Implication de "Liver X Receptors" dans la physiopathologie des gonades
271
0
0
Texte intégral
(2) !. !. UNIVERSITE BLAISE PASCAL N° D.U. 2713 ! ! !. !. !. !. UNIVERSITE D'AUVERGNE ANNEE : 2016 !. !. ECOLE DOCTORALE SCIENCES DE LA VIE, SANTE, AGRONOMIE, ENVIRONNEMENT N° d’ordre : 693. Thèse Présentée à l’Université Blaise Pascal Pour l’obtention du grade de DOCTEUR D’UNIVERSITE Spécialité : Génétique et Physiologie Moléculaire (Endocrinologie moléculaire et cellulaire). Soutenue publiquement par. Salwan MAQDASY le 04 Juillet 2016. Implication de « Liver X Receptors » dans la physiopathologie des gonades Président du jury Pr. Claude Dubray, Université d’Auvergne Examinateurs. Pr. Paolo Parini, Karolinska Institutet-Stockholm Pr. Igor Tauveron, Université d’Auvergne. Rapporteurs. Pr. Sophie Christin-Maître, Université de Paris Dr. Hervé Guillou, Université de Toulouse. Directeur. Dr. Silvère BARON, Université Blaise Pascal Laboratoire GReD : UMR CNRS 6293-INSERM U1103 Université Clermont Auvergne, France. !.
(3) !. !. UNIVERSITE BLAISE PASCAL !. D.U. No. 2713 ! !. !. !. !. UNIVERSITE D'AUVERGNE Year: 2016 !. ! !. DOCTORAL SCHOOL of LIFE SCIENCES, HEALTH and ENVIRONMENT Order number: 693 !. Thesis ! Presented to Blaise Pascal University In fulfillment of the requirements for the Degree of PHILOSOPHIÆ DOCTOR (PhD). In molecular Physiology and Genetics (Molecular and cellular Endocrinology). Defended in July 4th, 2016 By. Salwan MAQDASY. Implication of «Liver X Receptors» in the physiopathology of gonads President of jury Pr. Claude Dubray, University of Auvergne Examiners. Pr. Paolo Parini, Karolinska Institute-Stockholm Pr. Igor Tauveron, University of Auvergne. Reporters. Pr. Sophie Christin-Maître, University of Paris Dr. Hervé Guillou, University of Toulouse. Thesis director. Dr. Silvère BARON, University of Blaise Pascal GReD Lab : UMR CNRS 6293-INSERM U1103 Université Clermont Auvergne, France. !.
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`6U&413,&01&)$/,2+0+52%&4%&01&(%0060%&4%&D%'*+02"& 5067089*$;* PP9===TJ%&K+35'T,&4%&01&D+(2U*U&S'13V12,%&4WF34+('23+0+52%8&K0%'J+3*ZS%''1348&S'13(%8& MN!!"&& +2=03*4* a" >%,&'U(%)*%6',&4%,&+./,*U'+0%,&%*&01&'U5601*2+3&4%,&-+3(*2+3,&%34+('23%&%*&%.+('23%&4%,& 5+314,"& 5067089*$;& @+6'3U%,&4bU(+0%&4+(*+'10%8&K0%'J+3*ZS%''1348&S'13(%8&MN!E"& c" >2<%'&P&'%(%)*+',&134&+<1'/&)$/,2+0+5/d&4%%)&2J)1(*;& 5067089*$;&@+6'3U%,&4%&\I%:&K0%'J+3*ZS%''1348&S'13(%8&MN!E"& !N" K$+0%,*U'+0&%*&-%'*202*U&d&0b23(+336&4%,&'U(%)*%6',&36(0U12'%,&>PI,"&& 5067089*$"&A1'42&\I%:8&K0%'J+3*ZS%''1348&S'13(%8&MN!M"& &. !. !.
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�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
(8) !. !. "#$%&'()'*+,!. !"#$%&!'&()*+ !+ !"#$ $ !"&$ $ !#!%$ $ !##$ $ !;!<$$ !>;$ $ !@$ $ !<B$ $ !<&$ $ !<&-$ $ !E$ $ !E>$ $ $ "+ "<&FG$$ "%"$ $ "B%$ $ $ ,+ #-*+H$ $ #IB$ $ #I%&$ $ #8EI"&$ #*:KL$ $ #MN$ $ #O&$ $ #%$Q%#R$$ #S$QS#R$ $ -+ ;!N'F$ $ ;IT$ $ ;BI!$ $ ;>;$ $ ;M#U'F$ ;EK$ $ $ $+ IS@$ $ IX<M'F$ IE$ $ $ .+ @!T$ $. !%&'()*+)*,$-.//0110$12.*/342102/$ .*+24,0*$()*+)*,$32410)*$ .-56'#4!7$-8460/10246$.-5612.*/902./0$ .-0156'#4!$-.2(4:56./0$ .*+24,0*$+)990-)0*-5$49$.,)*,$=.60$ +04:52)(4*?-60)-$.-)+$ .-1)A.1)*,$9?*-1)4*$ .*1)==?6602).*$842=4*0$ .//)/1.*-0$=0+)-.6$C$6.$324-2D.1)4*$ -5-6)-$.+0*4/)*0$=4*4$384/38.10$ .*+24,0*$20-03142$ 2)(4*?-60)-$.-)+$. (4*0$=42384,0*)-$9.-142$ (644+$10/1)/$(.22)02$ 80=.1410/1)-?6.2$(.22)02$. -5-6)*$;H$ -8460/10256$0/102$85+246./0$ -8460/10246$0/102$12.*/902$32410)*J$ -.2(485+2.10$20/34*/0$060=0*1$()*+)*,$32410)*$ -4**0:)*$KL$ -5-644:5,0*./0$$ -514-824=0$&KGP$ 180-.$-066$ ,2.*?64/.$-066$. +4/.,0$/0*/)1)A0$/0:$20A02/.6$.+20*.6$853436./).$-2)1)-.6$20,)4*$-824=4/4=0$N$ +)01856$/1)6(0/1246$ +085+2403).*+24/1024*0$ ;>!$()*+)*,$+4=.)*$ +0+)-.142$49$-514V)*0/)/$F$ +)20-1$2030.1$. 03)+02=$,24W18$9.-142,$ I*,?69=0*1$.*+$-066$=41)6)15$32410)*$F$ 0/124,0*$20-03142$. 9.115$.-)+$/5*18./0$$ !. !. !.
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
(11) ! !" !"#$ $ !4567$ $ !;<$ $ !6>?#$$ !A5!$ $ !<$ $ $ #" CDE5$ $ C"<$ $ C;";$ $ $ $" GH6I$ $ $ K)<?$ $ $. !. %&'%()*+,-$./'0&1&'('$'/1.-23&$ %-,1')-(8%(21,+$3&.(,%2-'9(1%&-3&.(,-/$:,)%2-$7$ !2++6+(=&$-&)&8%2-'$ %&'%&'$3&(2'('6,)%(@,%(10$'%&-2+$ %*32-$1&)-2'(':,)%2-6!$ %B/-2(.$B2-321&$-&)&8%2-$. @,')*+,-$&1.2%B&+(,+$0-2F%B$:,)%2-$ @(%,3(1$"$-&)&8%2-$ @&-/6+2F6.&1'(%/$+(828-2%&(1'$. J21,$2))+*.&1'$ K6)('$-&%(12()$,)(.$. ! !. !. "#$%&'()'*+,!.
(12) !. !. "#$$%&'(!. !"##$%&'( )*+,-(./+-0(&12*13(45(6*-1+/-7+1(8888888888888888888888888888888888888888888888888888888888888888888888888888888888888888888(9( !"#$%&'()')*+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+-+ :;/.*-+1(%(.+/0"1(+2+3141'%)(*+5/236+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+7+ -,+ /1*+(841'%19(*+:94;8#0(1*+.+<8$8(#;0%8*+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+7+ 7,+ /0"1(+2+3141'%)(*+=/23*>+.+<8$8(#;0%8*+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+?+ ?,+ /23*+.+@A'(1**0)$+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+?+ B,+ C%(94%9(1+1%+D)E1+EF#4%0)$+E1*+/23*+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+G+ G,+ /1*+;0<#$E*+E1+/23*+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+H+ I,+ 3J;1*+'KL*0);)<0M91*+E1*+/23*+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+N+ ++!&+ /23*+1%+;1+D8%#O);0*D1+;0'0E0M91+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+N+ ++P&+ /23*+1%+0$Q;#DD#%0)$+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+-7+ ++R&+ /#+';#41+E1*+/23*+E#$*+;#+'KL*0)'#%K);)<01+E9+E0#OS%1+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+-?+ ++T&+ /23*+1%+;1+D8%#O);0*D1+;0'0E0M91+48(8O(#;+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+-G+ ++@&+ /23*+1%+;F#$<0)<1$S*1+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+-G+ ++U&+ /23*+1%+;1+*L*%SD1+1$E)4(0$01$+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+-I+ :;/.*-+1(%%+.+3J;1*+E1*+/23*+E#$*+;#+'KL*0);)<01+1%+;1*+'#%K);)<01*+E1*+<)$#E1*+,,,,,,,,,,,+-H+ ++V,+ /#+(1'()E94%0)$+D#*49;0$1+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+-H+ -,+ /F#$#%)D01+1%+;FK0*%);)<01+E9+%1*%049;1+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+-H+ 7,+ /#+'KL*0);)<01+%1*%049;#0(1+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+-H+ !,+ /#+*'1(D#%)<1$S*1+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+-H+ P,+ /1*+41;;9;1*+E1+C1(%);0+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+-W+ R,+ /1*+41;;9;1*+E1+/1LE0<+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+7?+ ?,+ /#+D#%9(#%0)$+')*%+%1*%049;#0(1+E9+<#DS%1+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+7I+ B,+ /FKL')<)$#E0*D1+1%+;1*+;0'0E1*+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+7H+ G,+ /23*+1%+(1'()E94%0)$+D#*49;0$1+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+7W+ !,+ /23*+1%+;#+*'1(D#%)<1$S*1+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+7W+ P,+ /23*+1%+;#+*%8()XE)<1$S*1+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+?7+ R,+ 3J;1+E1*+/23*+E#$*+;1*+'#%K);)<01*+<)$#E0M91*+4K1Y+;FK)DD1+,,,,,,,,,,,,,,,,,,,,,,,+?7+ T,+ 3J;1+E1*+/23*+E#$*+;#+D#%9(#%0)$+')*%&%1*%049;#0(1+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+?B+ ++VV,+ /#+(1'()E94%0)$+Q8D0$0$1+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+?G+ -,+ C%(94%9(1+1%+'KL*0);)<01+E1+;F)"#0(1+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+?G+ !,+ /#+Q);;049;)<1$S*1+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+?G+ P,+ /1*+41;;9;1*+E1+;#+<(#$9;)*#+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+BZ+ R,+ /1*+41;;9;1*+E1+;#+%KSM91+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+B7+ 7,+ [()9O;1*+E1+;#+Q1(%0;0%8+1%+;0'0E1*+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+B?+ ?,+ \()4(8#%0)$+]8E04#;1D1$%+!**0*%81+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+BG+ B,+ /23*+1%+(1'()E94%0)$+Q8D0$0$1+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+BH+ !,+ @A'(1**0)$+1%+;0<#$E*+E1*+/23*+E#$*+;F)"#0(1+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+BH+ P,+ 3J;1*+E1*+/23*+E#$*+;F)"#0(1+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+BN+ R,+ 3J;1*+E1*+/23*+E#$*+;F9%8(9*+1%+;#+';#41$%#+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+GZ+ !1<4=>(?/+-0(!<*1=-*5*<(<4=-1@-(A(&1,1/+<;(.+4B1<-(888888888888888888888888888888888888888888888888888888888888(CD( !,+ 31<9;#%0)$+)Q+%K1+%1*%049;#(+'KL*0);)<L+OL+/23!+=!(%04;1+->+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+GG+ P,+ 3);1+)Q+/23^+0$+%K1+<(#$9;)*#+41;;*+=!(%04;1+7>+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+GH+ E;*+>(?/+-0(&1,7F-,(/=>(?7GF*</-*4=,(888888888888888888888888888888888888888888888888888888888888888888888888888888888(CH( ++++T0*49**0)$+#$E+\1(*'14%0"1*+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+IZ+ -,+ /23+#$E+%1*%049;#(+'KL*0)'#%K);)<L+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,+IZ+ ! !. !.
(13) !. !. "#$$%&'(!. !"# $%&'(#)%*(+'#"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""#,-# ."# /01'#23(#425(6((7(3'#24289'5#(9*%:389(#*8'3&75%3'#;<&77+"#!358:+(#=>#"""""""""""""#,?# @"# @+898:2+#:%9'8*(3258%9'#"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""#,A# B"# 1%+(#%C#/01'#89#5D(#%E23829#7DF'8%725D%+%4F#"""""""""""""""""""""""""""""""""""""""""""""""""""""""#G-# !"# $%&'(#)%*(+'#"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""#G-# ."# @+898:2+#:%9'8*(3258%9'#"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""#GH# ####I(9(32+#:%9:+&'8%9'#""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""#GG# ####1(E8(J#!358:+('#""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""#G?# ####<&77+()(9523F#2358:+('#"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""#GA# .8K+8%4327DF#""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""#?-# # #. ! !. !.
(14) !. !. !. !. !. !. !. !. "#$%&!'($&)!*+,#+-!./!0#&+$(&1$+! 23('&+$!4)!"#$%&!'!(%)%*+,&-!.!"'(-!/!! 23('&+$!44)!(,0%-!,1!"'(-!#2!+3%!*34-#,0,54!627!*6+3,0,54!,1!+3%!5,267-! !. !. !. 45!. 860%!&%*&,79)+#,2!. 445!. :%;60%!&%*&,79)+#,2!. ! !. !. !.
(15) !"#$%&'()*%+#,&-$#(&./()&0"1$23& !"#$%&'()*%+#,&-$#(&./()&0"1$23& !"#$%&'()'*+,-.'/&%0.",1'%-,&'&2+.$0+3'"3',4&'5+%.6'-36'7+%&'89&:";:-..1'"3'<$%+9&'/%+7' (=>?',+'@?(AB'C.-:D':$%2&'%&9%&8&3,8'/&%0.",1'&2+.$0+3'"3'!%-3:&B' !"#$%&"'()*+',-&./'01'23#33&4#&3'&%'#.1'567/-*.'8&9'':;<=1'.
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`)$#0-.''"(+=%#a%'+#2+$#>&2("%+.'$#0-%+=%(+)$#'+)("=%#)+#$L=2'->+#>&%"A-)(F.+#+%#$+$# *-=$&F.+=*+$# $.'# )"# /+'%()(%&@# +%# a%'+# (>0)(F.&$# 2"=$# )"# 0+'%.'A"%(-=# +=2-*'(=(+==+# (=2.(%+# 0"'#2+$#/"*%+.'$#+=C('-==+>+=%".[#D33@6JE9# -!. ! !. !. !. !. !. !. !.
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`0;$ 0`0$ G$!"#$%&$'( )( !"*"+#&,$H;$ [[>0$ G$-",&.$/&0"( -,&1$2",3#&,( 4*#$53#"'( !"*"+#&,(H;$ W`0$ G$63,%$/&$'( )( !"*"+#&,(H;$ ")$ [`0$ G$-,"7%3%( )( !"*"+#&,(H=$ a"#$ %&'"()"*%#$ #3+)$ .6(,.7*&#$4-+#$,<?36&3#)-#."$4"#$,.(.4"#$")$3+)$*+"$5-.9,"$-55.+.)&$L$,"*%#$,.:-+4#=$$ I= !"#$ 01#$ 3%(?",.+#$ #-+#$ ,.:-+4;$ )",#$ 7*"$ aP[$ G(/0311( 8"#",&'$0",( +3,#%",(H;$ K>`bY$ 9('&/37"(/"%/$#$5"(/".(,"5",/31:(3',"%31(8;+&+13/$3(*&%7"%$#3:(*,$#$*31(,"7$&%(&%(#8"()( *8,&0&/&0":(7"%"(<(H;$!0PbY$G$=$5",(!"*"+#&,(>&0&1&7?<(H;$")$aWbY$G$@#",&$'&7"%$*( -! !. !. !. !. !. !. !.
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`T"#50#*2,*0'+#1%&#+3&&,&#%9*'3<%-+#,-.U(/),-.U0)%&+#%9*'3<(#,-38,%<%-+#0,# -36%0,#+%&+3),203'%#+0-13,%#,-.U1)#0#,-#+'C&#>0372%#-36%0,#1.%9*'%&&3/-"## $=%^#2.H/<<%F#2%#4C-%#)/10-+#5MAU#D2.(31L#%&+#&3+,(#&,'#2%#)='/</&/<%#II"#;2#%&+# )/-&+3+,(#1%#`#%9/-&F#06%)#1%&#&3+%/--%,'.(*3&&04%#D5MAUIEF#5MAUIaL#<03&#)/10-+#,-%# &%,2%# *'/+(3-%"# $=%^# 20# &/,'3&F# 2%# 4C-%# 2&(41# %&+# 2/)023&(# &,'# 2%# )='/</&/<%# VF# 32# %&+# )/<*/&(#1%#I]#%9/-&#RSYT"#5MAW#D2.(30L#%&+#&3+,(#&,'#2%#)='/</&/<%#Ib#)=%^#2.H/<<%#%+#_# )=%^#20#&/,'3&"#;2#%&+#)/<*/&(#1%#I]#%9/-
-%%,9#)0&"##. -! !. !. !. !. !. !. !.
(20) LXR! !. LXR" !. Figure 3: A-Northen blot analysis of tissue distribution of LXR! and LXR" in the adult mouse. Cyclophilin is included as a comparative control. Adapted from Repa and Mangelsdorf 2000. B-Expression profile of mRNA transcript for mouse LXR! and LXR" in two mouse strains. Adapted from Bookout et mangelsdorf 2003, 2006..
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`,)0&'#L'-%%J&"G0'9#0$#.+&",0'S#@MM9M\C#La).-%0#ASD# !0'# ,0-># )'+:+%?0'# *0-<0&$# "<+)%# ,0'# %bG0'# *Ec')+G+.)=-0'# ,)::J%0&$'# 0$# &+&# %0,+&,"&$'#,"&'#-&#?K?0#$)''-D#40$$0#(+&(-%%0&(0#0'$#(+&'$"$J0#G+%'#,0#GH"&"Gc'0#,0'#'+-%)'# ,J:)()0&$0'# '-%# -&# )'+:+%?0# ?")'# 0>*%)?"&$# GH"-$%0# )'+:+%?0# L!%&3'(') +-) !%&U'('$*) P"&'# G0'# $)''-'# +_# G0'# ,0-># )'+:+%?0'# '+&$# *%J'0&$'9# GH"W'0&(0# ,H"($)<)$J# ,0# !12U#*+-%%")$# K$%0# (+?*0&'J0# *"%# !1239# ?")'# !12U# 0'$# *0-# %J.-GJ# *"%# G0'# <+)0'# (0GG-G")%0'# 0$# &0# *0-$# (+?*0&'0%#G0#%bG0#,0#!123D#!123#0'$#,+&(#,+?)&"&$#0&#$0%?0#,H"($)<)$J#*Ec')+G+.)=-0#,"&'# G0'#$)''-'#+_#G0'#,0->#)'+:+%?0'#'+&$#0>*%)?J'9#(+??0#(H0'$#G0#("'#"-#&)<0"-#EJ*"$)=-0D#8"%# 0>0?*G09# GH)&<"G),"$)+&# ,-# ./&0# !%&+# (+&,-)$# d# -&0# '$J"$+'0# EJ*"$)=-0# (E0F# G0'# "&)?"-># &+-%%)'# "<0(# -&# %J.)?0# %)(E0# 0&# (E+G0'$J%+G# @M[C*) 40# *EJ&+$c*0# 0'$# ,e# d# -&0# "W'0&(0# ,H)&,-($)+&#,-#./&0#,-./019#-&#./&0#()WG0#,)%0($0#,0#!123#(E0F#G"#'+-%)'D#!H)'+:+%?0#WK$"#"-# &)<0"-#EJ*"$)=-0#&H0'$#*"'#("*"WG0#d#(+?*0&'0%#(0$#0::0$D#f&<0%'0?0&$9#!123#&0#*0-$#*"'# 0?*K(E0%#G0#*EJ&+$c*0#-$J%)&#(E0F#G"#'+-%)'#!%&2'(')@MYC*#fG#0>)'$0#,+&(#,0'#?+,0'#,H"($)+&# ,)'$)&($'#*+-%#(0'#,0->#%J(0*$0-%'D#8"%#")GG0-%'9#G0'#,0->#)'+:+%?0'#*0-<0&$#"<+)%#,0'#%bG0'# %0,+&,"&$'g# G"# *%J'0&(0# ,H-&# ,0'# ,0-># )'+:+%?0'# 0?*K(E0# GH"**"%)$)+&# ,H-&# *EJ&+$c*0# *"%$)(-G)0%9# (+??0# (H0'$# G0# ("'# ,"&'# GH+<")%0# +_# G0'# '+-%)'# !%&+'(') 34) !%&+2'(') &H+&$# "-(-&# *EJ&+$c*0D#. -! !. !. !. !. !. !. !.
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``>0# )%# 0>0A6# `-'$# &"&)3),%:# !X0# 4)'%# $)# <5I)&# $'&# .)$#+-+3),%$#5,;)&$)$#=U0@A:#G'5#$2,%#.)$#+-+3),%$#(-"$$5G')$#.)$#?X0$#LaNO6# >'#<5,"-:#.)#4"&%#-)'&#$4+(5<5(5%+#./5$2<2&3)#)%#-)'&#$4+(5<5(5%+#%5$$'-"5&):#()%%)#.5;)&$5%+# .",$#-)$#!X0K$#(2,<5)#',)#*&",.)#"(%5;5%+#4CW$52-2*5G')#"'I#!X0$6# -! !. !. !. !. !. !. !.
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
(26) !. !. "#$%#!&#!'())*+,)%+#!. !"#$ %&'()*#$ +,(-*).-#! "#$! #%$&'! "($)"! *"! +,+! "$! *"! -,+.! /"! 0123%("! 4")2"$! *3! )1$3$%1(! 0&! )'5"4$"&)! "$! *3! *%3%#1(! 36"5! &(! '*'2"($! 0"! )'41(#"! 0%)"5$"! 1&! %(6")#"! "$! *7"(5)38"!0"#!519)'4)"##"&)#!"(!3:#"(5"!0"!*%83(0!;<=>.!/"!0123%("!"#$!4*&#!*1(8!03(#!-?@A! B&"!03(#!-?@C.!D*!43)$%5%4"!'83*"2"($!03(#!*3!#4'5%E%5%$'!0"!5F3B&"!)'5"4$"&)!8)G5"!3&!5F1%H! 07&(!'*'2"($!0"!)'41(#"!43)$%5&*%").!$ !"#$ %&'()*#$ %#$ /)()0&*$ (1#+$ /#$ /)2(*%$ 3"456! "#$! &("! 415F"! #4'5%E%B&"! FI0)14F1:"! %0"($%E%3($! &("! #$)&5$&)"! 3**1#$')%B&"! J*"! *%83(0K.! L**"! "#$! #%$&'"! 0&! 5M$'! /9$")2%(3*"! 0"! *3! 4)1$'%("N!"$!4")2"$!07%0"($%E%")!&(!*%83(0!#4'5%E%B&"!"$!&(!0%2O)"!#4'5%E%B&".!+O#!*1)#!B&"!*"! *%83(0!#"!E%H"!03(#!*3!415F"!FI0)14F1:"N!&(!0123%("!0735$%63$%1(!JPQ9RK!4)'#"($!S!5M$'!0"! -,+!J*7F'*%H"!T=R!0&!-,+KN!3##&)"!&("!210%E%53$%1(!0"!*3!51(E1)23$%1(!%(0&%$"!43)!*"!*%83(0! "$! 4")2"$! 0"! E")2")! *3! 415F"! 0"! -,+! "$! 0'4*35")! *"#! 51)'4)"##"&)#.! /"$$"! 51(E1)23$%1(! 4")2"$!0"!4%'8")!*"!*%83(0!03(#!*3!415F"!FI0)14F1:"!"$!*"!)"5)&$"2"($!0"#!51935$%63$"&)#N! (1$322"($! U@/9=N! 4=VW! "$! XY/9=C!41&)! *"#! 4*&#! 51((&#! ;<RN<Z>.! /"$$"! 35$%63$%1(! )"(0! *3! 5F)123$%("! 4")2%##%6"! 4")2"$$3($! *3! $)3(#5)%4$%1(! 0"! 8O("#! 5%:*"#.! -,+! "#$! '83*"2"($! %24*%B&'!03(#!*7F'$')10%2")%#3$%1(!0"!-?@!36"5!@?@!JQ%8&)"![/N!Q%8&)"!<,K.! L(! *73:#"(5"! 0&! *%83(0N! *735$%6%$'! $)3(#5)%4$%1(("**"! 0&! @\! "#$! %(F%:'"! 43)! 0"#! 51)'4)"##"&)#!J\/]@N!T+P/N!U^@_K!B&%!:*1B&"($!*7PQ9=!;<=N<[N<<>!JQ%8&)"!<PK.! ! -?@#!E1)2"($!0"#!F'$')10%2O)"#!1:*%83$1%)"#!36"5!*"#!$)1%#!%#1E1)2"#!0"!@?@N!@?@CN! @?@AN! @?@`! J@?@a-?@K! ;<V>.! /"$$"! F'$')10%2')%#3$%1(! "#$! 4")2%##%6".! /7"#$! S! 0%)"! B&"! *"! 51&4*"!"#$!35$%6'!43)!*3!4)'#"(5"!07&(!*%83(0!-?@!J(3$&)"*!1&!#I($F'$%B&"N!61%)!5%90"##1&#K!1&! @?@!Jb!!"#!35%0"!)'$%(1cB&"K.!L(!4)'#"(5"!0"#!0"&H!*%83(0#N!&(!"EE"$!300%$%E!1&!#I(")8%B&"!#&)! *3!$)3(#5)%4$%1(!41&))3%$!d$)"!1:$"(&!;<e>!JQ%8&)"!<PK.!! /"$! F'$')12O)"! #"! E%H"! 0"! E3f1(! 4")23("($"! #&)! *7P+\N! "$! #1(! 35$%6%$'! "#$! :*1B&'"! 43)! 0"#! 51)'4)"##"&)#.! -735$%6%$'! $)3(#5)%4$%1(("**"! 0"! 5"#! )'5"4$"&)#! "#$! '83*"2"($! 3:1*%"! 43)!*3!4F1#4F1)I*3$%1(!0&!)'5"4$"&)!43)!0"#!4)1$'%("#!g%(3#"#N!0%2%(&3($!*735$%63$%1(!43)!*"! *%83(0N! '*%2%(3($! *"#! 51935$%63$"&)#! 1&! %(F%:3($! *7F'$')10%2")%#3$%1(! 36"5! @?@! ;<hN<b>.! -735$%6%$'! 41&))3%$! d$)"! '83*"2"($! :*1B&'"! 43)! &(! 3($381(%#$"! E%H3($! *"! -,+! :*1B&3($! *7%($")E35"!"$!"24d5F3($!*"!E1(5$%1(("2"($!0&!#I#$O2"!J61%)!*"#!*%83(0#!5%90"##1&#K!1&!43)! 0"#! )'5"4$"&)#! $%&&' &"()' *' "(! )3%#1(! 07&("! 5124'$%$%1(! 36"5! -?@! 41&)! *"#! 51935$%63$"&)#! ;ZWNVW>!J_3:*"!=K.!! -! !. !. !. !. !. !. !.
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`M=M?H?S$N`M=P$ "($ abH=>R$ #%,($ +"#$ A+1#$ 1(.+.#)#$ -6,#$ +"#$ )(1-"#$ ;SF9SH@$ NY.G1*"$ \P3$ 4"#$ 6G%,.#("#$ %,($ 1,"$ K%*("$ 6KK.,.()$ 61$ *)2"A("1*$ "($ 6##1*",($ +C62(./6(.%,$ -C0)()*%-.57*"$ EDEc!DE3$ `M=$ A"1($ )G6+"5",($K.&"*$+"#$dDE$"($YDE$;S<XS>@3$abH=>R$"#($#A)2.K.B1"$-"#$!DE#$;S>@3$4"#$5%+)21+"#$ %,($ )()$ ("#()"#$ -6,#$ -"#$ 5%-7+"#$ -"$ #%1*.#$ -)/"+%AA6,($ +C6(0)*%#2+)*%#"$ A%1*$ .,/"*#"*$ +C622151+6(.%,$ +.A.-.B1"$ ;SS@3$ !C1(.+.#6(.%,$ -"$ 2"#$ 6G%,.#("#$ 6$ )()$ 6##%2.)"$ Z$ 1,"$ 0'A"*(*.G+'2)*.-)5."$(*6,#.(%.*"$-1"$Z$+C62(./6(.%,$-$4-"5678(&61$,./"61$0)A6(.B1"9$1,$G7,"$ 2.8+"$ !DE$ *"#A%,#68+"$ -"$ #',(07#"$ -"#$ (*.G+'2)*.-"#3$ !"#$ +.G6,-#$ ab>H<M$ "($ e`QHF$ #%,($ *"#(*".,(#$ Z$ +C62(./6(.%,$ -"#$ !DE#$ 61$ ,./"61$ -"$ +C.,("#(.,3$ !C62(./6(.%,$ -"$ !DE$ 61$ ,./"61$ 0)A6(.B1"$"#($-%,2$68#",("9$"($A6*$2%,#)B1",2"9$+C0'A"*(*.G+'2)*.-)5."$;S\9S=@3$ -! !. !. !. !. !. !. !.
(29) !"#$%&'()'*+&,"-./'01%$-1$%&'23'-+2/&01&%2/'.45'1+&'4.1$%./'678'.#24"010'5&%"9&5' 3%2,'-+2/&01&%2/:'1+&'2;<01&%2/0='!"#$%&"'()*+',-&..*-/'&%'#01'234'5677'.
(30) !"#"$%$&'. ()%#*+'. -!/%0'. ()*%,"'. 45678' 123/*0%'. )-./*&0'. !"#$%&'()'*+&,"-./'01%$-1$%&'23'0451+&6-'789'.#25"010:' !"#'9:;'()%#*+'9<='>?='@AB>'CB=;'DEF9:;BG'-!/%0'9:;'()*%,"'9<='HBBC='BI=JEKJG' 1EF9:;'9L:E>M'EB'@A<='E@IA<>9:>'>?9:'>?=':9>C<9D'DEF9:;B'N$"/&'5'OB'$"/+'5P!'"#$%&'#( )*+,(-.'//+.0('&($1!(234(5677((.
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
(32) . . . . . . . . . . . .
(33) . .
(34) .
(35). . . . . .
(36) . . . . . . .
(37) . . . . . . . .
(38) . . . . . . .+('/ #. %7$%# 7$ # %7$# %7$ %7$# #. !"#$. %&'(!#. ,!,"$ 78)'"$ 9':;<$ 879$#. 879$#. %4025/6$'.%$. 45361 2#. )!*+,-#. %&'%($ %&')($ *!+,$. !"!#. $"!#. (0123.
(39) . '-./01203./$. *:;141<3#. $7$#. ,()=># $7$!#. ?@AB63# >C# .D)E453<@F# F0123453612# <35GH12@4<# G:;# !"!I$"!# GFJK@5EL# +D(322B2G6# F0123453612# <35GH12@4<L#,="1$>0?@A20$30B0310$4-./01203./$23AC1D.32$E3.>$2-0$D03@D-03A/$F11G0$2.$2-0$/@B03$ AC?$@C430A10$@21$0H430F.CI$ !"#$!%&$'()*()+, -.//0102, !34$.345(3436470()2, #8$-9450/706:5, 0/7062, #8%&$-9450/706:5, 0/706, 76.)/;06, 36470()2, #:3<.=$-9450/70645, <>$9:*64?:5./02, @AB$9(+9, *0)/(7:, 5(3436470()2, BAB$54C, *0)/(7:, 5(3436470()2, B#!%$50-(79(), -9450/70645, .-:5, 76.)/;06./02, BABD$BAB, 60-037462, EBAB$F06:, 54C,*0)/(7:,5(3436470()2,GD"=$/-.F0)+06,60-03746,-5.//,",H0H'06,=2,IAJB$()*K-('50,*0+6.*06,4;, 790, BAB, 60-037462, @LM#D$@LM#DNO$9:*64?:$O$H079:5+5K7.6:5$-40)P:H0, !, 60*K-7./02, !"#$ !%&,'()*()+,-.//0102,36436470(),-4)F067./0,/K'Q5(/()0RS0?()0,7:30,TU, !*.370*,;64H,L.V*./:,07,.5U,L!L,WX=YU,.
Figure
+7
Documents relatifs
Curated lists of the genes encoding human, mouse and rat GPCRs, VGICs and LGICs can be viewed as HTML pages that list the approved IUPHAR nomenclature, have links to the receptor
Based on credible simulations, it is shown that the nonlinear power of a Raman free-electron laser in a millimeter wave range goes up and gets an increase of at least 9% when
The dirhodium(II)-catalyzed intermolecular cyclopropanation of a set of olefins with either diazo free phenyliodonium ylides or diazo compounds afforded cyclopropanes derived
Dissipative boundary conditions for nonlinear 1-D hyper- bolic systems: sharp conditions through an approach via time-delay systems... Dissipative boundary conditions for nonlinear
(A-E) Expression levels of the FOXA2 target gene Igfbp1, of the FXR target gene Slc51b/Ostb and of the gluconeogenic genes Fbp1, Pck1 and G6pc in response to GW4064, insulin,
The dominant native single atom dopants we identify in our single crystals are intercalated Ti atoms, Se vacancies, and Se substitutions by residual iodine and oxygen..
Dans la section suivante, les outils mathématiques provenant de la théorie de la bifurcation dynamique, qui vont nous permettre d’étudier le comportement du modèle de
The FIT/CorteXlab platform is a wireless testbed situated in Lyon, France, where all radio nodes are confined to an electro-magnetically (EM) shielded environment and have
