self resetting molecular probes for nucleic acids enabled by fuel dissipative systems CORD-Papers-2021-10-25 (Version 1)

Title: Self-resetting Molecular Probes for Nucleic Acids Enabled by Fuel Dissipative Systems
Abstract: Amid of COVID-19 pandemic devastating the public health around the world, it become urgent to maintain a sufficiently large supply of nucleic acid tests to screen suspected cases timely. Reusable molecular probes in current testing method could potentially lead to enormous amount of screening capacity, critical for the disease control. Herein, we for the first time report a kind of self-resetting molecular probes for repeatedly detecting SARS-CoV-2 RNA, enabled by orchestrating a biomimetic fuel dissipative system via dynamic DNA nanotechnology. A set of simulation toolkits was utilized for the design and optimization of the self-resetting probe, allowing for highly consistent signal amplitudes across cyclic detections of SARS-CoV-2 RNA. Idiosyncratically, FWHM regulated by dissipative kinetics exhibits a fingerprint signal for high confidential identification of single-nucleotide mutation in the virus sequence. We further exploited our self-resetting probes to examine multiple human-infectious RNA virus including SARS-CoV-2, ZIKV, MERS-CoV, and SARS-CoV to demonstrate its generic nucleic acid detection capability and superior orthogonality. Self-resetting probes were also deployed for detection of 110 clinical nasopharyngeal swabs and correctly classify all the clinical samples from 55 COVID-19 patients and 55 controls. We anticipate that the DNA nanotechnology-enabled self-resetting probe could circumvent the lack of sustainability in the diagnostics of COVID-19 and other infectious diseases, thus helping disease control and building a broader global public health agenda.
Published: 6/1/2021
DOI: 10.1101/2021.06.01.21257665
DOI_URL: http://doi.org/10.1101/2021.06.01.21257665
Author Name: Li, N
Author link: https://covid19-data.nist.gov/pid/rest/local/author/li_n
Author Name: Liu, Y
Author link: https://covid19-data.nist.gov/pid/rest/local/author/liu_y
Author Name: Yin, Z
Author link: https://covid19-data.nist.gov/pid/rest/local/author/yin_z
Author Name: Liu, R
Author link: https://covid19-data.nist.gov/pid/rest/local/author/liu_r
Author Name: Zhang, L
Author link: https://covid19-data.nist.gov/pid/rest/local/author/zhang_l
Author Name: Zhao, Y
Author link: https://covid19-data.nist.gov/pid/rest/local/author/zhao_y
Author Name: Ma, L
Author link: https://covid19-data.nist.gov/pid/rest/local/author/ma_l
Author Name: Dai, X
Author link: https://covid19-data.nist.gov/pid/rest/local/author/dai_x
Author Name: Zhou, D
Author link: https://covid19-data.nist.gov/pid/rest/local/author/zhou_d
Author Name: Su, X
Author link: https://covid19-data.nist.gov/pid/rest/local/author/su_x
sha: 186c2451f79116680dead96311b65a77ebdc64c4
license: medrxiv
source_x: MedRxiv; WHO
source_x_url: https://www.who.int/
url: http://medrxiv.org/cgi/content/short/2021.06.01.21257665v1?rss=1 https://doi.org/10.1101/2021.06.01.21257665
has_full_text: TRUE
Keywords Extracted from Text Content: patients SARS-CoV-2 COVID-19 nasopharyngeal swabs SARS-CoV MERS-CoV DNA fuel-driven samples oligonucleotide-fueled orf1ab RNase P Figure 5F μ L example.dat GDP Figure 2 sequence-dependent VMMC D614G PM ( Figure S14A single-cycle Figure 2D FRET height/FWHM medRxiv SARS-CoV-2 isolates N (ROX TWJ cargo quencher-labeled receptor phosphodiester bonds 1-5 hydrogen bonds coronavirus cell Figure 5E PM Figure S9C medRxiv preprint Figure 5H strand Figure S21 quenchers Figure 3B Figure 3A quencher-modified base COVID- 19 [1] [2] [3] [4] SARS-CoV-2 coronavirus 2 Figure 5D TMSD toehold S9E HEX oxDNA R 2 T-T patients COVID-19 MM dsDNA ×10 3 M -1 s -1 FAM phosphonothioate bases Alexa Fluor 488 https://doi.org/10.1101/2021.06.01.21257665 doi SNV Fuel cat MM ( Figure 4J nasopharyngeal swabs Figure S26 nucleocapsid Figure 6E RT-asyRPA S5B D614A intermolecular TMSD Figure 2H SARS-CoV-2 K m SARS-CoV brown line labor Figure S15 B oropharyngeal swab samples DNA ssDNA quencher Figure S16 SNV D614G Figure 5G ROX Exo III E (HEX multiple-cycle Figure S3 Figure 2G patient Figure S22 instrument-free nasopharyngeal E PM ( Figure 4F Figure 6C Figure S25 signal-off states
Extracted Text Content in Record: First 5000 Characters:Amid of COVID-19 pandemic devastating the public health around the world, it become urgent to maintain a sufficiently large supply of nucleic acid tests to screen suspected cases timely. Self-resetting molecular probes in current testing method could potentially lead to enormous amount of screening capacity, critical for the disease control. Herein, we for the first time report a kind of self-resetting molecular probes for repeatedly detecting SARS-CoV-2 RNA, enabled by orchestrating a biomimetic fuel dissipative system via dynamic DNA nanotechnology. A set of simulation toolkits was utilized for the design and optimization of the self-resetting probe, allowing for highly consistent signal amplitudes across cyclic detections of SARS-CoV-2 RNA. Idiosyncratically, FWHM regulated by dissipative kinetics exhibits a fingerprint signal for high confidential identification of single-nucleotide mutation in the virus sequence. We further exploited our self-resetting probes to examine multiple human-infectious RNA virus including SARS-CoV-2, ZIKV, MERS-CoV, and SARS-CoV to demonstrate its generic nucleic acid detection capability and superior orthogonality. Self-resetting probes were also deployed for detection of 110 clinical nasopharyngeal swabs and correctly classify all the clinical samples from 55 COVID-19 patients and 55 controls. We anticipate that the DNA nanotechnology-enabled self-resetting probe could circumvent the lack of sustainability in the diagnostics of COVID-19 and other infectious disease, thus helping disease control and building a broader global public health agenda. COVID-19 is the disease underlying the ongoing coronavirus pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 has spread rapidly, with over 1 billion reported cases and 3 million deaths worldwide as of April 2021. The pandemic has resulted in significant global social and economic disruption, including the largest global recession since the Great Depression. Early diagnosis is essential to identify the disease and provide the correct treatment. Immediate and onsite diagnostic decisions also help to prevent the spread of epidemic and pandemic infectious diseases. Developing reliable and cost-effective nucleic acid diagnostic tools is critical during the COVID-19 pandemic, as diagnostic capacity at scale becomes critical to containing outbreaks and to reducing fatality rates. [1] [2] [3] [4] SARS-CoV-2 is a single-stranded RNA (ssRNA) virus. 5 Currently, the most reliable tool for COVID-19 diagnostics is reverse transcription quantitative PCR (RT-qPCR) ( Figure 1A ). 6, 7 RT-qPCR exhibits high sensitivity and specificity and is used as the gold standard by the CDC worldwide. However, RT-qPCR reagents are not self-resetting, particularly labeled fluorescent probes (Taqman probes), which are expensive and labor consuming ( Figure 1A ). This has led to a shortage of kits during the COVID-19 pandemic, particularly in countries and regions with poor development of biotechnology and related industries. Figure 1B shows the tests conducted per new confirmed case of COVID-19. Briefly, this value is higher in developed countries than in developing countries. Countries that perform very few nucleic acid tests per confirmed case are unlikely to be testing widely enough to find all cases. Nucleic acid testing capability may become the bottleneck for COVID-19 control in some developing countries because limited testing makes it likely that many cases will be missed. The WHO has suggested approximately 10 -30 tests per confirmed case as a general benchmark of adequate testing. In countries with limited tests per confirmed case (e.g., <10), the number of confirmed cases is likely to represent only a small fraction of the true number of infections. Where the positive rate (the reverse of the test per confirmed case metric) is rising in a country, this finding can suggest that the virus is actually spreading faster than the growth seen based on confirmed cases. In fact, the test per confirmed case value is positively correlated with GDP per capita ( Figure S1 ), and the control of COVID-19 in some countries is indeed limited by insufficient nucleic acid testing. Moreover, millions of daily COVID-19 tests worldwide not only consume many resources and require excessive labor but also produce abundant biomedical waste (BMW), which also consumes energy due to the need for disposal ( Figure S2 ). The global COVID-19 pandemic has culminated in escalating BMW accumulation worldwide, and management authorities are struggling with waste treatment. Figure 1 . The ongoing COVID-19 pandemic has resulted in massive costs of nucleic acid test kits, motivating the development of self-resetting probe systems for sustainability and limited test availability in developing countries. (A) RT-qPCR is the gold standard for COVID-19 confirmation and screening commonly used by the CDC worldwide. Taqman probe in RT-qPCR is not s
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