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Thermo Scientific Dharmacon miRIDIANmicroRNA Mimics & Hairpin Inhibitors
Highly potent oligonucleotides for modulating miRNA function
Reliable reagents for reproducible studies of miRNAs
Advanced design for all human, mouse and rat miRNAs
2
1
2
3
4
5
6
6a 6b
5a 5b
Pri-miRNA
mRNA
Nucleus
Cytoplasm
DROSHA
EXPORTIN 5
DICER
RISC
RISC RISC
RISC RISC
RISC
Pre-miRNA
Pre-miRNA
Supplement miRNA function in cells with LOW endogenous levels
Inhibit miRNA function in cells with HIGH endogenous levels
Decreased Protein Expression
EndogenousProtein Expression
Increased Protein Expression
Pre-miRNA
Supplement miRNA function in cells with
Add miRNAMimics
Add miRNAHairpin Inhibitors
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5a 5b
6
6a 6b
Thermo Scientifi c Dharmacon miRIDIAN microRNA Mimics and Hairpin Inhibitors: modulation of an endogenous RNAi mechanism
Transcribed pri-miRNA is cleaved by Drosha-DGCR8 protein complex to form a hairpin pre-miRNA.Pre-miRNA is transported out of the nucleus by an Exportin 5 protein complex.Pre-miRNA is cleaved by Dicer to form a short double-stranded miRNA duplex.miRNA duplex is loaded into RISC. Cleavage of inactive strand results in formation of programmed RISC.Programmed RISC binds to 3’-UTR of target mRNA (5/5a). miRNA inhibitors compete with mRNA for programmed RISC (5b).Target protein expression is decreased when miRNA mimic is added (6a) and increased when miRNA inhibitor is added (6b).
Effects of miRNA mimics and inhibitors on protein expression
microRNAs are endogenous non-coding ~22mer RNAs that are highly conserved and regulate gene transcript levels through RNA interference mechanisms. As key players in the fi ne-tuning of biological networks, microRNAs have signifi cant diagnostic and prognostic potential as biomarkers not only of fundamental cellular physiology but also of disease etiology and progression. To explore microRNA biology, we provide potent and specifi c tools for dissecting microRNA function.
123456
microRNA experimental workfl ow
Supplementing or inhibiting microRNA activity and examining the resulting phenotypic effects is crucial for understanding basic microRNA involvement in, for example:
RNA interference mechanisms
Fundamental cellular and physiological processes
Gene regulatory networks and pathways
Disease etiology and progression
Response to disease treatment regimens
Effects of miRNA mimics and inhibitors on protein expression
• microRNA Expression Profi ling Services - Global microRNA expression analysis through the Thermo Scientifi c RNAi Discovery and Therapeutic Services (RDTS)
• Mimic and Hairpin Inhibitor library screening services - End-point and high-content assay read-outs
• miRIDIAN microRNA Mimics and Hairpin Inhibitors - Individual molecules and plated libraries
• miRIDIAN microRNA Mimic and Hairpin Inhibitor Experimental Controls
• Thermo Scientifi c DharmaFECT Transfection Reagents
Product and services for the microRNA experimental workfl ow
DISCOVERY
DETECTION
MODULATION
TARGET ID
miRIDIAN microRNA Mimics effectively simulate miRNA function
Optimization of miRIDIAN microRNA Mimic design
miRIDIAN microRNA Mimic function for 11 human miRNAs was assayed in HeLa and HepG2 cells 48 hours after transfection of 10 nM mimic using a dual luciferase reporter system and normalized to the control (no mimic). Similar results were obtained with 1 nM miRIDIAN microRNA Mimic (data not shown).
miRNA mimic function was assayed in HeLa cells 24 and 48 hours after transfection of 10 nM miR-375 native-based mimic, modifi ed native-based mimic, or miRIDIAN microRNA Mimic using a dual luciferase reporter system and normalized to the control (no mimic).
1 http://microrna.sanger.ac.uk
HeLa HepG2
Nor
mal
ized
Luc
ifera
se E
xpre
ssio
n
miR
-342
miR
-375
miR
-210
miR
-107
miR
-141
miR
-224
miR
-185
miR
-18a
miR
-320
Cont
rol
Cont
rol
miR
-22
let-
7c
miR
-342
miR
-375
miR
-210
miR
-107
miR
-141
miR
-224
miR
-185
miR
-18a
miR
-320
Cont
rol
Cont
rol
miR
-22
let-
7c
1
0.8
0.6
0.4
0.2
0
Dharmacon® miRIDIAN microRNA Mimics
miRIDIAN microRNA Mimics are double-stranded RNA oligonucleotides, chemically enhanced with a proprietary design and available for all human, mouse and rat miRNAs in the miRBase Sequence Database.1
Supplement miRNA activity with miRIDIAN microRNA Mimics to study gain-of-function effects
Superior performance in comparison to native-based mimic design
Effective mimic of endogenous mature miRNA function
Preferential programming of RISC-like complex with active strand of miRNA andexclusion of passenger strand through a proprietary chemical modifi cation pattern
specifi c programming of RISC
Nor
mal
ized
Luc
ifera
se E
xpre
ssio
n
Cont
rol
miR
IDIA
NM
imic
Mod
ifi ed
N
ativ
e-ba
sed
Mim
ic
Nat
ive-
base
d M
imic
Cont
rol
miR
IDIA
NM
imic
Mod
ifi ed
N
ativ
e-ba
sed
Mim
ic
Nat
ive-
base
d M
imic
1
0.8
0.6
0.4
0.2
0
24 hours48 hours24 hours48 hours
Time course of inhibition by three different designs targeting endogenous miR-23 in a MCF-7 reporter cell line from a stably-integrated luciferase construct. miRIDIAN Hairpin Inhibitor, mature antisense (AS) and Competitor E inhibitors were transfected at 40 nM using DharmaFECT ®1. Data was normalized to cells with no inhibitor, so no inhibition is equal to 1.
* Patent pending1 http://microrna.sanger.ac.uk 2 This novel microRNA inhibitor design is based on fi ndings published by Vermeulen et al. (Double-stranded regions are essential design components of potent inhibitors of RISC function. RNA, May 2007. 13: 723 - 730).
Six co-expressed miRNAs (mir-17-5p, miR-18a-5p, miR-19a, miR-20, miR-19b-1 and miR-92-1) from the "Cancer Cluster" were inhibited by miRIDIAN Hairpin Inhibitors. All six miRIDIAN Hairpin Inhibitors were pooled together for a 0.8 nM total inhibitor concentration. Pools were co-transfected with DharmaFECT Duo into HeLa cells with one of six reporter plasmids specifi c for each miRNA. Data were normalized to similarly-treated empty reporter plasmid only.
miRIDIAN microRNA Hairpin Inhibitors* are potent and long-lived at low concentrations
miRIDIAN microRNA Hairpin Inhibitors allow combinatorial inhibition of clustered miRNAs
Dharmacon miRIDIAN microRNA Hairpin Inhibitors
miRIDIAN microRNA Hairpin Inhibitors2 are single-stranded, chemically enhanced oligonucleotides available for all human, mouse and rat miRNAs in the miRBase Sequence Database.1
Most effective inhibition of endogenous mature microRNA function by means of innovative design
Patent-pending molecule combines chemical modifi cations and completely novel secondary structure motif
Superior potency and longevity in comparison to any other synthetic product offered commercially
Enhanced potency and longevity allows for multiplexed microRNA inhibition at very low nanomolar concentrations with minimal toxicity
0
0.2
0.4
0.6
0.8
1
1.2mir-17-5p
mir-18a
-5p
mir-19a
mir-20a
mir-19b
-1
mir-92-1
No
rmal
ized
Rlu
c/Fl
uc
Rat
io
Nor
mal
ized
Luc
ifera
se E
xpre
ssio
n
Nor
mal
ized
Rlu
c/Fl
uc R
atio
Day 3 Day 5 Day 7 Day 10 Day 12 Day 14
9
8
7
6
5
4
3
2
1
1.2
1
0.8
0.6
0.4
0.2
0
Mature AS Oligo
miRIDIAN Hairpin
Competitor E
miR
-19a
miR
-18a
-5p
miR
-17-
5p
miR
-20a
miR
-19b
-1
miR
-92-
1
Reporter alonemiRIDIAN Hairpin Inhibitor
1
2
3
4
5
6
7
8
9
Day 3 Day 5 Day 7 Day 10 Day 12 Day 14
Fold
Inh
ibit
iion
No
rmal
ized
Lu
cife
rase
Exp
ress
ion
miRIDIAN microRNA Mimic and Hairpin Inhibitor Negative Controls
miRIDIAN microRNA Negative Control sequences are based on C. elegans miRNAs (#1: cel-miR-67, #2: cel-miR-239b) for use as negative experimental controls in human, mouse and rat cells. The Negative Controls have been analyzed by BLAST against all human, mouse and rat genomic sequences and miRNA sequences in the miRBase Sequence Database.1
Non-targeting mimics and inhibitors for use as controls for non-sequence-specifi ceffects in miRNA experiments
Allow distinction between mimic or inhibitor activity and background effects
Designs and modifi cations are identical to experimental miRIDIAN microRNA Mimics and Hairpin Inhibitors
No identifi able effects on tested miRNA function in multiple cell lines
miRIDIAN Hairpin Inhibitor Negative Controls are tools for distinguishing between miRNA-specifi c and non-specifi c effects
Effects of miRIDIAN microRNA Hairpin Inhibitor Negative Controls on the function of miR-21 were assayed at 48 hours after transfection of 5 nM inhibitor or negative control in H9c2, NIH3T3 or HeLa cells using DharmaFECT Duo and a dual luciferase reporter system.
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10
0
Fold
Inhi
bitio
n (R
luc/
Fluc
Exp
ress
ion)
N
orm
aliz
ed to
Pla
smid
Alo
ne
miR
-21
Hai
rpin
In
hibi
tor
miR
-21
Hai
rpin
In
hibi
tor
miR
-21
Hai
rpin
In
hibi
tor
Cont
rol #
1
Rat H9c2 Mouse NIH-3T3 Human HeLa
Cont
rol #
1
Cont
rol #
1
Cont
rol #
2
Cont
rol #
2
Cont
rol #
2
Plas
mid
Alo
ne
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mid
Alo
ne
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mid
Alo
ne
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miR
-21
Hairp
in In
hibi
tor
Cont
rol #
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rol #
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Plas
mid
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ne
miR
-21
Hairp
in In
hibi
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Cont
rol #
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rol #
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Alo
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miR
-21
Hairp
in In
hibi
tor
Cont
rol #
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rol #
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Plas
mid
Alo
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Fold
Inhi
bitio
nLu
cife
rase
Exp
erss
ion
Nor
mal
ized
to P
lasm
id A
lone
miRIDIAN microRNA Mimic Negative Controls have no apparent effect on miRNA function
Effects of miRIDIAN microRNA Mimic Negative Controls on the function of three human miRNAs were assayed at 24 hours after transfection of 10 nM mimic or negative control in HeLa cells using a dual luciferase reporter system.
1 http://microrna.sanger.ac.uk
1
0.8
0.6
0.4
0.2
0
Luci
fera
se E
xpre
ssio
n
Cont
rol #
1
Cont
rol #
1
Cont
rol #
1
Cont
rol #
2
Cont
rol #
2
Cont
rol #
2
Mim
ic
Mim
ic
Mim
ic
miR-107 miR-185 miR-342
miRIDIAN microRNA Mimic Positive Controls
Successful microRNA functional studies begin with optimization of the assay in a cell line and or type of interest. The miRIDIAN microRNA Mimic Housekeeping (HKG) Positive Controls provide the ability to monitor function of a mimic molecule at the mRNA level which can be assessed using standard transcript quantifi cation methods such as qRT-PCR.
The miRIDIAN microRNA Mimic Endogenous Positive Control provides the ability to monitor effects of a specifi c mimic on target protein levels in a validated endogenous assay. The assay is based upon the targeted activity of miR-122 on Aldolase A mRNA levels in cell lines that express low to moderate levels of miR-122.
Validated miRIDIAN microRNA Mimic that targets Aldolase A in human, mouse and rat
Provides the ability to optimize assay conditions by monitoring mimic functionon an endogenous gene target (Aldolase A) with a conserved miR-122 binding site
Employ the same structure and design as experimental miRIDIAN microRNA Mimics
Target the 3’ UTR (untranslated region) of standard housekeeping genes, PPIB or GAPDH
Allow a clean, straightforward cleavage-based readout of mimic function
Many cells lines express low to moderate levels of miR-122. Aldolase A is a predicted target of miR-122 and the 3‘ UTR is conserved in human, mouse and rat at the 8-mer miR-122 predicted seed site. miRIDIAN microRNA Mimic designed to modulate endogenous miR-122 was transfected at 50 nM (Huh-7 at 40 nM) using DharmaFECT 1 into the indicated cell lines and assessed for their ability to decrease AldoA mRNA levels. AldoA down-regulation was determined using the Quantigene branched DNA assay (Panomics) at 3 days (HepG2 at 5 days) post-transfection.
miRIDIAN microRNA Mimic Endogenous Control leads to regulation of Aldolase A in human, mouse and rat cell lines
Hep
G2
HUH-7
HeL
a
MCF-7
HEK29
3
NIH
3T3
H9c
2
0%
20%
40%
60%
80%
100%
% A
ldo
A m
RN
A E
xpre
ssio
n
No
rmal
ized
to
Mim
ic C
on
tro
l #1
%A
ldoA
mRN
A E
xpre
ssio
nN
orm
aliz
ed to
Mim
ic C
ontr
ol #
1 100
80
60
40
20
0
Hep
G2
HeL
a
MCF
-7
HEK
293
NIH
-3T3
H9c
2
HU
H-7
miRIDIAN microRNA Mimics designed to target the 3’ UTR of either PPIB or GAPDH were transfected at 50 nM using DharmaFECT 1 into the indicated cell lines and assessed for their ability to decrease target mRNA levels. PPIB or GAPDH down-regulation was determined using the Quantigene branched DNA assay (Panomics) at 48 hours post-transfection.
% m
RNA
Exp
ress
ion
Nor
mal
ized
to M
imic
Con
trol
#1
100
80
60
40
20
0
Hum
an G
APD
H M
imic
Hum
an P
PIB
Mim
ic
Cont
rol
Cont
rol
Cont
rol
Mou
se G
APD
H M
imic
Mou
se P
PIB
Mim
ic
Rat G
APD
H M
imic
Rat P
PIB
Mim
ic
0
20
40
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80
100
120
Co
ntr
ol
Co
ntr
ol
Co
ntr
ol
% m
RN
A E
xpre
ssio
n N
orm
aliz
ed t
o M
imic
Co
ntr
ol #
1
Hu
man
GA
PD
H M
imic
Hu
man
PP
IB M
imic
Mo
use
GA
PD
H M
imic
Mo
use
PP
IB M
imic
Rat
GA
PD
H M
imic
Rat
PP
IB M
imic
HUH-7 NIH-3T3 H9c2
miRIDIAN microRNA Hairpin Inhibitor Positive Controls
The miRIDIAN microRNA Hairpin Inhibitor Positive Control targets a well-conserved microRNA (miR-16) that is broadly expressed in many human, mouse and rat cell lines. This positive control allows the optimization of microRNA functional assays and evaluation of hairpin inhibitor function.
2 nM of miR-16 hairpin inhibitor is suffi cient to bind or sequester a majority of endogenous miR-16
Endogenous levels of miR-16 were assayed 48 hours after transfection of either miRIDIAN miR-16 Hairpin Inhibitor, miR-21 Hairpin Inhibitor or Hairpin Inhibitor Control #1. HeLa cells were transfected using DharmaFECT 1.
Detection of miR-16 by qRT-PCR was performed using a poly-A tailing method (Shi R and Chaing VL “Facile means for quantifying microRNA expression by real-time PCR” (Biotechniques 39:519-529 October 2005 ) and Thermo Scientifi c Verso SYBR Green 2-Step QRT-PCR Kit (ABgene) according to protocol. Relative expression of miR-16 fi rst normalized by miR-21 expression and then further normalized to miRIDIAN Hairpin Inhibitor Control #1 levels.
1600
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Fluo
resc
ene
(dR)
Cycles
Threshold
0 5 10 15 20 25 30 35 40
Hairpin miR-16, 2 nMHairpin miR-16, 50 nMHairpin miR-21, 2 nMHairpin miR-21, 50 nMHairpin Control #1, 2 nMHairpin Control #1, 50 nMLipid onlyUntreated
No RTNo Template}0
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0 5 10 15 20 25 30 35 40
Flu
ore
scen
ce (
dR
)
Cycles
Threshold
Relative Expression of miR-16Normalized to Hairpin Control #1
Hairpin miR-16, 50 nM 0.06%Hairpin miR-16, 2 nM 0.52%Hairpin Control #1, 50 nM 100%Lipid only 95%Untreated 118%
Targets miR-16 in human, mouse and rat cells resulting in reduced miR-16 activity
Allows the optimization of microRNA inhibition assays by targeting an endogenous microRNA in a cell line which expresses miR-16
Demonstrates specifi c inhibition of miR-16 which can be directly assessed by qRT-PCR and/or Northern blotting
Threshold
Dye-labeled miRIDIAN Mimic and Hairpin Inhibitor Transfection Controls allow for qualitative evaluation of transfection
validated experimental controls
miRIDIAN microRNA Mimic and Hairpin Inhibitor Transfection Controls
The miRIDIAN microRNA Mimic and Hairpin Inhibitor Transfection Controls are Dy547-labeled Mimic and Hairpin Inhibitor that are based on C. elegans miRNA (#1: cel-miR-67) for monitoring delivery into human, mouse and rat cells.
Non-targeting miRIDIAN Mimic and Hairpin Inhibitor labeled with Thermo Scientifi c Pierce Dy547 (absorbance/emission max: 557/570 nm)
Transfection can be monitored and visualized by epifl uorescence
Control designs and modifi cations are identical to experimental miRIDIAN microRNA Mimics and Hairpin Inhibitors
No identifi able effects on tested miRNA function in multiple cell lines
Dye-labeled miRIDIAN Mimic and Hairpin Inhibitor Transfection Controls allow for qualitative evaluation of transfection
Images shown are of human (left), rat (middle) and mouse (right) cells 48 hours after transfection with Pierce Dy547-labeled miRIDIAN Mimic Negative Control #1 (top panels) and miRIDIAN Hairpin Inhibitor Negative Control #1 (bottom panels). Cells were counterstained with Hoechst 33342 (blue, nuclei).
MCF 7
Mimic
HairpinInhibitor
H9c2 C2C12
Specifi c microRNA activity through use of chemical modifi cations to induce strand-bias
Potent and long-lasting microRNA inhibition demonstrated up to 14 days or longer
Validated negative controls to distinguish non-specifi c effects
Validated positive controls for assay development and optimization
Extended duration of effect enables microRNA target analysis
Potent and long-lived tools to validate microRNA targets
miRIDIAN microRNA Mimic and Hairpin Inhibitors can serve as complementary molecular tools providing critical phenotypic information and rapid confi rmation of putative miRNA-target interactions. The combination of gain-of-function (mimic-induced down regulation) and loss-of function (inhibitor-induced up regulation) experiments provide the necessary support to demonstrate microRNA-target relationships.
miRIDIAN microRNA Mimics
miRIDIAN microRNA Hairpin Inhibitors
miRIDIAN microRNA Mimic and Hairpin Inhibitor Negative Controls
miRIDIAN microRNA Mimic and Hairpin Inhibitor Positive Controls
Modulation of AldoA mRNA levels in Huh-7 cell line using miRNA miRIDIAN Mimics & Inhibitors. Orange line indicates AldoA expression level as a result of endogenous miR-122 regulation. AldoA mRNA expression values >1 indicates inhibition of miR-122, while values < 1 indicates additional down regulation of AldoA by miRNA. The miRIDIAN microRNA Inhibitor resulted in an increase in Aldo A mRNA levels even at 7 days, whereas a standard 2'-O-methyl-RNA oligo complementary to mature miR-122 showed a small effect. The miRIDIAN microRNA Mimic immediately reduced Aldo A mRNA levels and sustained suppression throughout the experiment.
%A
ldoA
mRN
A e
xpre
ssio
n (N
orm
aliz
ed to
miR
NA
inhi
bito
r ne
gativ
e co
ntro
l)
Reverse Complement Inhibitor: miR-122a
miRIDIAN Hairpin Inhibitor: miR-122a
miRIDIAN Mimic: miR-122a
1 day 3 day 5 day 7 day 1 day 3 day 5 day 7 day 1 day 3 day 5 day 7 dayDay 1
40 nM16 nM6 nM1 nM
Mature AS Oligo InhibitormiR-122
200%
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% A
ldo
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RN
A E
xpre
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orm
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o C
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tro
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Day 3 Day 5 Day 7 Day 1 Day 3 Day 5 Day 7 Day 1 Day 3 Day 5 Day 7
miRIDIAN Hairpin InhibitormiR-122
miRIDIAN MimicmiR-122
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1.6
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0
Aldolase A is a putative target of miR-122 with a conserved 8-mer miR-122 predicted seed site in the 3' UTR. microRNA mimics and inhibitors designed to modulate endogenous miR-122 were transfected at several concentrations using DharmaFECT 1 into the human liver cell line, Huh-7 (10K cells), and assessed for their ability to alter Aldo A mRNA levels. Aldo A up- or down-regulation was determined using the Quantigene branched DNA assay (Panomics) at 1, 3, 5 and 7 days post-transfection.
40 nM
16 nM
6 nM
1 nM
High-throughput Phenotypic Screening: miRIDIAN microRNA Mimic and Hairpin Inhibitor Libraries
Trust your screening results to the leader in RNAi technologies
miRIDIAN microRNA Mimic and Hairpin Inhibitor Libraries are complete collections of mimics and inhibitors in 96-well plates which enable classical genetic approaches to:
Why screen with miRIDIAN Libraries? Successful microRNA phenotypic screening requires best-in-class reagents to minimize false or misleading effects and achieve high-confi dence data. miRIDIAN Mimics and Hairpin Inhibitors are designed for robust and reproducible results.
Perform phenotypic high-throughput screening
Find potential biomarkers of normal or diseased cellular processes
Couple microRNA screening with high-content analysis for multi-parametric data
Identify microRNAs that synergize with drugs of interest for increased therapeutic benefi t
Mimics are modifi ed to prevent sense-strand uptake and ensure phenotypes resulting from only the mature microRNA
Hairpin inhibitors have long-lasting and potent inhibition, allowing enough time for full phenotypes to develop
Libraries are offered as complete collections for human, mouse and rat or as custom user-defi ned collections
PHENOTYPICEFFECTS
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Mimic Library
CellsmiRIDIAN controls
Hairpin Inhibitor library
plusmiRIDIANcontrols
Protein down-regulation Protein up-regulation
Gain-of-function Loss-of-function
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1 2 3 4 5 6 7 8 9 10 11 12
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Contact Information
North America2650 Crescent Dr., Suite 100Lafayette, CO 80026Toll free: 800 235 9880Tel: 303 604 9499Fax: 303 604 3286
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US web: www.thermo.com/dharmaconEuro web: www.thermo.com/perbioUS e-mail: dharmacon.lab@thermofi sher.com Euro e-mail: euromarketing@thermofi sher.com.
© 2009 Thermo Fisher Scientifi c Inc. All rights reserved. QuantiGene is a trademark of Bayer.
All other trademarks are the property of Thermo Fisher Scientifi c Inc. and its subsidiaries.
US Literature # 00074-06-D-03-U
Euro Literature # PB 2008 16
Thermo Scientifi c Dharmacon miRIDIAN
microRNA Mimics & Hairpin Inhibitors