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Article ; Online: Dynamin-mediated Nephrin phosphorylation regulates glucose-stimulated insulin release in pancreatic beta cells.

Jeon, Jongmin / Leibiger, Ingo / Moede, Tilo / Walter, Britta / Faul, Christian / Maiguel, Dony / Villarreal, Rodrigo / Guzman, Johanna / Berggren, Per-Olof / Mundel, Peter / Ricordi, Camillo / Merscher-Gomez, Sandra / Fornoni, Alessia

The Journal of biological chemistry

2012 Volume 287, Issue 34, Page(s) 28932–28942

Abstract: We have previously demonstrated a role for Nephrin in glucose stimulated insulin release (GSIR). We now hypothesize that Nephrin phosphorylation is required for GSIR and that Dynamin influences Nephrin phosphorylation and function. MIN6-C3 Nephrin- ... ...

Abstract	We have previously demonstrated a role for Nephrin in glucose stimulated insulin release (GSIR). We now hypothesize that Nephrin phosphorylation is required for GSIR and that Dynamin influences Nephrin phosphorylation and function. MIN6-C3 Nephrin-deficient pancreatic beta cells and human islets were transfected with WT-Nephrin or with a mutant Nephrin in which the tyrosine residues responsible for SH2 domain binding were substituted with phenylalanine (3YF-Nephrin). GSIR and live images of Nephrin and vesicle trafficking were studied. Immunoprecipitation experiments and overexpression of WT-Dynamin or dominant negative Dynamin mutant (K44A-Dynamin) in WT-Nephrin, 3YF-Nephrin, or Nephrin siRNA-transfected cells were utilized to study Nephrin-Dynamin interaction. In contrast to WT-Nephrin or to single tyrosine mutants, 3YF-Nephrin did not positively affect GSIR and led to impaired cell-cell contacts and vesicle trafficking. K44A-Dynamin prevented the effect of Nephrin on GSIR in the absence of protein-protein interaction between Nephrin and Dynamin. Nephrin gene silencing abolished the positive effects of WT-Dynamin on GSIR. The effects of protamine sulfate and vanadate on Nephrin phosphorylation and GSIR were studied in MIN6 cells and human islets. WT-Nephrin phosphorylation after glucose occurred at Tyr-1176/1193 and resulted in improved GSIR. On the contrary, protamine sulfate-induced phosphorylation at Tyr-1176/1193/1217 was associated with Nephrin degradation and impaired GSIR. Vanadate, which prevented Nephrin dephosphorylation after glucose stimulation, improved GSIR in human islets and MIN6 cells. In conclusion, Dynamin-dependent Nephrin phosphorylation occurs in response to glucose and is necessary for Nephrin-mediated augmentation of GSIR. Pharmacological modulation of Nephrin phosphorylation may thus facilitate pancreatic beta cell function.
MeSH term(s)	Amino Acid Substitution ; Dynamins/genetics ; Dynamins/metabolism ; Gene Silencing ; Glucose/metabolism ; Glucose/pharmacology ; HEK293 Cells ; Humans ; Insulin/metabolism ; Insulin Secretion ; Insulin-Secreting Cells/cytology ; Insulin-Secreting Cells/metabolism ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mutation, Missense ; Phosphorylation/drug effects ; Phosphorylation/physiology ; Proteolysis ; Sweetening Agents/metabolism ; Sweetening Agents/pharmacology ; Vanadates/pharmacology
Chemical Substances	Insulin ; Membrane Proteins ; Sweetening Agents ; nephrin ; Vanadates (3WHH0066W5) ; Dynamins (EC 3.6.5.5) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2012-06-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M112.389452
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Article ; Online: Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis.

Fornoni, Alessia / Sageshima, Junichiro / Wei, Changli / Merscher-Gomez, Sandra / Aguillon-Prada, Robier / Jauregui, Alexandra N / Li, Jing / Mattiazzi, Adela / Ciancio, Gaetano / Chen, Linda / Zilleruelo, Gaston / Abitbol, Carolyn / Chandar, Jayanthi / Seeherunvong, Wacheree / Ricordi, Camillo / Ikehata, Masami / Rastaldi, Maria Pia / Reiser, Jochen / Burke, George W

Science translational medicine

2011 Volume 3, Issue 85, Page(s) 85ra46

Abstract: Focal segmental glomerulosclerosis (FSGS) is a glomerular disease characterized by proteinuria, progression to end-stage renal disease, and recurrence of proteinuria after kidney transplantation in about one-third of patients. It has been suggested that ... ...

Abstract	Focal segmental glomerulosclerosis (FSGS) is a glomerular disease characterized by proteinuria, progression to end-stage renal disease, and recurrence of proteinuria after kidney transplantation in about one-third of patients. It has been suggested that rituximab might treat recurrent FSGS through an unknown mechanism. Rituximab not only recognizes CD20 on B lymphocytes, but might also bind sphingomyelin phosphodiesterase acid-like 3b (SMPDL-3b) protein and regulate acid sphingomyelinase (ASMase) activity. We hypothesized that rituximab prevents recurrent FSGS and preserves podocyte SMPDL-3b expression. We studied 41 patients at high risk for recurrent FSGS, 27 of whom were treated with rituximab at time of kidney transplant. SMPDL-3b protein, ASMase activity, and cytoskeleton remodeling were studied in cultured normal human podocytes that had been exposed to patient sera with or without rituximab. Rituximab treatment was associated with lower incidence of posttransplant proteinuria and stabilization of glomerular filtration rate. The number of SMPDL-3b(+) podocytes in postreperfusion biopsies was reduced in patients who developed recurrent FSGS. Rituximab partially prevented SMPDL-3b and ASMase down-regulation that was observed in podocytes treated with the sera of patients with recurrent FSGS. Overexpression of SMPDL-3b or treatment with rituximab was able to prevent disruption of the actin cytoskeleton and podocyte apoptosis induced by patient sera. This effect was diminished in cultured podocytes where SMPDL-3b was silenced. Our study suggests that treatment of high-risk patients with rituximab at time of kidney transplant might prevent recurrent FSGS by modulating podocyte function in an SMPDL-3b-dependent manner.
MeSH term(s)	Adolescent ; Antibodies, Monoclonal, Murine-Derived/pharmacology ; Antibodies, Monoclonal, Murine-Derived/therapeutic use ; Antigens, CD20/metabolism ; Apoptosis/drug effects ; Blotting, Western ; Cells, Cultured ; Child ; Female ; Fluorescent Antibody Technique ; Glomerulosclerosis, Focal Segmental/drug therapy ; Glomerulosclerosis, Focal Segmental/metabolism ; Humans ; Immunologic Factors/pharmacology ; Immunologic Factors/therapeutic use ; Immunoprecipitation ; Male ; Podocytes/cytology ; Podocytes/drug effects ; Podocytes/metabolism ; Polymerase Chain Reaction ; Retrospective Studies ; Rituximab ; Sphingomyelin Phosphodiesterase/metabolism
Chemical Substances	Antibodies, Monoclonal, Murine-Derived ; Antigens, CD20 ; Immunologic Factors ; Rituximab (4F4X42SYQ6) ; SMPDL3B protein, human (EC 3.1.4.12) ; Sphingomyelin Phosphodiesterase (EC 3.1.4.12)
Language	English
Publishing date	2011-06-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.3002231
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Article ; Online: The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A.

Faul, Christian / Donnelly, Mary / Merscher-Gomez, Sandra / Chang, Yoon Hee / Franz, Stefan / Delfgaauw, Jacqueline / Chang, Jer-Ming / Choi, Hoon Young / Campbell, Kirk N / Kim, Kwanghee / Reiser, Jochen / Mundel, Peter

Nature medicine

2008 Volume 14, Issue 9, Page(s) 931–938

Abstract: The immunosuppressive action of the calcineurin inhibitor cyclosporine A (CsA) stems from the inhibition of nuclear factor of activated T cells (NFAT) signaling in T cells. CsA is also used for the treatment of proteinuric kidney diseases. As it stands, ... ...

Abstract	The immunosuppressive action of the calcineurin inhibitor cyclosporine A (CsA) stems from the inhibition of nuclear factor of activated T cells (NFAT) signaling in T cells. CsA is also used for the treatment of proteinuric kidney diseases. As it stands, the antiproteinuric effect of CsA is attributed to its immunosuppressive action. Here we show that the beneficial effect of CsA on proteinuria is not dependent on NFAT inhibition in T cells, but rather results from the stabilization of the actin cytoskeleton in kidney podocytes. CsA blocks the calcineurin-mediated dephosphorylation of synaptopodin, a regulator of Rho GTPases in podocytes, thereby preserving the phosphorylation-dependent synaptopodin-14-3-3 beta interaction. Preservation of this interaction, in turn, protects synaptopodin from cathepsin L-mediated degradation. These results represent a new view of calcineurin signaling and shed further light on the treatment of proteinuric kidney diseases. Novel calcineurin substrates such as synaptopodin may provide promising starting points for antiproteinuric drugs that avoid the serious side effects of long-term CsA treatment.
MeSH term(s)	14-3-3 Proteins/metabolism ; Actins/metabolism ; Animals ; Calcineurin Inhibitors ; Cyclosporine/pharmacology ; Cytoskeleton/metabolism ; Gene Expression Regulation/drug effects ; Immunosuppressive Agents/pharmacology ; Mice ; Mice, Transgenic ; Microfilament Proteins/metabolism ; Phosphorylation/drug effects ; Podocytes/cytology ; Podocytes/drug effects ; Proteinuria/drug therapy ; Signal Transduction/drug effects
Chemical Substances	14-3-3 Proteins ; Actins ; Calcineurin Inhibitors ; Immunosuppressive Agents ; Microfilament Proteins ; Synpo protein, mouse ; Cyclosporine (83HN0GTJ6D)
Language	English
Publishing date	2008-08-24
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/nm.1857
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Article ; Online: Podocyte-specific GLUT4-deficient mice have fewer and larger podocytes and are protected from diabetic nephropathy.

Diabetes

2013 Volume 63, Issue 2, Page(s) 701–714

Abstract: Podocytes are a major component of the glomerular filtration barrier, and their ability to sense insulin is essential to prevent proteinuria. Here we identify the insulin downstream effector GLUT4 as a key modulator of podocyte function in diabetic ... ...

Abstract	Podocytes are a major component of the glomerular filtration barrier, and their ability to sense insulin is essential to prevent proteinuria. Here we identify the insulin downstream effector GLUT4 as a key modulator of podocyte function in diabetic nephropathy (DN). Mice with a podocyte-specific deletion of GLUT4 (G4 KO) did not develop albuminuria despite having larger and fewer podocytes than wild-type (WT) mice. Glomeruli from G4 KO mice were protected from diabetes-induced hypertrophy, mesangial expansion, and albuminuria and failed to activate the mammalian target of rapamycin (mTOR) pathway. In order to investigate whether the protection observed in G4 KO mice was due to the failure to activate mTOR, we used three independent in vivo experiments. G4 KO mice did not develop lipopolysaccharide-induced albuminuria, which requires mTOR activation. On the contrary, G4 KO mice as well as WT mice treated with the mTOR inhibitor rapamycin developed worse adriamycin-induced nephropathy than WT mice, consistent with the fact that adriamycin toxicity is augmented by mTOR inhibition. In summary, GLUT4 deficiency in podocytes affects podocyte nutrient sensing, results in fewer and larger cells, and protects mice from the development of DN. This is the first evidence that podocyte hypertrophy concomitant with podocytopenia may be associated with protection from proteinuria.
MeSH term(s)	Albuminuria ; Animals ; Cell Size ; Diabetic Nephropathies ; Doxorubicin/toxicity ; Female ; Gene Expression Regulation/physiology ; Glomerular Filtration Barrier/cytology ; Glomerular Filtration Barrier/pathology ; Glucose Transporter Type 1/genetics ; Glucose Transporter Type 1/metabolism ; Glucose Transporter Type 4/genetics ; Glucose Transporter Type 4/metabolism ; Lipopolysaccharides/toxicity ; Mice ; Podocytes/cytology ; Podocytes/metabolism
Chemical Substances	Glucose Transporter Type 1 ; Glucose Transporter Type 4 ; Lipopolysaccharides ; Slc2a1 protein, mouse ; Slc2a4 protein, mouse ; Doxorubicin (80168379AG)
Language	English
Publishing date	2013-10-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db13-0752
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Article ; Online: Cyclodextrin protects podocytes in diabetic kidney disease.

Diabetes

2013 Volume 62, Issue 11, Page(s) 3817–3827

Abstract: Diabetic kidney disease (DKD) remains the most common cause of end-stage kidney disease despite multifactorial intervention. We demonstrated that increased cholesterol in association with downregulation of ATP-binding cassette transporter ABCA1 occurs in ...

Abstract	Diabetic kidney disease (DKD) remains the most common cause of end-stage kidney disease despite multifactorial intervention. We demonstrated that increased cholesterol in association with downregulation of ATP-binding cassette transporter ABCA1 occurs in normal human podocytes exposed to the sera of patients with type 1 diabetes and albuminuria (DKD(+)) when compared with diabetic patients with normoalbuminuria (DKD(-)) and similar duration of diabetes and lipid profile. Glomerular downregulation of ABCA1 was confirmed in biopsies from patients with early DKD (n = 70) when compared with normal living donors (n = 32). Induction of cholesterol efflux with cyclodextrin (CD) but not inhibition of cholesterol synthesis with simvastatin prevented podocyte injury observed in vitro after exposure to patient sera. Subcutaneous administration of CD to diabetic BTBR (black and tan, brachiuric) ob/ob mice was safe and reduced albuminuria, mesangial expansion, kidney weight, and cortical cholesterol content. This was followed by an improvement of fasting insulin, blood glucose, body weight, and glucose tolerance in vivo and improved glucose-stimulated insulin release in human islets in vitro. Our data suggest that impaired reverse cholesterol transport characterizes clinical and experimental DKD and negatively influences podocyte function. Treatment with CD is safe and effective in preserving podocyte function in vitro and in vivo and may improve the metabolic control of diabetes.
MeSH term(s)	ATP Binding Cassette Transporter 1/biosynthesis ; Adult ; Albuminuria/physiopathology ; Animals ; Cells, Cultured ; Cholesterol/metabolism ; Cyclodextrins/pharmacology ; Cyclodextrins/therapeutic use ; Diabetes Mellitus, Type 1/blood ; Diabetes Mellitus, Type 1/physiopathology ; Diabetic Nephropathies/blood ; Diabetic Nephropathies/physiopathology ; Down-Regulation ; Humans ; Islets of Langerhans/drug effects ; Kidney Glomerulus/physiopathology ; Male ; Mice ; Mice, Obese ; Middle Aged ; Podocytes/drug effects ; Podocytes/pathology
Chemical Substances	ABCA1 protein, human ; ATP Binding Cassette Transporter 1 ; Cyclodextrins ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2013-07-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db13-0399
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Article ; Online: Rituximab is a safe and effective long-term treatment for children with steroid and calcineurin inhibitor-dependent idiopathic nephrotic syndrome.

Ravani, Pietro / Ponticelli, Alessandro / Siciliano, Chiara / Fornoni, Alessia / Magnasco, Alberto / Sica, Felice / Bodria, Monica / Caridi, Gianluca / Wei, Changli / Belingheri, Mirco / Ghio, Luciana / Merscher-Gomez, Sandra / Edefonti, Alberto / Pasini, Andrea / Montini, Giovanni / Murtas, Corrado / Wang, Xiangyu / Muruve, Daniel / Vaglio, Augusto /

Martorana, Davide / Pani, Antonello / Scolari, Francesco / Reiser, Jochen / Ghiggeri, Gian M

Kidney international

2013 Volume 84, Issue 5, Page(s) 1025–1033

Abstract: In children with idiopathic nephrotic syndrome, rituximab can maintain short-term remission with withdrawal of prednisone and calcineurin inhibitors. Long-term effects including the number of repeated infusions to maintain remission are unknown. To test ... ...

Abstract	In children with idiopathic nephrotic syndrome, rituximab can maintain short-term remission with withdrawal of prednisone and calcineurin inhibitors. Long-term effects including the number of repeated infusions to maintain remission are unknown. To test this, we treated 46 consecutive children with idiopathic nephrotic syndrome lasting for at least 1 year (mean 6.3 years), maintained in remission with oral prednisone and calcineurin inhibitors. They received 1-5 rituximab courses during a median follow-up of 3 years. Oral agents were tapered after each infusion, and completely withdrawn within 45 days. Rituximab was well tolerated. Six-month probabilities of remission were 48% after the first infusion and 37% after subsequent infusions. One- and 2-year-remission probabilities were, respectively, 20 and 10%. Median time intervals between complete oral-agent withdrawal and relapse were 5.6 and 8.5 months, respectively, following the first and subsequent courses. The time to reconstitution of CD20 cells correlated with the duration of remission, but was not associated with variation in FcyR, CD20, or SMPDL-3B polymorphisms. Podocyte Src phosphorylation was normal. Thus, rituximab can be safely and repeatedly used as a prednisone and calcineurin inhibitor-sparing therapy in a considerable proportion of children with dependent forms of idiopathic nephrotic syndrome. Further study is needed to identify patients who will benefit most from rituximab therapy.
MeSH term(s)	Administration, Oral ; Adolescent ; Age Factors ; Antibodies, Monoclonal, Murine-Derived/administration & dosage ; Antibodies, Monoclonal, Murine-Derived/adverse effects ; Antibodies, Monoclonal, Murine-Derived/therapeutic use ; Antigens, CD20/genetics ; Antigens, CD20/metabolism ; Calcineurin/metabolism ; Calcineurin Inhibitors ; Child ; Child, Preschool ; Drug Administration Schedule ; Female ; Glucocorticoids/administration & dosage ; Glucocorticoids/adverse effects ; Glucocorticoids/therapeutic use ; Humans ; Immunosuppressive Agents/administration & dosage ; Immunosuppressive Agents/adverse effects ; Immunosuppressive Agents/therapeutic use ; Infusions, Intravenous ; Kaplan-Meier Estimate ; Kidney/drug effects ; Kidney/immunology ; Kidney/metabolism ; Male ; Nephrotic Syndrome/diagnosis ; Nephrotic Syndrome/drug therapy ; Nephrotic Syndrome/genetics ; Nephrotic Syndrome/immunology ; Phosphorylation ; Podocytes/drug effects ; Podocytes/immunology ; Podocytes/metabolism ; Polymorphism, Genetic ; Prednisone/administration & dosage ; Prednisone/adverse effects ; Prednisone/therapeutic use ; Prospective Studies ; Receptors, IgG/genetics ; Recurrence ; Remission Induction ; Risk Factors ; Rituximab ; Sphingomyelin Phosphodiesterase/genetics ; Time Factors ; Treatment Outcome ; src-Family Kinases/metabolism
Chemical Substances	Antibodies, Monoclonal, Murine-Derived ; Antigens, CD20 ; Calcineurin Inhibitors ; FCGR2B protein, human ; FCGR3A protein, human ; Glucocorticoids ; Immunosuppressive Agents ; Receptors, IgG ; Rituximab (4F4X42SYQ6) ; src-Family Kinases (EC 2.7.10.2) ; Calcineurin (EC 3.1.3.16) ; SMPDL3B protein, human (EC 3.1.4.12) ; Sphingomyelin Phosphodiesterase (EC 3.1.4.12) ; Prednisone (VB0R961HZT)
Language	English
Publishing date	2013-06-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120573-0
ISSN	1523-1755 ; 0085-2538
ISSN (online)	1523-1755
ISSN	0085-2538
DOI	10.1038/ki.2013.211
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Article: The role of neural crest during cardiac development in a mouse model of DiGeorge syndrome.

Kochilas, Lazaros / Merscher-Gomez, Sandra / Lu, Min Min / Potluri, Vijaya / Liao, Jun / Kucherlapati, Raju / Morrow, Bernice / Epstein, Jonathan A

Developmental biology

2002 Volume 251, Issue 1, Page(s) 157–166

Abstract: The velo-cardio-facial syndrome (VCFS)/DiGeorge syndrome (DGS) is a genetic disorder characterized by phenotypic abnormalities of the derivatives of the pharyngeal arches, including cardiac outflow tract defects. Neural crest cells play a major role in ... ...

Abstract	The velo-cardio-facial syndrome (VCFS)/DiGeorge syndrome (DGS) is a genetic disorder characterized by phenotypic abnormalities of the derivatives of the pharyngeal arches, including cardiac outflow tract defects. Neural crest cells play a major role in the development of the pharyngeal arches, and defects in these cells are likely responsible for the syndrome. Most patients are hemizygous for a 1.5- to 3.0-Mb region of 22q11, that is suspected to be critical for normal pharyngeal arch development. Mice hemizygous for a 1.5-Mb homologous region of chromosome 16 (Lgdel/+) exhibit conotruncal cardiac defects similar to those seen in affected VCFS/DGS patients. To investigate the role of Lgdel genes in neural crest development, we fate mapped neural crest cells in Lgdel/+ mice and we performed hemizygous neural crest-specific inactivation of Lgdel. Hemizygosity of the Lgdel region does not eliminate cardiac neural crest migration to the forming aortic arches. However, neural crest cells do not differentiate appropriately into smooth muscle in both fourth and sixth aortic arches and the affected aortic arch segments develop abnormally. Tissue-specific hemizygous inactivation of Lgdel genes in neural crest results in normal cardiovascular development. Based on our studies, we propose that Lgdel genes are required for the expression of soluble signals that regulate neural crest cell differentiation.
MeSH term(s)	Animals ; DiGeorge Syndrome/embryology ; DiGeorge Syndrome/genetics ; Disease Models, Animal ; Heart/embryology ; Mice ; Morphogenesis/genetics ; Neural Crest/embryology ; T-Box Domain Proteins/genetics
Chemical Substances	T-Box Domain Proteins ; Tbx1 protein, mouse
Language	English
Publishing date	2002-11-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	1114-9
ISSN	1095-564X ; 0012-1606
ISSN (online)	1095-564X
ISSN	0012-1606
DOI	10.1006/dbio.2002.0819
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Article ; Online: Dynamin-mediated Nephrin phosphorylation regulates glucose-stimulated insulin release in pancreatic beta cells.

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Article ; Online: Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis.

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Article ; Online: The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A.

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Article ; Online: Podocyte-specific GLUT4-deficient mice have fewer and larger podocytes and are protected from diabetic nephropathy.

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Article ; Online: Cyclodextrin protects podocytes in diabetic kidney disease.

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Article ; Online: Rituximab is a safe and effective long-term treatment for children with steroid and calcineurin inhibitor-dependent idiopathic nephrotic syndrome.

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Article: The role of neural crest during cardiac development in a mouse model of DiGeorge syndrome.

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