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F79:FF:FM G5;L8HG5N O!" H6=6N:M DJE<PG6 65H 6Q:99657LJ 6;7GI67:H 7985;67:H K<9= <K E-. 7D67 68N=:57F 3GLHZ7JE: E-. 6;7GIG7J4 dG;:
<5;<N:5:FM 65H =6J G5H8;: ;:LL ;J;L: 699:F7 <9 6E<E7<FGF,R.4 S78HG:F 3G7D 7DGF H:K:;7GI: E-. 6LL:L: [3DG;D 3: 7:9= 7D: e=f 6LL:L:\ 69: DGNDLJ
<5 ;8L789:H E9G=69J ;:LLF D6I: LG5T:H E-. 6;7GI67G<5 7< ;:LL8L69 9:FGF7657 7< 78=<89F 65H HGFEL6J :69LJ <5F:7 <K ED:5<7JE:F 6FF<Z
9:ELG;67GI: F:5:F;:5;:U6 7:9=G56L ;:LL ;J;L: 699:F7 F767: 9:6;D:H ;G67:H 3G7D 6N:G5N4 " F:;<5H LG5: <K 7965FN:5G; =G;: ;<576G5G5N
6K7:9 6 V5G7: 58=Q:9 <K ;:LL HGIGFG<5F+4 WD:5 ;8L789:H D8=65 =8L7GEL: ;<EG:F <K 6 7:=E:96789:ZF:5FG7GI: =87657 E-. 6LL:L:11 6LF<
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Y579<H8;7G<5 <K IG96L <5;<E9<7:G5FM =87657 E-. K<9=FM <9 657GZE-. =G;:4 #D: <QF:9I67G<5 <K F8;D :69LJ 6N:G5N ED:5<7JE:F G5 73<
657GQ<HG:F [3DG;D G56;7GI67: 3GLHZ7JE: E-.\ H:L6J F:5:F;:5;: <K HGF7G5;7 E-. =87657 LG5:F G=ELG;67:F E-. 6F 6 9:N8L67<9 <K <9N65GF=6L
D8=65 E9G=69J ;:LLF]R,24 Y579<H8;7G<5 <K <5;<N:5G; %6F G57< E9GZ 6N:G5N4
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H676 69: ;<5FGF7:57 3G7D DJE<7D:F:F 7D67 ;:LL8L69 9:ELG;67GI: F:5:FZ #D: 4JDgh= =<8F: 36F <Q76G5:H K<LL<3G5N 65 6Q:99657 N:5:Z769N:7Z
;:5;: F:9I:F 6F 6 =:;D65GF= <K 78=<89 F8EE9:FFG<5+M,1M,.4 G5N :I:57 G5 :=Q9J<5G; F7:= ;:LLF4 Y5G7G6LLJM 6 E-. 769N:7G5N ;<5F798;7
%:;:57 9:E<97F 6Q<87 N:5:7G;6LLJ :5NG5::9:H =G;: 3G7D 6L7:9:H ;<576G5G5N 6 =8767G<5 67 ;<H<5 1+- ["9N1+-#9E\ G5 E-. 36F
L<5N:IG7J ED:5<7JE:F G=ELG;67: E-. 6F 6 =:HG67<9 <K <9N65GF=6L G579<H8;:H G57< :=Q9J<5G; F7:= ;:LLF [iGN4 ,6\4 Y5 <5: :=Q9J<5G;
F:5:F;:5;:,+R,]4 *67:ZN:5:967G<5 7:L<=:96F:ZH:V;G:57 =G;: :PDGQG7 F7:= ;:LL ;L<5:M 7D: .! F:N=:57 <K 7D: 769N:7G5N ;<5F798;7 9:;<=Z
FD<97:5:H 7:L<=:9:FM H:;9:6F:H L<5N:IG7J 65H :69LJ F:5:F;:5;:Z QG5:H 3G7D 7D: :5H<N:5<8F E-. 6LL:L:4 S<87D:95 DJQ9GHGj67G<5 65H
9:L67:H ED:5<7JE:F,+4 ^:LLF K9<= 7D:F: =G;: FD<3:H DGND L:I:LF <K E<LJ=:96F: ;D6G5 9:6;7G<5 [k^%\ 6FF6JF 9:I:6L:H 7D67 7D: =<HGV:H
6;7GI67:H E-. [9:K4 ,-\4 ^9<FFG5N <K 7D: 7:L<=:96F:ZH:V;G:57 =G;: 6LL:L: 9:76G5:H E-. :P<5F XR,, [G5;L8HG5N 7D: ;<H<5 1+- =8767G<5\
3G7D E-.ZH:V;G:57 =G;: 9:F8L7:H G5 9:F;8: <K F<=: F:5:F;:5;:Z 3DGL: H:L:7G5N E-. :P<5F ,R` 65H 65 85H:V5:H 9:NG<5 8EF79:6= <K
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87:H 7< 6 _8]2ZH:V;G:57 =<8F: 7D67 36F H:K:;7GI: K<9 H<8QL:Z =Z6LL:L: H:L:7G<5 :P7:5HF <I:9 12 TGL<Q6F:F [TQ\ 8EF79:6= <K E-.4
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=G;: FD<3:H 6 E9:=6789: F:5:F;:5;: 7D67 36F 9:F;8:H QJ E-. [S4O4#4 65H l4*4M 85E8QLGFD:H H676\4
H:V;G:5;J,X4 E``SD; 58LL =G;: HGFEL6J:H .2a :5D65;:H L<5N:IG7J W: N:5:967:H =G;: ;<576G5G5N 7D: E-. = 6LL:L: [4JDgh= =G;:\4
;<=E69:H 3G7D 3GLHZ7JE: =G;:,]4 E``SD; =:HG67:F 6 F79:FF 9:FE<5F: WD:5 7D: 4JDgh= =G;: Q:N65 7< FD<3 85:PE:;7:H ED:5<7JE:F [F::
7< 9:6;7GI: <PJN:5 FE:;G:FM 65H ;:LLF K9<= 7D: H:V;G:57 =G;: Q:L<3\M 3: H:7:9=G5:H 7D67 7D: E-. = 6LL:L: 36F :PE9:FF:H 6F 6
:PDGQG7:H 6 H:K:;7GI: E-. 6E<E7<7G; 9:FE<5F:,]4 =:FF:5N:9 %!"4 $FG5N 7D: -! 96EGH 6=ELGV;67G<5 <K ;<=EL:=:5769J
" HG9:;7 7:F7 <K 7D: G5I<LI:=:57 <K E-. G5 7D: L<5N:IG7J <K O!" :5HF [%"^&\ E9<;:H89:M 3: GH:57GV:H 6 HGF;9:7: 6=ELGV:H
<9N65GF=F ;<8LH G5I<LI: =<H8L67G<5 <K E-. L:I:LF G5 7D: =<8F:4 K96N=:57 G5 7GFF8:F <K 4JDgh= =G;: 7D67 36F 5<7 K<85H G5 7GFF8:F <K
W:M 65H <7D:9FM D6I: N:5:967:H E-.ZH:V;G:57 =G;:,bR1,M Q87 3:9: 4JDghg =G;:4 #D: F:m8:5;: 9:I:6L:H 6 ;DG=6:9G; =:FF6N: ;<576G5G5N
E9:I:57:H K9<= F78HJG5N 6N:G5N QJ :69LJ 78=<89F4 ^<5I:9F:LJM 6 --ZQE L:6H:9 <K 85T5<35 <9GNG5 FELG;:H G57< :P<5 X <K E-.
677:=E7F 7< N:5:967: =G;: 7D67 <I:9:PE9:FF 3GLHZ7JE: E-. D6I: [iGN4 ,;\4 #D: K<9:GN5 L:6H:9 F:m8:5;: ;<576G5:H 5< "$n ;<H<5FM
Q::5 85F8;;:FFK8LM E9<Q6QLJ <3G5N 7< H:L:7:9G<8F :KK:;7F <K 3D:9:6F 7D: E-. :P<5 X E<97G<5 <K 7D: =:FF6N: ;<576G5:H 7D9:: G5Z
G5;9:6F:H E-. <5 7D: H:I:L<EG5N :=Q9J< ["4 c:95F7:G5 65H /4 K96=: "$n ;<H<5FM 7D: 7DG9H [d:7 ;<H<5 1+.\ Q:G5N 6Ho6;:57 7<
c87:LM E:9F<56L ;<==85G;67G<5\4 W: 9:E<97 7D: F:9:5HGEG7<8F 6 IG6QL: 7965FL67G<5 G5G7G67G<5 FGN56L [iGN4 ,;\4 #D8FM 7D: ;DG=6:9G;

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=Z6LL:L: =:FF6N: ;<8LH E9<H8;: 6 ^Z7:9=G56L E-. K96N=:57 3G7D 6 #< H:7:9=G5: 7D: :PE9:FFG<5 E677:95 <K E-. =Z6LL:L: =%!" -%
9:L67GI: =<L:;8L69 =6FF <K 9<8NDLJ 1+M222 ['9 1+_\4 #< ;<5V9= 9-9(M 3: ;699G:H <87 k^% 3G7D 9:I:9F: 7965F;9GE7G<5 [%#Zk^%\
7DGFM 7965F;9GE7F <K 7D: = 6LL:L: 3:9: N:5:967:H QJ -% 9-5+( 7965F;9GEZ 6FF6JF FE:;GV; K<9 =Z6LL:L: 65H 3GLHZ7JE: E-. =%!"F4 d<F7 7GFF8:F
7G<5 65H 7D:5 7965FL67:H QJ -% 9-5+( 7965FL67G<54 "F :PE:;7:HM 6 <K 7D: 4JDgh= =G;:M Q87 5<7 7D: 4JDghg =G;:M :PE9:FF:H =Z6LL:L:
E9<7:G5 <K 1+_ 36F E9<H8;:H 7D67 ;<8LH Q: G==85<E9:;GEG767:H QJ =%!"M Q87 67 L<3:9 L:I:LF 7D65 7D67 K<9 3GLHZ7JE: E-. %!"
6 =<5<;L<56L 657GQ<HJ FE:;GV; K<9 7D: ^ 7:9=G58F <K E-. [iGN4 ,:\4 [iGN4 ,H\4
p<3:I:9M 7< H67: 3: D6I: Q::5 856QL: 7< H:7:;7 7D: = E9<7:G5 G5
4JDgh= =<8F: 7GFF8:F4 H4".4/#1 '()*(+ +#,-,'.4/# .41 .6'#+#1 6*48#0-'3
W: =<5G7<9:H 7D: 4JDgh= =G;: K<9 7D: E9:F:5;: <K 78=<89F <I:9
7D:G9 LGK:FE654 !<5: <K 7D: .- 4JDgh= =G;: H:I:L<E:H <I:97M LGK:Z
7D9:67:5G5N 78=<89FM 3D:9:6F <I:9 ]2a <K 4JDgh! =G;: 65H <I:9
a BamHI BamHI StuI
+-a <K 4JDghg =G;: H:I:L<E:H F8;D 78=<89F [#6QL: ,\4 )5 DGF7<Z
EcoRI Pr pA EcoRI
p53 WT allele
E67D<L<NG;6L :P6=G567G<5 <K 7D: 4JDgh= =G;:M 1 <87 <K .- 3:9:
E1 E2 E3 E4 E5 E6 E7 E8 E9 E10 E11 <QF:9I:H 7< D6I: L<;6LGj:H 78=<89 L:FG<5F4 )5: =<8F: D6H 6 K<;6L
Pr E1–E6 StuI pA EcoRI L85N 6H:5<=6 65H 65<7D:9 D6H 6 3:LLZHGKK:9:57G67:H Q9<5;DG<Z
p53m allele
* 6LI:<L69 L85N 6H:5<;69;G5<=6 [#6QL: ,\4 Y5 ;<5796F7M 4JDghg 65H
L E7 E8 E9 E10 E11 4JDgh! =G;: H:I:L<E:H L69N: 78=<89F <K I69G:H 7JE:M G5;L8HG5N
m allele mRNA AAAA
LJ=ED<=6FM <F7:<F69;<=6FM F<K7 7GFF8: F69;<=6F 65H ;69;G5<=6F4
nGI:5 7D: :5D65;:H 78=<89 9:FGF765;: G5 4JDgh= =G;:M G7 =GND7 Q:
+/m +/+ +/– :PE:;7:H 7D67 7D:G9 L<5N:IG7J 3<8LH :P;::H 7D67 <K 7D: =<9:
b
Pseudo 78=<89ZE9<5: 4JDghg =G;:4 Y5 K6;7M 7D: =:HG65 LGK:FE65 <K 7D:
BamHI: Null 4JDgh= =G;: 36F b` 3::TF ;<=E69:H 3G7D ,,] 3::TF K<9 7D:G9
WT 4JDghg LG77:9=67:F [iGN4 16 65H #6QL: 1\4 #D: =6PG=6L LGK:FE65 <K
7D: 4JDgh= =G;: 36F ,.` 3::TF ;<=E69:H 3G7D ,`+ 3::TF K<9 7D:
WT
4JDghg =G;:4 S767GF7G;6L ;<=E69GF<5 <K 7D: 4JDgh= 65H 4JDghg F89IGI6L
StuI: ;89I:F G5HG;67:H 7D67 7D: HGKK:9:5;:F G5 L<5N:IG7J 3:9: DGNDLJ
WT
FGN5GV;657 [0 ! 24222,\4 pGF7<E67D<L<NG;6L :P6=G567G<5 <K 7D:
m
4JDgh= =G;: K6GL:H 7< 9:I:6L 65J <QIG<8F HGF:6F:Z6FF<;G67:H ED:5<Z
7JE:F4 " E9:;GF: ;68F: <K H:67D 36F HGKV;8L7 7< H:7:9=G5: G5 =65J
c 5'-C GCC CGG GCA GGT TCT GAA GGC AGT TTC AGA TCT GGC
;6F:F4 !< G5q6==67G<5 <9 <7D:9 G5HG;67<9F <K G5K:;7G<8F HGF:6F:F
6Q<I: L:I:LF F::5 G5 4JDghg =G;: 3:9: 5<7:HM 6L7D<8ND F8Q7L:
<-- Unknown leader | p53 exon 7 -->
TGT GGA AGC TCC TCA GAG GCC GGC TCT GAG TAT ACC ACC CAC TAC HGKK:9:5;:F G5 G==85: F7678F <9 K85;7G<5 ;655<7 Q: 98L:H <874
#< H:7:9=G5: 3D:7D:9 7D: 6L7:9:H L<5N:IG7J 65H 78=<89 9:FGFZ
AAG TAC ATG TGT AAT AGC TCC TGC ATG GGG GGC ATG AAC TGG GCA 765;: G5 7D: 4JDgh= =G;: 3:9: H:E:5H:57 <5 7D: E9:F:5;: <K 3GLHZ
Met Met Met Asn Trp Arg 7JE: E-.M 3: ;9<FF:H 4JDgh= =G;: 7< 4JD!h! =G;: 65H <Q76G5:H 4JD!h=
<KKFE9G5N4 YK 7D: =Z6LL:L: E9<H8;7 68N=:57F 7D: 6;7GIG7J <K 3GLHZ7JE:
e
E-. 7< :5D65;: 78=<89 9:FGF765;:M 7D:5 7D: 6QF:5;: <K 3GLHZ7JE:
d
e

Lu in ( T) e

WT C m
E-. G5 7D: 4JD!h= =G;: FD<8LH 9:F8L7 G5 LG77L: <9 5< 78=<89
cl

in
us

Br g (W est

n RT
RT
Br g n T)
e lm

n nt

ai o
n W

F8EE9:FFG<5 :KK:;7 3D:5 7D: F89IGI6L ;89I:F <K 4JD!h= 65H 4JD!h!
no
Ey leta
a s

Lu ll i
Sk ney
Ki leen

H es
Br mu

Te on

Sm t
Li g

a
Sp r
Sk e

r
Lu in

ve

st
ea
Th n

a
n

ol
y
i

53K
Bo

=G;: 69: ;<=E69:H4 "L7D<8ND 7D:9: GF 6 FLGND7 H:L6J G5 =:65

m allele 78=<9GN:5:FGF G5 4JD!h= =G;: ;<=E69:H 3G7D 4JD!h! =G;:M =6PG=6L
LGK:FE65F <K 7D: 73< N:5<7JE:F 69: FG=GL69 [bR,2 =<57DF\ [iGN4 1Q\4
24K
#D: 78=<89 7JE:F <QF:9I:H G5 7D: 4JD!h= =G;: 3:9: FG=GL69 7< 7D<F:
WT p53 allele <K 7D: 4JD!h! =G;:UE9G=69GLJ #Z;:LL LJ=ED<=6F 65H F<K7 7GFF8:
7K F69;<=6F4 #D8FM 7D: :5D65;:H 78=<89 9:FGF765;: ;<5K:99:H QJ 7D: =
L19 6LL:L: GF H:E:5H:57 <5 7D: E9:F:5;: <K 3GLHZ7JE: E-.4

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8-4)9":+& ;<=> '() 1 '44&4&,5 ?*.(, @AB '() $+,"#&'1 ,&C$&(%&, '#& )&4&"&) -( "0& #< 6FF:FF =:;D65GF=F <K 78=<89 9:FGF765;: G5 4JDgh= =G;:M 3:
+23 1 '44&4&6 D$*"'+.,-(E &*.(, FA@@ ". '( $(G(.8( +#.1."&# "0'" -(-"-'"&, ' %0-1'&#-% :P6=G5:H ;:LLF 65H 7GFF8:F K9<= 4JDgh=M 4JDghgM 4JDgh!M 4JD!h= 65H
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p53+/+ I:;7<9 :PE9:FFG<5 ;<5F798;7F4 ^:LLF 7965FK:;7:H 3G7D 3GLHZ7JE: E-. <9
n = 56
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Cumulative survival

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0.6 0.6 n = 34
p53+/– K:;7:H 3G7D :=E7J I:;7<9 <9 = :PE9:FFG<5 ;<5F798;7F 6L<5: [iGN4 .H\4
n = 217
0.4 >80% tumour 0.4 Y5 K<89 G5H:E:5H:57 :PE:9G=:57FM 3GLHZ7JE: E-. EL8F =Z6LL:L:
p53–/– :PE9:FFG<5 ;<5F798;7F G5H8;:H 6 =:65 14.ZK<LH G5;9:6F: G5 L8;GK:96F:
n = 72
0.2 p53+/m 0.2 6;7GIG7J ;<=E69:H 3G7D ;:LLF 7965FK:;7:H 3G7D 3GLHZ7JE: E-. 6L<5:4
n = 35
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7D:F: ;:LLF 3:9: IG9786LLJ 6QF:57 G5 FTG5 <K <LH 4JDgh= =G;: 65H
Mean foci number

150 300
9:H8;:H G5 FTG5 <K <LH 4JDghg =G;: [iGN4 `;M HM K\4
100 200 #D: D6G9 <5 7D: <LH:9 4JDgh= =G;: 6EE:69:H 7< Q: FE69F:9 7D65 7D67
<K 7D:G9 4JDghg ;<857:9E697F4 p6G9 FE69F:5:FF ;<8LH Q: 6 K85;7G<5 <K
50 100 7D: 967G< <K D6G9 K<LLG;L: ;:LLF G5 7D: 656N:5 [N9<37D\ ED6F: 7< 7D<F: G5
7D: 7:L<N:5 [9:F7G5N\ ED6F:4 $FG5N 6 D6G9ZN9<37D 6FF6JU3DG;D
0 0 G5I<LI:F FD6IG5N 6 H<9F6L F:N=:57 <K FTG5 <5 7D: =<8F: 65H
p53+/+ p53+/m p53–/– p53–/m
=:6F89G5N 7D: 6=<857 <K D6G9 N9<37D 6K7:9 12R1- H6JFUD6G9
b N9<37D H:;LG5:F LG5:69LJ 6F 6 K85;7G<5 <K 6N: G5 =G;:1X4 )5LJ 6
+/+ –/– +/– +/m
(hours)
=<H:F7 9:H8;7G<5 G5 D6G9 N9<37D 36F <QF:9I:H G5 7D: J<85N 4JDgh=
0 4 24 0 0 4 24 0 4 24
=G;: ;<=E69:H 3G7D J<85N 4JDghg =G;: [iGN4 `D\4 Y5 11R1`Z=<57DZ
p53
<LH 4JDgh= =G;:M 6L=<F7 5< D6G9 N9<37D 36F <QF:9I:HM 3D:9:6F <LH
4JDghg =G;: HGFEL6J:H 9<Q8F7 D6G9 N9<37D [iGN4 `NM D\4
Actin
" 9:H8;:H 6QGLG7J 7< 7<L:967: F79:FF:F GF 6 D6LL=69T <K 6N:G5N1]4 )5:
0.07 1.0 0.41 0.01 0.02 0.56 0.05 0.02 1.6 0.64
F8;D 6N:Z9:L67:H F79:FFM 3<85H D:6LG5NM GF H:L6J:H 6F 6 K85;7G<5 <K
6N: G5 Q<7D =G;: 65H D8=65F,+M1b4 #< 7:F7 7DGF ;6E6;G7JM 3: EL6;:H 73<
c +/+ +/– +/m
.Z== E85;D QG<EFG:F G5 7D: H<9F6L FTG5 <K J<85N 65H <LH 656:FZ
0 4 24 48 0 4 24 48 0 4 24 48 (hours)
7D:7Gj:H 4JDgh= 65H 4JDghg =G;:4 p<3:I:9M 3: K<85H 7D67 =65J <K
7D: <LH 4JDgh= =G;: HG:H 6K7:9 G5o:;7G<5 3G7D 7D: F765H69H H<F6N: <K
p21
7D: 656:F7D:7G; "I:97G5M 65H 6 N9:67LJ 9:H8;:H H<F: D6H 7< Q: 8F:H
GAPDH K<9 7DGF 6N:hN:5<7JE: ;67:N<9J4 #DGF <QF:9I67G<5 6N9::F 3G7D 9:E<97F
4.3 5.9 6.1 7.0 1.0 3.4 3.0 1.3 2.6 6.0 2.8 4.4 7D67 6N:H <9N65GF=F 69: L:FF 6QL: 7< 7<L:967: 7D: F79:FF <K 656:F7D:FG6
d 7D65 69: J<85N:9 <9N65GF=F.2M.,4
2.5 "K7:9 6Ho8F7=:57 <K 656:F7D:7G; H<F:FM 3<85HF 3:9: G5H8;:H 65H
Relative luciferase activity

2 =<5G7<9:H <I:9 6 E:9G<H <K + H6JF K<9 ;L<F89: Q:K<9: F6;9GV;:4

W<85H HG6=:7:9F 67 1M . 65H + H6JF 6K7:9 3<85HG5N 3:9: FG=GL69 K<9
1.5
3<85HF <K J<85N 4JDgh= 65H 4JDghg =G;: [iGN4 X6\r D<3:I:9M <LH
1 4JDgh= =G;: :PDGQG7:H 6 FGN5GV;657 H:L6J G5 3<85H ;L<F89: [iGN4 XQ\4
WD:5 ;9<FFZF:;7G<5F <K 7D: 3<85H 67 + H6JF 6K7:9 3<85HG5N 3:9:
0.5
:P6=G5:H QJ DGF7<E67D<L<NJM 7D:9: 36F 6 K9:m8:57 9:H8;7G<5 G5 9:Z
0 :EG7D:LG6LGj67G<5 K9<= 7D: 3<85H :HN: G5 7D: <LH 4JDgh= 3<85H
Te Vector m p53 p53 + V p53 + m p53 + m
1:1 10:1
;<=E69:H 3G7D 7D67 G5 7D: 3<85HF <K <LH 4JDghg =G;: [iGN4 `;M H\4
"5 6;87: F79:FF 7D67 =:6F89:F 7D: 9:FE<5F: 7< D6:=67<E<G:7G;
I-8(+# & =#'(,/.#1'"-.( '() +23 #&,+.(,& +0&(.":+&,5 .6 =#'(,/.#1'"-.( ,$,%&+"-T-4-": E9:;89F<9 ;:LL 6QL67G<5 GF 79:67=:57 3G7D -Zq8<9<896;GL [-Zi$\.14 Y5
./ !"#OPO6 !"#OP16 !"#!P! '() !"#!P1 &1T#:.(-% \T#.T4',",5 K&/"6 Z.1+'#-,.( ./ "."'4 /.%- 7DGF 6FF6JM 3: K<85H 7D67 J<85N 4JDghg 65H 4JDgh= =G;: FD<3:H
+#.)$%&) T: -%/ +4$, &01 #&"#.Q-#'4 -(/&%"-.( ./ [ +4'"&, &'%0 ./ !"#OP1 '() !"#OPO 7?`,5 9:H8;:H 3DG7: QL<<H ;:LL ;<857F 67 H6J ` 6K7:9 -Zi$ G5o:;7G<5M Q87
H-E0"6 %.1+'#-,.( ./ "."'4 /.%- +#.)$%&) T: -%/ +4$, &01 #&"#.Q-#'4 -(/&%"-.( ./ !"#!P! '() D6H 9:;<I:9:H QJ H6J ,, [iGN4 X:\4 #D: <LH 4JDghg =G;: 3:9: 5<7
!"#!P1 7?`,5 26 J('4:,-, ./ +23 +#."&-( -( G-)(&: %&44, ./ !"#OPO6 !"#OP1 '() !"#OP! 1-%& <I:97LJ 6KK:;7:H QJ -Zi$ 79:67=:57M 65H 7D:G9 3DG7: QL<<H ;:LL ;<857F
T&/.#& '() '/"&# "#&'"1&(" 8-"0 2 Y: ./ -.(-U-(E #')-'"-.(5 =0& ".+ +'(&4 ,0.8, +23 4&Q&4, D6H 9:;<I:9:H QJ H6J ,,4 p<3:I:9M 7D: 4JDgh= =G;: HGFEL6J:H 6
)&"&%"&) 8-"0 '( '("-T.): ". +23M "0& 4.8&# +'(&4 )-,+4':, '%"-( 4&Q&4,5 _'4$&, T&4.8 &'%0 =69T:H =<9QGHG7J 6K7:9 79:67=:57M 65H <5: <87 <K FGP <K 7D: <LH
4'(& -()-%'"& #&4'"-Q& +23 4&Q&4, '/"&# (.#1'4-U'"-.( ". '%"-(5 /6 I.#"0&#( T4." 0:T#-)-U'"-.( 4JDgh= =G;: G5o:;7:H 3G7D -Zi$ HG:H4 "L7D<8ND <LH 4JDghg 65H 4JDgh=
,0.8-(E &*+#&,,-.( ./ +V@<'/@PZ-+@ 1HIJ -( 7?`, ./ !"#OPO6 !"#OP1 '() !"#OP! 1-%& =G;: FD<3:H FG=GL69 9:H8;7G<5F G5 3DG7: QL<<H ;:LL ;<857F 67 ` H6JF
T&/.#& '() '/"&# 2 Y: ./ -.(-U-(E #')-'"-.(5 =0& $++&# T'() -, "0& +V@ 1HIJ ,-E('4M "0& 6K7:9 -Zi$ G5o:;7G<5M 7D: 9:;<I:9J 67 H6J ,, 36F FGN5GV;657LJ =<9:
4.8&# T'() %.("'-(, "0& YJLNR ,-E('45 _'4$&, T&4.8 &'%0 4'(& -()-%'"& #&4'"-Q& +V@ 9<Q8F7 K<9 4JDghg =G;: 7D65 K<9 4JDgh= =G;: [0 s 2421\ [iGN4 XK\4
1HIJ 4&Q&4, '/"&# (.#1'4-U'"-.( ". YJLNR 4&Q&4,5 16 ?(0'(%&1&(" ./ 8-4)9":+& +23 "L7D<8ND 6 58=Q:9 <K 6N:Z6FF<;G67:H ED:5<7JE:F 6EE:69:H :69Z
"#'(,'%"-Q'"-.( '%"-Q-": T: "0& 1 '44&4&5 !'.,9V %&44 %.9"#'(,/&%"-.( ',,':, 8&#& +&#/.#1&) LG:9 G5 7D: 4JDgh= =G;: 7D65 G5 7D: 3GLHZ7JE: =G;:M <7D:9 6N:Z9:L67:H
8-"0 ' +V@ +#.1."&#9)#-Q&( 4$%-/&#',& %.(,"#$%" '() Q'#-.$, %.1T-('"-.(, ./ 8-4)9":+& ;D65N:F 3:9: 5<7 5<7:H4 &P6=G567G<5 <K L85NFM D:697M Q96G5 65H
+236 1 '44&4&6 .# &1+": Q&%".# &*+#&,,-.( %.(,"#$%",5 H&4'"-Q& 4$%-/&#',& '%"-Q-": 8', G57:F7G5:F K6GL:H 7< 9:I:6L 65J ;L:69 HGKK:9:5;:F G5 7D: <LH 4JDghg 65H
(.#1'4-U&) ". ' Q'4$& ./ @5W +#.)$%&) T: 8-4)9":+& +23 '4.(&5 @a@ '() @Wa@ #&/&# ". "0& 4JDgh= =G;:4 "N:G5N ED:5<7JE:F <QF:9I:H G5 <7D:9 =<H:LFM F8;D 6F
#'"-. ;-( #E> ./ 8-4)9":+& +23 ". 19'44&4& &*+#&,,-.( %.(,"#$%" /.# &'%0 %.9"#'(,/&%"-.(5 LGI:9 E67D<L<NG:F12M D6G9 N9:JG5N 65H 6L<E:;G6,]M 679<EDJ <K G57:F7G56L
=&6 1.%G "#'(,/&%"&) %&44,M _6 &1+": Q&%".#5 IGLLG,]M FTG5 8L;:967G<5,]M..M 6=JL<GH H:E<FG7F..M Q96G5 679<EDJ..M o<G57

!- © 2002 Macmillan Magazines Ltd !"#$%& ' ()* +,- ' . /"!$"%0 1221 ' 333456789:4;<=
 #$%&'()*
HGF:6F:F..M <9 ;67696;7F.. 3:9: 5<7 G5;9:6F:H G5 K9:m8:5;J G5 7D: <LH:9 FG=GL69 7< 7D<F: <K 7D: <LH:9 4JDgh= =G;:4 i<9 :P6=EL:M QJ ,]R12
4JDgh= =G;:4 cL<<H ;D:=GF79JM QL<<H ;:LL ;<857F 65H =6L: K:;85HG7J =<57DFM =65J <K 7D: E*-. =G;: :PDGQG7:H FE69F:M 98Kq:H K89M L<FF <K
G5 7D: <LH:9 4JDgh= =G;: HGH 5<7 HGKK:9 K9<= 7D67 <K <LH:9 4JDghg =G;: 3:GND7M L<9H<TJED<FGF 65H L:7D69NJ4 !:;9<EFG:F <K 7D:F: =G;:
[#6QL: 1\4 #D8FM 7D: <LH:9 4JDgh= =G;: HGFEL6J 65 :69LJ <5F:7 <K 8F86LLJ K6GL:H 7< 9:I:6L 65J <I:97 <9 =G;9<F;<EG; 78=<89F <9 <7D:9
F<=:M Q87 5<7 6LLM ED:5<7JE:F 6FF<;G67:H 3G7D 6N:G5N4 E67D<L<NG:F4 p<3:I:9M lZ96JF <K 9:E9:F:5767GI: ,]Z=<57DZ<LH 65GZ
=6LF FD<3:H :IGH:5;: <K G5;9:6F:H <F7:<E<9<FGF G5 E*-. 7965FN:5G;
$L%& )-/# #<"-2-' #.+63 .8#-48@+#6.'#1 $"#4*'3$#, =G;: [iGN4 ];\4 #D: 6QGLG7J <K 7D: E*-. 7965FN:5G; =G;: 7< 9:N9<3 D6G9
O89G5N <89 <QF:9I67G<5F <5 7D: 6N:G5N 4JDgh= =G;:M 3: =<5G7<9:H 6 36F 6LF< =69T:HLJ HG=G5GFD:H G5 ;<=E69GF<5 3G7D =67;D:H 5<5Z
;<L<5J <K =87657 E-. 7965FN:5G; [E*-.\ =G;: ;<576G5G5N 9<8NDLJ 12 7965FN:5G; LG77:9=67:F [iGN4 ]H\4 d<9:<I:9M ;9<FFZF:;7G<56L 656LJFGF
;<EG:F <K 6 =8767G<5 67 ;<H<5 ,.- ["L6,.-(6L\M 3DG;D D6F Q::5 <K FTG5 G5HG;67:H 7D67 7D: 7965FN:5G; =G;: D6H FGN5GV;657LJ 9:H8;:H
H:F;9GQ:H E9:IG<8FLJ114 #D: E9<7:G5 E9<H8;:H QJ 7DGF =87657 6LL:L: F8Q;8765:<8F 6HGE<F: 7GFF8: ;<=E69:H 3G7D 7D:G9 6N:Z 65H F:PZ
<K E-. GF 7:=E:96789: F:5FG7GI:M 65H 6FF8=:F 6 3GLHZ7JE: ;<5K<9=6Z =67;D:H 5<9=6L LG77:9=67:F [0 s 2422,\ [iGN4 ]:\4 iG56LLJM 7D:
7G<5 67 .14- "^ 65H 6 =87657 ;<5K<9=67G<5 67 .X4- "^ [9:K4 .+\4 #DGF 3<85HZD:6LG5N 6FF6J FD<3:H 6 FGN5GV;657 9:H8;7G<5 G5 3<85H
=87657 E-. 7965FN:5G; =<8F: GF =<H:F7LJ F8F;:E7GQL: 7< 6 Q9<6H 6996J ;L<F89: K<9 7D: E*-. 7965FN:5G; =G;: + H6JF 6K7:9 G5H8;7G<5 <K 6
<K 78=<89 7JE:FM 3G7D 6 12a 78=<89 G5;GH:5;: QJ ,] =<57DF <K 6N: .Z== E85;D QG<EFJ G5 7D: H<9F6L FTG5 [0 s 242-\ [iGN4 ]K\4
[#6QL: ,\114 p<3:I:9M =<F7 <K 7D: E*-. 7965FN:5G; =G;: 9:=6G5 "L7D<8ND Q<HJ 3:GND7 36F <K7:5 9:H8;:H G5 7D: ,]Z=<57DZ<LH
78=<89 K9:: 67 ,] =<57DFM J:7 :PDGQG7 6 N:5:96LGj:H L6;T <K 9<Q8F7Z E*-. 7965FN:5G; =G;: G5 ;<=E69GF<5 3G7D FG=GL69LJ 6N:H 5<5Z
5:FF ;<=E69:H 3G7D 7D:G9 5<5Z7965FN:5G; LG77:9=67:F [iGN4 ]6M Q\4 7965FN:5G; =G;:M <9N65 3:GND7F [FEL::5M TGH5:JM LGI:9M 7:F7:FM
S<=: ED:5<7JE:F :PDGQG7:H QJ 7D: E*-. 7965FN:5G; =G;: 3:9: FT:L:76L =8F;L:\ 3:9: <5LJ =<H:F7LJ 6KK:;7:H4 #D8FM 7D: <LH:9

a b e
d
0.3
40
0.25
Mean mass (g)
30 0.2

0.15
20
c
0.1
10
0.05

0 0
3 12 18 24 30 3 12 24
Age (months) Age (months)

f g
2 0.6

0.5
1.5
Mean mass (g)

0.4

1 0.3

0.2
0.5
0.1

0 0
3 12 24 3 12 24
Age (months) Age (months)

h i

WP

I-8(+# M L0&(.":+&, ./ 'E&) !"#OPO '() !"#OP1 1-%&5 .6 L0.".E#'+0 ./ ' V[91.("09.4) ;80-"& %.4$1(,> T.): ;1>6 ,+4&&( ;#>6 4-Q&# ;9> '() G-)(&: ;8> 1',,&,5 "6 -6 R'&1'".*:4-(
!"#OPO 1'4& 1.$,&5 26 L0.".E#'+0 ./ ' V[91.("09.4) !"#OP1 1'4& 1.$,& ,0.8-(E '() &.,-(9,"'-(&) %#.,, ,&%"-.( ./ V[91.("09.4) !"#OPO ,+4&&( ;"> '() !"#OP1 ,+4&&(
#&)$%&) ,-U& '() 4.#).G:+0.,-,5 /6 H&+#&,&("'"-Q& VW91.("09.4) ,G-((&) !"#OPO ;-> '" "@W 1'E(-\%'"-.(5 <0-"& +$4+ ;<L> -, -()-%'"&) T: '( '##.8 -( "0& !"#OPO
/&1'4& 1.$,& ;".+> '() 'E&9 '() ,&*91'"%0&) !"#OP1 1.$,& ;T."".1>5 L#.(.$(%&) ,+4&&(5 =0& 4'%G ./ '#"&#-.4&9',,.%-'"&) 80-"& +$4+ -, -()-%'"&) T: '( '##.8 -( "0& !"#OP1
4.#).G:+0.,-,6 4.,, ./ T.): 1',,6 1$,%4& '"#.+0: '() 4.,, ./ ')-+.,& "-,,$& -, &Q-)&(" -( ,+4&&(5
"0& !"#OP1 1.$,&5 1A86 Z.1+'#-,.(, ./ 1&'( !"#OPO ;T4'%G %.4$1(,> '() !"#OP1

!"#$%& ' ()* +,- ' . /"!$"%0 1221 ' 333456789:4;<= © 2002 Macmillan Magazines Ltd !.
#$%&'()*
E*-. 7965FN:5G; =G;: 9:;6EG78L67:H F<=: <K 7D: 6N:G5NZ9:L67:H N:5:F4 p<3:I:9M 7DGF H<:F 5<7 98L: <87 7D: E<FFGQGLG7J 7D67 FJF7:=G;
ED:5<7JE:F <QF:9I:H G5 7D: 4JDgh= =G;:M E697G;8L69LJ 7D<F: 9:L67:H ;D65N:FM F8;D 6F 6L7:967G<5F G5 D<9=<5: <9 N9<37D K6;7<9 L:I:LFM
7< FTG5 65H Q<5:4 ;<8LH ;<579GQ87: 7< 7D: 78=<89 9:FGF765;: ED:5<7JE:F4 O:FEG7: 65
:5D65;:H 78=<89 9:FGF765;:M 7D: 4JDgh= =G;: FD<3:H 6 9:H8;:H
N-,/(,,-*4 L<5N:IG7J G5 ;<=E69GF<5 3G7D 7D:G9 4JDghg LG77:9=67:F4 #DGF 9:H8;:H
#D: 4JDgh= =G;: N:5:967:H G5 7DGF F78HJ 3:9: DGNDLJ 9:FGF7657 7< L<5N:IG7J GF 6FF<;G67:H 3G7D 7D: :69LJ 6EE:6965;: <K 6 58=Q:9 <K
FE<5765:<8F 78=<89F4 #DGF 9:FGF765;: H:E:5HF <5 3GLHZ7JE: E-.M 6F 6N:G5NZ6FF<;G67:H ED:5<7JE:F4 #D:F: E697G;8L69 6N:G5N ED:5<7JE:F
G5 G7F 6QF:5;: [K<9 :P6=EL:M 7D: 4JD!h= =G;:\ 7D: = 6LL:L: ;<5K:9F ;<99:L67: 3G7D 6 1.a 9:H8;7G<5 G5 =:HG65 LGK:FE65M F8NN:F7G5N 7D67
LG77L: E9<7:;7G<5 K9<= 78=<89F4 #DGF GF ;<5FGF7:57 3G7D <89 DJE<7DZ 7D:J 69: G=E<97657 K<9 <9N65GF=6L L<5N:IG7J4
:FGF 7D67 7D: N:5: E9<H8;7 <K 7D: = 6LL:L: 68N=:57F 7D: 6;7GIG7J #D: :P7:57 <K 7D: =Z6LL:L: H:L:7G<5 G5 7D: 4JDgh= =<8F: D6F 5<7
<K 3GLHZ7JE: E-. 7< E9:I:57 78=<89 K<9=67G<54 #D: 78=<89 Q::5 ;<=EL:7:LJ H:V5:H4 #D: E-.Z6FF<;G67:H H:L:7G<5 G5;L8H:F E-.
9:FGF765;: <K 4JDgh= =G;: =6J Q: E697LJ G579G5FG; 7< 7D: G5HGIGH86L :P<5F ,R` 6F 3:LL 6F F:m8:5;:F 8EF79:6= <K 7D: 4JD N:5:4 Y7 GF
;:LLF <K 7D: 65G=6LFM 6F VQ9<QL6F7F H:9GI:H K9<= 4JDgh= :=Q9J<F 69: E<FFGQL: 7D67 7D: 4JDgh=Z6FF<;G67:H ED:5<7JE:F ;<8LH Q: 6 9:F8L7 <K
=<9: 9:FGF7657 7< 7965FK<9=67G<5 QJ 6;7GI67:H +$> EL8F 1/) <5;<Z :G7D:9 D6EL<G5F8KV;G:5;J G5 N:5:F 8EF79:6= <K 4JD <9 7D: E9<H8;Z
7G<5 <K 6 7985;67:H E-. N:5: E9<H8;74 "L7D<8ND D6EL<G5F8KV;G:5;J
;655<7 Q: 98L:H <87M 3: K6I<89 7D: DJE<7D:FGF 7D67 6 7985;67:H
a ^Z7:9=G56L N:5: E9<H8;7 <K E-. GF 7D: E9G=69J :KK:;7<9 [F:: Q:L<3\4
" 7985;67:H =:FF6N: ;6E6QL: <K :PE9:FFG5N 7D: ^Z7:9=G56L E-.
E9<7:G5 GF :PE9:FF:H G5 =65J 7GFF8:F <K 7D: 4JDgh= =<8F:M 65H
F:I:96L L6Q<967<9G:F D6I: FD<35 7D67 E-. ^Z7:9=G56L K96N=:57F <9
E:E7GH:F ;65 68N=:57 3GLHZ7JE: E-. 6;7GIG7G:F.-R.b4 W: D6I: FD<35
7D67 E-. =Z6LL:L: :PE9:FFG<5 ;<5F798;7F :5D65;: 3GLHZ7JE: E-.
7965F6;7GI67G<5 6;7GIG7J 65H ;65 F8EE9:FF ;65;:9 ;:LL N9<37D G5 7D:
E9:F:5;: <K 3GLHZ7JE: E-. [S4(4M S4O4#4M !4n4 65H p4Y4M 85E8QLGFD:H
H676\4 #D: ;:LLF <K 4JDgh= =G;: D6I: G5;9:6F:H 3GLHZ7JE: E-.
9:FE<5F:F 7< G<5GjG5N 96HG67G<5 ;<=E69:H 3G7D ;:LLF <K 4JDgh!
=G;:4 #D: :5D65;:H 78=<89 9:FGF765;: G5 4JDgh= =G;: GF H:E:5H:57
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9:m8G9:F 3GLHZ7JE: E-. 7< E9<=<7: 78=<89 F8EE9:FFG<54 "5<7D:9
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"/ © 2002 Macmillan Magazines Ltd !"#$%& ' ()* +,- ' . /"!$"%0 1221 ' 333456789:4;<=
 #$%&'()*

a E b c
E
D E
D
D

A A
A M
M M
e 0.7 f 0.3
d

Adipose thickness (mm)

E 0.6

Dermal thickness (mm)

0.5 0.2
D 0.4
M
0.3
0.1
0.2
0.1
0 0
m WT m WT m WT m WT
3 months 24 months 3 months 24 months

g h 0.9
0.8

Fraction hair regrowth

0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
m WT m WT
3–6 months 22–26 months

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a 3 b 3
c
Wound diameter (mm)
Wound diameter (mm)

2.5 2.5

D
2 2
D
E
1.5 1.5

1 1
0 1 2 3 4 0 1 2 3 4
Days after wounding Days after wounding
e 12 f 12
d
10 10
WBC × 10 6

WBC × 10 6

8 8

6 6

4 4
D
D
2 2
Day 0 Day 6 Day 11 Day 0 Day 6 Day 11

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Adipose thickness (mm)

Wound diameter (mm)

Hair regrowth fraction

2.4
0.75 0.15
!+.4,9*+).'-*4 .41 '+.4,9#/'-*4 .,,.3,
2.3
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0.25 0.05
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