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Article ; Online: Targeting ER stress and calpain activation to reverse age-dependent mitochondrial damage in the heart.

Thompson, Jeremy / Maceyka, Michael / Chen, Qun

2020 Volume 192, Page(s) 111380

Abstract: Severity of cardiovascular disease increases markedly in elderly patients. In addition, many therapeutic strategies that decrease cardiac injury in adult patients are invalid in elderly patients. Thus, it is a challenge to protect the aged heart in the ... ...

Abstract	Severity of cardiovascular disease increases markedly in elderly patients. In addition, many therapeutic strategies that decrease cardiac injury in adult patients are invalid in elderly patients. Thus, it is a challenge to protect the aged heart in the context of underlying chronic or acute cardiac diseases including ischemia-reperfusion injury. The cause(s) of this age-related increased damage remain unknown. Aging impairs the function of the mitochondrial electron transport chain (ETC), leading to decreased energy production and increased oxidative stress due to generation of reactive oxygen species (ROS). Additionally, ROS-induced oxidative stress can increase cardiac injury during ischemia-reperfusion by potentiating mitochondrial permeability transition pore (MPTP) opening. Aging leads to increased endoplasmic reticulum (ER) stress, which contributes to mitochondrial dysfunction, including reduced function of the ETC. The activation of both cytosolic and mitochondrial calcium-activated proteases termed calpains leads to mitochondrial dysfunction and decreased ETC function. Intriguingly, mitochondrial ROS generation also induces ER stress, highlighting the dynamic interaction between mitochondria and ER. Here, we discuss the role of ER stress in sensitizing and potentiating mitochondrial dysfunction in response to ischemia-reperfusion, and the promising potential therapeutic benefit of inhibition of ER stress and / or calpains to attenuate cardiac injury in elderly patients.
MeSH term(s)	Aging/metabolism ; Calpain/antagonists & inhibitors ; Calpain/metabolism ; Drug Discovery ; Endoplasmic Reticulum Stress/drug effects ; Endoplasmic Reticulum Stress/physiology ; Humans ; Mitochondria, Heart/physiology ; Myocardium/metabolism ; Reperfusion Injury/metabolism ; Reperfusion Injury/prevention & control
Chemical Substances	Calpain (EC 3.4.22.-)
Language	English
Publishing date	2020-10-09
Publishing country	Ireland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	183915-9
ISSN	1872-6216 ; 0047-6374
ISSN (online)	1872-6216
ISSN	0047-6374
DOI	10.1016/j.mad.2020.111380
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Article ; Online: Sphingolipids in metabolic disease: The good, the bad, and the unknown.

Green, Christopher D / Maceyka, Michael / Cowart, L Ashley / Spiegel, Sarah

Cell metabolism

2021 Volume 33, Issue 7, Page(s) 1293–1306

Abstract: The bioactive sphingolipid metabolites ceramide and sphingosine-1-phosphate (S1P) are a recent addition to the lipids accumulated in obesity and have emerged as important molecular players in metabolic diseases. Here we summarize evidence that ... ...

Abstract	The bioactive sphingolipid metabolites ceramide and sphingosine-1-phosphate (S1P) are a recent addition to the lipids accumulated in obesity and have emerged as important molecular players in metabolic diseases. Here we summarize evidence that dysregulation of sphingolipid metabolism correlates with pathogenesis of metabolic diseases in humans. This review discusses the current understanding of how ceramide regulates signaling and metabolic pathways to exacerbate metabolic diseases and the Janus faces for its further metabolite S1P, the kinases that produce it, and the multifaceted and at times opposing actions of S1P receptors in various tissues. Gaps and limitations in current knowledge are highlighted together with the need to further decipher the full array of their actions in tissue dysfunction underlying metabolic pathologies, pointing out prospects to move this young field of research toward the development of effective therapeutics.
MeSH term(s)	Animals ; Humans ; Lipid Metabolism/physiology ; Metabolic Diseases/etiology ; Metabolic Diseases/metabolism ; Metabolic Diseases/pathology ; Metabolic Networks and Pathways/physiology ; Obesity/etiology ; Obesity/metabolism ; Obesity/pathology ; Sphingolipids/metabolism ; Sphingolipids/physiology
Chemical Substances	Sphingolipids
Language	English
Publishing date	2021-07-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2176834-1
ISSN	1932-7420 ; 1550-4131
ISSN (online)	1932-7420
ISSN	1550-4131
DOI	10.1016/j.cmet.2021.06.006
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Article: Role of Sphingosine Kinase 1 and Sphingosine-1-Phosphate Axis in Hepatocellular Carcinoma.

Maceyka, Michael / Rohrbach, Timothy / Milstien, Sheldon / Spiegel, Sarah

Handbook of experimental pharmacology

2019 Volume 259, Page(s) 3–17

Abstract: Hepatocellular carcinoma (HCC) is primarily diagnosed in the latter stages of disease progression and is the third leading cause of cancer deaths worldwide. Thus, there is a need to find biomarkers of early HCC as well as the development of more ... ...

Abstract	Hepatocellular carcinoma (HCC) is primarily diagnosed in the latter stages of disease progression and is the third leading cause of cancer deaths worldwide. Thus, there is a need to find biomarkers of early HCC as well as the development of more effective treatments for the disease. Sphingosine-1-phosphate (S1P) is a pleiotropic lipid signaling molecule produced by two isoforms of sphingosine kinase (SphK1 and SphK2) that is involved in regulation of many aspects of mammalian physiology and pathophysiology, including inflammation, epithelial and endothelial barrier function, cancer, and metastasis, among many others. Abundant evidence indicates that SphK1 and S1P promote cancer progression and metastasis in multiple types of cancers. However, the role of SphK/S1P in HCC is less well studied. Here, we review the current state of knowledge of SphKs and S1P in HCC, including evidence for the correlation of SphK1 expression and S1P levels with progression of HCC and negative outcomes, and discuss how this information could lead to the design of more effective diagnostic and treatment modalities for HCC.
MeSH term(s)	Animals ; Carcinoma, Hepatocellular/enzymology ; Carcinoma, Hepatocellular/pathology ; Liver Neoplasms/enzymology ; Liver Neoplasms/pathology ; Lysophospholipids/analysis ; Phosphotransferases (Alcohol Group Acceptor)/metabolism ; Sphingosine/analogs & derivatives ; Sphingosine/analysis
Chemical Substances	Lysophospholipids ; sphingosine 1-phosphate (26993-30-6) ; Phosphotransferases (Alcohol Group Acceptor) (EC 2.7.1.-) ; sphingosine kinase (EC 2.7.1.-) ; Sphingosine (NGZ37HRE42)
Language	English
Publishing date	2019-07-18
Publishing country	Germany
Document type	Journal Article ; Review
ISSN	0171-2004
ISSN	0171-2004
DOI	10.1007/164_2019_217
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Article ; Online: New insights into functions of the sphingosine-1-phosphate transporter SPNS2.

Spiegel, Sarah / Maczis, Melissa A / Maceyka, Michael / Milstien, Sheldon

Journal of lipid research

2019 Volume 60, Issue 3, Page(s) 484–489

Abstract: Sphingosine-1-phosphate (S1P) is a potent bioactive signaling molecule that regulates many physiological processes important for development, epithelial and endothelial barrier integrity, and the immune system, as well as for pathologies, such as ... ...

Abstract	Sphingosine-1-phosphate (S1P) is a potent bioactive signaling molecule that regulates many physiological processes important for development, epithelial and endothelial barrier integrity, and the immune system, as well as for pathologies, such as autoimmune diseases, cancer, and metastasis. Most of the well-known actions of S1P are mediated by five specific G protein-coupled receptors located on the plasma membrane. Because S1P is synthesized intracellularly by two sphingosine kinase isoenzymes, we have proposed the paradigm of inside-out signaling by S1P, suggesting that S1P must be exported out of cells to interact with its receptors. While several transporters of S1P have previously been identified, spinster homologue 2 (SPNS2), a member of the large family of non-ATP-dependent organic ion transporters, has recently attracted much attention as an S1P transporter. Here, we discuss recent advances in understanding the physiological actions of SPNS2 in regulating levels of S1P and the S1P gradient that exists between the high circulating concentrations of S1P and low tissue levels that control lymphocyte trafficking. Special emphasis is on the functions of SPNS2 in inflammatory and autoimmune diseases and its recently discovered unexpected importance in metastasis.
MeSH term(s)	Animals ; Anion Transport Proteins/chemistry ; Anion Transport Proteins/metabolism ; Homeostasis ; Humans ; Immunity ; Inflammation/metabolism ; Lysophospholipids/metabolism ; Signal Transduction ; Sphingosine/analogs & derivatives ; Sphingosine/metabolism
Chemical Substances	Anion Transport Proteins ; Lysophospholipids ; sphingosine 1-phosphate (26993-30-6) ; Sphingosine (NGZ37HRE42)
Language	English
Publishing date	2019-01-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	80154-9
ISSN	1539-7262 ; 0022-2275
ISSN (online)	1539-7262
ISSN	0022-2275
DOI	10.1194/jlr.S091959
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Zs.A 175: Show issues

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Article ; Online: Sphingolipid metabolites in inflammatory disease.

Maceyka, Michael / Spiegel, Sarah

Nature

2014 Volume 510, Issue 7503, Page(s) 58–67

Abstract: Sphingolipids are ubiquitous building blocks of eukaryotic cell membranes. Progress in our understanding of sphingolipid metabolism, state-of-the-art sphingolipidomic approaches and animal models have generated a large body of evidence demonstrating that ...

Abstract	Sphingolipids are ubiquitous building blocks of eukaryotic cell membranes. Progress in our understanding of sphingolipid metabolism, state-of-the-art sphingolipidomic approaches and animal models have generated a large body of evidence demonstrating that sphingolipid metabolites, particularly ceramide and sphingosine-1-phosphate, are signalling molecules that regulate a diverse range of cellular processes that are important in immunity, inflammation and inflammatory disorders. Recent insights into the molecular mechanisms of action of sphingolipid metabolites and new perspectives on their roles in regulating chronic inflammation have been reported. The knowledge gained in this emerging field will aid in the development of new therapeutic options for inflammatory disorders.
MeSH term(s)	Adipokines/metabolism ; Animals ; Autoimmune Diseases/metabolism ; Autoimmune Diseases/pathology ; Ceramides/metabolism ; Endothelium/metabolism ; Humans ; Inflammation/drug therapy ; Inflammation/metabolism ; Lymphocytes/cytology ; Lymphocytes/metabolism ; Lysophospholipids/metabolism ; Signal Transduction ; Sphingolipids/metabolism ; Sphingosine/analogs & derivatives ; Sphingosine/metabolism ; Tumor Necrosis Factor-alpha/metabolism
Chemical Substances	Adipokines ; Ceramides ; Lysophospholipids ; Sphingolipids ; Tumor Necrosis Factor-alpha ; ceramide 1-phosphate ; sphingosine 1-phosphate (26993-30-6) ; Sphingosine (NGZ37HRE42)
Language	English
Publishing date	2014-06-05
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/nature13475
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Zs.A 26: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Sphingosine kinase and sphingosine-1-phosphate in liver pathobiology.

Rohrbach, Timothy / Maceyka, Michael / Spiegel, Sarah

Critical reviews in biochemistry and molecular biology

2017 Volume 52, Issue 5, Page(s) 543–553

Abstract: Over 20 years ago, sphingosine-1-phosphate (S1P) was discovered to be a bioactive signaling molecule. Subsequent studies later identified two related kinases, sphingosine kinase 1 and 2, which are responsible for the phosphorylation of sphingosine to S1P. ...

Abstract	Over 20 years ago, sphingosine-1-phosphate (S1P) was discovered to be a bioactive signaling molecule. Subsequent studies later identified two related kinases, sphingosine kinase 1 and 2, which are responsible for the phosphorylation of sphingosine to S1P. Many stimuli increase sphingosine kinase activity and S1P production and secretion. Outside the cell, S1P can bind to and activate five S1P-specific G protein-coupled receptors (S1PR1-5) to regulate many important cellular and physiological processes in an autocrine or paracrine manner. S1P is found in high concentrations in the blood where it functions to control vascular integrity and trafficking of lymphocytes. Obesity increases blood S1P levels in humans and mice. With the world wide increase in obesity linked to consumption of high-fat, high-sugar diets, S1P is emerging as an accomplice in liver pathobiology, including acute liver failure, metabolic syndrome, control of blood lipid and glucose homeostasis, nonalcoholic fatty liver disease, and liver fibrosis. Here, we review recent research on the importance of sphingosine kinases, S1P, and S1PRs in liver pathobiology, with a focus on exciting insights for new therapeutic modalities that target S1P signaling axes for a variety of liver diseases.
MeSH term(s)	Animals ; Fatty Liver/enzymology ; Fatty Liver/pathology ; Humans ; Liver/enzymology ; Liver/metabolism ; Liver/pathology ; Liver Diseases/enzymology ; Liver Diseases/metabolism ; Liver Failure/enzymology ; Liver Failure/pathology ; Lysophospholipids/metabolism ; Metabolic Syndrome/enzymology ; Metabolic Syndrome/pathology ; Phosphotransferases (Alcohol Group Acceptor)/metabolism ; Sphingosine/analogs & derivatives ; Sphingosine/metabolism
Chemical Substances	Lysophospholipids ; sphingosine 1-phosphate (26993-30-6) ; Phosphotransferases (Alcohol Group Acceptor) (EC 2.7.1.-) ; sphingosine kinase (EC 2.7.1.-) ; Sphingosine (NGZ37HRE42)
Language	English
Publishing date	2017-06-15
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	1000977-2
ISSN	1549-7798 ; 1381-3455 ; 1040-9238
ISSN (online)	1549-7798
ISSN	1381-3455 ; 1040-9238
DOI	10.1080/10409238.2017.1337706
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Article ; Online: Sphingosine Kinase 2 in Stromal Fibroblasts Creates a Hospitable Tumor Microenvironment in Breast Cancer.

Weigel, Cynthia / Maczis, Melissa A / Palladino, Elisa N D / Green, Christopher D / Maceyka, Michael / Guo, Chunqing / Wang, Xiang-Yang / Dozmorov, Mikhail G / Milstien, Sheldon / Spiegel, Sarah

Cancer research

2022 Volume 83, Issue 4, Page(s) 553–567

Abstract: Reciprocal interactions between breast cancer cells and the tumor microenvironment (TME) are important for cancer progression and metastasis. We report here that the deletion or inhibition of sphingosine kinase 2 (SphK2), which produces sphingosine-1- ... ...

Abstract	Reciprocal interactions between breast cancer cells and the tumor microenvironment (TME) are important for cancer progression and metastasis. We report here that the deletion or inhibition of sphingosine kinase 2 (SphK2), which produces sphingosine-1-phosphate (S1P), markedly suppresses syngeneic breast tumor growth and lung metastasis in mice by creating a hostile microenvironment for tumor growth and invasion. SphK2 deficiency decreased S1P and concomitantly increased ceramides, including C16-ceramide, in stromal fibroblasts. Ceramide accumulation suppressed activation of cancer-associated fibroblasts (CAF) by upregulating stromal p53, which restrained production of tumor-promoting factors to reprogram the TME and to restrict breast cancer establishment. Ablation of p53 in SphK2-deficient fibroblasts reversed these effects, enabled CAF activation and promoted tumor growth and invasion. These data uncovered a novel role of SphK2 in regulating non-cell-autonomous functions of p53 in stromal fibroblasts and their transition to tumor-promoting CAFs, paving the way for the development of a strategy to target the TME and to enhance therapeutic efficacy. Significance: Sphingosine kinase 2 (SphK2) facilitates the activation of stromal fibroblasts to tumor-promoting cancer-associated fibroblasts by suppressing host p53 activity, revealing SphK2 as a potential target to reprogram the TME.
MeSH term(s)	Animals ; Mice ; Cancer-Associated Fibroblasts/metabolism ; Fibroblasts/metabolism ; Lung Neoplasms/pathology ; Lung Neoplasms/secondary ; Mammary Neoplasms, Animal/metabolism ; Mammary Neoplasms, Animal/pathology ; Phosphotransferases (Alcohol Group Acceptor)/genetics ; Phosphotransferases (Alcohol Group Acceptor)/metabolism ; Tumor Microenvironment/physiology ; Tumor Suppressor Protein p53/genetics
Chemical Substances	Phosphotransferases (Alcohol Group Acceptor) (EC 2.7.1.-) ; sphingosine 1-phosphate (26993-30-6) ; sphingosine kinase (EC 2.7.1.-) ; Tumor Suppressor Protein p53
Language	English
Publishing date	2022-12-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-22-1638
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Article ; Online: Revisiting the sphingolipid rheostat: Evolving concepts in cancer therapy.

Newton, Jason / Lima, Santiago / Maceyka, Michael / Spiegel, Sarah

Experimental cell research

2015 Volume 333, Issue 2, Page(s) 195–200

MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Cell Transformation, Neoplastic/metabolism ; Ceramides/physiology ; Humans ; Lysophospholipids/physiology ; Molecular Targeted Therapy ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors ; Phosphotransferases (Alcohol Group Acceptor)/metabolism ; Receptors, Lysophospholipid/metabolism ; Signal Transduction ; Sphingosine/analogs & derivatives ; Sphingosine/physiology
Chemical Substances	Antineoplastic Agents ; Ceramides ; Lysophospholipids ; Receptors, Lysophospholipid ; sphingosine 1-phosphate (26993-30-6) ; Phosphotransferases (Alcohol Group Acceptor) (EC 2.7.1.-) ; sphingosine kinase (EC 2.7.1.-) ; Sphingosine (NGZ37HRE42)
Language	English
Publishing date	2015-03-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	1493-x
ISSN	1090-2422 ; 0014-4827
ISSN (online)	1090-2422
ISSN	0014-4827
DOI	10.1016/j.yexcr.2015.02.025
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Article ; Online: Lysophospholipid receptor nomenclature review: IUPHAR Review 8.

Kihara, Yasuyuki / Maceyka, Michael / Spiegel, Sarah / Chun, Jerold

British journal of pharmacology

2014 Volume 171, Issue 15, Page(s) 3575–3594

Abstract: Lysophospholipids encompass a diverse range of small, membrane-derived phospholipids that act as extracellular signals. The signalling properties are mediated by 7-transmembrane GPCRs, constituent members of which have continued to be identified after ... ...

Abstract	Lysophospholipids encompass a diverse range of small, membrane-derived phospholipids that act as extracellular signals. The signalling properties are mediated by 7-transmembrane GPCRs, constituent members of which have continued to be identified after their initial discovery in the mid-1990s. Here we briefly review this class of receptors, with a particular emphasis on their protein and gene nomenclatures that reflect their cognate ligands. There are six lysophospholipid receptors that interact with lysophosphatidic acid (LPA): protein names LPA1 - LPA6 and italicized gene names LPAR1-LPAR6 (human) and Lpar1-Lpar6 (non-human). There are five sphingosine 1-phosphate (S1P) receptors: protein names S1P1 -S1P5 and italicized gene names S1PR1-S1PR5 (human) and S1pr1-S1pr5 (non-human). Recent additions to the lysophospholipid receptor family have resulted in the proposed names for a lysophosphatidyl inositol (LPI) receptor - protein name LPI1 and gene name LPIR1 (human) and Lpir1 (non-human) - and three lysophosphatidyl serine receptors - protein names LyPS1 , LyPS2 , LyPS3 and gene names LYPSR1-LYPSR3 (human) and Lypsr1-Lypsr3 (non-human) along with a variant form that does not appear to exist in humans that is provisionally named LyPS2L . This nomenclature incorporates previous recommendations from the International Union of Basic and Clinical Pharmacology, the Human Genome Organization, the Gene Nomenclature Committee, and the Mouse Genome Informatix.
MeSH term(s)	Animals ; Humans ; Ligands ; Receptors, Lysophospholipid/metabolism ; Terminology as Topic
Chemical Substances	Ligands ; Receptors, Lysophospholipid
Language	English
Publishing date	2014-07-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1111/bph.12678
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Article ; Online: CRISPR/Cas9 deletion of ORMDLs reveals complexity in sphingolipid metabolism.

Green, Christopher D / Weigel, Cynthia / Oyeniran, Clement / James, Briana N / Davis, Deanna / Mahawar, Usha / Newton, Jason / Wattenberg, Binks W / Maceyka, Michael / Spiegel, Sarah

Journal of lipid research

2021 Volume 62, Page(s) 100082

Abstract: The serine palmitoyltransferase (SPT) complex catalyzes the rate-limiting step in the de novo biosynthesis of ceramides, the precursors of sphingolipids. The mammalian ORMDL isoforms (ORMDL1-3) are negative regulators of SPT. However, the roles of ... ...

Abstract	The serine palmitoyltransferase (SPT) complex catalyzes the rate-limiting step in the de novo biosynthesis of ceramides, the precursors of sphingolipids. The mammalian ORMDL isoforms (ORMDL1-3) are negative regulators of SPT. However, the roles of individual ORMDL isoforms are unclear. Using siRNA against individual ORMDLs, only single siORMDL3 had modest effects on dihydroceramide and ceramide levels, whereas downregulation of all three ORMDLs induced more pronounced increases. With the CRISPR/Cas9-based genome-editing strategy, we established stable single ORMDL3 KO (ORMDL3-KO) and ORMDL1/2/3 triple-KO (ORMDL-TKO) cell lines to further understand the roles of ORMDL proteins in sphingolipid biosynthesis. While ORMDL3-KO modestly increased dihydroceramide and ceramide levels, ORMDL-TKO cells had dramatic increases in the accumulation of these sphingolipid precursors. SPT activity was increased only in ORMDL-TKO cells. In addition, ORMDL-TKO but not ORMDL3-KO dramatically increased levels of galactosylceramides, glucosylceramides, and lactosylceramides, the elevated N-acyl chain distributions of which broadly correlated with the increases in ceramide species. Surprisingly, although C16:0 is the major sphingomyelin species, it was only increased in ORMDL3-KO, whereas all other N-acyl chain sphingomyelin species were significantly increased in ORMDL-TKO cells. Analysis of sphingoid bases revealed that although sphingosine was only increased 2-fold in ORMDL-TKO cells, levels of dihydrosphingosine, dihydrosphingosine-1-phosphate, and sphingosine-1-phosphate were hugely increased in ORMDL-TKO cells and not in ORMDL3-KO cells. Thus, ORMDL proteins may have a complex, multifaceted role in the biosynthesis and regulation of cellular sphingolipids.
MeSH term(s)	CRISPR-Cas Systems
Language	English
Publishing date	2021-04-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80154-9
ISSN	1539-7262 ; 0022-2275
ISSN (online)	1539-7262
ISSN	0022-2275
DOI	10.1016/j.jlr.2021.100082
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