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Summary Base editing technologies allow for the precise and efficient installation of defined nucleotide substitutions into a target genome without the introduction of double strand breaks or DNA templates. Here we describe two recombinant, protein format cytosine base editors (CBEs) that efficiently catalyze the installation of cytosine-to-thymine edits, termed “Flexible” and “Precision.” Flexible exhibits a wide editing window, while Precision uses a fused single-stranded DNA binding protein to narrow the editing window, lowering the risk of editing multiple cytosine residues at the target site. We show that co-transfection with uracil glycosylase inhibitor protein increases the proportion of substitutions that are C-to-T and the ratio of C-to-T editing to indel formation, thus reducing undesired editing outcomes. We use in vitro editing assays to characterize our editors and show a preference for cytosine residues preceded by thymine (TpC dinucleotides) and unmethylated cytosine residues.

Bacterial CRISPR–Cas systems comprise diverse effector endonucleases with different targeting ranges, specificities and enzymatic properties, but many of them are inactive in mammalian cells and are thus precluded from genome-editing applications. Here we show that the type II-B FnCas9 from Francisella novicida possesses novel properties, but its nuclease function is frequently inhibited at many genomic loci in living human cells. Moreover, we develop a proximal CRISPR (termed proxy-CRISPR) targeting method that restores FnCas9 nuclease activity in a target-specific manner. We further demonstrate that this proxy-CRISPR strategy is applicable to diverse CRISPR–Cas systems, including type II-C Cas9 and type V Cpf1 systems, and can facilitate precise gene editing even between identical genomic sites within the same genome. Our findings provide a novel strategy to enable use of diverse otherwise inactive CRISPR–Cas systems for genome-editing applications and a potential path to modulate the impact of chromatin microenvironments on genome modification. Bacteria possess a diverse collection of CRISPR-Cas systems but many do not function in mammalian cells, precluding their use in genome editing. Here the authors show that by manipulating local chromatin structures, inhibited Cas9s can have their activity restored in human cells.

Background Bleomycin, a potent antitumor agent, is limited in clinical use due to the potential for fatal pulmonary toxicity. The accelerated DNA damage and senescence in alveolar epithelial cells (AECs) is considered a key factor in the development of lung pathology. Understanding the mechanisms for bleomycin-induced lung injury is crucial for mitigating its adverse effects. Methods Human lung epithelial (A549) cells were exposed to bleomycin and subsequently assessed for cellular senescence, DNA damage, and double-strand break (DSB) repair. The impact of Rad51 overexpression on DSB repair and senescence in AECs was evaluated in vitro. Additionally, bleomycin was intratracheally administered in C57BL/6 mice to establish a pulmonary fibrosis model. Results Bleomycin exposure induced dose- and time-dependent accumulation of senescence hallmarks and DNA lesions in AECs. These effects are probably due to the inhibition of Rad51 expression, consequently suppressing homologous recombination (HR) repair. Mechanistic studies revealed that bleomycin-mediated transcriptional inhibition of Rad51 might primarily result from E2F1 depletion. Furthermore, the genetic supplement of Rad51 substantially mitigated bleomycin-mediated effects on DSB repair and senescence in AECs. Notably, decreased Rad51 expression was also observed in the bleomycin‐induced mouse pulmonary fibrosis model. Conclusions Our works suggest that the inhibition of Rad51 plays a pivotal role in bleomycin-induced AECs senescence and lung injury, offering potential strategies to alleviate the pulmonary toxicity of bleomycin.

The building information modeling (BIM) methods for construction management of railway tunnel, including naming rules of structuralized components and modeling precision requirements are studied by means of BIM technology. The methods and advantages of visualized design of 3D model of construction technologies for railway tunnel are explored. The methods for deducing and optimizing 4D model of construction of railway tunnel are studied. The automatic construction quantity calculating method based on BIM software is established. The construction practices show that the BIM technology can improve the construction scheme and technology management, and can provide visualized version for construction organization and management decision.

Hemiacetal compounds are valuable building blocks in synthetic chemistry, but their enzymatic synthesis is limited and often hindered by the instability of hemiacetals in aqueous environments. Here, we show that this challenge can be addressed through reaction engineering by using immobilized peroxygenase from Agrocybe aegerita ( Aae UPO) under neat reaction conditions, which allows for the selective C-H bond oxyfunctionalization of environmentally significant cyclic ethers to cyclic hemiacetals. A wide range of chiral cyclic hemiacetal products are prepared in >99% enantiomeric excess and 95170 turnover numbers of Aae UPO. Furthermore, by changing the reaction medium from pure organic solvent to alkaline aqueous conditions, cyclic hemiacetals are in situ transformed into lactones. Lactams are obtained under the applied conditions, albeit with low enzyme activity. These findings showcase the synthetic potential of Aae UPO and offer a practical enzymatic approach to produce chiral cyclic hemiacetals through C-H oxyfunctionalization under mild conditions. Hemiacetal compounds are valuable building blocks in synthetic chemistry, but difficult to obtain by enzymatic synthesis. Here, the authors use reaction engineering of an immobilized unspecific peroxygenase from Agrocybe aegerita for selective C-H bond oxyfunctionalisation of environmentally significant cyclic ethers to chiral cyclic hemiacetals.

Steam reforming is an effective method for improving heat sinks of hypersonic aircraft at high flight Mach numbers. However, unlike the industrial process of producing hydrogen with a high water content, the catalytic steam reforming mechanism for the regeneration cooling process of hydrocarbon fuels with a water content below 30% is still unclear. Catalytic steam reforming (CSR) and catalytic thermal cracking (CTC) reactions occur at low temperatures, with the main products being hydrogen and carbon oxides. Thermal cracking (TC) reactions occur at high temperatures, with the main products being alkanes and alkenes. The above reaction exists simultaneously in the regeneration cooling channel, which is referred to as partial catalytic steam reforming (PCSR). Based on the experimental measurement results, an improved neural network correction method was used to establish a four-step global reaction model for the PCSR of n-decane under low water conditions. The reliability of the four-step model was verified by combining the model with a numerical simulation program and comparing it with the experimental results obtained by electric heating hydrocarbon fuels with a pressure of 3 MPa and a water content of 5/10/15%. The experimental and predicted results using the developed kinetic model are consistent with an error of less than 5% in the decane conversion rate. The average absolute error between the fuel outlet temperature and total heat sink is less than 10%. Using the PCSR model to predict the heat transfer characteristics of mixed fuels with different water contents, the convective heat transfer coefficient is basically the same, and the Nu number is affected by the thermal conductivity coefficient, showing different patterns with changes in the water content.

The effect of light has raised attention on wastewater treatment. However, little research has concentrated on the influences of light on activated sludge. In this study, the influences of light on the performance, quorum sensing (QS) and metagenomic characteristics of anoxic/oxic reactors were investigated. The reactor without light (AO1) showed higher total nitrogen (TN) removal (79.15 ± 1.69%) than the reactor with light (AO2) (74.54 ± 1.30%), and significant differences were observed. It was observed that light facilitated the production of protein-like and tryptophan-like substances by employing parallel factor analysis for extracellular polymeric substance (EPS), resulting in more EPS production in AO2, indicating light was beneficial to EPS production. The concentrations of N-acyl-homoserine lactones (AHLs) were various in the two reactors, so the AHLs-mediated QS behaviors in both reactors were also different. These results revealed that light significantly influenced nitrogen removal, EPS, and QS. Metagenomic analysis based on Tax4Fun demonstrated that light reduced the denitrification, stimulated the polysaccharide and protein biosynthesis pathways and down-regulated the AHLs synthesis pathway, resulting in lower TN removal, more EPS production, and lower AHLs concentrations. Based on the above, the likely mechanism was proposed for the influences of light on the reactor.

Enzymes are making a significant impact on chemical synthesis. However, the range of chemical products achievable through biocatalysis is still limited compared to the vast array of products possible with organic synthesis. For instance, azoxy products have rarely been synthesized using enzyme catalysts. In this study, we discovered that fungal unspecific peroxygenases are promising catalysts for synthesizing azoxy products from simple aniline starting materials. The catalytic features (up to 48,450 turnovers and a turnover frequency of 6.7 s –1 ) and substrate transformations (up to 99% conversion with 98% chemoselectivity) highlight the synthetic potential. We propose a mechanism where peroxygenase-derived hydroxylamine and nitroso compounds spontaneously (non-enzymatically) form the desired azoxy products. This work expands the reactivity repertoire of biocatalytic transformations in the underexplored field of azoxy compound formation reactions. Azoxy products have rarely been synthesized using enzyme catalysts. Herein, the authors report that fungal unspecific peroxygenases are promising catalysts for synthesizing azoxy products from simple aniline starting materials.

With the rapid development of large model technology, data storage as well as collection is very important to improve the accuracy of model training, and Feature Selection (FS) methods can greatly eliminate redundant features in the data warehouse and improve the interpretability of the model, which makes it particularly important in the field of large model training. In order to better reduce redundant features in data warehouses, this paper proposes an enhanced Secretarial Bird Optimization Algorithm (SBOA), called BSFSBOA, by combining three learning strategies. First, for the problem of insufficient algorithmic population diversity in SBOA, the best-rand exploration strategy is proposed, which utilizes the randomness and optimality of random individuals as well as optimal individuals to effectively improve the population diversity of the algorithm. Second, to address the imbalance in the exploration/exploitation phase of SBOA, the segmented balance strategy is proposed to improve the balance by segmenting the individuals in the population, targeting individuals of different natures with different degrees of exploration and exploitation performance, and improving the quality of the FS subset when the algorithm is solved. Finally, for the problem of insufficient exploitation performance of SBOA, a four-role exploitation strategy is proposed, which strengthens the effective exploitation ability of the algorithm and enhances the classification accuracy of the FS subset by different degrees of guidance through the four natures of individuals in the population. Subsequently, the proposed BSFSBOA-based FS method is applied to solve 36 FS problems involving low, medium, and high dimensions, and the experimental results show that, compared to SBOA, BSFSBOA improves the performance of classification accuracy by more than 60%, also ranks first in feature subset size, obtains the least runtime, and confirms that the BSFSBOA-based FS method is a robust FS method with efficient solution performance, high stability, and high practicality.

Feature selection (FS) is a pivotal technique in big data analytics, aimed at mitigating redundant information within datasets and optimizing computational resource utilization. This study introduces an enhanced zebra optimization algorithm (ZOA), termed FTDZOA, for superior feature dimensionality reduction. To address the challenges of ZOA, such as susceptibility to local optimal feature subsets, limited global search capabilities, and sluggish convergence when tackling FS problems, three strategies are integrated into the original ZOA to bolster its FS performance. Firstly, a fractional order search strategy is incorporated to preserve information from the preceding generations, thereby enhancing ZOA’s exploitation capabilities. Secondly, a triple mean point guidance strategy is introduced, amalgamating information from the global optimal point, a random point, and the current point to effectively augment ZOA’s exploration prowess. Lastly, the exploration capacity of ZOA is further elevated through the introduction of a differential strategy, which integrates information disparities among different individuals. Subsequently, the FTDZOA-based FS method was applied to solve 23 FS problems spanning low, medium, and high dimensions. A comparative analysis with nine advanced FS methods revealed that FTDZOA achieved higher classification accuracy on over 90% of the datasets and secured a winning rate exceeding 83% in terms of execution time. These findings confirm that FTDZOA is a reliable, high-performance, practical, and robust FS method.