The titin N2B and N2A regions: biomechanical and metabolic signaling hubs in cross-striated muscles.
Mechanosensor
Muscle
Muscle mechanics
Sarcomere
Signaling
Titin
Journal
Biophysical reviews
ISSN: 1867-2450
Titre abrégé: Biophys Rev
Pays: Germany
ID NLM: 101498573
Informations de publication
Date de publication:
Oct 2021
Oct 2021
Historique:
received:
27
07
2021
accepted:
23
08
2021
entrez:
8
11
2021
pubmed:
9
11
2021
medline:
9
11
2021
Statut:
epublish
Résumé
Muscle specific signaling has been shown to originate from myofilaments and their associated cellular structures, including the sarcomeres, costameres or the cardiac intercalated disc. Two signaling hubs that play important biomechanical roles for cardiac and/or skeletal muscle physiology are the N2B and N2A regions in the giant protein titin. Prominent proteins associated with these regions in titin are chaperones Hsp90 and αB-crystallin, members of the four-and-a-half LIM (FHL) and muscle ankyrin repeat protein (Ankrd) families, as well as thin filament-associated proteins, such as myopalladin. This review highlights biological roles and properties of the titin N2B and N2A regions in health and disease. Special emphasis is placed on functions of Ankrd and FHL proteins as mechanosensors that modulate muscle-specific signaling and muscle growth. This region of the sarcomere also emerged as a hotspot for the modulation of passive muscle mechanics through altered titin phosphorylation and splicing, as well as tethering mechanisms that link titin to the thin filament system.
Identifiants
pubmed: 34745373
doi: 10.1007/s12551-021-00836-3
pii: 836
pmc: PMC8553726
doi:
Types de publication
Journal Article
Review
Langues
eng
Pagination
653-677Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL152251
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL145534
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL121500
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL128457
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL142251
Pays : United States
Informations de copyright
© The Author(s) 2021.
Déclaration de conflit d'intérêts
Conflict of interestFarah Sheikh is a cofounder of Papillon Therapeutics Inc. All other co-authors (R.v.d.P., A.D., C.O., E.E. and S.L.) declare that they have no conflicts of interest.
Références
Front Physiol. 2016 Mar 01;7:76
pubmed: 26973541
Somat Cell Mol Genet. 1998 May;24(3):197-202
pubmed: 10226657
Gene. 1998 Aug 17;216(1):163-70
pubmed: 9714789
Biophys J. 2007 Sep 15;93(6):2102-9
pubmed: 17513381
J Muscle Res Cell Motil. 1996 Aug;17(4):449-61
pubmed: 8884600
Hum Mol Genet. 2014 Jan 1;23(1):209-25
pubmed: 23975679
J Muscle Res Cell Motil. 2006;27(5-7):435-44
pubmed: 16897574
J Mol Biol. 2003 Nov 7;333(5):951-64
pubmed: 14583192
PLoS One. 2013;8(1):e55034
pubmed: 23383046
J Gen Physiol. 2014 Feb;143(2):215-30
pubmed: 24470489
FEBS J. 2005 May;272(10):2578-90
pubmed: 15885106
J Biol Chem. 1995 Apr 28;270(17):10236-45
pubmed: 7730328
Heart Rhythm. 2012 Mar;9(3):390-6
pubmed: 22004663
J Mol Biol. 2021 Apr 30;433(9):166901
pubmed: 33647290
Nat Med. 2004 Mar;10(3):248-54
pubmed: 14966518
Circulation. 2014 May 13;129(19):1924-36
pubmed: 24599837
J Mol Cell Cardiol. 2010 Sep;49(3):449-58
pubmed: 20507834
Int J Biol Sci. 2018 Mar 9;14(4):369-380
pubmed: 29725258
J Struct Biol. 2010 May;170(2):270-7
pubmed: 20149875
Cytotechnology. 2008 Jun;57(2):161-8
pubmed: 19003161
Biochim Biophys Acta. 2013 Apr;1833(4):812-22
pubmed: 23047121
J Biol Chem. 2006 Mar 17;281(11):7666-83
pubmed: 16407297
Mol Cell Biol. 2000 Nov;20(22):8613-22
pubmed: 11046156
Circ Res. 2013 Feb 15;112(4):664-74
pubmed: 23283722
Cardiovasc Res. 2015 May 1;106(2):261-71
pubmed: 25770146
Circ Res. 2004 Mar 5;94(4):505-13
pubmed: 14707027
J Exp Biol. 2016 May 1;219(Pt 9):1311-6
pubmed: 26944495
Int J Mol Sci. 2017 Jun 26;18(7):
pubmed: 28672880
J Muscle Res Cell Motil. 2009;30(5-6):171-85
pubmed: 19830582
PLoS One. 2014 Aug 19;9(8):e104709
pubmed: 25137373
Circ Res. 2006 Sep 1;99(5):468-76
pubmed: 16888242
J Mol Biol. 2004 May 28;339(2):313-25
pubmed: 15136035
Circulation. 2019 Nov 12;140(20):1647-1660
pubmed: 31587567
PLoS One. 2018 Jun 11;13(6):e0198492
pubmed: 29889873
Arch Biochem Biophys. 2010 Oct 1;502(1):60-7
pubmed: 20599664
J Mol Biol. 1989 Jan 5;205(1):263-8
pubmed: 2926807
Proc Natl Acad Sci U S A. 2013 Jan 2;110(1):318-23
pubmed: 23251030
J Mol Cell Cardiol. 2013 Jan;54:90-7
pubmed: 23220127
Cell. 2014 Nov 20;159(5):1212-1226
pubmed: 25416956
Metabolism. 2021 Aug;121:154815
pubmed: 34119536
J Cell Sci. 2007 Apr 15;120(Pt 8):1423-35
pubmed: 17389685
J Mol Biol. 2008 Dec 12;384(2):299-312
pubmed: 18824175
Sci Rep. 2020 Oct 14;10(1):17239
pubmed: 33057072
EMBO J. 2000 Feb 1;19(3):359-69
pubmed: 10654935
JAMA. 2013 Mar 27;309(12):1268-77
pubmed: 23478662
Sci Rep. 2018 Oct 1;8(1):14575
pubmed: 30275509
PLoS One. 2014 Mar 19;9(3):e92259
pubmed: 24647531
J Cell Biol. 2014 Jan 20;204(2):187-202
pubmed: 24421331
Proc Natl Acad Sci U S A. 2014 Oct 7;111(40):14589-94
pubmed: 25246556
Commun Biol. 2021 Mar 19;4(1):355
pubmed: 33742095
J Mol Biol. 2021 Jun 25;433(13):166977
pubmed: 33811919
Proc Natl Acad Sci U S A. 2016 Nov 1;113(44):E6813-E6822
pubmed: 27742790
PLoS One. 2012;7(12):e50436
pubmed: 23227174
Int J Mol Sci. 2021 Mar 17;22(6):
pubmed: 33802723
J Biol Chem. 2007 May 11;282(19):14493-504
pubmed: 17371879
Am J Physiol Cell Physiol. 2003 Mar;284(3):C681-95
pubmed: 12397030
Biochem Biophys Res Commun. 1996 Aug 14;225(2):632-8
pubmed: 8753811
J Mol Cell Cardiol. 1999 Mar;31(3):569-80
pubmed: 10198188
Biochem Biophys Res Commun. 1989 Jan 16;158(1):319-25
pubmed: 2912453
Am J Hum Genet. 2009 Sep;85(3):338-53
pubmed: 19716112
Dev Cell. 2020 Nov 23;55(4):468-482.e7
pubmed: 33058779
J Mol Cell Cardiol. 2019 Aug;133:47-56
pubmed: 31158359
Cell Death Dis. 2019 May 8;10(5):372
pubmed: 31068580
J Biol Chem. 2016 Nov 25;291(48):25227-25238
pubmed: 27765816
3 Biotech. 2019 Jun;9(6):206
pubmed: 31139537
FEBS Lett. 2016 Sep;590(18):3098-110
pubmed: 27531639
Circulation. 2003 Dec 9;108(23):2926-33
pubmed: 14623810
J Gen Physiol. 2021 Jul 5;153(7):
pubmed: 33836065
J Mol Biol. 2004 Feb 6;336(1):145-54
pubmed: 14741210
J Cachexia Sarcopenia Muscle. 2020 Feb;11(1):169-194
pubmed: 31647200
Front Physiol. 2020 Mar 18;11:173
pubmed: 32256378
Curr Mol Med. 2013 Jan;13(1):24-57
pubmed: 22834835
J Muscle Res Cell Motil. 2005;26(6-8):367-74
pubmed: 16465475
PLoS One. 2010 Mar 17;5(3):e9748
pubmed: 20305823
Basic Res Cardiol. 2020 Jan 24;115(2):17
pubmed: 31980934
Neurogenetics. 2013 May;14(2):113-21
pubmed: 23456229
Circ Res. 2018 Jul 20;123(3):342-355
pubmed: 29760016
Diabetologia. 2017 Sep;60(9):1577-1585
pubmed: 28776086
PLoS One. 2011;6(10):e25519
pubmed: 22016770
PLoS One. 2015 Sep 23;10(9):e0138624
pubmed: 26398569
Nucleic Acids Res. 2006 Jan 1;34(Database issue):D535-9
pubmed: 16381927
J Am Coll Cardiol. 2014 Dec 30;64(25):2765-76
pubmed: 25541130
Nature. 2015 Mar 5;519(7541):114-7
pubmed: 25470062
Mech Dev. 2000 Jul;95(1-2):259-65
pubmed: 10906474
Biophys Rev. 2017 Jun;9(3):201-206
pubmed: 28510117
J Muscle Res Cell Motil. 2020 Mar;41(1):125-139
pubmed: 31289970
Nat Genet. 2002 May;31(1):25-32
pubmed: 11923873
J Cell Biol. 1999 Aug 9;146(3):631-44
pubmed: 10444071
J Biol Chem. 2004 Jul 2;279(27):28641-52
pubmed: 15117962
Handb Clin Neurol. 2011;101:155-66
pubmed: 21496632
Nat Commun. 2018 Oct 18;9(1):4341
pubmed: 30337525
Neuropediatrics. 2010 Feb;41(1):43-6
pubmed: 20571991
J Gen Physiol. 2005 Mar;125(3):257-71
pubmed: 15738048
FEBS J. 2010 Oct;277(20):4322-37
pubmed: 20860623
Genes Cells. 2014 Nov;19(11):830-41
pubmed: 25252031
Int J Mol Med. 2015 Apr;35(4):893-900
pubmed: 25695617
Trends Cardiovasc Med. 2013 Jul;23(5):165-71
pubmed: 23295080
J Biol Chem. 2003 Jun 27;278(26):24139-52
pubmed: 12704194
Curr Heart Fail Rep. 2020 Oct;17(5):234-246
pubmed: 32789749
Am J Respir Crit Care Med. 2018 Aug 15;198(4):472-485
pubmed: 29578749
J Cell Biol. 2001 Apr 16;153(2):413-27
pubmed: 11309420
Circ Res. 2004 Apr 16;94(7):967-75
pubmed: 14988228
Nat Commun. 2018 Jan 17;9(1):262
pubmed: 29343782
J Cell Biol. 2008 Dec 15;183(6):1033-48
pubmed: 19075112
Circ Res. 2002 Jun 14;90(11):1181-8
pubmed: 12065321
Semin Cell Dev Biol. 2000 Feb;11(1):53-60
pubmed: 10736264
J Exp Biol. 2014 Oct 15;217(Pt 20):3629-36
pubmed: 25147246
Muscle Nerve. 2013 Jan;47(1):127-34
pubmed: 23169582
Cell. 2015 Jul 16;162(2):425-440
pubmed: 26186194
J Am Coll Cardiol. 2009 Sep 1;54(10):930-41
pubmed: 19712804
Br J Pharmacol. 2018 Jul;175(13):2554-2565
pubmed: 29667180
J Cell Biol. 2000 Oct 30;151(3):495-506
pubmed: 11062252
Protein J. 2019 Apr;38(2):181-189
pubmed: 30719619
Compr Physiol. 2017 Jun 18;7(3):891-944
pubmed: 28640448
J Biomed Biotechnol. 2011;2011:310791
pubmed: 22162634
Gene. 2017 Sep 20;629:68-75
pubmed: 28754631
Mol Cell Biol. 1998 Jan;18(1):644-54
pubmed: 9418910
PLoS One. 2012;7(4):e35743
pubmed: 22532871
Cell Signal. 2016 Jan;28(1):60-73
pubmed: 26499038
Circulation. 2011 Dec 20;124(25):2882-91
pubmed: 22144574
Circulation. 1989 Sep;80(3 Pt 1):I65-76
pubmed: 2670330
Development. 1999 Oct;126(19):4223-34
pubmed: 10477291
Nucleic Acids Res. 2013 Feb 1;41(4):2659-72
pubmed: 23307558
Semin Pediatr Neurol. 2011 Dec;18(4):257-63
pubmed: 22172421
Elife. 2018 Dec 19;7:
pubmed: 30565562
Anat Rec (Hoboken). 2014 Sep;297(9):1615-29
pubmed: 25125175
Development. 1997 Feb;124(4):793-804
pubmed: 9043061
Cancer Biol Med. 2020 May 15;17(2):270-281
pubmed: 32587768
Nat Genet. 2002 Feb;30(2):205-9
pubmed: 11788825
J Virol. 2020 Dec 9;95(1):
pubmed: 33055253
Clin Res Cardiol. 2017 Feb;106(2):127-139
pubmed: 27576561
Cell Signal. 2017 Apr;32:115-123
pubmed: 28108261
J Gen Physiol. 2021 Jul 5;153(7):
pubmed: 34152365
Circ Res. 2009 Sep 11;105(6):557-64
pubmed: 19679835
Elife. 2015 Oct 16;4:e09406
pubmed: 26473617
J Cell Biochem. 2012 Apr;113(4):1265-73
pubmed: 22105831
Basic Res Cardiol. 2010 Sep;105(5):597-608
pubmed: 20376467
Biochemistry. 2008 Sep 2;47(35):9174-83
pubmed: 18690715
Cell Death Dis. 2014 Jan 16;5:e1002
pubmed: 24434510
J Mol Med (Berl). 2016 Dec;94(12):1349-1358
pubmed: 27889803
J Cell Sci. 2002 Dec 15;115(Pt 24):4925-36
pubmed: 12432079
J Biol Chem. 2003 Feb 7;278(6):3514-20
pubmed: 12456686
J Struct Biol. 2002 Jan-Feb;137(1-2):248-58
pubmed: 12064950
Biophys J. 2012 Oct 3;103(7):1480-9
pubmed: 23062340
Biochem J. 2003 Sep 15;374(Pt 3):687-95
pubmed: 12816538
J Muscle Res Cell Motil. 1986 Dec;7(6):550-67
pubmed: 3543050
Circulation. 2006 Aug 8;114(6):574-82
pubmed: 16880328
FEBS J. 2009 Feb;276(3):669-84
pubmed: 19143834
J Biol Chem. 2001 Mar 9;276(10):7442-9
pubmed: 11084039
Circ Res. 2009 Sep 25;105(7):631-8, 17 p following 638
pubmed: 19679839
Mol Cell Biol. 2014 Apr;34(8):1500-11
pubmed: 24515436
Int J Mol Sci. 2020 Jun 01;21(11):
pubmed: 32492876
Arch Biochem Biophys. 2006 Oct 1;454(1):16-25
pubmed: 16949547
FASEB J. 2012 Feb;26(2):757-65
pubmed: 22085644
J Mol Cell Cardiol. 2015 Feb;79:104-14
pubmed: 25450617
Biophys J. 2001 Oct;81(4):2297-313
pubmed: 11566799
J Biol Chem. 2004 Feb 27;279(9):7917-24
pubmed: 14676215
PLoS One. 2014 Apr 15;9(4):e93638
pubmed: 24736439
Nat Commun. 2016 Jun 29;7:12120
pubmed: 27353086
DNA Cell Biol. 1997 Apr;16(4):433-42
pubmed: 9150430
Biol Chem. 2014 Nov 1;395(11):1341-52
pubmed: 25205716
J Clin Invest. 2014 Mar;124(3):1364-70
pubmed: 24509080
J Cell Sci. 2004 Nov 15;117(Pt 24):5781-9
pubmed: 15507486
EMBO J. 2007 Apr 4;26(7):1902-12
pubmed: 17363903
Mol Cell Biol. 2004 Feb;24(3):1081-95
pubmed: 14729955
Biochem Biophys Res Commun. 1999 Feb 16;255(2):245-50
pubmed: 10049693
Circ Res. 2001 Nov 23;89(11):1065-72
pubmed: 11717165
Biophys J. 2009 Aug 5;97(3):825-34
pubmed: 19651040
J Biol Chem. 2012 Feb 24;287(9):6139-49
pubmed: 22219185
Circ Res. 2016 Sep 2;119(6):764-72
pubmed: 27470639
Nature. 2002 Aug 29;418(6901):998-1002
pubmed: 12198551
J Clin Invest. 2008 Dec;118(12):3870-80
pubmed: 19033658
FEBS Lett. 2002 Dec 18;532(3):273-8
pubmed: 12482578
J Mol Biol. 2006 Sep 29;362(4):664-81
pubmed: 16949617
Circ Res. 2014 Mar 14;114(6):1052-68
pubmed: 24625729
J Mol Cell Cardiol. 2009 Apr;46(4):490-8
pubmed: 19639676
Biophys J. 1997 Aug;73(2):905-19
pubmed: 9251807
J Clin Invest. 2014 Aug;124(8):3419-30
pubmed: 24960161
Skelet Muscle. 2013 Feb 15;3(1):3
pubmed: 23414517
J Clin Invest. 2009 Feb;119(2):349-61
pubmed: 19139564
Cell. 1997 Feb 7;88(3):393-403
pubmed: 9039266
Sci Rep. 2018 Jun 12;8(1):8970
pubmed: 29895960
J Exp Biol. 2016 Jan;219(Pt 2):135-45
pubmed: 26792323
Circulation. 2001 Jun 5;103(22):2731-8
pubmed: 11390345
Exp Physiol. 2010 Dec;95(12):1145-55
pubmed: 20851858
Nature. 2020 Apr;580(7803):402-408
pubmed: 32296183
J Gen Physiol. 2019 Jan 7;151(1):42-52
pubmed: 30567709
Mol Cell Biol Res Commun. 2000 Mar;3(3):136-40
pubmed: 10860860
PLoS One. 2015 Mar 27;10(3):e0117634
pubmed: 25816319
PLoS One. 2013 Dec 19;8(12):e84281
pubmed: 24367651
Circ Heart Fail. 2013 Nov;6(6):1239-49
pubmed: 24014826
Genomics. 2002 Feb;79(2):146-9
pubmed: 11829483
Front Physiol. 2020 May 29;11:494
pubmed: 32547410
Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8052-7
pubmed: 9653138
Small GTPases. 2019 Sep;10(5):361-366
pubmed: 28489964
J Biol Chem. 2012 Aug 24;287(35):29273-84
pubmed: 22778266
Circ Res. 2000 Jun 9;86(11):1114-21
pubmed: 10850961
Nat Commun. 2017 Oct 19;8(1):1041
pubmed: 29051486
Mol Cell Biol. 2000 Oct;20(20):7460-2
pubmed: 11003643
Biochim Biophys Acta Mol Cell Res. 2020 Mar;1867(3):118440
pubmed: 30738787
J Muscle Res Cell Motil. 2015 Feb;36(1):25-36
pubmed: 25373878
J Cell Biochem. 2001;80(3):293-303
pubmed: 11135358
Circ Res. 2001 Nov 9;89(10):874-81
pubmed: 11701614
Circ Res. 2009 Mar 27;104(6):780-6
pubmed: 19179657
Nat Rev Mol Cell Biol. 2004 Nov;5(11):920-31
pubmed: 15520811
Am J Physiol Cell Physiol. 2017 Sep 1;313(3):C327-C339
pubmed: 28615162
Science. 1995 Oct 13;270(5234):293-6
pubmed: 7569978
Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3444-9
pubmed: 17360664
J Biol Chem. 2013 Aug 23;288(34):24560-8
pubmed: 23824195
J Biol Chem. 1999 Sep 17;274(38):27083-91
pubmed: 10480922
IUBMB Life. 2012 Nov;64(11):921-30
pubmed: 23086815
J Mol Biol. 2008 Dec 5;384(1):60-72
pubmed: 18817784
Adv Biophys. 1996;33:101-22
pubmed: 8922106
Biochim Biophys Acta Proteins Proteom. 2017 Jan;1865(1):1-10
pubmed: 27742555
Mol Biol Cell. 2011 Aug 15;22(16):2946-56
pubmed: 21737686
Cardiovasc Res. 2020 Jul 1;116(8):1458-1472
pubmed: 31688894
J Cell Mol Med. 2010 Dec;14(12):2702-20
pubmed: 20874719
Proteins. 2001 May 1;43(2):145-9
pubmed: 11276084
EMBO J. 2006 Aug 23;25(16):3843-55
pubmed: 16902413
Oxid Med Cell Longev. 2019 Jul 24;2019:7318796
pubmed: 31428229
J Biol Chem. 2009 Sep 25;284(39):26964-77
pubmed: 19643733
J Struct Biol. 2002 Jan-Feb;137(1-2):194-205
pubmed: 12064946
Eur J Biochem. 1996 Jan 15;235(1-2):317-23
pubmed: 8631348
J Mol Cell Cardiol. 2017 Jul;108:24-33
pubmed: 28476659
Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10655-9
pubmed: 7938009
Mol Cell. 2004 Dec 22;16(6):867-80
pubmed: 15610731
J Biol Chem. 2008 May 23;283(21):14801-14
pubmed: 18310072
Proc Natl Acad Sci U S A. 2014 Mar 4;111(9):E817-26
pubmed: 24550490
Chem Rev. 2014 Jul 9;114(13):6589-631
pubmed: 24773235
Am J Physiol Cell Physiol. 2007 Jul;293(1):C218-27
pubmed: 17392382
Protein Sci. 2020 May;29(5):1160-1171
pubmed: 32112607
J Am Coll Cardiol. 2001 Oct;38(4):1175-80
pubmed: 11583900
Cardiovasc Res. 2008 Mar 1;77(4):637-48
pubmed: 17475230
Genes Dev. 2012 Jan 15;26(2):114-9
pubmed: 22241783
Methods Mol Biol. 2004;267:15-52
pubmed: 15269414
Circ Res. 2009 Jan 2;104(1):87-94
pubmed: 19023132
J Mol Biol. 1996 Jun 28;259(5):896-903
pubmed: 8683592
J Biol Chem. 2003 Feb 14;278(7):5188-94
pubmed: 12466281
Acta Neuropathol Commun. 2017 Sep 15;5(1):72
pubmed: 28915917
Eur Heart J. 2003 Dec;24(24):2161-3
pubmed: 14659766
J Cachexia Sarcopenia Muscle. 2018 Oct;9(5):947-961
pubmed: 29978560
Hum Mol Genet. 2014 Feb 1;23(3):618-36
pubmed: 24087791
Neuromuscul Disord. 2011 Apr;21(4):237-51
pubmed: 21310615
Gene. 1998 Apr 14;210(2):345-50
pubmed: 9573400
Nat Med. 2012 May;18(5):766-73
pubmed: 22466703
J Mol Biol. 2001 Oct 19;313(2):431-47
pubmed: 11800567
Biochem Biophys Res Commun. 2015 Aug 14;464(1):208-13
pubmed: 26102030
Med Mol Morphol. 2021 Jun;54(2):146-155
pubmed: 33492483
J Muscle Res Cell Motil. 2005;26(6-8):401-8
pubmed: 16450059
Biochem Biophys Res Commun. 2002 Feb 22;291(2):385-93
pubmed: 11846417
Mol Cell Biol. 2004 Dec;24(24):10689-702
pubmed: 15572674
Genomics. 2008 Apr;91(4):347-55
pubmed: 18255255
J Neuromuscul Dis. 2016 Nov 29;3(4):497-510
pubmed: 27911330
J Clin Invest. 2010 Aug;120(8):2672-83
pubmed: 20592470
PLoS One. 2013 Apr 23;8(4):e62687
pubmed: 23626847
Biophys J. 2011 Sep 21;101(6):1385-92
pubmed: 21943419
Biophys Rev. 2018 Aug;10(4):1187-1199
pubmed: 29353351