Photoacoustic (PA) computed tomography (PACT) benefits from genetically encoded probes with photochromic behavior, which dramatically increase detection sensitivity and specificity through photoswitching and differential imaging. Starting with a DrBphP bacterial phytochrome, we have engineered a near-infrared photochromic probe, DrBphP-PCM, which is superior to the full-length RpBphP1 phytochrome previously used in differential PACT. DrBphP-PCM has a smaller size, better folding, and higher photoswitching contrast. We have imaged both DrBphP-PCM and RpBphP1 simultaneously on the basis of their unique signal decay characteristics, using a reversibly switchable single-impulse panoramic PACT (RS-SIP-PACT) with a single wavelength excitation. The simple structural organization of DrBphPPCM allows engineering a bimolecular PA complementation reporter, a split version of DrBphP-PCM, termed DrSplit. DrSplit enables PA detection of protein-protein interactions in deep-seated mouse tumors and livers, achieving 125-mu m spatial resolution and 530-cell sensitivity in vivo. The combination of RS-SIP-PACT with DrBphP-PCM and DrSplit holds great potential for noninvasive multi-contrast deep-tissue functional imaging.Peer reviewe

Baloban, Mikhail

Hu, Peng

Li, Lei

Shcherbakova, Daria M.

Shemetov, Anton A.

Shi, Junhui

Verkhusha, Vladislav V.

Wang, Lihong V.

Yao, Junjie

Zhang, Ruiying

Zhu, Liren

English

Helsingin yliopiston digitaalinen arkisto

Small near-infrared photochromic protein for photoacoustic multi-contrast imaging and detection of protein interactions in vivo

Photoacoustic (PA) computed tomography (PACT) benefits from genetically encoded probes with photochromic behavior, which dramatically increase detection sensitivity and specificity through photoswitching and differential imaging. Starting with a DrBphP bacterial phytochrome, we have engineered a near-infrared photochromic probe, DrBphP-PCM, which is superior to the full-length RpBphP1 phytochrome previously used in differential PACT. DrBphP-PCM has a smaller size, better folding, and higher photoswitching contrast. We have imaged both DrBphP-PCM and RpBphP1 simultaneously on the basis of their unique signal decay characteristics, using a reversibly switchable single-impulse panoramic PACT (RS-SIP-PACT) with a single wavelength excitation. The simple structural organization of DrBphP-PCM allows engineering a bimolecular PA complementation reporter, a split version of DrBphP-PCM, termed DrSplit. DrSplit enables PA detection of protein–protein interactions in deep-seated mouse tumors and livers, achieving 125-µm spatial resolution and 530-cell sensitivity in vivo. The combination of RS-SIP-PACT with DrBphP-PCM and DrSplit holds great potential for noninvasive multi-contrast deep-tissue functional imaging

Caltech Authors - Main

1 
 
Small near-infrared photochromic protein for photoacoustic multi-
contrast imaging and detection of protein interactions in vivo 
 
Lei Li, Anton A. Shemetov, Mikhail Baloban, Peng Hu, Liren Zhu, Daria M. Shcherbakova, 
Ruiying Zhang, Junhui Shi, Junjie Yao, Lihong V. Wang and Vladislav V. Verkhusha 
 
Supplementary Materials 
 
2 
 
Supplementary Tables 
 
Supplementary Table 1. Spectral and photoacoustic properties of RpBphP1 and DrBphP-PCM in vitro. 
 
Protein 
Photo 
switching 
state 
Maximum 
absorption 
wavelength 
(nm) 
Maximum 
emission 
wavelength 
(nm) 
Molar 
extinction 
coefficient
(M–1 cm–1)
Fluoresc
ence 
quantum 
yield (%)
PA 
excitation 
wavelengtha
(nm) 
ON-to-OFF 
photoswitching 
rateb (s-1) 
PA signal-
to-noise 
ratioc 
PA 
switching 
ratiod 
Temporal 
frequency 
PA image 
CNRe 
0 mm 
depth
12 
mm 
depth
0 mm 
depth
12 mm 
depth
0 mm 
depth
12 mm 
depth
RpBphP1 
Pfr (ON) 756 none 78,300 none 
780 1.56 501.4 ±15.3
15.2 
±0.3
4.3 
±0.2
2.3 
±0.2 
380.3 
±12.0
21.3 
±0.2 Pr (OFF) 678 n.d. 87,500 n.d. 
DrBphP-
PCM 
Pfr (ON) 750 none 59,200 none 
780 0.54 636.2 ±17.2
25.4 
±1.3
8.7 
±1.5
4.7 
±1.2 
550.4 
±16.0
38.3 
±0.3 Pr (OFF) 700 720 98,000 2.9% 
 
aThe laser fluence was 8 mJ cm–2. The wavelengths were chosen on the basis of the absorption of the proteins and the power spectra of 
the lasers. bThe ON-to-OFF photoswitching rate is defined as the reciprocal of the time when the PA signal drops to 1/e of its 
maximum, measured at a a laser fluence of 4 mJ cm–2. cThe protein concentration was 30 µM, and the reduced scattering coefficient of 
the scattering media was ~10 cm–1. Data are reported as mean ± s.d. dThe switching ratio is the ratio of the PA signal amplitudes 
acquired in the ON and the OFF states. Data are reported as mean ± s.d. eContrast-to-noise ratio (CNR). The hemoglobin 
concentration was 2.3 mM. Data are reported as mean ± s.d. 
3 
 
Supplementary Table 2. Quantified coefficients of the decay functions of the PA signals from 
cellsa. 
 
Coefficientsb 
High fluencec Low fluenced Scattering mediae 
HEK-293 U87 HEK-293 U87 HEK-293 U87 
HEK-293:U87
mixture with 
about 1:1 ratio
ܽ 0.014 0 0.001 0 0.035 0 0.266 
ܾ 0.493 0.968 0.515 1.01 0.500 1.00 0.169 
ܿ 0.488 0.082 0.483 0 0.481 0.0930 0.581 
ଶܶ 1.45 1.72 2.01 2.14 0.591 0.596 0.756 
݇f 1.01 11.8 1.07 100 1.04 10.8 3.44 
ݏg 0.005 0.844 0.03 0.980 0.02 0.830 0.549 
 
aThe signals from the cells were spatially averaged first, and the calculations were based on their 
spatial mean values. bThe decay function can be expressed in the form of ݃ሺݐሻ ൌ ܽ ൅
ܾ ∙ ݁ሺି
೟
೅భሻ ൅ ܿ ∙ ݁ሺି
೟
೅మሻ, where ଵܶ ൐ ଶܶ, and the ratio ܴ ൌ ଵܶ/ ଶܶ is within the range of 2.2–3.0. 
cThe cells were embedded in clear media, and the illumination fluence is 5 mJ/cm2. dThe cells 
were embedded in clear media, and the illumination fluence is 0.5 mJ/cm2. eThe cells were 
embedded in scattering media, and the local fluence is unknown. fAs defined in Online Methods, 
݇ ൌ ௠௔௫ሼ௕,௖ሽ௠௜௡ሼ௕,௖ሽ , which was used as a criterion to distinguish two types of cells. It can be seen from 
Table 2, regardless of local fluence, the ݇ of HEK-293 cells is approximately 1, whereas the ݇ of 
U87 cells is much larger, normally greater than 10, to avoid infinity in computation, the upper 
limit of k was set to 50. gAs defined in Online Methods, we define	ݏ ൌ ௞ିଵ௞ାଵ to quantify the 
concentration of U87 cells if a mixture of the two types of cells was imaged. 
  
 Supplem
Developm
 
 
Monome
domain s
PAS-GA
covalentl
chromop
is ~80 kD
PCM an
Deinococ
(HisK) d
achieving
 
entary Figu
ent of a 1.5
rs (shown) 
tructure. It i
F-PHY dom
y bound w
hore-binding
a. BphP1 f
d the outpu
cus radiodu
omain. We t
 a 1.5-fold r
S
re 1.  
-fold smalle
of naturall
s represente
ain triad, 
ith conser
 pocket in 
rom Rhodop
t PAS/PAS
rans, DrBp
runcated ful
eduction in
 
upplem
r photochro
y dimeric b
d here by th
and output
vative cyst
the GAF do
seudomona
 and HOS 
hP, is com
l-length DrB
 the molecul
entary F
 
mic probe f
acterial ph
e photosen
 domains. 
eine from 
main. The m
s palustris, 
domains. T
prised of th
phP to its P
ar weight of
igures 
or differenti
ytochromes
sory core m
The bilive
the PAS 
olecular w
called RpB
he domain 
e PCM and
CM and ca
 the PA pro
al photoaco
 (BphPs) s
odule (PCM
rdin (BV) 
domain an
eight of the 
phP1, consi
organizatio
 the output
lled the resu
be. 
ustic imagin
 
hare a com
), formed b
chromopho
d secured 
BphPs mon
sts of the re
n of BphP 
 histidine k
lt DrBphP-P
4 
g. 
mon 
y the 
re is 
to a 
omer 
gular 
from 
inase 
CM, 
 Supplem
Quanfica
 
 
(a) An im
(b) The P
versus th
plane re
photoaco
plane. (e
and at 7.5
 
entary Figu
tion of the s
age of thre
A amplitud
e shift in th
solution, de
ustic image
) The line p
 mm off-ce
re 2.  
patial resolu
e tungsten w
e distributio
e sum of the
fined as th
 of a tungste
rofiles of (d
nter (indicat
 
tion of the R
ires, each w
n along the 
 original lin
e shift cor
n wire with
) at the cent
ed in (d) by
S-SIP-PAC
ith a nomin
red line in (
e profile sh
responding 
 a nominal 
er of the rin
 the green da
T system. 
al diameter
a). (c) The c
own in (b) a
to 6-dB C
diameter of
g (indicated
shed line).
 of 50 µm. 
ontrast-to-n
nd the shift
NR, is 12
 50 µm, pro
 in (d) by t
Scale bar, 2
oise ratio (C
ed copy. Th
5 µm. (d) 
jected on th
he red solid
5 
 
 mm. 
NR) 
e in-
The 
e x-z 
 line) 
 Supplem
Characte
 
 
(a) Mola
RpBphP1
(b) Mola
RpBphP1
of RpBph
intensity
curves). 
gradual i
kinetic c
Depende
intensity 
light-indu
s.e.m.).  
entary Figu
rizations of 
r extinction
, showing t
r extinction
 at 780 nm
P1 at 780 n
. The kineti
(d) Depend
ncrease in a
urves can b
nce of the 
of 636/20-n
ced Pfr→P
re 3.  
DrBphP-PC
 coefficien
he superior 
 coefficien
, showing th
m. (с) Dep
c curves ca
ence of the 
bsorbance o
e fitted wi
half-time of
m light (n 
r photoconv
M photochr
t ratios betw
switching c
t ratio betw
at DrBphP-
endence of t
n be fitted 
Pfr→Pr ph
f the Pr sta
th monoexp
 light-induc
= 3; error b
ersion on th
 
omic proper
een the P
ontrast of D
een the P
PCM has 2-
he Pr→Pfr 
with monoe
otoconversi
te was obse
onential fu
ed DrBphP
ars are s.e.
e intensity o
ties. 
fr and Pr s
rBphP-PCM
fr and Pr s
times better
photoconve
xponential 
on on the 7
rved for all
nctions (R2
-PCM Pr→
m.). (f) Dep
f 780/20-nm
tates of Dr
 in the NIR
tates of Dr
 switching c
rsion on the
functions (R
80/20 nm l
 tested ligh
≥0.958 for
Pfr photoco
endence of
 light (n =
BphP-PCM
 spectral re
BphP-PCM
ontrast than
 636/20 nm
2≥0.958 fo
ight intensi
t intensities
 all curves
nversion o
 the half-tim
 3; error bar
6 
 
 and 
gion. 
 and 
 that 
 light 
r all 
ty. A 
. The 
). (e) 
n the 
e of 
s are 
 Supplem
Frequenc
 
 
(a) Norm
(b) The t
and its ha
BphPs th
the pixel 
 
entary Figu
y lock-in re
alized photo
emporal freq
rmonics. (c
an the diffe
values from
re 4.  
construction
acoustic (P
uency spec
) Frequency
rential imag
 regions of i
 
 provides be
A) signal of
trum of the 
 lock-in rec
ing method
nterest.  
tter contras
 BphPs chan
signal in (a)
onstruction 
; error bars 
ts of BphPs.
ges during 
 clearly show
(LIR) provi
are s.e.m. (
 
the illumina
s the modu
des ~2–3-fo
n = 40), cal
tion modula
lation frequ
ld better CN
culated base
7 
 
tion. 
ency 
R of 
d on 
 Supplem
Compari
 
 
(a) Flow 
that co-e
peptide (
Error bar
(c) PA im
and Pr (O
(right co
cells exp
 
entary Figu
son of RpBp
cytometry w
xpressed Rp
in BphP-T2
s, s.e.m. (n =
ages of hem
FF) state (
lumn). Scale
ressing eithe
re. 5.  
hP1 and Dr
as used to 
BphP1 or D
A-EGFP co
 3; transfec
oglobin, R
middle colu
 bar, 2 mm
r RpBphP1 
 
BphP-PCM 
analyze the 
rBphP-PCM
nstructs). T
tion experim
pBphP1, an
mn). LIR im
. (d) Fractio
or DrBphP-
expression l
fluorescence
 with EGF
he mean EG
ents). (b) Q
d DrBphP-P
ages of hem
nal change
PCM during
evels.  
 intensity d
P downstrea
FP fluores
uantificatio
CM in the 
oglobin, R
 of PA sign
 780 nm illu
istribution o
m of the T2
cence inten
n of the dat
Pfr (ON) st
pBphP1, an
als from bo
mination.  
f live HeLa
A self-cleav
sity is prese
a presented 
ate (left col
d DrBphP-
vine blood,
8 
 
 cells 
able 
nted. 
in (a). 
umn) 
PCM 
 U87 
 Supplem
Lock-in r
 
 
(a) Norm
during th
clearly sh
(LIR) pro
than the d
values fro
entary Figu
econstructio
alized PA si
e illuminatio
ows the mo
vides ~2–3
ifferential i
m regions o
re 6. 
n of U87 cu
gnal of U87
n modulatio
dulation fre
-fold better C
maging met
f interest. 
ltured cells 
 cells expre
n. (b) The t
quency and 
NR of U87
hod; error b
expressing 
ssing change
emporal fre
its harmonic
 cells expre
ars are s.e.m
either DrBph
s in either D
quency spec
s. (c) Frequ
ssing either 
. (n = 40), c
 
P-PCM or 
rBphP-PCM
trum of the 
ency lock-in
DrBphP-PC
alculated ba
RpBphP1. 
 or RpBph
signal in (a)
 reconstruc
M or RpBp
sed on the p
9 
 
P1 
 
tion 
hP1 
ixel 
 Supplem
Separatio
depths. 
 
 
(a) Top a
U87 cells
and RpB
scattering
light was
types of c
k, of the
coefficien
inside all
 
entary Figu
n of three 
nd side view
 expressing
phP1, bottom
 media wit
 used. (b) L
ells. (d) Co
 three type
ts, s, of the
 cells well. S
re 7. 
types of ce
s of the sch
 DrBphP-PC
, a mixture
h different 
IR images o
mputed coef
s of cells, w
 three type
cale bar, 2 
 
lls expressin
ematics of 
M only, mi
 of U87 cel
distances to
f three type
ficients, c, o
hich enabl
s of cells, w
mm. 
g different 
the phantom
ddle, HEK-
ls and HEK
 the phanto
s of cells. (c
f the three t
es a good s
hich illustr
BphPs in s
 containing
293 cells ex
-293 cells), 
m surface. 
) Computed
ypes of cell
eparation o
ates the con
cattering m
 the three ty
pressing bo
which were 
Top illumin
 coefficien
s. (e) Comp
f each othe
centrations 
edia at diff
pes of cells
th DrBphP-
embedded i
ation of 78
ts, b, of the 
uted coeffic
r. (f) Comp
of the U87 
10 
erent 
 
 (top, 
PCM 
n the 
0 nm 
three 
ients, 
uted 
cells 
 Supplem
In vivo P
 
 
The brain
expressin
with DrB
cortex va
entary Figu
A detection 
 of a nude m
g DrBphP-P
phP-PCM in
sculature, sh
re 8.  
of a brain tu
ouse was im
CM ~3 mm
 its ON stat
owing the b
mor express
aged two w
 underneath
e (a) and OF
rain tumor 
ing DrBphP
eeks after t
 the surface
F state (b).
with high co
-PCM. 
he injection
. PA image 
 (c) LIR ima
ntrast. Scale
 of U87 glio
of the mous
ge overlaid 
 bar, 2 mm
blastoma ce
e brain corte
on the brain
. 
11 
 
lls 
x 
 
 Supplem
Compari
 
(a) Fluor
(treated w
of U87 c
rapamyci
photoswi
contrast t
in the pre
PA signa
the illum
the LIR 
presence 
measurem
values fro
entary Figu
son of photo
escence spe
ith rapamy
ells express
n. The L
tching abili
han DrBphP
sence of ra
ls of the co
ination mod
images. On
or absenc
ent cycles 
m regions o
re 9. 
switching p
ctra of lysa
cin). (b) ON
ing DrBphP
IR image 
ty in the pr
-PCM. Sca
pamycin ch
ntrolled MT
ulation. (d) 
e sample w
e of rapam
on each sam
f interests. 
roperties of 
tes of HeL
 state (left 
-PCM and 
(right col
esence of ra
le bar, 2 mm
ange follow
Ln3 cells w
Comparison
as imaged f
ycin) or D
ple; error b
Rapa is shor
DrSplit and
a cells exp
column) and
MTLn3 cel
umn) dem
pamycin. In
. (c) PA sig
ing the illum
ithout rapa
 of CNRs q
or each typ
rBphP-PCM
ars are s.e.m
t for rapamy
 DrBphP-PC
ressing eith
 OFF state 
ls expressin
onstrates th
 addition, 
nals of MT
ination mo
mycin have
uantified fr
e of cells e
. The dat
. (n = 40), 
cin.
M in MTLn
er DrBphP-
(middle col
g DrSplit in
at DrSplit
DrSplit has 
Ln3 cells ex
dulation. In
 non-detecta
om the ON-
xpressing e
a were av
calculated b
3 cells. 
PCM or Dr
umn) PA im
 the presen
 recovered
lower switc
pressing Dr
 comparison
ble respons
state image
ither DrSpl
eraged over
ased on the 
12 
 
Split 
ages 
ce of 
 its 
hing 
Split 
, the 
es to 
s and 
it (in 
 ten 
pixel 
 Supplem
Cytotoxi
 
Flow cyt
and U87 
IRES2 s
IRES2 se
and mCh
transfecte
DrPAS-F
lines co
mCherry
entary Figu
city of DrSp
ometry was
(c, d) cells 
equence fro
quence fro
erry (b, d)
d cells, red
RB and m
rrespond to
-IRES2-FKB
re 10. 
lit in mamm
 used to ana
expressing 
m EGFP-I
m mCherry
 fluorescen
 lines corr
Cherry-IRE
 distributio
P-DrGAF-
alian cells.
lyze the flu
both EGFP 
RES2-DrPA
-IRES2-FKB
ce intensity
espond to d
S2-FKBP-D
n of cells 
PHY and tre
orescence i
and mCherr
S-FRB. mC
P-DrGAF-P
 are presen
istribution 
rGAF-PHY
transfected
ated with 10
ntensity dis
y. EGFP w
herry was
HY. The m
ted. Black 
of cells tran
 but non-tr
 with EGF
 nM of rapa
tribution of 
as co-expre
 co-express
ean values
lines corre
sfected wit
eated with 
P-IRES2-D
mycin. 
 
live HeLa (
ssed upstrea
ed upstream
 of EGFP (
spond to m
h EGFP-IR
rapamycin, 
rPAS-FRB
13 
a, b) 
m of 
 of 
a, c) 
ock-
ES2-
blue 
 and 
 
14 
 
Supplementary Figure 11. 
Validation of the existence of reconstituted DrSplit via near-infrared fluorescence. 
 
 
MTLn3 cells stably expressing both, EGFP-IRES2-DrPAS-FRB and mCherry-IRES2-FKBP-
DrGAF-PHY. Constructs were treated with rapamycin. The fluorescence of non-treated (‒ 
RAPA) and treated (+ RAPA) cells was compared by the fluorescence of EGFP (green; ex 
480/40 nm, Em 535/40 nm), mCherry (red; ex 570/30 nm, Em 615/30 nm) and DrSplit (NIR; ex 
605/40 nm, Em 640/LP nm). (a) Fluorescence microscopy images of non-treated (top row) and 
treated (bottom row) cells. (b) Flow cytometry was used to analyze the fluorescence intensity 
distribution of live MTLn3 cells, that stably expressing DrBphP-PAS downstream of IRES2 
sequence with EGFP and DrBphP-GAF-PHY downstream of IRES2 with mCherry. The mean 
values of EGFP, mCherry and DrSplit fluorescence intensity are presented. Gray curves 
correspond to non-treated samples, red curves correspond to samples treated with rapamycin. (c) 
Quantification of the data presented in (a). Error bars, s.e.m. (n=3; transfection experiments). 
Scale bars, 10 µm. RAPA is short for rapamycin.  
 Supplem
In vivo R
PPIs at d
 
 
(a) PACT
injection
was dete
injection 
showing 
H&E his
green lin
in (c). Sc
entary Figu
S-SIP-PAC
epth. 
 image of t
. The LIR im
cted. Scale 
(44 h after r
the PPI-ind
tological im
e. Scale bar
ale bar, 1 m
re 12.  
T of liver t
he mouse li
age was ov
bar, 5 mm
apamycin in
uced compl
age of a harv
, 2 mm. (d) 
m. 
umors expr
ver on Day 
erlaid on th
. (b) PACT
jection). Th
ementation 
ested tumo
Close-up of
essing DrSp
32 after tum
e anatomica
 image of t
e LIR imag
of DrBphP
rous liver, w
 the black re
 
lit, showin
or cells inj
l image, bu
he mouse o
e was overl
-PCM from
here the tum
ctangular b
g photoacou
ection but b
t no lock-in 
n Day 34 
aid on the a
 DrSplit. (c
or region i
ordered port
stically det
 
efore rapam
frequency s
after tumor 
natomical im
) Represent
s bordered b
ion of the im
15 
ected 
ycin 
ignal 
cells 
age, 
ative 
y the 
age 
 Supplem
In vivo f
PPIs. 
 
Fluoresce
expressin
hours aft
subtractin
Day 5 af
image (in
mouse on
differenti
 
entary Figu
luorescence 
nce imagin
g DrSplit w
er injection 
g the Pfr st
ter the injec
 color) was
 Day 32 af
al image (in
re 13. 
imaging of
g of tumor g
ere injected
of rapamyci
ate image fr
tion of tum
 overlaid on
ter the inje
 color) was 
 
 liver tumor
rowth and 
 in the mou
n through th
om the Pr st
or cells (~4
 the anatom
ction of tum
overlaid on 
s expressin
metastasis o
se liver. Flu
e tail vein.
ate image. (
0 hours aft
ical image
or cells (~4
the anatomi
g DrSplit, c
f cells expr
orescence im
The differen
a) Fluoresc
er rapamyc
(in gray). (b
4 hours aft
cal image (i
onfirming t
essing DrSp
ages were 
tial image w
ence images
in injection)
) Fluoresce
er rapamyc
n gray). Sca
he occurren
 
lit. MTLn3 
acquired ~4
as compute
 of the mou
, the differe
nce image o
in injection)
le bar, 5 mm
16 
ce of 
cells 
0-44 
d by 
se on 
ntial 
f the 
, the 
. 
 Supplem
Hydrody
 
 
(a) ON s
plasmid. 
expressio
image ov
backgrou
 
entary Figu
namic liver 
tate and (b)
Due to the 
n of DrBph
erlaid on 
nd blood sig
re 14.  
transfection 
 OFF state 
overwhelmi
P-PCM is n
the anatomi
nal in gray.
 
of mice wit
images of a
ng backgrou
ot visible i
cal image 
 Scale bar, 5
h plasmid en
 mouse liv
nd signal fr
n either the
shows the 
 mm. 
coding DrB
er 24 h afte
om blood, t
 ON state o
DrBphP-PC
phP-PCM i
r injection 
he injected 
r OFF state
M signal i
n vivo. 
of DrBphP-
plasmid-ind
 image. (c)
n color and
17 
 
PCM 
uced 
 LIR 
 the 
 Supplem
RS-SIP-P
 
 
The liver
and (b) O
liver, sele
(d) Overl
the DrBp
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 images of
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 the left lob
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 imaging of
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https://authors.library.caltech.edu/87871/1/s41467-018-05231-3.pdf

Small near-infrared photochromic protein for photoacoustic multi-contrast imaging and detection of protein interactions in vivo

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Caltech Authors - Main