Exploiting Polydopamine Nanospheres to DNA ... - ACS Publications

Subscriber access provided by University of Newcastle, Australia

Article

Exploiting Polydopamine Nanospheres to DNA Computing: A Simple, Enzyme-free and G-quadruplex-free DNA Parity Generator/Checker for Error Detection during Data Transmission Daoqing Fan, Erkang Wang, and Shaojun Dong ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.6b14317 • Publication Date (Web): 19 Dec 2016 Downloaded from http://pubs.acs.org on December 27, 2016

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

ACS Applied Materials & Interfaces is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Applied Materials & Interfaces

Exploiting Polydopamine Nanospheres to DNA Computing: A Simple, Enzyme-free and G-quadruplex-free DNA Parity Generator/Checker for Error Detection during Data Transmission Daoqing Fan, †‡ Erkang Wang, †‡* Shaojun Dong†‡* †

State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of

Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, China. ‡

University of Chinese Academy of Sciences, Beijing, 100039, China.

*Corresponding Author E-mail: [email protected]; [email protected].

ACS Paragon Plus Environment

1


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 29

ABSTRACT

Molecular logic devices with various functions played an indispensable role in molecular data transmission/processing. However, during any kinds of data transmission, a constant and unavoidable circumstance is the appearance of bit errors, which have serious effects on the regular logic computation. Fortunately, these errors can be detected via plugging a parity generator (pG) at the transmitting terminal and a parity checker (pC) at the receiving terminal. Herein, taking advantage of the efficient adsorption/quenching ability of polydopamine nanospheres toward fluorophore-labeled single-stranded DNA, we explored this biocompatible nanomaterial to DNA logic computation and constructed the first simple, enzyme-free and Gquadruplex-free DNA pG/pC for error detection through data transmission. Besides, graphene oxide (GO) was innovatively introduced as the “corrective element” to perform the “OutputCorrection” function of pC. All the erroneous outputs were corrected to normal conditions completely, ensured the regular operation of later logic computing. The total operation of this non-G4 pG/pC system (error checking/output-correction) could be completed within 1 h (about 1/3 of previous G4 platform) in a simpler and more efficient way. Notably, the odd pG/pC with analogous functions was also achieved through negative logic conversion to the fabricated even one. Furthermore, the same system could also perform three-input concatenated logic computation (XOR-INHIBIT), enriched the complexity of PDs based logic computation.

KEYWORDS：Polydopamine nanosphere, DNA parity generator/checker, Enzyme-free, Gquadruplex-free, Output-Correction function.


2

Page 3 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


INTRODUCTION Boolean logic gates played the role of overlord among silicon-based electronic devices in the past several decades.1 As a result of the giant differences between people’s infinite demand and silicon’s finite capability, scientists have pursued efficient materials to mimic Boolean operation. Under above background, unconventional molecular computation operated upon various systems gained extensive advancements in recent years.2-6 Among which, DNA logic platforms have been the prominent due to the high computing capability, cost-effective, flexible-design and controllable-structure. Many basic/advanced,

7-11

concatenated,

13-15

or even functional

16

DNA

logic circuits were fabricated through reasonable design. For the further development of DNA computing, one of the remaining challenges is to construct a universal platform which could not only mimic the operation of novel functional logic devices but also perform complicated logic computation. 17-19 Through any kinds of data transmission, a frequent circumstance encountered is the appearance of erroneous bits. 20, 42 These errors have serious effect on the normal performance of logic computing, especially in sophisticated circuits. While, they can be detected via plugging a parity generator (pG) at the transmitting terminal and a parity checker (pC) at the receiving terminal. 20, 42 In the light of the definition, 20, 21 the even pG could produce an extra parity bit (P) and add it to the original binary bits Dn, making the total number of 1’s (∑) in the DnP string even. For instance, if two bits of data (D1 and D2) are to be transmitted, the 2-Bit even pG will distribute the binary value to P (output of pG) in accordance with the truth table of an XOR logic gate

22

(see Scheme 1A and Table 1). Subsequently, the above D1D2P string (produced by the

2-Bit even pG) will be transmitted to a 3-Bit even pC and detected by it (Scheme 1A). In the case of a normal transmission, the three bits (D1, D2 and P) will not be changed. Then the ∑


3


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 29

value of the D1D2P string received by the pC is still even, and the pC presents “normal” (blue “√” in Scheme 1A), producing output C=0. While, if errors occurred during the transmission of the three bits, the ∑ value of the received wrong 3-Bit string will be odd (see Table 2), then the pC gives an “alarm” (red “×” in Scheme 1A) in the form of output C=1.

20, 21

The parity

generating/checking regulation described above illustrated the “error detection” procedure of the even pG/pC. And similar functions could also be performed by the odd pG/pC. Considering the significance of this functional device in data transmission, many different types of pG/pCs were constructed. However, most of them were fabricated upon semiconductor system, 23-28 which restricted their applications to molecular logic computing. In 2013, Pischel et al. pioneered the operation of molecular pG/pC based on organic molecules,

20

but tedious

synthesis methods were required and only common signal-to-noise (S/N) ratio was obtained. Not long ago, our group constructed the first DNA-based molecular pG/pC which could present both fluorescent and visual outputs with satisfactory S/N ratio using G-quadruplex (G4) and its DNAzyme (G4zyme) as signal transducers.

42

And an “Output-Correction” function was

introduced into the pC, in which the erroneous outputs could be completely corrected to normal states after giving “alarm” to the erroneous transmission, ensured the regular operation of downstream devices. Though the erroneous outputs could be readily recognized by the naked eye in the G4 system, the DNA strands need special, complicated and elaborate design and the total operating time is about 3h due to the pre-hybridization between different input strands and incubation of G4zyme. Considering further advancements of the pG/pC and its efficient application to molecular computing, a simple, enzyme-free and G4-free DNA pG/pC system with high S/N ratio and “Output-Correction” function that can be operated in a more efficient way will undoubtedly present obvious advantages and requires further study.


4

Page 5 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Due to the excellent adsorption/quenching ability of nanomaterial toward fluorophore-labeled DNA, various logic platforms 29, 30 and biosensors 31-33 were constructed through the assembly of nanoquencher and DNA strands. Polydopamine nanosphere (PD)

34

and its derivatives

33

are

biopolymerized material with superior biocompatibility and efficient fluorescence quenching ability. They have been broadly employed to diverse biological areas, such as biosensing, bioimaging,

35

photothermal therapy,

36

31

drug load/delivery and so on. While, to the best of our

knowledge, this kind of biocompatible nanomaterial has not been utilized to DNA logic computation. Herein, by utilizing the efficient adsorption/quenching ability of PDs toward fluorophore-labeled single-stranded DNA,

34

we explored the application of this biocompatible

nanomaterial to DNA logic computation and fabricated the first simple, enzyme-free and Gquadruplex-free (G4-free) DNA pG/pC system for error detection through data transmission. (Scheme 1B) Graphene oxide

37

was innovatively introduced as the “corrective element” to

perform the “Output-Correction” function of pC. All the erroneous outputs can be corrected to normal conditions completely. The total operation of this non-G4 pG/pC system could be completed in just 1 h, which is only 1/3 of previous G4 platform. Besides, the odd pG/pC with identical functions was also achieved through negative logic conversion to the operated even one. Furthermore, the same system could also perform concatenated logic computation (XORINHIBIT).


5


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 29

RESULTS AND DISCUSSION PDs synthesis and fluorescent verification Polydopamine nanospheres (PDs) used in the pG/pC were synthesized according to a previous report.34 As observed in Figure 1A, the obtained monodisperse PDs presented excellent uniformity with a diameter of about 265 nm. And the characteristic IR peaks of monomer dopamine between 1700 cm-1 and 400 cm-1 almost disappeared after polymerization, 31, 34 further indicated the successful synthesis of PDs, Figure 1B. As described above, the adsorption/quenching ability of PDs toward fluorophore-labeled single-stranded DNA is the key for the construction of logic devices. Thus, 5’ terminal FAM-labeled T strand was used as the probe DNA to perform the preliminary verification experiments. In the presence of increasing amounts of PDs, T strand was trapped on the surface of PDs via π-π stacking or other noncovalent interactions,

34

the fluorescence intensity at 520 nm (FI520) decreased gradually and

reached a minimum at about 0.3 mg/mL (which was used in subsequent experiments), and the fluorescence could be quenched within 100 s, Figure 1C. However, in the presence of excess amount of complementary strand cT, it will hybridize with T and form duplex to desorb T from PDs as for the weaker affinity of this nanoquencher towards duplex,

34

finally bringing an

obvious enhanced signal. Figure 1D showed corresponding fluorescent recovery kinetics, the FI520 gained enough recovery in no more than 30 min. The satisfactory S/N ratio and above simple, efficient procedure fully proved the feasible application of PDs to DNA logic computation.


6

Page 7 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Operation of the 2-Bit even pG A complete system for “error detection” through data transmission is composed of an n-Bit pG and (n+1)-Bit pC, in which the pG is the basis of the pC.

20

In this work, the 2-Bit even pG and

3-Bit even pC were taken as the model device and constructed based on the assembly of PDs and DNA. A 2-Bit even pG was fabricated at first (Truth table, Table 1), of which a two-input XOR logic gate

22

satisfied the requirements properly. Scheme 2 illustrated the operation of the PDs

based 2-Bit even pG, in which the mixture of PDs and T strand was used as the universal platform. Unlike previous G4 system 42 that each input was the mixture of two DNA strands, the DNA inputs introduced here were all single-stranded DNAs. Strand Ha (purple strand) and Hb (green strand), which could partially complementary to different parts of T strand were used as input D1 and D2 of the pG, respectively (Scheme 2). Solely Ha or Hb could partially hybridize with T to produce duplex T/Ha and T/Hb (Scheme 2), respectively, finally desorbing it from PDs. While Ha could also hybridize with Hb to from more stable duplex Ha/Hb than T/Ha or T/Hb as a result of more complementary bases between the two input strands. 38 The interactions between different DNA strands were verified by the native polyacrylamide gel electrophoresis (PAGE). As shown in Figure 2A, the bands of T, Ha and Hb appeared at different positions from Lane 1 to Lane 3. After the addition of Ha (Hb) to T, a new band appeared in Lane 5 (Lane 6), indicating the formation of duplex T/Ha (T/Hb). And in the presence of Ha and Hb, a darker band appeared at higher position than T/Ha (T/Hb) in Lane 7 proved the production of duplex Ha/Hb. However, in the coexisting of three strands, two separate bands were observed in Lane 9, a band appeared at similar position to that in Lane 7 was the duplex Ha/Hb and another band was solely T, which suggested the stronger binding ability of Ha/Hb than T/Ha or T/Hb. All the above proved that the interactions between different strands were in accord well with the


7


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 8 of 29

reasonable design. Corresponding optimization experiments were presented in Figure S1, and the sequences of different strands were summarized in Table S1. On the basis of above hybridization mode, a 2-Bit even pG was fabricated. FI520 was defined as the output P of the pG. In the absence of any inputs (Entry 1 in Scheme 2 and Table 1), the fluorescence of T strand is quenched by PDs, producing output P=0. In the presence of any input, Ha or Hb will partially hybridize with T and produce duplex T/Ha or T/Hb (Entry 2 and 3 in Scheme 2) to desorb T from PDs, finally generating obviously enhanced signal (P=1). However, in the coexistence of strands Ha and Hb, Ha will preferably hybridize with Hb to from more stable duplex Ha/Hb than T/Ha or T/Hb strand, the formed duplex could not interact with T anymore, and T will still be trapped on the surface of PDs, bringing negligible recovered signal (P=0). Figure 2B presented the normalized fluorescent intensities of different entries of the pG. Threshold value was taken as 0.40 to determine the high and low signals with satisfactory S/N ratio. The input and output states fitted the truth table (Table 1) well, which indicated the successful operation of the 2-Bit even pG. Operation of the 3-Bit even pC After the operation of the 2-Bit even pG, a 3-Bit even pC was subsequently fabricated to perform the “error detection” procedure. The platform of pC was still the mixture of T and PDs, whereas the third input P was introduced into the system to fulfil the requirements. Table 2 illustrated corresponding input variations of the pC, which can be divided into two sections. 20, 42 The first section was P=0 cases (Entry 1 to 4), as can be seen, the outputs of pC (now FI520 was identified as output C) were the same with above pG that without the introduction of input P. The circuit was equivalent to an XOR gate, in which the DNA hybridizations were identical with


8

Page 9 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


the 2-Bit pG and have been described above. The second part of Table 2 was P=1 cases (Entry 5 to 8), in which input P needs to perform the XNOR function complementary to both inputs D1 and D2. 20, 42 The DNA reactions of different entries (Entry 5 to 8) were presented in Scheme 3. Another strand AHb, which was 8 adenine (blue part) longer than strand Hb at 5’ terminal, was introduced as another input to properly mimic the function of 3-Bit pC (P=1 cases). As verified by the PAGE results in Figure 2A, strand AHb has similar ability to Hb. Just like previous report,20, 42 to implement the 3-Bit even pC (P=1 cases) properly, the inputs Ha and Hb together with input AHb were defined as follows, strand AHb acts as input D1 and Hb acts as D2, while Ha is used as input P. In the presence of solely P (Entry 5), the reaction was identical with that of Entry 3 (Scheme 2), yielding output C=1. In the presence of D2 and P (Entry 6), the DNA hybridizations were also the same with that of Entry 4, bringing output C=0. For Entry 7 (input D1 and P), AHb will interact with Ha to form more stable duplex Ha/AHb, unable to desorb T from the surface of PDs, producing negligible background signal (C=0). In the coexistence of D1, D2 and P, similar to Entry 7, AHb (or Hb) will hybridize with Ha and from duplex Ha/AHb (or Ha/Hb), while the resident Hb (or AHb) could still desorb T from PDs and recover the fluorescence accompanied with the output C=1. (The reaction between AHb and Ha was taken as an example in Scheme 3). Figure 3A showed the fluorescence spectra of all eight entries under different input combinations. The erroneous (red “×”) and normal outputs (blue “√”) with high S/N ratio can be clearly distinguished by corresponding normalized column bars in Figure 3B with the threshold setting as 0.40.


9


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 10 of 29

“Output-Correction” for the 3-Bit even pC Though the pG/pCs have gained large advancements, the “Output-Correction” function 42 was barely added into previous pCs. As a kind of functional logic device for “error detection”, the pG/pCs were often inserted between two logic circuits. After recognized the occurrence of errors during data transmission, the introduction of erroneous outputs (produced by pC) to later logic devices will induce fatal effects. 42 Considering the following case, if the erroneous output of pC was transmitted as the input of subsequent logic gates, the original output “1” (or 0) of later logic devices may be changed into “0” (or 1), which will undoubtedly lead to another erroneous output in downstream devices, finally destroying the normal logic computation of the total circuits. Therefore, only the normal outputs of preceding pC could ensure the regular performance of later devices, making the “Output-Correction” function necessary to the pC. As depicted in our previous work,

42

to make all the outputs of pC normal, the correct parity of 1’s

in the normal DnP string should be maintained and the wrong one in the erroneous string needs to be inverted to correct states. Hence, another “parity bit” (Ib) provided by the “parity invertor” (inserted after the pC) was added to the received DnP string to perform the function of parity inverting, Scheme 1A (red colored “1” was added to the erroneous outputs, while blue colored “0” was added to the normal ones). For instance, if errors occurred during the transmission of 3Bit D1D2P string (normal “110” changed to erroneous “100”, 1-bit error, e.g., Entry 3 in Table a

2; ∑ =1, odd), the parity invertor will add “1” to erroneous string and produce the 4-Bit f

D1D2PIb string (1001), in which the number of 1’s in the 4-Bit string (∑ ) is even (2), correcting erroneous output “1” to “0”. While, in the case of normal data transmission (110, e.g., Entry 4 in


10

Page 11 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


a

Table 2; ∑ =2, even), the parity invertor will add “0” to the 3-Bit string and yield the 4-Bit f

string (1100), ∑ =2, even), maintaining normal output “0”. In this PDs based pC system, the property of graphene oxide (GO) to adsorb and quench the fluorescence of fluorophore-labeled duplex 39 was applied to correct the erroneous outputs (Entry 2, 3, 5 and 8). Figure 3C showed the comparison between the fluorescent quenching kinetics of the mixture of T and PDs (a) and that of duplex T/Hb and enough amounts of GO (b). Though the later one was much slower than the preceding one, the fluorescence of duplex T/Hb was still quenched within 10 min. The TEM image of GO and corresponding exploration of GO’s amounts were presented in Figure S2, which proved above ability of GO. After the addition of GO, the high fluorescent intensities of erroneous entries were all quenched to low states, Figure 3D. The column bars of FI520 of all eight entries after GO’s correction further demonstrated the normal states of pC’s final outputs, Figure S2 (C). Till now, the construction of PDs based enzyme-free and G4-free DNA pG/pC system with high S/N ratio and “Output-Correction” function was accomplished. It should be noted that the total operation of this system could be completed within 1 h (40 min for error checking and 10 min for output-correction) which is only 1/3 of previous G4 platform. And it was operated in a simpler, faster and more efficient way, which presented apparent advantages over former conventional and molecular pG/pC systems. 20, 23-28, 42 Negative logic conversion for the odd pG/pC According to the parity generating/checking principle, the pG/pCs were divided into two kinds, the even and odd ones. And the odd pG/pC possesses identical function to the even one. What is


11


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 12 of 29

worth mentioning is that the 2-Bit odd pG and 3-Bit odd pC could also be obtained after negative logic conversion towards above even ones. The negative logic conversion

29, 40, 41

has been

broadly utilized in various logic devices’ construction, in which the output “0” was designated as “1”, and output “1” was designated as “0”. The scheme (Scheme S1), logic circuits and truth tables (Figure S3) indicated its reasonable construction. And the odd pC could also execute “Output-Correction” function using strand T as the corrective element, Figure 4 A, B. PDs Based Concatenated Logic Computation As mentioned initially, one of the future challenges for DNA computing is designing a universal platform that could not only mimic the performance of functional logic devices

16, 29

but also operate complicated logic computation. This type of molecular logic platform will largely fulfil the needs of sophisticated computing.

1, 13, 15

The above pG/pC constructed upon

PDs was a functional logic device, to further broaden the applications of PDs to DNA logic computation, a three-input concatenated logic circuit was designed by virtue of the same DNA reactions. In this concatenated logic circuit, the platform was still the mixture of PDs and strand T, and strands Ha, Hb and GO functioned as three individual inputs. Definitions of the fluorescent outputs were the same with above even pG/pC. This circuit was composed of an XOR logic gate cascaded by an INHIBIT logic gate (XOR-INHIBIT), Figure 5A. Herein, Ha and Hb were the two inputs of the first XOR gate, and GO was used as one input of later INHIBIT gate, whose another input was different mixtures of Ha, Hb and T/PDs. (The formation of duplex T/Ha or T/Hb was defined as output “1” of the XOR gate and other conditions were “0”, respectively). The input and output states fitted the truth table (Figure 5C) well, and corresponding normalized fluorescence column bars under different input variations (Figure 5B)


12

Page 13 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


further proved the rational fabrication of the concatenated logic circuit, which greatly enriched the computing complexity.

CONCLUSIONS In summary, we for the first time applied polydopamine nanospheres to DNA logic computation and fabricated a simple, enzyme-free and G-quadruplex-free DNA pG/pC system for error detection through data transmission based on the efficient adsorption/quenching ability of PDs toward fluorophore-labeled single-stranded DNA. This system exhibited apparent advantages over previous ones. Firstly, the pG/pC with high S/N ratio was operated in a simpler way without the usage of G-quadruplex, in which there were only four individual strands that do not need complicated sequence-design. Secondly, graphene oxide (GO) was innovatively employed as the “corrective element” to perform the “Output-Correction” function of pC. All the erroneous outputs were corrected to normal conditions thoroughly, ensured the regular operation of later logic computing. Thirdly, the total operation (error checking/output-correction) of this PDs based pG/pC system was completed within 1 h due to the simple hybridization and fast fluorescent quenching/recovery, which was only one third of previous G4 system. Last but not least, a threeinput concatenated logic circuit (XOR-INHIBIT) was also efficiently constructed on the same platform, greatly improved the complexity of PDs based logic computation. This study not only broadened the logic operating utilization of PDs but also enlightened the construction of more sophisticated DNA pG/pCs and it may open new paths for future intelligent biological applications of this functional logic device as for the superior biocompatibility of both PDs and DNA.


13


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 29

EXPERIMENTAL SECTION Materials. The DNAs were synthesized by Shanghai Sangon Biotechnology Co. (Shanghai, China) and the sequences were given in Table S1. All the strands were dissolved with distilled water as stock solutions and quantified by UV-vis absorption spectroscopy (ε260 nm, M−1 cm−1): A= 15400, G= 11500, C= 7400, T = 8700. Tris-HCl buffer (20 mM Tris-HCl, 200 mM KCl, 10 mM MgCl2, pH=8.0) was used through the experiments. Tris (tris (hydroxymethyl) aminomethane) was purchased from Sinopharm Chemical Regent Co. (Shanghai, China). Dopamine hydrochloride (99%) was obtained from Alfa Aesar (USA). Graphene oxide was synthesized according to a modified Hummer’s method. 37 Distilled water used in this work was purified by a Millipore system. Synthesis of polydopamine nanospheres. Polydopamine nanospheres (PDs) were synthesized according to a previous report.

34

Generally, 100 mL Tris-buffer was premixed with 40 mL

isopropyl alcohol, then 100 mg dopamine hydrochloride (99%) was added to the mixture and stirred for about 72 h. The final product was obtained through centrifugation and washed with distilled water for more than five times. Finally, suitable volume of distilled water was added to form the stock solution of PDs. Native polyacrylamide gel electrophoresis (PAGE). The DNA solutions (10 µM) were heated at 88 ℃ for 10 min and gradually cooled down to room temperature. Then, different DNA strands were mixed with suitable volume of 1×Tris-HCl buffer (20 mM Tris-HCl, 200 mM KCl, 10 mM MgCl2, pH=8.0) to the final volume of 50 µL. After incubated for about 30 min, the electrophoresis was conducted in 1×TBE buffer (17.80 mM Tris, 17.80 mM Boric Acid and 2


14

Page 15 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


mM EDTA, pH=8.0) for about 1 h with the voltage set as 120 V. After stained with Gel-Red, the gels were scanned by a UV transilluminator. Fluorescence measurement. The fluorescence emission spectra of different samples were collected from 505 to 650 nm after excited at 494 nm on Cary Eclipse Fluorescence Spectrophotometer (Agilent Technologies, USA) at room temperature. The slit widths for the excitation and emission were all 10 nm. Preparation of the universal platform. 0.30 mg/ml PDs were mixed with 50 nM T strand (5’ end FAM-labeled) to quench the fluorescence of it and the mixture was used as the universal platform for pG/pC. 2-Bit even pG. For Entry 1, nothing was added to above platform; for Entry 2, 350 nM Hb was added to the platform; for Entry 3, 300 nM Ha was added to the platform; for Entry 4, 300 nM Ha and 350 nM Hb were simultaneously added to the platform. Then suitable volume of 1×TrisHCl buffer was added to form the final volume of 500 µL. After reacted at room temperature for 30 min, the fluorescence spectra of different samples were collected. 3-Bit even pC. The operations of Entry 1, 2, 3 and 4 in the 3-Bit even pC were the same with that in the 2-Bit pG, respectively; and the reactions of Entry 5 and 6 were also identical with that of Entry 3 and 4, respectively; for Entry 7, 300 nM Ha and 350 nM AHb were simultaneously added to the platform; for Entry 8, 300 nM Ha, 350 nM Hb and 350 nM AHb were added to the platform. Then suitable volume of 1×Tris-HCl buffer was added to form the final volume of 500 µL. After reacted at room temperature for 30 min, the fluorescence spectra of different samples were collected.


15


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 29

Output-Correction for the 3-Bit even pC. For the “Output-Correction” of pC’s outputs, 100 µg/mL graphene oxide was added to the erroneous samples (Entry 2, 3, 5 and 8), while nothing was added to the normal samples. After incubated at room temperature for 10 min, fluorescence spectra of the corrected entries were recorded. Output-Correction for the 3-Bit odd pC. To correct the erroneous outputs of the odd pC, 30 nM T strand was added to above erroneous samples (Entry 1, 4, 6 and 7). After reacted at room temperature for 5 min, the fluorescence spectra of corrected entries were recorded. Three-input concatenated logic circuit: XOR-INHIBIT. The initial platform, concentrations of PDs, DNAs and GO, reaction time and other conditions in the concatenated logic circuit were all the same with that of above pG/pC.

ASSOCIATED CONTENT The Supporting Information is available free of charge on the ACS Publications website at DOI: ……. The sequences of DNA strands and other optimization experiments. The following files are available free of charge.

AUTHOR INFORMATION Corresponding Author * Email: [email protected]; [email protected]. Fax: +86-43185689711.


16

Page 17 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


All authors have given approval to the final version of the manuscript. Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This work was supported by the National Natural Science Foundation of China (Nos. 21375123, 21427811 & 21675151).

REFERENCES 1.

Zhu, J.; Zhang, L.; Li, T.; Dong, S.; Wang, E., Enzyme-free Unlabeled DNA Logic Circuits

Based on Toehold-mediated Strand Displacement and Split G-quadruplex Enhanced Fluorescence. Adv. Mater., 2013, 25 (17), 2440-24444. 2.

de Silva, P. A.; Gunaratne, N. H. Q.; McCoy, C. P., A Molecular Photoionic AND Gate Based

on Fluorescent Signalling. Nature 1993, 364 (6432), 42-44. 3.

Jiang, X. J.; Ng, D. K., Sequential Logic Operations with a Molecular Keypad Lock with

Four inputs and Dual Fluorescence Outputs. Angew. Chem. Int. Ed., 2014, 53 (39), 10481-10484. 4.

Mailloux, S.; Gerasimova, Y. V.; Guz, N.; Kolpashchikov, D. M.; Katz, E., Bridging the Two

Worlds: a Universal Interface between Enzymatic and DNA Computing Systems. Angew. Chem. Int. Ed., 2015, 54 (22), 6562-6566. 5.

Prokup, A.; Deiters, A., Interfacing Synthetic DNA Logic Operations with Protein Outputs.

Angew. Chem. Int. Ed., 2014, 53 (48), 13192-13195. 6.

Janssen, B. M.; van Rosmalen, M.; van Beek, L.; Merkx, M., Antibody Activation Using

DNA-based Logic Gates. Angew. Chem. Int. Ed., 2015, 54 (8), 2530-2533. 7.

Adleman, L., Molecular Computation of Solutions to Combinatorial Problems. Science

1994, 266 (5187), 1021-1024.


17


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

8.

Page 18 of 29

Seelig, G.; Soloveichik, D.; Zhang, D. Y.; Winfree, E., Enzyme-free Nucleic Acid Logic

Circuits. Science 2006, 314 (5805), 1585-1588. 9.

Orbach, R.; Wang, F.; Lioubashevski, O.; Levine, R. D.; Remacle, F.; Willner, I., A Full-adder

Based on Reconfigurable DNA-hairpin Inputs and DNAzyme Computing Modules. Chem. Sci., 2014, 5 (9), 3381-3387. 10.

Orbach, R.; Remacle, F.; Levine, R. D.; Willner, I., DNAzyme-based 2:1 and 4:1

Multiplexers and 1:2 Demultiplexer. Chem. Sci.,2014, 5 (3), 1074-1081. 11.

You, M.; Zhu, G.; Chen, T.; Donovan, M. J.; Tan, W., Programmable and Multiparameter

DNA-based Logic Platform for Cancer Recognition and Targeted Therapy. J. Am. Chem. Soc., 2015, 137 (2), 667-674. 12.

Zhu, J.; Zhang, L.; Dong, S.; Wang, E., Four-Way Junction-Driven DNA Strand

Displacement and Its Application in Building Majority Logic Circuit. ACS Nano 2013, 7 (11), 10211-10217. 13.

Fan, D.; Wang, K.; Zhu, J.; Xia, Y.; Han, Y.; Liu, Y.; Wang, E., DNA-based Visual Majority

Logic Gate with One-vote Veto Function. Chem. Sci. 2015, 6 (3), 1973-1978. 14.

Chen, J.; Zhou, S.; Wen, J., Concatenated Logic Circuits Based on A Three-way DNA

Junction: A Keypad-lock Security System with Visible Readout and An Automatic Reset Function. Angew. Chem. Int. Ed., 2015, 54 (2), 446-450. 15.

Feng, L.; Lyu, Z.; Offenhausser, A.; Mayer, D., Multi-level Logic Gate Operation Based on

Amplified Aptasensor Performance. Angew. Chem. Int. Ed., 2015, 54 (26), 7693-7697. 16.

Fan, D.; Zhu, J.; Zhai, Q.; Wang, E.; Dong, S., Cascade DNA Logic Device Programmed

Ratiometric DNA Analysis and Logic Devices Based on A Fluorescent Dual-signal Probe of A Gquadruplex DNAzyme. Chem. Commun., 2016, 52 (19), 3766-3769. 17.

Liu, H.; Wang, J.; Song, S.; Fan, C.; Gothelf, K. V., A DNA-based System for Selecting and

Displaying the Combined Result of Two Input Variables. Nat. Commun., 2015, 6, 10089. 18.

He, X.; Li, Z.; Chen, M.; Ma, N., DNA-programmed Dynamic Assembly of Quantum Dots

for Molecular Computation. Angew. Chem. Int. Ed., 2014, 53 (52), 14447-14450. 19.

Bi, S.; Chen, M.; Jia, X.; Dong, Y.; Wang, Z., Hyperbranched Hybridization Chain Reaction

for Triggered Signal Amplification and Concatenated Logic Circuits. Angew. Chem. Int. Ed., 2015,


18

Page 19 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


54 (28), 8144-8148. 20.

Balter, M.; Li, S.; Nilsson, J. R.; Andreasson, J.; Pischel, U., An All-photonic Molecule-

Based Parity Generator/Checker for Error Detection in Data Transmission. J. Am. Chem. Soc., 2013, 135 (28), 10230-10233. 21.

Wang, F.; Gong, Z.; Hu, X.; Yang, X.; Yang, H.; Gong, Q., Nanoscale On-chip All-optical

Logic Parity Checker in Integrated Plasmonic Circuits in Optical Communication range. Sci. Rep., 2016, 6, 24433. 22.

Liu, Y.; Offenhausser, A.; Mayer, D., An Electrochemically Transduced XOR Logic Gate at

the Molecular Level. Angew. Chem. Int. Ed., 2010, 49 (14), 2595-2598. 23.

Mehra, R.; Jaiswal, S.; Dixit, H. K., Parity Checking and Generating Circuit with

Semiconductor Optical Amplifier in All-optical Domain. Optik., 2013, 124 (21), 4744-4745. 24.

Bhattacharyya, A.; Kumar Gayen, D.; Chattopadhyay, T., All-optical Parallel Parity

Generator Circuit with the Help of Semiconductor Optical Amplifier (SOA)-assisted Sagnac Switches. Opt. Commun., 2014, 313, 99-105. 25.

Dimitriadou, E.; Zoiros, K. E.; Chattopadhyay, T.; Roy, J. N., Design of Ultrafast All-optical

4-bit Parity Generator and Checker Using Quantum-dot Semiconductor Optical Amplifier-based Mach-Zehnder Interferometer. J. Comput. Electron., 2013, 12 (3), 481-489. 26.

Mandal, S.; Mandal, D.; Garai, S. K., An All-optical Method of Developing Data

Communication System with Error Detection Circuit. Opt. Fiber Technol., 2014, 20 (2), 120-129. 27.

Kumar, A.; Raghuwanshi, S. K., Implementation of Optical Gray Code Converter and Even

Parity Checker Using the Electro-optic Effect in the Mach–Zehnder Interferometer. Opt. Quant. Electron., 2014, 47 (7), 2117-2140. 28.

Kumar, S.; Chanderkanta; Amphawan, A., Design of Parity Generator and Checker Circuit

Using Electro-optic Effect of Mach–Zehnder Interferometers. Opt. Commun., 2016, 364, 195-224. 29.

Fan, D.; Zhu, J.; Liu, Y.; Wang, E.; Dong, S., Label-free and Enzyme-free Platform for the

Construction of Advanced DNA Logic Devices Based on the Assembly of Graphene Oxide and DNA-templated AgNCs. Nanoscale 2016, 8 (6), 3834-3840. 30.

Xu, S.; Li, H.; Miao, Y.; Liu, Y.; Wang, E., Implementation of Half adder and Half Subtractor

with a Simple and Universal DNA-based Platform. NPG Asia Mater., 2013, 5 (12), e76.


19


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

31.

Page 20 of 29

Fan, D.; Wu, C.; Wang, K.; Gu, X.; Liu, Y.; Wang, E., A Polydopamine Nanosphere Based

Highly Sensitive and Selective Aptamer Cytosensor with Enzyme Amplification. Chem. Commun., 2016, 52 (2), 406-409. 32.

Fan, D.; Zhai, Q.; Zhou, W.; Zhu, X.; Wang, E.; Dong, S., A Label-free Colorimetric

Aptasensor for Simple, Sensitive and Selective Detection of Pt (II) Based on Platinum (II)oligonucleotide Coordination Induced Gold Nanoparticles Aggregation. Biosens. & Bioelectron., 2016, 85, 771-776. 33.

Fan, D.; Zhu, X.; Zhai, Q.; Wang, E.; Dong, S., Polydopamine Nanotubes as an Effective

Fluorescent Quencher for Highly Sensitive and Selective Detection of Biomolecules Assisted with Exonuclease III Amplification. Anal. Chem., 2016, 88 (18), 9158-9165. 34.

Qiang, W.; Li, W.; Li, X.; Chen, X.; Xu, D., Bioinspired Polydopamine Nanospheres: a

Superquencher for Fluorescence Sensing of Biomolecules. Chem. Sci., 2014, 5 (8), 3018-3024. 35.

Qiang, W.; Hu, H.; Sun, L.; Li, H.; Xu, D., Aptamer/Polydopamine Nanospheres

Nanocomplex for in Situ Molecular Sensing in Living Cells. Anal. Chem., 2015, 87 (24), 1219012196. 36.

Liu, Y.; Ai, K.; Liu, J.; Deng, M.; He, Y.; Lu, L., Dopamine-melanin Colloidal Nanospheres:

an Efficient Near-infrared Photothermal Therapeutic Agent for in Vivo Cancer Therapy. Adv. Mater. 2013, 25 (9), 1353-1359. 37.

Hummers, W. S.; Offeman, R. E., Preparation of Graphitic Oxide. J. Am. Chem. Soc., 1958,

80 (6), 1339-1339. 38.

Li, H.; Hong, W.; Dong, S.; Liu, Y.; Wang, E., A Resettable and Reprogrammable DNA-

Based Security System to Identify Multiple Users with Hierarchy. ACS Nano 2014, 8 (3), 27962803. 39.

Tang, L.; Chang, H.; Liu, Y.; Li, J., Duplex DNA/Graphene Oxide Biointerface: From

Fundamental Understanding to Specific Enzymatic Effects. Adv. Funct. Mater., 2012, 22 (14), 3083-3088. 40.

Margulies, D.; Melman, G.; Shanzer, A., A Molecular Full-Adder and Full-Subtractor, an

Additional Step toward a Moleculator. J. Am. Chem. Soc., 2006, 128 (14), 4865-4871. 41.

Li, H.; Guo, S.; Liu, Q.; Qin, L.; Dong, S.; Liu, Y.; Wang, E., Implementation of Arithmetic


20

Page 21 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Functions on a Simple and Universal Molecular Beacon Platform. Adv. Sci., 2015, 2 (5), 1500054. 42. Fan, D.; Wang, E.; Dong, S., A DNA-based Parity Generator/Checker for Error Detection through Data Transmission, with Visual Readout and an Output-correction Function. Chem. Sci., 2016, DOI: 10.1039/C6SC04056J.


21


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 22 of 29

Figures and Schemes

Scheme 1. (A) Scheme of the 2-Bit even pG and 3-Bit even pC for error detection through data transmission with “Output-Correction” function (red “×” represents the erroneous outputs and blue “√” indicates the normal outputs); (B) Operation mechanism of PDs based pG/pC system using GO as the “corrective element” to perform “Output-Correction” function. (The notes “Error” and “Normal” are annotated for the outputs of 3-Bit pC).


22

Page 23 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 1. (A) SEM image of as synthesized polydopamine nanospheres; (B) Comparison of the IR spectra of monomer dopamine and PDs; (C) Fluorescent quenching kinetics of 50 nM T strand in the presence of 0.30 mg/ml PDs; (D) Fluorescent recovery kinetics of 50 nM T strand and 0.30 mg/ml PDs after the addition of enough amounts of complementary cT strand.

a

Table 1. Truth table of the 2-Bit even pG ( Number of 1’s in the D1D2P string,

b

strand Ha,

c

d

strand Hb, FI520.


23


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 24 of 29

Scheme 2. DNA reaction mechanism of different entries for PDs based 2-Bit even pG and 3-Bit even pC (P=0 conditions). Strand Ha acts as input D1 and strand Hb functions as input D2. 5’ terminals of the DNA strands are marked with squares. The partial hybridizations are illustrated by dashed lines.


24

Page 25 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 2. (A) PAGE analysis of the reactions between different strands T, Ha, Hb and AHb. The existence of strand was depicted by “+”, the comics represented corresponding duplexes formed via hybridization. Lane 1 (T), Lane 2 (Ha), Lane 3 (Hb), Lane 4 (AHb), Lane 5 (T and Hb), Lane 6 (T and Ha), Lane 7 (Ha and Hb), Lane 8 (Ha and AHb), Lane 9 (T, Ha and Hb); (B) Normalized fluorescent column bars of different entries for the 2-Bit even pG.

a

Table 2. Truthtable of the 3-Bit even pC ( Number of 1’s in the D1D2P string, strand Hb,

d

strand Ha,

e

FI520 of T strand,

f

b

strand AHb,

c

Number of 1’s in the D1D2PIb string). (The

erroneous outputs are represented by the red “×”)


25


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 29

Scheme 3. DNA reaction mechanism of different entries for PDs based 3-Bit even pC (P=1 conditions). Strand AHb acts as input D1, strand Hb acts as input D2 and strand Ha functions as input P. 5’ terminals of the DNA strands are marked with squares. The partial hybridizations are illustrated by dashed lines.


26

Page 27 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 3. (A) Fluorescence spectra of all eight entries of the 3-Bit even pC; (B) Corresponding normalized column bars of Figure 3(A) (the red “×” and blue “√” represent erroneous and normal outputs, respectively); (C) Fluorescent quenching kinetics of T/PDs (a) and T/Hb in the presence of 100 µg/ml GO (b); (D) Column bars of FI520 of the erroneous entries (Entry 2, 3, 5 and 8) before (purple columns) and after (blue columns) corrected by 100 µg/ml GO.


27


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 28 of 29

Figure 4. (A) Normalized column bars of all eight entries of the odd pC (Same with that of the even pC); (B) Normalized column bars of all eight entries of the odd pC after corrected the erroneous outputs (Entry 1, 4, 6 and 7, green columns) using 30 nM T strand.

Figure 5. (A) Equivalent logic symbol of the concatenated logic circuit XOR-INHIBIT; (B) Normalized column bars under different input variations; (C) Corresponding truth table of the XOR-INHIBIT logic circuit (outputs “1” were colored in blue).


28

Page 29 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


For TOC Only


29

Exploiting Polydopamine Nanospheres to DNA ... - ACS Publications

Recommend Documents