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Base editors, including dual base editors, are innovative techniques for efficient base conversions in genomic DNA. However, the low efficiency of A-to-G base conversion at positions proximal to the protospacer adjacent motif (PAM) and the A/C simultaneous conversion of the dual base editor hinder their broad applications. In this study, through fusion of ABE8e with Rad51 DNA-binding domain, we generate a hyperactive ABE (hyABE) which offers improved A-to-G editing efficiency at the region (A 10 -A 15 ) proximal to the PAM, with 1.2- to 7-fold improvement compared to ABE8e. Similarly, we develop optimized dual base editors (eA&C-BEmax and hyA&C-BEmax) with markedly improved simultaneous A/C conversion efficiency (1.2-fold and 1.5-fold improvement, respectively) compared to A&C-BEmax in human cells. Moreover, these optimized base editors catalyze efficiently nucleotide conversions in zebrafish embryos to mirror human syndrome or in human cells to potentially treat genetic diseases, indicating their great potential in broad applications for disease modeling and gene therapy. There is a low efficiency of A-to-G base conversion in at specific positions using base editors. Here the authors fuse ABE8e with the Rad51 DNA-binding domain to generate a hyperactive ABE allowing improved A-to-G editing efficiency at the region proximal to the PAM and improved simultaneous A/C conversion efficiency.

Adenine base editors (ABEs) catalyze A-to-G transitions showing broad applications, but their bystander mutations and off-target editing effects raise safety concerns. Through structure-guided engineering, we found ABE8e with an N108Q mutation reduced both adenine and cytosine bystander editing, and introduction of an additional L145T mutation (ABE9), further refined the editing window to 1–2 nucleotides with eliminated cytosine editing. Importantly, ABE9 induced very minimal RNA and undetectable Cas9-independent DNA off-target effects, which mainly installed desired single A-to-G conversion in mouse and rat embryos to efficiently generate disease models. Moreover, ABE9 accurately edited the A 5 position of the protospacer sequence in pathogenic homopolymeric adenosine sites (up to 342.5-fold precision over ABE8e) and was further confirmed through a library of guide RNA–target sequence pairs. Owing to the minimized editing window, ABE9 could further broaden the targeting scope for precise correction of pathogenic single-nucleotide variants when fused to Cas9 variants with expanded protospacer adjacent motif compatibility. bpNLS, bipartite nuclear localization signals. A precise adenine base editor variant, ABE9, was developed to generate single adenine transition at pathogenic homopolymeric adenine sites with minimal DNA/RNA off-target effects, suggesting promising potential for gene therapeutics.

Cytosine base editors (CBEs) efficiently generate precise C·G-to-T·A base conversions, but the activation-induced cytidine deaminase/apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (AID/APOBEC) protein family deaminase component induces considerable off-target effects and indels. To explore unnatural cytosine deaminases, we repurpose the adenine deaminase TadA-8e for cytosine conversion. The introduction of an N46L variant in TadA-8e eliminates its adenine deaminase activity and results in a TadA-8e-derived C-to-G base editor (Td-CGBE) capable of highly efficient and precise C·G-to-G·C editing. Through fusion with uracil glycosylase inhibitors and further introduction of additional variants, a series of Td-CBEs was obtained either with a high activity similar to that of BE4max or with higher precision compared to other reported accurate CBEs. Td-CGBE/Td-CBEs show very low indel effects and a background level of Cas9-dependent or Cas9-independent DNA/RNA off-target editing. Moreover, Td-CGBE/Td-CBEs are more efficient in generating accurate edits in homopolymeric cytosine sites in cells or mouse embryos, suggesting their accuracy and safety for gene therapy and other applications. Improved cytosine base editors are created by repurposing an adenine deaminase.

Adenine base editors (ABEs) catalyze A-to-G transitions showing broad applications, but their bystander mutations and off-target editing effects raise the concerns of safety issues. Through structure-guided engineering, we found ABE8e with an N108Q mutation reduced both adenine and cytosine bystander editing, and introduction of an additional L145T mutation (ABE9), further refined the editing window to 1-2nt with eliminated cytosine editing. Importantly, ABE9 induced very minimal RNA and undetectable Cas9-independent DNA off-target effects, which mainly installed desired single A-to-G conversion in mouse and rat embryos to efficiently generate disease models. Moreover, ABE9 accurately edited A5 position of the protospacer sequence in pathogenic homopolymeric adenosine sites (up to 342.5-fold precision than ABE8e) and was further confirmed through a library of guide RNA-target sequence pairs. Due to the minimized editing window, ABE9 could further broaden the targeting scope for precise correction of pathogenic SNVs when fused to Cas9 variants with expanded PAM compatibility. Competing Interest Statement The authors have declared no competing interest.

Background Hand, foot, and mouth disease (HFMD) is a highly prevalent and contagious disease, particularly in children under five years old. Its transmission route resembles that of COVID-19. During the COVID-19 pandemic, non-pharmaceutical interventions (NPIs) were implemented to curb viral spread, which may have concurrently reduced HFMD incidence. Methods Utilizing HFMD surveillance data from the Anhui Provincial Center for Disease Control and Prevention (2015–2020) and varying levels of COVID-19 emergency measures, a Bayesian structural time series model predicted the counterfactual HFMD incidence and quantified the causal relationships with NPIs. Results During the implementation of NPIs, the 915 cases observed between weeks 4 and 20 of 2020 reflected a 94.9% reduction from the expected cases number (915 vs. 17,790), avoiding approximately 16,875 cases. The relative reduction of male cases (95.2%) was similar to that of female cases (94.3%). Different age groups the number of cases decline roughly similar were 93.1%, 95.3%, 97.8%, 94.9%. Conclusion During the COVID-19 pandemic, NPIs implemented in response to COVID-19 effectively reduced HFMD incidence. NPIs should be promoted for future control of enteric infectious diseases such as HFMD.

Currently, due to the rapid development and popularization of smartphones, the usage of ubiquitous smartphones has attracted growing interest in the field of structural health monitoring (SHM). The portable and rapid cable force measurement for cable-supported structures, such as a cable-stayed bridge and a suspension bridge, has an important and practical significance in the evaluation of initial damage and the recovery of transportation networks. The extraction of dynamic characteristics (natural frequencies) of cable is considered as an essential issue in the cable force estimation. Therefore, in this study, a vision-based approach is proposed for identifying the natural frequencies of cable using handheld shooting of smartphone camera. The boundary of cable is selected as a target to be tracked in the region of interest (ROI) of video image sequence captured by smartphone camera, and the dynamic characteristics of cable are identified according to its dynamic displacement responses in frequency domain. The moving average is adopted to eliminate the noise associated with the shaking of smartphone camera during measurement. A laboratory scale cable model test and a pedestrian cable-stayed bridge test are carried out to evaluate the proposed approach. The results demonstrate the feasibility of using smartphone camera for cable force estimation.

It has been widely reported that SERS can detect foodborne pathogenic bacteria, but SERS has only been limited to the detection of purified single bacteria. However, there’s few single bacterial infections in the natural state were found at the most time, and rare comparative investigations of different Gram-negative and Gram-positive bacteria by SERS exist. At the present study, we are aiming at the comparative analysis of the detection efficiency toward different foodborne pathogenic microbes by a conventional citrate-reduced gold colloid, including Escherichia coli, Salmonella enteritidis, Staphylococcus aureus and Listeria monocytogenes. The SERS spectra of samples were collected with sterile 0.5% NaCl solution as aggregating compound. First, the stability of each bacterial were detected with gold nanoparticles. Afterward, SERS signals of the four bacteria were compared at different concentrations, and it was found that Gram-positive and Gram-negative bacteria have different minimum sensitivity and detection stability. Next, the mixed bacterial SERS detection was applied to classify and identify the similar Raman spectra. Spectral data were analyzed using multivariate data analysis methods, including principal component analysis (PCA) and hierarchical cluster analysis (HCA). The SERS procedure we proposed, which utilized gold nanoparticles adsorbing on bacteria and multivariate analysis, allowed differentiation of species. The results of this pilot study demonstrate the potential of SERS to rapidly identify Gram-negative and Gram-positive foodborne pathogens.Article HighlightsComparative analysis of the detection sensitivity toward different foodborne pathogenic microbes.SERS signal might be interrupted by the different structure of bacterial wall.The mixed bacterial liquid could also be effectively distinguished by SERS detection.