
Activating Transcription Factor ◽  
Leukaemia Therapy ◽  
Jnk Activation

The present study was conducted to verify whether caffeine is beneficial for improving leukaemia therapy. Co-treatment with adaphostin (a Bcr/Abl inhibitor) was found to potentiate caffeine-induced Fas/FasL up-regulation. Although adaphostin did not elicit ASK1 (apoptosis signal-regulating kinase 1)-mediated phosphorylation of p38 MAPK (mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase), co-treatment with adaphostin notably increased p38 MAPK/JNK activation in caffeine-treated cells. Suppression of p38 MAPK and JNK abrogated Fas/FasL up-regulation in caffeine- and caffeine/adaphostin-treated cells. Compared with caffeine, adaphostin markedly suppressed Akt/ERK (extracellular-signal-regulated kinase)-mediated MKP-1 (MAPK phosphatase 1) protein expression in K562 cells. MKP-1 down-regulation eventually elucidated the enhanced effect of adaphostin on p38 MAPK/JNK activation and subsequent Fas/FasL up-regulation in caffeine-treated cells. Knockdown of p38α MAPK and JNK1, ATF-2 (activating transcription factor 2) and c-Jun by siRNA (small interfering RNA) proved that p38α MAPK/ATF-2 and JNK1/c-Jun pathways were responsible for caffeine-evoked Fas/FasL up-regulation. Moreover, Ca2+ and ROS (reactive oxygen species) were demonstrated to be responsible for ASK1 activation and Akt/ERK inactivation respectively in caffeine- and caffeine/adaphostin-treated cells. Likewise, adaphostin functionally enhanced caffeine-induced Fas/FasL up-regulation in leukaemia cells that expressed Bcr/Abl. Taken together, the results of the present study suggest a therapeutic strategy in improving the efficacy of adaphostin via Fas-mediated death pathway activation in Bcr/Abl-positive leukaemia.

scholarly journals p38 MAPK α and β isoforms differentially regulate plasma membrane localization of MRP2

2016 ◽  
Vol 310 (11) ◽  
pp. G999-G1005 ◽  
Author(s):  
Christopher M. Schonhoff ◽  
Se Won Park ◽  
Cynthia R.L. Webster ◽  
M. Sawkat Anwer
Keyword(s):  
Plasma Membrane ◽  
P38 Mapk ◽  
Hepatoma Cell ◽  
Sodium Taurocholate ◽  
Mitogen Activated Protein Kinase ◽  
Hepatoma Cell Line ◽  
Mitogen Activated Protein ◽  
P38α Mapk ◽  
Opposing Effects ◽  
Interfering Rna

In hepatocytes, cAMP both activates p38 mitogen-activated protein kinase (MAPK) and increases the amount of multidrug resistance-associated protein-2 (MRP2) in the plasma membrane (PM-MRP2). Paradoxically, taurolithocholate (TLC) activates p38 MAPK but decreases PM-MRP2 in hepatocytes. These opposing effects of cAMP and TLC could be mediated via different p38 MAPK isoforms (α and β) that are activated differentially by upstream kinases (MKK3, MKK4, and MKK6). Thus we tested the hypothesis that p38α MAPK and p38β MAPK mediate increases and decreases in PM-MRP2 by cAMP and TLC, respectively. Studies were conducted in hepatocytes isolated from C57BL/6 wild-type (WT) and MKK3-knockout (MKK3−/−) mice and in a hepatoma cell line (HuH7) that overexpresses sodium-taurocholate cotransporting polypeptide (NTCP) (HuH-NTCP). Cyclic AMP activated MKK3, p38 MAPK, and p38α MAPK and increased PM-MRP2 in WT hepatocytes, but failed to activate p38α MAPK or increase PM-MRP2 in MKK3−/− hepatocytes. In contrast to cAMP, TLC activated total p38 MAPK but decreased PM-MRP2, and did not activate MKK3 or p38α MAPK in WT hepatocytes. In MKK3−/− hepatocytes, TLC still decreased PM-MRP2 and activated p38 MAPK, indicating that these effects are not MKK3-dependent. Additionally, TLC activated MKK6 in MKK3−/− hepatocytes, and small interfering RNA knockdown of p38β MAPK abrogated TLC-mediated decreases in PM-MRP2 in HuH-NTCP cells. Taken together, these results suggest that p38α MAPK facilitates plasma membrane insertion of MRP2 by cAMP, whereas p38β MAPK mediates retrieval of PM-MRP2 by TLC.

scholarly journals p38 Mitogen-Activated Protein Kinase Is Critical for Synergistic Induction of the FSHβ Gene by Gonadotropin-Releasing Hormone and Activin through Augmentation of c-Fos Induction and Smad Phosphorylation

2007 ◽  
Vol 21 (12) ◽  
pp. 3071-3086 ◽  
Author(s):  
Djurdjica Coss ◽  
Cameron M. Hand ◽  
Karen K. J. Yaphockun ◽  
Heather A. Ely ◽  
Pamela L. Mellon
Keyword(s):  
P38 Mapk ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Limiting Factor ◽  
Activator Protein 1 ◽  
Mapk Activity ◽  
C Terminus ◽  
Smad Phosphorylation ◽  
Mitogen Activated Protein ◽  
Smad 3

Abstract GnRH and activin independently and synergistically activate transcription of the FSH β-subunit gene, the subunit that provides specificity and is the limiting factor in the synthesis of the mature hormone. This synergistic interaction, as determined by two-way ANOVA, is specific for FSHβ and may, therefore, contribute to differential expression of the two gonadotropin hormones, which is critical for the reproductive cycle. We find that the cross-talk between the GnRH and activin signaling pathways occurs at the level of p38 MAPK, because the synergy is dependent on p38 MAPK activity, which is activated by GnRH, and activin cotreatment augments p38 activation by GnRH. Both the Smad and activator protein-1 binding sites on the FSHβ promoter are necessary and sufficient for synergy. After cotreatment, Smad 3 proteins are more highly phosphorylated on the activin-receptor signaling-dependent residues on the C terminus than with activin treatment alone, and c-Fos is more highly expressed than with GnRH treatment alone. Inhibition of p38 by either of two different inhibitors or a dominant-negative p38 kinase abrogates synergy on FSHβ expression, reduces c-Fos induction by GnRH, and prevents the further increase in c-Fos levels that occurs with cotreatment. Additionally, p38 is necessary for maximal Smad 3 C-terminal phosphorylation by activin treatment alone and for the further increase caused by cotreatment. Thus, p38 is the pivotal signaling molecule that integrates GnRH and activin interaction on the FSHβ promoter through higher induction of c-Fos and elevated Smad phosphorylation.

scholarly journals p38 MAPK inhibits autophagy and promotes microglial inflammatory responses by phosphorylating ULK1

2017 ◽  
Vol 217 (1) ◽  
pp. 315-328 ◽  
Author(s):  
Yingli He ◽  
Hua She ◽  
Ting Zhang ◽  
Haidong Xu ◽  
Lihong Cheng ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Morphological Changes ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Activity ◽  
Dependent Inhibition ◽  
Mitogen Activated Protein ◽  
P38α Mapk ◽  
Mechanistic Basis

Inflammation and autophagy are two critical cellular processes. The relationship between these two processes is complex and includes the suppression of inflammation by autophagy. However, the signaling mechanisms that relieve this autophagy-mediated inhibition of inflammation to permit a beneficial inflammatory response remain unknown. We find that LPS triggers p38α mitogen-activated protein kinase (MAPK)–dependent phosphorylation of ULK1 in microglial cells. This phosphorylation inhibited ULK1 kinase activity, preventing it from binding to the downstream effector ATG13, and reduced autophagy in microglia. Consistently, p38α MAPK activity is required for LPS-induced morphological changes and the production of IL-1β by primary microglia in vitro and in the brain, which correlates with the p38α MAPK-dependent inhibition of autophagy. Furthermore, inhibition of ULK1 alone was sufficient to promote an inflammatory response in the absence of any overt inflammatory stimulation. Thus, our study reveals a molecular mechanism that enables the initial TLR4-triggered signaling pathway to inhibit autophagy and optimize inflammatory responses, providing new understanding into the mechanistic basis of the neuroinflammatory process.

scholarly journals Phosphorylation of Fibroblast Growth Factor (FGF) Receptor 1 at Ser777 by p38 Mitogen-Activated Protein Kinase Regulates Translocation of Exogenous FGF1 to the Cytosol and Nucleus

2008 ◽  
Vol 28 (12) ◽  
pp. 4129-4141 ◽  
Author(s):  
Vigdis Sørensen ◽  
Yan Zhen ◽  
Malgorzata Zakrzewska ◽  
Ellen Margrethe Haugsten ◽  
Sébastien Wälchli ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Fibroblast Growth Factor ◽  
P38 Mapk ◽  
Activity Level ◽  
Mitogen Activated Protein Kinase ◽  
Target Cells ◽  
Fibroblast Growth ◽  
Mitogen Activated Protein ◽  
P38α Mapk

ABSTRACT Exogenous fibroblast growth factor 1 (FGF1) signals through activation of transmembrane FGF receptors (FGFRs) but may also regulate cellular processes after translocation to the cytosol and nucleus of target cells. Translocation of FGF1 occurs across the limiting membrane of intracellular vesicles and is a regulated process that depends on the C-terminal tail of the FGFR. Here, we report that translocation of FGF1 requires activity of the α isoform of p38 mitogen-activated protein kinase (MAPK). FGF1 translocation was inhibited after chemical inhibition of p38 MAPK or after small interfering RNA knockdown of p38α. Translocation was increased after stimulation of p38 MAPK with anisomycin, mannitol, or H2O2. The activity level of p38 MAPK was not found to affect endocytosis or intracellular sorting of FGF1/FGFR1. Instead, we found that p38 MAPK regulates FGF1 translocation by phosphorylation of FGFR1 at Ser777. The FGFR1 mutation S777A abolished FGF1 translocation, while phospho-mimetic mutations of Ser777 to Asp or Glu allowed translocation to take place and bypassed the requirement for active p38 MAPK. Ser777 in FGFR1 was directly phosphorylated by p38α in a cell-free system. These data demonstrate a crucial role for p38α MAPK in the regulated translocation of exogenous FGF1 into the cytosol/nucleus, and they reveal a specific role for p38α MAPK-mediated serine phosphorylation of FGFR1.

Stretch-dependent activation and desensitization of mitogen-activated protein kinase in carotid arteries

1997 ◽  
Vol 273 (6) ◽  
pp. C1819-C1827 ◽  
Author(s):  
Michael T. Franklin ◽  
C. L.-Albert Wang ◽  
Leonard P. Adam
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase ◽  
Vascular Function ◽  
Carotid Arteries ◽  
Mitogen Activated Protein Kinase ◽  
Muscle Stretch ◽  
Mapk Activity ◽  
Kinase C ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

Arterial smooth muscle stretch is an important physiological modulator of vascular function. To identify intracellular processes altered during muscle stretch, we found previously that extracellular signal-regulated kinase-mitogen-activated protein kinase (MAPK) activity increased in response to the application of mechanical loads. In the present study, stretch-dependent activation of MAPK in porcine carotid arteries was investigated as was the phosphorylation of the thin filament-binding protein caldesmon, which is known to be a substrate for the kinase in fully differentiated smooth muscle. MAPK activity was 67 pmol ⋅ min−1 ⋅ mg protein−1 in unloaded muscle strips immediately after attachment to force transducers and 139 pmol ⋅ min−1 ⋅ mg protein−1 within 30 s of muscle stretch. When muscle strips were continually stretched, MAPK activity remained elevated for ∼2 h and then decreased over 16 h to 16 pmol ⋅ min−1 ⋅ mg protein−1. When muscle strips were stretched and then unloaded, MAPK activity decreased within 1 h to the level present in the muscle before the stretch. These effects of muscle stretch on MAPK activity were additive to the effects of KCl or phorbol ester stimulation and were partially inhibited by reducing extracellular Ca2+. Eliminating extracellular Ca2+ had no effect on phorbol 12,13-dibutyrate (PDBu)-dependent contractions or MAPK activity; however, KCl-dependent contractions and MAPK activity were completely abolished by this procedure. An antibody specific for detecting caldesmon phosphorylated by MAPK, vs. protein kinase C (PKC), was developed and used to assess relative caldesmon phosphorylation in unstimulated and PDBu-stimulated muscle strips. In all cases investigated, the level of MAPK activity correlated with phosphocaldesmon immunoreactivity. Because arterial MAPK activity is regulated by PKC- and stretch-dependent mechanisms, these data are consistent with a role for MAPK and the subsequent phosphorylation of caldesmon as mediators in the stretch activation of vascular smooth muscle.

Role of p38 mitogen-activated protein kinase in cardiac myocyte secretion of the inflammatory cytokine TNF-α

2001 ◽  
Vol 280 (5) ◽  
pp. H1970-H1981 ◽  
Author(s):  
Cherry Ballard-Croft ◽  
D. Jean White ◽  
David L. Maass ◽  
Dixie Peters Hybki ◽  
Jureta W. Horton
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Cardiac Myocyte ◽  
Total Body Surface Area ◽  
Mitogen Activated Protein Kinase ◽  
Kinase Assay ◽  
Burn Trauma ◽  
Mapk Activity ◽  
Tnf Α ◽  
Mitogen Activated Protein

This study examined the hypothesis that burn trauma promotes cardiac myocyte secretion of inflammatory cytokines such as tumor necrosis factor (TNF)-α and produces cardiac contractile dysfunction via the p38 mitogen-activated protein kinase (MAPK) pathway. Sprague-Dawley rats were divided into four groups: 1) sham burn rats given anesthesia alone, 2) sham burn rats given the p38 MAPK inhibitor SB203580 (6 mg/kg po, 15 min; 6- and 22-h postburn), 3) rats given third-degree burns over 40% total body surface area and treated with vehicle (1 ml of saline) plus lactated Ringer solution for resuscitation (4 ml · kg−1 · percent burn−1), and 4) burn rats given injury and fluid resuscitation plus SB203580. Rats from each group were killed at several times postburn to examine p38 MAPK activity (by Western blot analysis or in vitro kinase assay); myocardial function and myocyte secretion of TNF-α were examined at 24-h postburn. These studies showed significant activation of p38 MAPK at 1-, 2-, and 4-h postburn compared with time-matched shams. Burn trauma impaired cardiac mechanical performance and promoted myocyte secretion of TNF-α. SB203580 inhibited p38 MAPK activity, reduced myocyte secretion of TNF-α, and prevented burn-mediated cardiac deficits. These data suggest p38 MAPK activation is one aspect of the signaling cascade that culminates in postburn secretion of TNF-α and contributes to postburn cardiac dysfunction.

scholarly journals p38 Mitogen-Activated Protein Kinase (MAPK) Is a Key Mediator in Glucocorticoid-Induced Apoptosis of Lymphoid Cells: Correlation between p38 MAPK Activation and Site-Specific Phosphorylation of the Human Glucocorticoid Receptor at Serine 211

2005 ◽  
Vol 19 (6) ◽  
pp. 1569-1583 ◽  
Author(s):  
Aaron L. Miller ◽  
M. Scott Webb ◽  
Alicja J. Copik ◽  
Yongxin Wang ◽  
Betty H. Johnson ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Mapk Signaling ◽  
Lymphoid Cells ◽  
Mitogen Activated Protein Kinase ◽  
Enzymatic Assays ◽  
Mapk Activity ◽  
Mitogen Activated Protein ◽  
Elevated Activity ◽  
Induced Apoptosis

Abstract Glucocorticoids (GCs) induce apoptosis in lymphoid cells through activation of the GC receptor (GR). We have evaluated the role of p38, a MAPK, in lymphoid cell apoptosis upon treatment with the synthetic GCs dexamethasone (Dex) or deacylcortivazol (DAC). The highly conserved phosphoprotein p38 MAPK is activated by specific phosphorylation of its threonine180 and tyrosine182 residues. We show that Dex and DAC stimulate p38 MAPK phosphorylation and increase the mRNA of MAPK kinase 3, a specific immediate upstream activator of p38 MAPK. Enzymatic assays confirmed elevated activity of p38 MAPK. Pharmacological inhibition of p38 MAPK activity was protective against GC-driven apoptosis in human and mouse lymphoid cells. In contrast, inhibition of the MAPKs, ERK and cJun N-terminal kinase, enhanced apoptosis. Activated p38 MAPK phosphorylates specific downstream targets. Because phosphorylation of the GR is affected by MAPKs, we examined its phosphorylation state in our system. We found serine 211 of the human GR to be a substrate for p38 MAPK both in vitro and intracellularly. Mutation of this site to alanine greatly diminished GR-driven gene transcription and apoptosis. Our results clearly demonstrate a role for p38 MAPK signaling in the pathway of GC-induced apoptosis of lymphoid cells.

scholarly journals p38δMAPK: Emerging Roles of a Neglected Isoform

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Carol O’Callaghan ◽  
Liam J. Fanning ◽  
Orla P. Barry
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Molecular Mechanisms ◽  
Mitogen Activated Protein Kinase ◽  
Biological Processes ◽  
Cellular Processes ◽  
Mapk Activity ◽  
Pathological Conditions ◽  
Mapk Signalling ◽  
Mitogen Activated Protein

p38δmitogen activated protein kinase (MAPK) is a unique stress responsive protein kinase. While the p38 MAPK family as a whole has been implicated in a wide variety of biological processes, a specific role for p38δMAPK in cellular signalling and its contribution to both physiological and pathological conditions are presently lacking. Recent emerging evidence, however, provides some insights into specific p38δMAPK signalling. Importantly, these studies have helped to highlight functional similarities as well as differences between p38δMAPK and the other members of the p38 MAPK family of kinases. In this review we discuss the current understanding of the molecular mechanisms underlying p38δMAPK activity. We outline a role for p38δMAPK in important cellular processes such as differentiation and apoptosis as well as pathological conditions such as neurodegenerative disorders, diabetes, and inflammatory disease. Interestingly, disparate roles for p38δMAPK in tumour development have also recently been reported. Thus, we consider evidence which characterises p38δMAPK as both a tumour promoter and a tumour suppressor. In summary, while our knowledge of p38δMAPK has progressed somewhat since its identification in 1997, our understanding of this particular isoform in many cellular processes still strikingly lags behind that of its counterparts.

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