Underlying mechanisms of

biochemical oscillations
(YUGI, Katsuyuki)
Kuroda Lab., The University of Tokyo

2012724

Electrocardiograph

2012724

2012724

BorisukandTyson(1998)

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k<1.2x102sec1 k>1.2x102sec1

Hes1(Notch signalling system)

mRNA2

Hirata et al. (2002) Science

MAPK2

, 2006

Nakayama et al. (2008) Curr. Biol.

In depth

2012724



Relaxation oscillator

(e.g. Selkov model)

Hopf
Negative feedback oscillator

(e.g. Repressilator)

2012724

Selkov

2012724

Selkov

v1

v2

F6P(y)

ADP(x)

v3

PFK

x
y

=
=

v2 v3
v1 v2

v1 = b
v2 = ay + x2y

v3 =x
Strogatz(1994)pp.205

2012724

Kennedy et al. (2007)

2012724

insulin

Bertram et al. (2007)

2012724

Corkey et al. (1988)

Insulin
Luteinizing hormone

Growth hormone (
Adrenocorticotropic hormone
)
2012724

15

11 min

11 min

2012724

insulin

insulin

insulin

Continuous insulin

glucose production
mol/kg/min

13min

26min

1(MATLAB): Selkov model

v1

v2

F6P(y)

ADP(x)

v3

PFK

x
y

=
=

v2 v3
v1 v2

: a = 0.06, b = 0.6

2012724

: ADP = 1.0, F6P = 1.0

v1 = b
v3 = x

v2 = ay + x2y

Strogatz(1994)pp.205


function selkov( )
time = 0.001:1:100;
s0 = [1.0 , 1.0];
% Initial values
param = [0.06 , 0.6]; % Constants
[t,time_course] = ode15s(@(t,s) ODE(t,s,param),time,s0);
figure;
plot(t,time_course);
end
function dsdt = ODE(t,s,param)
ADP = s(1); F6P = s(2);
a = param(1); b = param(2);
v1 =
v2 =
v3 =
dsdt(1,:) =
dsdt(2,:) =
end
2012724

:F6P

: ADP

2012724


function selkov( )
time = 0.001:1:100;
s0 = [1.0 , 1.0]; % Initial values
param = [0.06 , 0.6]; % Constants
[t,time_course] = ode15s(@(t,s) ODE(t,s,param),time,s0);
figure;
plot(t,time_course);
end
function dsdt = ODE(t,s,param)
ADP = s(1);
F6P = s(2);
a = param(1); b = param(2);
v1 = b;
v2 = a * F6P + ADP^2 * F6P;
v3 = ADP;
dsdt(1,:) = v2 v3;
dsdt(2,:) = v1 v2;
end
2012724

1David Baltimore

2012724

Baltimore

RockefellerCaltech

2012724

Baltimore

2012724

Hoffmann et al. (2002) Science

2012724

NF-B

NF-B

IBNF-B

IKKIB

IB NF-B

NF-BIB

NF-B

2012724

()

()

EMSA(Electrophoretic Mobility Shift Assay)

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(feedback)

2012724

2012724

Phase plane ()

x-y

[F6P]
y = 0

x = 0

Nullcline ()

= 0

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[ADP]

2:

Selkov (MATLAB)

([ADP],[F6P])2

MATLAB

2012724


function selkov_phaseplane( )
time = 0.001:1:50;

plot_phase_plane(time_course,param(1),param(2));
end
function plot_phase_plane(time_course,a,b)
figure;
hold on;
%
plot(

);

ADP = 0:0.1:3;
F6P = ADP ./ ( a + ADP.^2 ); % dADP / dt == 0
plot(ADP,F6P,r); % rredr
ADP = 0:0.1:3;

plot(
hold off;
end

% d F6P / dt == 0
,

);

function dsdt = ODE(t,s,param) ()

2012724

2012724


function selkov_phaseplane( )
time = 0.001:1:50;

plot_phase_plane(time_course,param(1),param(2));
end
function plot_phase_plane(time_course,a,b)
figure;
hold on;
%
plot(time_course(:,1),time_course(:,2));
ADP = 0:0.1:3;
F6P = ADP ./ ( a + ADP.^2 ); % dADP / dt == 0
plot(ADP,F6P,r); % rredr
ADP = 0:0.1:3;
F6P = b ./ ( a + ADP.^2 ); % d F6P / dt == 0
plot(ADP,F6P,r);
hold off;
end

2012724

!
x = f (x, y)
y = g(x, y)

( x , y ) ( , )

[F6P]
!

x = x + 2y
y =
8 2y

+ x2 y
x2 y

5
2
(1,2)
[ADP]

2012724

[F6P]

( , ) = ( 0 ,p )

=0
=0

: =0
: =0

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[ADP]

3a: Selkov

()

x()

2012724

[F6P]
=0
=0

2012724

[ADP]

3b: Selkov
Selkov
figure
(MATLAB)

quiver
meshgrid

2012724

: MATLAB

[X,Y] = meshgrid(0.01:0.2:2, 0.01:0.2:2);

DX = -X + a * Y + X.^2 .* Y;
DY = b - a * Y - X.^2 .* Y;

(X,Y)(DX,DY)
quiver(X,Y,DX,DY);

2012724

function selkov_vector_field () ()
function ODE(t,s,param)()
function plot_phase_plane(time_course, a, b)()
function plot_vector_field(a,b)
figure(1);
[X,Y] = meshgrid(
);
DX =
DY =
quiver(
); %(X,Y)(DX,DY)
end

2012724

2012724

function selkov_vector_field () ()
function ODE(t,s,param)()
function plot_phase_plane(time_course, a, b)()
function plot_vector_field(a,b)
figure(1);
[X,Y] = meshgrid(0.01:0.2:3, 0.01:0.2:10);
DX = -X + a * Y + X.^2 .* Y;
DY = b - a * Y - X.^2 .* Y;
quiver(X,Y,DX,DY); %(X,Y)(DX,DY)
end

2012724

2Arnold Levine

2012724

p53Levine

Rockefeller

2012724

Lev Bar-Or et al. (2000) PNAS

2012724

p53Mdm2

p53

()

2012724

2012724

2012724


[F6P]

=0
=0

[ADP]
2012724


[F6P]

[F6P]

[ADP]

2012724

[ADP]

dx1
= F1 (x1 , , xn )
dt

F1
x1

dx1
= F1 (x1 , , xn )
dt

F1
F1

x1
xn

x1

dt

d xn
dt

2012724

= F1 (x1 , , xn )
..
.
= Fn (x1 , , xn )

x1
d .
.. =
dt
xn

F1
x1

..
.

Fn
x1

..
.

F1
xn

..
.

Fn
xn

x1
..
.
xn

4: Selkov

Selkov (MATLAB)

x =
(x + ay + x2 y)
x
x

x =
(x + ay + x2 y)
y
y

(MATLAB)

(MATLAB)

"

x
x

x
y
y
y
(MATLAB)
x
y

2012724

MATLAB

f
diff(f, x);

f
f = -x + a * y + x^2 * y;

J =[ diff(f,x) , diff(f,y) ; diff(g,x) , diff(g,y) ];

2012724

Symbolic Math ToolBox

syms x y a b; %x, y, a, b

x, y
S = solve( -x + a * y + x^2 * y=0,'b - a * y - x^2 *y=0', 'x', 'y');

Sx,y
xS.x
2012724

J = subs(J, [a,b] ,[0.06,0.6])

% Ja,b0.06,0.6

A
eig(A)

2012724


function selkov_jacobian( )
syms x y a b;
S = solve('
','
',' ',' ');
% x, y
f = -x + a * y + x^2 * y;
g =
J = [

%fx,y

]; %gx,y

fix = subs([S.x,S.y],[ , ],[

,
%a,b0.06,0.6

])

J = subs(J, [ , ,,a,b] ,[
,
,0.06,0.6])
%Ja,b0.06,0.6

end

2012724


>> selkov_jacobian
fix =
0.6000 1.4286

J =
0.7143 0.4200
-1.7143 -0.4200

ans =
0.1471 + 0.6311i
0.1471 - 0.6311i
>>

2012724

x =
(x + ay + x2 y) = 1 + 2xy
x
x

x =
(x + ay + x2 y) = a + x2
y
y

y =
(b ay x2 y) = 2xy
x
x

y =
(b ay x2 y) = a x2
y
y

b
b,
a + b2

"

2b
1 + a+b
2
2b2
a+b2

2012724

a + b2
a b2

"

1 + 2xy
2xy

a + x2
a x2

"


function selkov_jacobian( )
syms x y a b;
S = solve('-x + a * y + x^2 * y=0','b - a * y - x^2 * y=0','x','y');

% x, y
f = -x + a * y + x^2 * y;
g = b - a * y - x^2 * y;
J = [ diff(f,x) , diff(f,y);

%fx,y

diff(g,x) , diff(g,y) ]; %gx,y

fix = subs([S.x,S.y],[a,b],[0.06,0.6])
%a,b0.06,0.6
J = subs(J, [x,y,a,b] ,[fix(1),fix(2),0.06,0.6])
%Ja,b0.06,0.6
eig(J) %
end

2012724

(Node)

d
x = Jx
dt

(attractor)

x(t)

: (repellor)

= exp(Jt)x0
= c1 exp(1 t)v1 + cn exp(n t)vn

(Saddle)

2012724

StableNode

Saddle

(Spiral)
(Focus)

StableSpiral

UnstableSpiral

(Center)

(Eulers formula)

Center
2012724

5: Selkov

Selkov
()a=0.06, b=0.6

1:
Ax=x|A-I|=0
2x2 2-tr(A) +det(A)=0

2:

= tr(A) = 1 + 2

= det(A) =12

< 0 > 0

24 > 0

2012724

J=

> 0 2
a,b

2b2
+ a+b
2
2b2
a+b
2

a+b
a b2
2

= det(J) = a + b2 > 0
a b2
= tr(J) = (a + b )
a + b2
2

a=0.06, b=0.6

24 < 0
> 0

2012724

"

2012724

http://www.nig.ac.jp/hot/2006/saga0606-j.html

8130

260

http://bsw3.naist.jp/courses/courses106.html
2012724

NIH

2012724

Q. 2hr?

A. Hes1, Smad, Stat

2012724

2012724

2012724

2012724

()

2012724

(limit cycle)
(trajectory)

Center ()

Limitcycle

Center

Poincar-Bendixson

2012724

Center

Supercritical Hopf
Im

Re <0

1.
2.
3.

2012724

Re

Hopf
Stable Spiral Unstable Spiral

Unstable Spiral

Hopf

2012724

6: SelkovHopf
Selkov 2
Hopf
()
1: a=0.14, b=0.6
2: a=0.06, b=0.6

MATLAB
2012724


a b2
= (a + b )
a + b2
2

a=0.06, b=0.6 >0

a=0.14, b=0.6 <0

= a + b2 > 0

a b2

4 = 5(a + b )
a + b2
2

1,2 -4 < 0

2012724

a=0.14, b=0.6

2012724

a=0.06, b=0.6


Relaxation oscillator
and
Negative feedback oscillator

2012724

Relaxation oscillator ()

Negative feedback oscillator ()

? Bendixson

2012724

Bendixson

f1
f2
+
D
x1
x2

([F6P]) ([ADP])

+
[F6P]
[ADP]

2012724

Relaxation oscillator

1(positive)

1negative feedback loop

J=

+
?

"

()

2012724

Negative feedback oscillator

2negative feedback oscillators (Bendixson)

J=

"

()

2012724

Bendixson

7: SelkovBendixson

Selkov

> 0

2012724


function selkov_bendixson( )
syms x y a b;
f=
% ODE
g=

% ODE

J=

% f, gJ

J = subs(J, [a,b] ,[0.06 , 0.6]); % a,b

B=

figure(1)
hold on;
for i=0:0.5:3

% x

for j=0:1:10 % y
B_value = subs(

); % Bx,yi,j

if( B_value > 0 )

plot(i,j,'ko','MarkerFaceColor','w');
else
plot(i,j,'ko','MarkerFaceColor','k');
end
end
end
end
2012724

2012724


function selkov_bendixson( )
syms x y a b;
f = -x + a * y + x^2 * y;
g = b - a * y - x^2 * y;
J = [ diff(f,x) , diff(f,y);
diff(g,x) , diff(g,y)];
J = subs(J, [a,b] ,[0.06 , 0.6]); % a,b
B = J(1,1)+J(2,2); %
figure(1)
hold on;
for i=0:0.5:3

% x

for j=0:1:10 % y
B_value = subs( B, [x,y], [i,j] ); % Bx,yi,j
if( B_value > 0 )
plot(i,j,'ko','MarkerFaceColor','w');
else
plot(i,j,'ko','MarkerFaceColor','k');
end
end
end
end
2012724

(bifurcation diagram)
(phase diagram)
1 ()

2(a, b)

LacY-GFP

2012724

8: Selkov
()

2012724

plot(x,y,'ko','MarkerFaceColor','k');
plot(x,y,'ko','MarkerFaceColor','w');
plot(x,y,'ko','MarkerEdgeColor','r','MarkerFaceColor','r');
plot(x,y,'ko','MarkerEdgeColor','r','MarkerFaceColor','w');

1 isreal(n)
real(c)

2012724

for a , b

if

if ( isreal(v(1)) )

OK ()

if

2012724

if( real(v(1)) < 0 )

(1/2)
function selkov_phase_diagram()
figure;
hold on;
for a=0.01:0.01:0.15
for b=0.1:0.1:1.0

end
end
end
function v=jacobian( p , q )
syms x y a b;
S = solve(' -x + a * y + x^2 * y=0','b - a * y - x^2 * y=0','x','y');

f = -x + a * y + x^2 * y;
g = b - a * y - x^2 * y;
J = [ diff(f,x) , diff(f,y);
diff(g,x) , diff(g,y)];
fix = subs([S.x,S.y],[a,b],[p,q]);
J = subs(J, [x,y,a,b] ,[fix(1),fix(2),p,q]);
v = eig(J);
end
2012724

(2/2)
function phase_diagram( a , b )
v=jacobian(a,b);
if ( isreal(v(1)) ) % v(1)v(2)v(1)
if( v(1) < 0 && v(2) < 0 )
plot();
else
plot();
end
else
if(
plot(
else
plot(
end
end
end

2012724

< 0 ) % v(1) < 0

);
);

(1/2)
function selkov_phase_diagram()
figure;
hold on;
for a=0.01:0.01:0.15
for b=0.1:0.1:1.0
phase_diagram(a,b);
end
end
end
function v=jacobian( p , q )
syms x y a b;
S = solve(' -x + a * y + x^2 * y=0','b - a * y - x^2 * y=0','x','y');

f = -x + a * y + x^2 * y;
g = b - a * y - x^2 * y;
J = [ diff(f,x) , diff(f,y);
diff(g,x) , diff(g,y)];
fix = subs([S.x,S.y],[a,b],[p,q]);
J = subs(J, [x,y,a,b] ,[fix(1),fix(2),p,q]);
v = eig(J);
end
2012724

(2/2)
function phase_diagram( a , b )
v=jacobian(a,b);
if ( isreal(v(1)) ) % v(1)v(2)v(1)
if( v(1) < 0 && v(2) < 0 )
plot(a,b,'ko','MarkerFaceColor','k');
else
plot(a,b,'ko','MarkerFaceColor','w');
end
else
if( real(v(1)) < 0 ) % v(1) < 0
plot(a,b,'ko','MarkerEdgeColor','r','MarkerFaceColor','r');
else
plot(a,b,'ko','MarkerEdgeColor','r','MarkerFaceColor','w');
end
end
end

2012724

: a, b

Hopf
b

2012724

Selkov

2012724

Supercritical Hopf

Hopf

Poincar-Bendixson

2012724

Negative feedback oscillator

2012724

Repressilator

Elowitz and Leibler (2000) Nature

2012724

(NOT)

1 / ( 2n )

Repressilator

2012724

hUp://133.6.66.95/mizutanilab3/ROC_ROCirc.html

: Ring Oscillator

2012724

Repressilator

3()

d[mRNA]
dt
d[Protein]
dt

2012724

= 0 +

1+[Repressor]n

[mRNA]

= ([mRNA] [Protein])

Phase diagram

n=2, 0=0

n=2.1, 0=0

n=2, 0/=103

2012724

inset

2012724


40

0.2-0.5 h-1

2012724

9:

d[mRNA]
dt
d[Protein]
dt

0 +

([mRNA] [Protein])

1+[Repressor]n

[mRNA]

(lacI, cI, tetR, LacI, CI, TetR) = (0.2, 0.3, 0.1, 0.1, 0.5, 0.4)

=20, 0=0, =0.2, n=2

2012724

MATLAB(1/2)
function repressilator( input_args )
time = 0.001:1:200;
s0 = [0.2, 0.3, 0.1, 0.1, 0.5, 0.4]; % Initial values
param = [20, 0, 0.2, 2]; % Constants
[t,time_course] = ode15s(@(t,s) ODE(t,s,param),time,s0);
plot_time_course(t,time_course);
plot_phase_plane(time_course);
end

2012724

MATLAB(2/2):
function dsdt = ODE(t,s,param)
lacI = s(1); cI = s(2); tetR = s(3);
LacI = s(4); CI = s(5); TetR = s(6);
alpha = param(1);
alpha_zero = param(2);
beta = param(3);
n = param(4);
dsdt(1,:) =
dsdt(2,:) =
dsdt(3,:) =
dsdt(4,:) =
dsdt(5,:) =
dsdt(6,:) =
end

2012724

2012724


function dsdt = ODE(t,s,param)
lacI = s(1); cI = s(2); tetR = s(3);
LacI = s(4); CI = s(5); TetR = s(6);
alpha = param(1);
alpha_zero = param(2);
beta = param(3);
n = param(4);
dsdt(1,:) = alpha_zero + alpha / ( 1 + CI^n ) - lacI;
dsdt(2,:) = alpha_zero + alpha / ( 1 + TetR^n ) - cI;
dsdt(3,:) = alpha_zero + alpha / ( 1 + LacI^n ) - tetR;
dsdt(4,:) = - beta * ( LacI - lacI );
dsdt(5,:) = - beta * ( CI - cI );
dsdt(6,:) = - beta * ( TetR - tetR );
end

2012724

Hopf
Plan A:

2

Plan B:

Repressilator6Plan B

2012724

Hopf

J=

1
0
0

0
0

0
1
0
0

0
0
1
0
0

0
X
0

0
0

0
0
X
0

npn1
m
1
3

=
=X
p3
(1 + p23 )2

p
=
+ 0
3
p3
n
1 + p3

( + 1) (2X + 4) 3X < 0
2

2012724

X
0
0
0
0

10: Hopf

( + 1)2 (2X + 4) 3X 2 < 0

=10, 0=0, n=2

npn1
3
p
=
+ 0
3
X =
p3
n
1 + p3
(1 + p23 )2
() =10, 0=0, n=2
p3 = 2
2012724


=0.13

=0.14

(+1)2(2X+4)-3X2 = 0.0231 > 0

(+1)2(2X+4)-3X2 = -0.0355 < 0

2012724

Hill

(0)m

2012724


Toggle switchPitchfork

2012724

Toggle switchPitchfork
x

LacI (x)

x =
y

x
1 + y2
a

y
1 + x2

: xy

2012724

CI (y)

Gardner et al. (2000)

=0

Pitchfork
y

=0

a=2
y

a>2

Stable

Unstable
Stable
2012724

pitchfork

1.

Toggle switch
a 1 3

2.

11
Stable Node 3 Stable Node 2 Unstable
Node 1

2012724

3.

y x
x x5 - ax4 + 2x3 - 2ax2 + (1 + a2)x a = 0

4.

3 x x5 - ax4 + 2x3 - 2ax2

+ (1 + a2) x - a = 0 (x3 + x - a)(x2 - ax + 1) = 0

2012724

: (1/2)

5.

x3 + ax + b = 0 3
D = - 4a3 - 27b2 D > 0
3 D = 0D < 0 1
2
x3 + x - a x3 + x - a = 0 1

2012724

: (2/2)
6.

x2 - ax + 1
x2 - ax + 1 = 0 a > 2 2a = 2
1a < 2

7.

56 x (x3 + x a)(x2 - ax + 1) = 0 (x3 + x - a)1

(x2 - ax + 1) a = 202
Toggle switch 0 < a < 2 a = 2 a > 2
a = 2

2012724

: (1/2)
8.

Toggle-switch

9.

2ax
(1+x
2 )2

2ay
(1+y
2 )2

a > 2 x2 - ax + 1 = 0

(i)

(ii)

a2

4 a
,

a2

"

2
(: )

2012724

"

: (2/2)
10.

x3 + x - a = 0 x

!
$
"
' (3
"
%
&
2
3 a
a
1
1
#
x=
+
+
)
*+ ,
2
2
3
+ 1 ,3
3
a 2
3 a2 +
+
2
3

x
(i)

a = 2 x = 1 x a
0 < a < 2 0 < x < 1
a > 2 x > 1

(ii)

0 < x < 1 0 < a < 2 > 0

x > 1 a > 2 < 0

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: Pitchfork
11.

7.10.
a
x

0<a<2
a=2
a>2

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x3 + x - a = 0
x2 - ax + 1 = 0
x3 + x - a = 0
x2 - ax + 1 = 0
x3 + x - a = 0
x2 - ax + 1 = 0

1
0
1
1
1
2

Node x 1

Node x 2
Saddle x 1

1(1/2)
= 0

a
y=
1 + x2

y!

=
=

0 (1 + x2 ) a 2x
(1 + x2 )2
2ax

(1 + x2 )2

y
y
2012724

!!

=
=
=

2a(1 + x2 )2 (2ax) 2(1 + x2 ) 2x

(1 + x2 )4
2a(1 + x2 ){(1 + x2 ) 2x 2x}
(1 + x2 )4

2a(1 + x2 )(1 3x)(1 + 3x)

(1 + x2 )4

a
+

=0

1(2/2)
= 0 y = x
2

y
a

=0

y=x

=0

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2
y

=0

=0

x
y

=0

=0

a
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3
a
a
x=
y=

2
1+y
1 + x2

=
1+

a
a
1+x2

"2

a(1 + x2 )2
(1 + x2 )2 + a2

(1 + x2 )2 x + a2 x

a(1 + x2 )2

x + 2x3 + x5 + a2 x

a + 2ax2 + ax4

x5 ax4 + 2x3 2ax2 + (1 + a2 )x a = 0

2012724

(x3 + x a)(x2 ax + 1)

x5 ax4 + x3 + x3 ax2 + x ax2 + a2 x a

x5 ax4 + 2x3 2ax2 + (1 + a2 )x a

2012724

5-7
5.

x3 + x - a = 0 D = - 4 - 27a2 < 0
12

6.

x2 - ax + 1 = 0 D = a2 - 4 a > 2
D > 0 2a = 2 D = 0
1 a < 2 D < 0

7.

0<a<2
a=2
a>2
2012724

x3 + x - a = 0
x2

- ax + 1 = 0

x3

+x-a=0

x2

- ax + 1 = 0

x3 + x - a = 0
x2 - ax + 1 = 0

1
0
1
1
1
2

1
32

x=1


x =
y

8
a
x
2
1+y
a
y
2
1+x

2ay
x =
y
(1 + y 2 )2

x = 1
x

2ax
x =
y
(1 + x2 )2

2012724

2ax
(1+x
2 )2

y = 1
y
2ay
(1+y
2 )2

"

9-(ii)

xy =

4a2 xy
=1
(1 + x2 )2 (1 + y 2 )2
4a2 xy
= 1
(1 + x2 + y 2 + x2 y 2 )2

(a

a2

4)(a
4

a2 4)

4a2
=1
(2 + x2 + y 2 )2
4a2
= 1
2
(2 + 4a 48 )2
4a2
= 1 4
a
4
= 1 2 > 0 ( a > 2)
a

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=1

<0, >0, 2-4>0

2

10
(i)

0 < a < 2 x x
a = 0 x = 0 a = 2 x
= 1 x a 0 < a < 2
x 0 1
0 < x < 1

(ii)

y=x

4a2 xy
=1
(1 + x2 )2 (1 + y 2 )2
4a2 x2
= 1
(1 + x2 )4

d
8a2 x(1 + x2 )3 (x 1)2
=1
dx
(1 + x2 )4

a = 0, x = 0 = 1a = 2, x = 1 = 0
0 < a < 2 1 > > 0a > 2 < 0
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11
x

x2 - ax + 1 = 0

x3 + x - a = 0

x2 - ax + 1 = 0

NodeSaddle
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(SaddleNode, Pitchfork)

(Hopf)

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Further readings

Strogatz, S.H, Nonlinear dynamics and chaos, Perseus Books Publishing, 1994. (ISBN
0-7382-0453-6)

Borisuk and Tyson (1998)

Fall, C.P., Marland, E.S., Wagner, J.M. and Tyson, J.J. Computational cell biology,
Springer, 2002. (ISBN 0-387-95369-8)

Bendixson

Borisuk, M.T. and Tyson, J.J., Bifurcation analysis of a model of mitotic control in frog eggs, J.
Theor. Biol. 195:69-85, 1998.

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