Search

The solar-driven overall water splitting (2H 2 O→2H 2 + O 2 ) is considered as one of the most promising strategies for reducing carbon emissions and meeting energy demands. However, due to the sluggish performance and high H 2 cost, there is still a big gap for the current photocatalytic systems to meet the requirements for practical sustainable H 2 production. Economic feasibility can be attained through simultaneously generating products of greater value than O 2 , such as hydrogen peroxide (H 2 O 2 , 2H 2 O→H 2 + H 2 O 2 ). Compared with overall water splitting, this approach is more kinetically feasible and generates more high-value products of H 2 and H 2 O 2 . In several years, there has been an increasing surge in exploring the possibility and substantial progress has been achieved. In this review, a concise overview of the importance and underlying principles of PIWS is first provided. Next, the reported typical photocatalysts for PIWS are discussed, including commonly used semiconductors and cocatalysts, essential design features of these photocatalysts, and connections between their structures and activities, as well as the selected approaches for enhancing their stability. Then, the techniques used to quantify H 2 O 2 and the operando characterization techniques that can be employed to gain a thorough understanding of the reaction mechanisms are summarized. Finally, the current existing challenges and the direction needing improvement are presented. This review aims to provide a thorough summary of the most recent research developments in PIWS and sets the stage for future advancements and discoveries in this emerging area., (© 2024 Wiley‐VCH GmbH.)

Antibiotic pollution in water environment is an emerging threat to plant health. Developing efficient strategies to reassemble the antibiotic-tolerating endophytes will confer fitness benefits on host plants to alleviate antibiotic stress. Here, introducing environmental microbes was proved as a promising approach to reshape the antibiotic-tolerating plant endophytes under antibiotic stress in aquatic microcosms. The introduction of environmental microbes effectively relieved antibiotic-driven perturbation on plant endophytes, with reduced changes in bacterial diversity and differential bacterial taxa and functional genes. Moreover, introducing environmental microbes facilitated the enrichment of endophytic bacterial genera and functional genes related to drug metabolism, which possessed the potentials to degrade antibiotics. In addition, environmental microbes boosted antibiotic-reshaped endophytes to form more stable bacterial networks for stronger antibiotic tolerance. In consequence, the decreased growth inhibition of antibiotics on host plants and enhanced antibiotic removal from microcosms were achieved by introducing environmental microbes. These findings pursue environmental microbes as practical resources to assist plants in reshaping the stress-alleviating endophytes, potentially improving plant tolerance to water pollution., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

We aimed to build a deep learning-based pathomics model to predict the early recurrence of non-muscle-infiltrating bladder cancer (NMIBC) in this work. A total of 147 patients from Xuzhou Central Hospital were enrolled as the training cohort, and 63 patients from Suqian Affiliated Hospital of Xuzhou Medical University were enrolled as the test cohort. Based on two consecutive phases of patch level prediction and WSI-level predictione, we built a pathomics model, with the initial model developed in the training cohort and subjected to transfer learning, and then the test cohort was validated for generalization. The features extracted from the visualization model were used for model interpretation. After migration learning, the area under the receiver operating characteristic curve for the deep learning-based pathomics model in the test cohort was 0.860 (95% CI 0.752-0.969), with good agreement between the migration training cohort and the test cohort in predicting recurrence, and the predicted values matched well with the observed values, with p values of 0.667766 and 0.140233 for the Hosmer-Lemeshow test, respectively. The good clinical application was observed using a decision curve analysis method. We developed a deep learning-based pathomics model showed promising performance in predicting recurrence within one year in NMIBC patients. Including 10 state prediction NMIBC recurrence group pathology features be visualized, which may be used to facilitate personalized management of NMIBC patients to avoid ineffective or unnecessary treatment for the benefit of patients., (© 2024. The Author(s).)

The contents of eight heavy metals （Cr, Ni, Cu, Zn, Cd, Pb, As, and Hg） were determined based on the surface soil samples of sewage irrigation and industrial complex in Kaifeng City. The absolute factor analysis-multiple linear regression （APCS-MLR） model and positive matrix factorization （PMF） model were used to analyze the sources and contribution rates of heavy metals in soil combined with correlation analysis and systematic cluster analysis. The results showed that： ① The average values of ω （Cr）, ω （Ni）, ω （Cu）, ω （Zn）, ω （Cd）, ω （Pb）, ω （As）, and ω （Hg） in the study area were 52.19, 25.00, 42.03, 323.53, 1.79, 53.45, 9.43, and 0.20 mg·kg -1 , respectively, and Cr, Ni, and As are lower than the background values of tidal soil. Cu, Zn, Cd, Pb, and Hg are higher than the background values of the tidal soil. ② There were four sources of the eight heavy metals： natural sources, agricultural sewage irrigation sources, industrial atmospheric sedimentation sources, and transportation sources. Cr and Ni were mainly from natural sources； Cu, Zn, Cd, and Pb were mainly from agricultural sewage irrigation and transportation sources； As was mainly from natural sources and agricultural sewage irrigation； and Hg was mainly from industrial atmospheric sedimentation. ③ The APCS-MLR and PMF source analysis results indicated that industrial and agricultural activities were the main sources of heavy metals in the soil of the study area. The average contribution rates of APCS-MLR in the nine sampling areas of the research area were 76.01% （natural sources and agricultural sewage irrigation sources）, 22.71% （industrial atmospheric sedimentation sources and transportation sources）, and 1.28% （unknown sources）. The average contribution rates of PMF were 59.66% （natural sources and agricultural sewage irrigation sources） and 40.34% （industrial atmospheric sedimentation sources and transportation sources）. The source analysis results of the LZ, XZ, NLT, PT, YLZ, and BC models were basically consistent, and WL was better in the APCS-MLR model, whereas SG and QT were better in the PMF model. The research results can provide a scientific basis for the prevention and control of soil heavy metal pollution and environmental remediation.

Cardiac fibrosis is a typical feature of cardiac pathological remodeling, which is associated with adverse clinical outcomes and has no effective therapy. Nicotine is an important risk factor for cardiac fibrosis, yet its underlying molecular mechanism remains poorly understood. This study aimed to identify its potential molecular mechanism in nicotine-induced cardiac fibrosis. Our results showed nicotine exposure led to the proliferation and transformation of cardiac fibroblasts (CFs) into myofibroblasts (MFs) by impairing autophagy flux. Through the use of drug affinity responsive target stability (DARTS) assay, cellular thermal shift assay (CETSA), and surface plasmon resonance (SPR) technology, it was discovered that nicotine directly increased the stability and protein levels of lactate dehydrogenase A (LDHA) by binding to it. Nicotine treatment impaired autophagy flux by regulating the AMPK/mTOR signaling pathway, impeding the nuclear translocation of transcription factor EB (TFEB), and reducing the activity of cathepsin B (CTSB). In vivo, nicotine treatment exacerbated cardiac fibrosis induced in spontaneously hypertensive rats (SHR) and worsened cardiac function. Interestingly, the absence of LDHA reversed these effects both in vitro and in vivo. Our study identified LDHA as a novel nicotine-binding protein that plays a crucial role in mediating cardiac fibrosis by blocking autophagy flux. The findings suggest that LDHA could potentially serve as a promising target for the treatment of cardiac fibrosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Activation-induced cytidine deaminase (AID) initiates somatic hypermutation (SHM) by introducing base substitutions into antibody genes, a process enabling antibody affinity maturation in immune response. How a mutator is tamed to precisely and safely generate programmed DNA lesions in a physiological process remains unsettled, as its dysregulation drives lymphomagenesis. Recent research has revealed several hidden features of AID-initiated mutagenesis: preferential activity on flexible DNA substrates, restrained activity within chromatin loop domains, unique DNA repair factors to differentially decode AID-caused lesions, and diverse consequences of aberrant deamination. Here, we depict the multifaceted regulation of AID activity with a focus on emerging concepts/factors and discuss their implications for the design of base editors (BEs) that install somatic mutations to correct deleterious genomic variants., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Appropriate DNA end synapsis, regulated by core components of the synaptic complex including KU70-KU80, LIG4, XRCC4, and XLF, is central to non-homologous end joining (NHEJ) repair of chromatinized DNA double-strand breaks (DSBs). However, it remains enigmatic whether chromatin modifications can influence the formation of NHEJ synaptic complex at DNA ends, and if so, how this is achieved. Here, we report that the mitotic deacetylase complex (MiDAC) serves as a key regulator of DNA end synapsis during NHEJ repair in mammalian cells. Mechanistically, MiDAC removes combinatorial acetyl marks on histone H2A (H2AK5acK9ac) around DSB-proximal chromatin, suppressing hyperaccumulation of bromodomain-containing protein BRD4 that would otherwise undergo liquid-liquid phase separation with KU80 and prevent the proper installation of LIG4-XRCC4-XLF onto DSB ends. This study provides mechanistic insight into the control of NHEJ synaptic complex assembly by a specific chromatin signature and highlights the critical role of H2A hypoacetylation in restraining unscheduled compartmentalization of DNA repair machinery., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Antibody-coding genes accumulate somatic mutations to achieve antibody affinity maturation. Genetic dissection using various mouse models has shown that intrinsic hypermutations occur preferentially and are predisposed in the DNA region encoding antigen-contacting residues. The molecular basis of nonrandom/preferential mutations is a long-sought question in the field. Here, we summarize recent findings on how single-strand (ss)DNA flexibility facilitates activation-induced cytidine deaminase (AID) activity and fine-tunes the mutation rates at a mesoscale within the antibody variable domain exon. We propose that antibody coding sequences are selected based on mutability during the evolution of adaptive immunity and that DNA mechanics play a noncoding role in the genome. The mechanics code may also determine other cellular DNA metabolism processes, which awaits future investigation., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In this study, a novel method that can detect carbon dioxide (CO 2 ) concentration and realize temperature immunity based on only one fiber Bragg grating (FBG) is proposed. The outstanding contribution lies in solving the temperature crosstalk issue of FBG and ensuring the accuracy of detection results under the condition of anti-temperature interference. To achieve immunity to temperature interference without changing the initial structure of FBG, the optical fiber cladding of FBG and adjacent optical fiber cladding at both ends of FBG are modified by a polymer coating. Moreover, a universal immune temperature demodulation algorithm is derived. The experimental results demonstrate that the temperature response sensitivity of the improved FBG is controlled within the range of 0.00407 nm/°C. Compared with the initial FBG (the temperature sensitivity of the initial FBG is 0.04 nm/°C), it decreases by nearly 10 times. Besides, the gas response sensitivity of FBG reaches 1.6 pm/ppm and has overwhelmingly ideal linearity. The detection error results manifest that the gas concentration error in 20 groups of data does not exceed 3.16 ppm. The final reproducibility research shows that the difference in detection sensitivity between the two sensors is 0.08 pm/ppm, and the relative error of linearity is 1.07%. In a word, the proposed method can accurately detect the concentration of CO 2 gas and is efficiently immune to temperature interference. The sensor we proposed has the advantages of a simple production process, low cost, and satisfactory reproducibility. It also has the prospect of mass production.

Base editors (BEs) introduce base substitutions without double-strand DNA cleavage. Besides precise substitutions, BEs generate low-frequency 'stochastic' byproducts through unclear mechanisms. Here, we performed in-depth outcome profiling and genetic dissection, revealing that C-to-G BEs (CGBEs) generate substantial amounts of intermediate double-strand breaks (DSBs), which are at the centre of several byproducts. Imperfect DSB end-joining leads to small deletions via end-resection, templated insertions or aberrant transversions during end fill-in. Chromosomal translocations were detected between the editing target and off-targets of Cas9/deaminase origin. Genetic screenings of DNA repair factors disclosed a central role of abasic site processing in DSB formation. Shielding of abasic sites by the suicide enzyme HMCES reduced CGBE-initiated DSBs, providing an effective way to minimize DSB-triggered events without affecting substitutions. This work demonstrates that CGBEs can initiate deleterious intermediate DSBs and therefore require careful consideration for therapeutic applications, and that HMCES-aided CGBEs hold promise as safer tools., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Iron plaque, as a natural barrier between rice and soil, can reduce the accumulation of pollutants in rice by adsorption, contributing to the safe production of rice in contaminated soil. In this study, we unveiled a new role of iron plaque, i.e., producing hydroxyl radicals (·OH) by activating root-secreted oxygen to degrade pollutants. The ·OH was produced on the iron plaque surface and then diffused to the interfacial layer between the surface and the rhizosphere environment. The iron plaque activated oxygen via a successive three-electron transfer to produce ·OH, involving superoxide and hydrogen peroxide as the intermediates. The structural Fe(II) in iron plaque played a dominant role in activating oxygen rather than the adsorbed Fe(II), since the structural Fe(II) was thermodynamically more favorable for oxygen activation. The oxygen vacancies accompanied by the structural Fe(II) played an important role in oxygen activation to produce ·OH. The interfacial ·OH selectively degraded rhizosphere pollutants that could be adsorbed onto the iron plaque and was less affected by the rhizosphere environments than the free ·OH. This study uncovered the oxidative role of iron plaque mediated by its produced ·OH, reshaping our understanding of the role of iron plaque as a barrier for rice.

circRNADisease v2.0 is an enhanced and reliable database that offers experimentally verified relationships between circular RNAs (circRNAs) and various diseases. It is accessible at http://cgga.org.cn/circRNADisease/ or http://cgga.org.cn:9091/circRNADisease/. The database currently includes 6998 circRNA-disease entries across multiple species, representing a remarkable 19.77-fold increase compared to the previous version. This expansion consists of a substantial rise in the number of circRNAs (from 330 to 4246), types of diseases (from 48 to 330) and covered species (from human only to 12 species). Furthermore, a new section has been introduced in the database, which collects information on circRNA-associated factors (genes, proteins and microRNAs), molecular mechanisms (molecular pathways), biological functions (proliferation, migration, invasion, etc.), tumor and/or cell line and/or patient-derived xenograft (PDX) details, and prognostic evidence in diseases. In addition, we identified 7 159 865 relationships between mutations and circRNAs among 30 TCGA cancer types. Due to notable enhancements and extensive data expansions, the circRNADisease 2.0 database has become an invaluable asset for both clinical practice and fundamental research. It enables researchers to develop a more comprehensive understanding of how circRNAs impact complex diseases., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Cytidine deaminases as DNA mutators play important roles in immunity and genome stability. Here, we present a high-throughput protocol for deamination of long single-stranded (ss) DNA or oligo pools containing complex sequences. We describe steps for the preparation of both enzyme (activation-induced deaminase, AID) and ssDNA substrates, the deamination reaction, uracil-friendly amplification, and data analysis. This assay can be used to determine the intrinsic mutation profile of a single antibody gene or a pool of selected regions on genomic DNA. For complete details on the use and execution of this protocol, please refer to Wang et al. (2023). 1 ., Competing Interests: Declaration of interests Shanghai Institute of Biochemistry and Cell Biology and Shanghai Jiao Tong University School of Medicine have filed a patent application based on the protocol in this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Stroke is one of the predominant causes of death and disability. Currently, besides thrombolytic therapy, neuroprotection is also generally recognized as a promising way for stroke treatment, which would be very important for the functional recovery of stroke patients. However, it's reported that all the current available neuroprotective drugs have failed in clinical investigations of stroke treatments so far. Lyoniresinol (LNO) is a natural lignan with powerful antioxidant and cytoprotective activities. In this study, OGD/R leaded HT22 cell damage models and Middle Cerebral Artery Occlusion (MCAO) rats were used to investigate the effect of LNO on cerebral ischemic stroke injury and related mechanisms. The cell experiments revealed LNO can suppress the oxygen glucose deprivation-reoxygenation (OGD/R) induced apoptosis of HT22 cells. Subsequently, LNO can improve nerve function deficit and brain injury in MCAO rats with a higher neurological function scores and less infarct size. And the further molecular mechanisms studies suggested LNO activated the PI3K/AKT/GSK-3β/NRF2 signaling and improved the oxidative stress in cells to inhibit the OGD/R induced apoptosis in HT22 cells. Collectively, our findings would be useflu for the further drug development of LNO as new drug for stroke and its related diseases., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objective: To understand the population structure of food-borne Staphylococcus (S.) aureus in China. Methods: Whole genome sequencing was used to analyze 763 food-borne S. aureus strains from 16 provinces in China from 2006 to 2020. Multilocus sequence typing (MLST), staphylococcal protein A gene ( spa ) typing, and staphylococcal chromosome cassettemec (SCC mec ) typing were conducted, and minimum spanning tree based on ST types (STs) was constructed by BioNumerics 7.5 software. Thirty-one S. aureus strains isolated from imported food products were also included in constructing the genome phylogenetic tree. Results: A total of 90 STs (20 novel types) and 160 spa types were detected in the 763 S. aureus isolates. The 72 STs (72/90, 80.0%) were related to 22 clone complexes. The predominant clone complexes were CC7, CC1, CC5, CC398, CC188, CC59, CC6, CC88, CC15, and CC25, accounting for 82.44% (629/763) of the total. The STs and spa types in the predominant clone complexes changed over the years. The methicillin-resistant S . aureus (MRSA) detection rate was 7.60%, and 7 SCC mec types were identified. The ST59-t437-Ⅳa (17.24%, 10/58), ST239-t030-Ⅲ (12.07%, 7/58), ST59-t437-Ⅴb (8.62%, 5/58), ST338-t437-Ⅴb (6.90%, 4/58) and ST338-t441-Ⅴb (6.90%, 4/58) were the main types in MRSA strains. The genome phylogenetic tree had two clades, and the strains with the same CC, ST, and spa types clustered together. All CC7 methicillin sensitive S. aureus strains were included in Clade1, while 21 clone complexes and all MRSA strains were in Clade2. The MRSA strains clustered according to the SCC mec and STs. The strains from imported food products in CC398, CC7, CC30, CC12, and CC188 had far distances from Chinese strains in the tree. Conclusions: In this study, the predominant clone complexes of food-borne strains were CC7, CC1, CC5, CC398, CC188, CC59, CC6, CC88, CC15, and CC25, which overlapped with the previously reported clone complexes of hospital and community-associated strains in China, suggesting that close attention needs to be paid to food, a vehicle of pathogen transmission in community and food poisoning.

Mismatch repair (MMR) deficiency has been linked to thiopurine resistance and hypermutation in relapsed acute lymphoblastic leukemia (ALL). However, the repair mechanism of thiopurine-induced DNA damage in the absence of MMR remains unclear. Here, we provide evidence that DNA polymerase β (POLB) of base excision repair (BER) pathway plays a critical role in the survival and thiopurine resistance of MMR-deficient ALL cells. In these aggressive resistant ALL cells, POLB depletion and its inhibitor oleanolic acid (OA) treatment result in synthetic lethality with MMR deficiency through increased cellular apurinic/apyrimidinic (AP) sites, DNA strand breaks and apoptosis. POLB depletion increases thiopurine sensitivities of resistant cells, and OA synergizes with thiopurine to kill these cells in ALL cell lines, patient-derived xenograft (PDX) cells and xenograft mouse models. Our findings suggest BER and POLB's roles in the process of repairing thiopurine-induced DNA damage in MMR-deficient ALL cells, and implicate their potentials as therapeutic targets against aggressive ALL progression., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Somatic hypermutation (SHM), initiated by activation-induced cytidine deaminase (AID), generates mutations in the antibody-coding sequence to allow affinity maturation. Why these mutations intrinsically focus on the three nonconsecutive complementarity-determining regions (CDRs) remains enigmatic. Here, we found that predisposition mutagenesis depends on the single-strand (ss) DNA substrate flexibility determined by the mesoscale sequence surrounding AID deaminase motifs. Mesoscale DNA sequences containing flexible pyrimidine-pyrimidine bases bind effectively to the positively charged surface patches of AID, resulting in preferential deamination activities. The CDR hypermutability is mimicable in in vitro deaminase assays and is evolutionarily conserved among species using SHM as a major diversification strategy. We demonstrated that mesoscale sequence alterations tune the in vivo mutability and promote mutations in an otherwise cold region in mice. Our results show a non-coding role of antibody-coding sequence in directing hypermutation, paving the way for the synthetic design of humanized animal models for optimal antibody discovery and explaining the AID mutagenesis pattern in lymphoma., Competing Interests: Declaration of interests Shanghai Institute of Biochemistry and Cell Biology and Shanghai Jiao Tong University School of Medicine have filed a patent application based on the findings in this article., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: The docking and superantigen activity sites of staphylococcal enterotoxin-like W (SElW) and T cell receptor (TCR) were predicted, and its SElW was cloned, expressed and purified. Methods: AlphaFold was used to predict the 3D structure of SElW protein monomers, and the protein models were evaluated with the help of the SAVES online server from ERRAT, Ramachandran plot, and Verify_3D. The ZDOCK server simulates the docking conformation of SElW and TCR, and the amino acid sequences of SElW and other serotype enterotoxins were aligned. The primers were designed to amplify selw , and the fragment was recombined into the pMD18-T vector and sequenced. Then recombinant plasmid pMD18-T was digested with BamH Ⅰand Hind Ⅲ. The target fragment was recombined into the expression plasmid pET-28a(+). After identification of the recombinant plasmid, the protein expression was induced by isopropyl-beta-D- thiogalactopyranoside. The SElW expressed in the supernatant was purified by affinity chromatography and quantified by the BCA method. Results: The predicted three-dimensional structure showed that the SElW protein was composed of two domains, the amino-terminal and the carboxy-terminal. The amino-terminal domain was composed of 3 α-helices and 6 β-sheets, and the carboxy-terminal domain included 2 α-helices and 7 antiparallel β-sheets composition. The overall quality factor score of the SElW protein model was 98.08, with 93.24% of the amino acids having a Verify_3D score ≥0.2 and no amino acids located in disallowed regions. The docking conformation with the highest score (1 521.328) was selected as the analysis object, and the 19 hydrogen bonds between the corresponding amino acid residues of SElW and TCR were analyzed by PyMOL. Combined with sequence alignment and the published data, this study predicted and found five important superantigen active sites, namely Y18, N19, W55, C88, and C98. The highly purified soluble recombinant protein SElW was obtained with cloning, expression, and protein purification. Conclusions: The study found five superantigen active sites in SElW protein that need special attention and successfully constructed and expressed the SElW protein, which laid the foundation for further exploration of the immune recognition mechanism of SElW.

Insertions and deletions (indels) are low-frequency deleterious genomic DNA alterations. Despite their rarity, indels are common, and insertions leading to long complementarity-determining region 3 (CDR3) are vital for antigen-binding functions in broadly neutralizing and polyreactive antibodies targeting viruses. Because of challenges in detecting indels, the mechanism that generates indels during immunoglobulin diversification processes remains poorly understood. We carried out ultra-deep profiling of indels and systematically dissected the underlying mechanisms using passenger-immunoglobulin mouse models. We found that activation-induced cytidine deaminase-dependent ±1-base pair (bp) indels are the most prevalent indel events, biasing deleterious outcomes, whereas longer in-frame indels, especially insertions that can extend the CDR3 length, are rare outcomes. The ±1-bp indels are channeled by base excision repair, but longer indels require additional DNA-processing factors. Ectopic expression of a DNA exonuclease or perturbation of the balance of DNA polymerases can increase the frequency of longer indels, thus paving the way for models that can generate antibodies with long CDR3. Our study reveals the mechanisms that generate beneficial and deleterious indels during the process of antibody somatic hypermutation and has implications in understanding the detrimental genomic alterations in various conditions, including tumorigenesis.

The functional interaction between microorganisms is key in symbiotic microalga-bacteria systems; however, evaluations of fungi and pathogenic microorganisms are not clear. In this study, the roles of three groups (i.e., microalgae-activated sludge (MAS), Microalgae, and activated sludge) in pollutant removal and biomass recovery were comparatively studied. The data implied that microalgal assimilation and bacterial heterotrophic degradation were the major approaches for degradation of nutrients and organic matter, respectively. According to 16S rRNA and internal transcribed spacer sequencing, the relative abundance of Rhodotorula increased remarkably, favoring nutrient exchange between the microalgae and bacteria. The abundances of two types of pathogenic genes (human pathogens and animal parasites) were reduced in the MAS system. The oleic acid content in the MAS system (51.2 mg/g) was 1.7 times higher than that in the Microalgae system. The results can provide a basis for practical application and resource utilization of symbiotic microalgae-bacteria systems., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Quzhou county is a county in the North China Plain with intensive agricultural production. Based on data collected on the local anthropogenic activity level and the ammonia (NH 3 ) emission factor, the anthropogenic NH 3 emission inventory in Quzhou county from 2002 to 2019 was established using the emission factor method, and the NH 3 emission inventory in 2019 was optimized using the locally measured nitrogen (N) fertilizer application NH 3 emission factor and activity data from farmer surveys. We found that the total NH 3 emission in Quzhou county showed a bimodal pattern: it increased from 6682.9 t in 2002 to 7195.0 t in 2004 and then decreased to 5872.0 t in 2008. The second peak occurred in 2015 (7010.5 t) and then gradually decreased to 5636.3 t in 2018. Livestock husbandry (61%-75%) and N fertilizer application (14%-28%) were the primary NH 3 emission sources. In 2019, the total NH 3 emission in Quzhou county was 6559.7 t, of which N fertilizer application and livestock husbandry contributed 28% and 61%, respectively. Wheat planting contributed the highest NH 3 emissions, accounting for 40% of the total NH 3 emission of crop production. Laying hens had the largest NH 3 emission in livestock production, contributing 40% of the total emissions. NH 3 emissions were higher in the south than those in the north at the county level, with the average NH 3 emission intensity reaching 13.5 t·km -2 . Nanliyue and Baizhai towns were hot spots of NH 3 emission. Taken together NH 3 emission reduction in wheat production and layer hen breeding will help to control atmospheric NH 3 pollution in the North China Plain.

Breakthrough infection of SARS-CoV-2 is a serious challenge, as increased infections were documented in fully-vaccinated individuals. Recipients with poor antibody response are highly vulnerable to reinfection, whereas those with strong antibody responses achieve sterilizing immunity. Thus far, biomarkers associated with levels of vaccine-elicited antibody response are still lacking. Here, we studied the antibody response of age- and gender-controlled healthy cohort, who received inactivated SARS-CoV-2 vaccines and profiled the B cell receptor repertoires in longitudinally consecutive samples. Upon vaccination, all vaccinated individuals displayed a convergent antibody response with shared common antibody clones and public neutralizing antibodies. Strikingly, poor vaccine-responders are distinguishable from strong vaccine-responders by a biased V-usage before vaccination and IgG to IgM mRNA ratio. These findings reveal molecular signatures associated with the different levels of vaccine-induced antibody response, which could be further developed into biomarkers for the design of vaccination strategies.

Background: With the continued advancement of RNA-seq (RNA-sequencing), microRNA (miRNA) editing events have been demonstrated to play an important role in different malignancies. However, there is yet no description of the miRNA editing events in recurrent bladder cancer. Objective: To identify and compare miRNA editing events in primary and recurrent bladder cancer, as well as to investigate the potential molecular mechanism and its impact on patient prognosis. Methods: We examined the mRNA and miRNA transcriptomes of 12 recurrent bladder cancer cases and 13 primary bladder cancer cases. The differentially expressed mRNA sequences were analyzed. Furthermore, we identified the differentially expressed genes (DEGs) in recurrent bladder cancer. The Gene Ontology (GO) functional enrichment analyses on DEGs and gene set enrichment analysis were performed. The consensus molecular subtype (CMS) classification of bladder cancer was identified using the Consensus MIBC package in R (4.1.0); miRNA sequences were then further subjected to differentially expressed analysis and pathway enrichment analysis. MiRNA editing events were identified using miRge3.0. miRDB and TargetScanHuman were used to predict the downstream targets of specific differentially edited or expressed miRNAs. The expression levels of miR-154-5p and ADAR were validated by RT-qPCR. Finally, survival and co-expression studies were performed on the TCGA-BLCA cohort. Results: First, the mRNA expression levels in recurrent bladder cancer changed significantly, supporting progression via related molecular signal pathways. Second, significantly altered miRNAs in recurrent bladder cancer were identified, with miR-154-5p showing the highest level of editing in recurrent bladder cancer and may up-regulate the expression levels of downstream targets HS3ST3A1, AQP9, MYLK, and RAB23. The survival analysis results of TCGA data revealed that highly expressed HS3ST3A1 and RAB23 exhibited poor prognosis. In addition, miR-154 editing events were found to be significant to CMS classification. Conclusion: MiRNA editing in recurrent bladder cancer was detected and linked with poor patient prognosis, providing a reference for further uncovering the intricate molecular mechanism in recurrent bladder cancer. Therefore, inhibiting A-to-I editing of miRNA may be a viable target for bladder cancer treatment, allowing current treatment choices to be expanded and individualized., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Qin, Liu, Wang, Wang, Liang, Dong, Pang, Hao, Xue, Zhao, Hu, Li, Lv, Chao, Meng, Shi and Han.)

In activated B cells, activation-induced cytidine deaminase (AID) generates programmed DNA lesions required for antibody class switch recombination (CSR), which may also threaten genome integrity. AID dynamically shuttles between cytoplasm and nucleus, and the majority stays in the cytoplasm due to active nuclear export mediated by its C-terminal peptide. In immunodeficient-patient cells expressing mutant AID lacking its C-terminus, a catalytically active AID-delC protein accumulates in the nucleus but nevertheless fails to support CSR. To resolve this apparent paradox, we dissected the function of AID-delC proteins in the CSR process and found that they cannot efficiently target antibody genes. We demonstrate that AID-delC proteins form condensates both in vivo and in vitro, dependent on its N-terminus and on a surface arginine-rich patch. Co-expression of AID-delC and wild-type AID leads to an unbalanced nuclear AID-delC/AID ratio, with AID-delC proteins able to trap wild-type AID in condensates, resulting in a dominant-negative phenotype that could contribute to immunodeficiency. The co-condensation model of mutant and wild-type proteins could be an alternative explanation for the dominant-negative effect in genetic disorders., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

The development of a simple and cost-effective method to map the distribution of RNA polymerase II (RNPII) genome-wide at a high resolution is highly beneficial to study cellular transcriptional activity. Here we report a mutation-based and enrichment-free global chromatin run-on sequencing (mGRO-seq) technique to locate active RNPII sites genome-wide at near-base resolution. An adenosine triphosphate (ATP) analog named N 6 -allyladenosine triphosphate (a 6 ATP) was designed and could be incorporated into nascent RNAs at RNPII-located positions during a chromatin run-on reaction. By treatment of the run-on RNAs with a mild iodination reaction and subjection of the products to reverse transcription into complementary DNA (cDNA), base mismatch occurs at the original a 6 A incorporation sites, thus making the RNPII locations detected in the high-throughput cDNA sequencing. The mGRO-seq yields both the map of RNPII sites and the chromatin RNA abundance and holds great promise for the study of single-cell transcriptional activity.

As an aberrant base in DNA, uracil is generated by either deoxyuridine (dU) misincorporation or cytosine deamination, and involved in multiple physiological and pathological processes. Genome-wide profiles of uracil are important for study of these processes. Current methods for whole-genome mapping of uracil all rely on uracil-DNA N-glycosylase (UNG) and are limited in resolution, specificity, and/or sensitivity. Here, we developed a UdgX cross-linking and polymerase stalling sequencing ("Ucaps-seq") method to detect dU at single-nucleotide resolution. First, the specificity of Ucaps-seq was confirmed on synthetic DNA. Then the effectiveness of the approach was verified on two genomes from different sources. Ucaps-seq not only identified the enrichment of dU at dT sites in pemetrexed-treated cancer cells with globally elevated uracil but also detected dU at dC sites within the "WRC" motif in activated B cells which have increased dU in specific regions. Finally, Ucaps-seq was utilized to detect dU introduced by the cytosine base editor (nCas9-APOBEC) and identified a novel off-target site in cellular context. In conclusion, Ucaps-seq is a powerful tool with many potential applications, especially in evaluation of base editing fidelity.

Somatic hypermutation (SHM) drives the genetic diversity of Ig genes in activated B cells and supports the generation of Abs with increased affinity for Ag. SHM is targeted to Ig genes by their enhancers (diversification activators [DIVACs]), but how the enhancers mediate this activity is unknown. We show using chicken DT40 B cells that highly active DIVACs increase the phosphorylation of RNA polymerase II (Pol II) and Pol II occupancy in the mutating gene with little or no accompanying increase in elongation-competent Pol II or production of full-length transcripts, indicating accumulation of stalled Pol II. DIVAC has similar effect also in human Ramos Burkitt lymphoma cells. The DIVAC-induced stalling is weakly associated with an increase in the detection of ssDNA bubbles in the mutating target gene. We did not find evidence for antisense transcription, or that DIVAC functions by altering levels of H3K27ac or the histone variant H3.3 in the mutating gene. These findings argue for a connection between Pol II stalling and cis -acting targeting elements in the context of SHM and thus define a mechanistic basis for locus-specific targeting of SHM in the genome. Our results suggest that DIVAC elements render the target gene a suitable platform for AID-mediated mutation without a requirement for increasing transcriptional output., (Copyright © 2021 by The American Association of Immunologists, Inc.)

An essential step for SARS-CoV-2 infection is the attachment to the host cell receptor by its Spike receptor-binding domain (RBD). Most of the existing RBD-targeting neutralizing antibodies block the receptor-binding motif (RBM), a mutable region with the potential to generate neutralization escape mutants. Here, we isolated and structurally characterized a non-RBM-targeting monoclonal antibody (FD20) from convalescent patients. FD20 engages the RBD at an epitope distal to the RBM with a K D of 5.6 nM, neutralizes SARS-CoV-2 including the current Variants of Concern such as B.1.1.7, B.1.351, P.1, and B.1.617.2 (Delta), displays modest cross-reactivity against SARS-CoV, and reduces viral replication in hamsters. The epitope coincides with a predicted "ideal" vulnerability site with high functional and structural constraints. Mutation of the residues of the conserved epitope variably affects FD20-binding but confers little or no resistance to neutralization. Finally, in vitro mode-of-action characterization and negative-stain electron microscopy suggest a neutralization mechanism by which FD20 destructs the Spike. Our results reveal a conserved vulnerability site in the SARS-CoV-2 Spike for the development of potential antiviral drugs., (© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)

Herein, a new organic-inorganic hybrid cuprous iodide of [(Me) 2 -DABCO]Cu 6 I 8 was prepared and structurally characterized with a novel three-dimensional (3D) [Cu 6 I 8 ] 2- framework. Significantly, this 3D cuprous iodide displays infrequent broadband red-to-near-infrared light emission (600-1000 nm) stemming from the radiative recombination of self-trapped excitons.

Preparation of porphyrin-based covalent organic frameworks (Por-COFs) with high photosensitizing activity for photodynamic inactivation of bacteria is of great challenge, but significant for economy and human health. Herein, we show a conjugation-regulating strategy to design and synthesize Por-COFs with high photosensitizing activity for the photodynamic inactivation of bacteria. Terephthalaldehyde (Da), 2,5-Dihydroxyterephthalaldehyde (Dha), and 2,5-Diethoxyterephthalaldehyde (Deta) with different conjugation degrees are selected to condense with 5,10,15,20-Tetrakis(4-aminophenyl)porphyrin (Tph) to synthesize COF-366, DhaTph, and JNU-2, respectively. The higher conjugation of Dha and Deta than Da leads to the higher conjugation of DhaTph and JNU-2, respectively. Moreover, the hydroxyl group in Dha and the ethoxy group in Deta further expand the conjugation of DhaTph and JNU-2 via the formation of intralayer extended π-cloud delocalization and p-π conjunction, respectively. The extension of conjugation for DhaTph and JNU-2 results in the increase of intersystem crossing process and significantly improves their photosensitizing activity. Furthermore, JNU-2 with the highest photosensitizing activity exhibits superior antibacterial effects toward Staphylococcus aureus (99.1%) and Escherichia coli (96.8%). This study offers a new conjugation-regulating strategy for designing high photosensitizing activity of Por-COFs for the inactivation of bacteria., (Copyright © 2021 Elsevier B.V. All rights reserved.)

CRISPR-Cas9 generates double-stranded DNA breaks (DSBs) to activate cellular DNA repair pathways for genome editing. The repair of DSBs leads to small insertions or deletions (indels) and other complex byproducts, including large deletions and chromosomal translocations. Indels are well understood to disrupt target genes, while the other deleterious byproducts remain elusive. We developed a new in silico analysis pipeline for the previously described primer-extension-mediated sequencing assay to comprehensively characterize CRISPR-Cas9-induced DSB repair outcomes in human or mouse cells. We identified tremendous deleterious DSB repair byproducts of CRISPR-Cas9 editing, including large deletions, vector integrations, and chromosomal translocations. We further elucidated the important roles of microhomology, chromosomal interaction, recurrent DSBs, and DSB repair pathways in the generation of these byproducts. Our findings provide an extra dimension for genome editing safety besides off-targets. And caution should be exercised to avoid not only off-target damages but also deleterious DSB repair byproducts during genome editing., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Five new zero-dimensional hybrid manganese halides based on discrete [MnCl4]2- tetrahedrons were prepared and used as highly efficient green-light emitters. Through rational management of organic cations to tailor the MnMn separation distances between neighboring [MnCl4]2- tetrahedrons, the photoluminescence quantum yield increased significantly from 7.98% to 81.11%.

Nicotine contained in traditional cigarettes, hookahs, and e-cigarettes is an important risk factor for cardiovascular disease. Our previous study showed that macroautophagic flux impairment occurred under nicotine stimulation. However, whether nicotine influences mitochondrial dynamics in neonatal rat ventricular myocytes (NRVMs) is unclear. The purpose of this study was to explore the effects and potential mechanism of nicotine on mitophagy, mitochondrial dynamics, apoptosis, and the relationship between these processes in NRVMs. Our results showed that nicotine exposure increased mitochondria-derived superoxide production, decreased mitochondrial membrane potential, and impaired PINK1/Parkin-mediated mitophagic flux in NRVMs. Interestingly, nicotine significantly promoted dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and suppressed mitofusin (MFN)-mediated fusion, which was also observed in the bafilomycin A1-treated group. These results suggest that mitophagic flux impairment may contribute to Drp-1-mediated mitochondrial fission. Finally, nicotine caused excessive mitochondrial fission and contributed to apoptosis, which could be alleviated by mdivi-1, an inhibitor of Drp1. In addition to CTSB, as we previously reported, the enzyme activity of cathepsin L (CTSL) was also decreased in lysosomes after stimulation with nicotine, which may be the main cause of the hindered mitophagic flux induced by nicotine in NRVMs. Pretreatment with Torin 1, which is an inhibitor of mTOR, activated CTSL and ameliorated nicotine-induced mTOR activation and mitophagy impairment, decreased mitochondria-derived superoxide production, and blunted mitochondrial fission and apoptosis. Pretreatment with the ROS scavenger N-acetyl-cysteine (NAC) or inhibitors of p38 and JNK, which could also alleviate mitophagy impairment, exhibited similar effects as Torin1 on mitochondria. Taken together, our study demonstrated that nicotine treatment may lead to an increase in Drp1-mediated mitochondrial fission by blocking mitophagic flux by weakening the enzyme activity of CTSL and activating the ROS/p38/JNK signaling pathway. Excessive mitochondrial fission induced by nicotine ultimately leads to apoptosis. Torin1 restored the decreased CTSL enzyme activity by removing excessive ROS and alleviated the effects of nicotine on mitophagic flux, mitochondrial dynamics, and apoptosis. These results may provide new evidence on the relationship between mitophagic flux and mitochondrial dynamics and new perspectives on nicotine's effects on mitochondrial dynamics in cardiomyocytes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Meng, Wang, Meng, Wang, Wu, Chen, Zheng, Wang, Zhang, Li and Su.)

lsa (E) is a pleuromutilin, lincosamide, and streptogramin A (PLSA phenotype) resistance gene that was first described in S. aureus and was thought to have been transferred from Enterococcus sp. This study aimed to elucidate the prevalence of the lsa (E) gene among E. faecium isolates at a tertiary teaching hospital and to evaluate the transferability of the lsa (E) gene from E. faecium to S. aureus in vitro . A total of 96 E. faecium strains isolated from one hospital in Beijing in 2013 were analysed for quinupristin-dalfopristin (QDA) resistance genes, and multilocus sequence typing (MLST) was performed. The transferability of QDA resistance between ten E. faecium strains and four S. aureus strains was determined by filter mating. Genome sequencing of the transconjugant was performed. A total of 46 E. faecium isolates (46/96, 47.92%) tested positive for lsa (E), while two isolates (2/96, 2.08%) tested positive for lsa (A). Thirty-six lsa (E)-positive strains (36/46, 78.3%) belonged to ST78. Among 40 mating tests, lsa (E) was successfully transferred through one conjugation at a frequency of 1.125 × 10 -7 transconjugants per donor. The QDA resistance of the transconjugant N7435-R3645 was expressed at a higher level (MIC = 16 mg/L) than that of the parent S. aureus strain (MIC = 0.38 mg/L). Next-generation sequencing (NGS) analysis of the transconjugant N7435-R3645 showed that the complete sequence of the lsa (E)-carrying plasmid pN7435-R3645 had a size of 92,396 bp and a G + C content of 33% (accession no. MT022086). The genetic map of pN7435-R3645 had high nucleotide similarity and shared the main open reading frame (ORF) features with two plasmids: E. faecium pMG1 (AB206333.1) and E. faecium LS170308 (CP025078.1). The rep gene of pN7435-R3645 showed 100% identity with that of pMG1, although it did not belong to the rep 1-19 family but instead a unique rep family. Multiple antibiotic resistance genes, including lsa (E), aadE and lnu (B), erm (B), ant6 -Ia, and lnu (B), were present on the plasmid. In conclusion, an lsa (E)-carrying plasmid that can be transferred by conjugation from E. faecium to S. aureus in vitro was identified. This multidrug resistance (MDR) pMG1-like plasmid may act as a vector in the dissemination of antimicrobial resistance among species., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yan, Wang, Tao, Jia, Meng, Yang, You, Zheng, Hu, Bu and Zhang.)

Ciprofloxacin (CIP), a widely used fluoroquinolone antibiotic, is frequently detected in aqueous environments, and could be assimilated by vegetable plants to possess potential threats to human and animal health through food chains. However, plant uptake of CIP in different chemical speciation has still far from clear now. Thus, the toxicity and uptake of CIP by rice plants were investigated under different solution pH, owing to its contribution to different chemical speciation of CIP. Results display that high pH-driven changes of CIP from cation (CIP + ) to anion (CIP - ) decreased its adsorption and uptake by excised roots and intact plants, respectively. However, CIP concentrations in roots, stems and leaves all exhibited no significant differences with increasing solution pH. Moreover, six intermediates of CIP were detected and two possible transformation pathways were proposed in rice plants, including firstly oxidation and following consecutive cleavage of piperazine ring. After accumulated in plant tissues, CIP significantly inhibited the plant growth, decreased the photosynthetic pigments contents and enhanced the antioxidant enzyme activities in a concentration-dependent manner. Besides, high pH exacerbated the growth inhibition and changed the oxidative damage responses of rice plants to CIP. These findings indicate that the uptake and toxicity of CIP in rice plants were influenced by solution pH-driven changes of its chemical speciation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Cardiac fibrosis will increase wall stiffness and diastolic dysfunction, which will eventually lead to heart failure. Asenapine maleate (AM) is widely used in the treatment of schizophrenia. In the current study, we explored the potential mechanism underlying the role of AM in angiotensin II (Ang II)-induced cardiac fibrosis., Methods: Cardiac fibroblasts (CFs) were stimulated using Ang II with or without AM. Cell proliferation was measured using the cell counting kit-8 assay and the Cell-Light EdU Apollo567 In Vitro Kit. The expression levels of proliferating cell nuclear antigen (PCNA) and α-smooth muscle actin (α-SMA) were detected using immunofluorescence or western blotting. At the protein level, the expression levels of the components of the transforming growth factor beta 1 (TGFβ1)/mitogen-activated protein kinase (MAPK) signaling pathway were also detected., Results: After Ang II stimulation, TGFβ1, TGFβ1 receptor, α-SMA, fibronectin (Fn), collagen type I (Col1), and collagen type III (Col3) mRNA levels increased; the TGFβ1/MAPK signaling pathway was activated in CFs. After AM pretreatment, cell proliferation was inhibited, the numbers of PCNA -positive cells and the levels of cardiac fibrosis markers decreased. The activity of the TGFβ1/MAPK signaling pathway was also inhibited. Therefore, AM can inhibit cardiac fibrosis by blocking the Ang II-induced activation through TGFβ1/MAPK signaling pathway., Conclusions: This is the first report to demonstrate that AM can inhibit Ang II-induced cardiac fibrosis by down-regulating the TGFβ1/MAPK signaling pathway. In this process, AM inhibited the proliferation and activation of CFs and reduced the levels of cardiac fibrosis markers. Thus, AM represents a potential treatment strategy for cardiac fibrosis., Competing Interests: Declaration of competing interest The authors report no conflicts of interest in this work., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Freshwater production is one of the biggest global challenges today. Though desalination can provide a climate-independent source of clean water, the process requires a high energy consumption. Emerging advancement of photothermal nanomaterials and the urgent demand for a green technology transition have reinvigorated the established solar distillation technology. The current development of photothermal vaporization focuses on material innovation and interfacial heating, which largely emphasizes vapor generation efficiency, without considering pragmatic water collection. Moreover, salt accumulation is another critical issue of seawater solar-driven vaporization. The incorporation of photothermal materials into a photothermal membrane distillation (PMD) solar evaporator design harmoniously resolves these issues through combination of renewable energy and efficient interfacial distillation, to achieve the ultimate goal of practical saline water into freshwater conversion. At this juncture, it is imperative to review the recent opportunities and progresses of the PMD system. Here, the fundamental photothermal processes, strategies for efficient evaporator design, evaluation of various criteria for photothermal material incorporation with desired properties, discussions on desalination, water treatment, and energy generation applications are covered. Guidelines in material and system designs to further advance the PMD system that is highly promising in delivering portable water for both large-scale and decentralized systems are provided., (© 2021 Wiley-VCH GmbH.)

m 6 A RNA modification is implicated in multiple cellular responses. However, its function in the innate immune cells is poorly understood. Here, we identified major m 6 A "writers" as the top candidate genes regulating macrophage activation by LPS in an RNA binding protein focused CRISPR screening. We have confirmed that Mettl3- deficient macrophages exhibited reduced TNF-α production upon LPS stimulation in vitro. Consistently, Mettl3 flox/flox ; Lyzm- Cre mice displayed increased susceptibility to bacterial infection and showed faster tumor growth. Mechanistically, the transcripts of the Irakm gene encoding a negative regulator of TLR4 signaling were highly decorated by m 6 A modification. METTL3 deficiency led to the loss of m 6 A modification on Irakm mRNA and slowed down its degradation, resulting in a higher level of IRAKM, which ultimately suppressed TLR signaling-mediated macrophage activation. Our findings demonstrate a previously unknown role for METTL3-mediated m 6 A modification in innate immune responses and implicate the m 6 A machinery as a potential cancer immunotherapy target., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

AMP-activated protein kinase (AMPK) is an energy sensor that plays roles in multiple biological processes beyond metabolism. Several studies have suggested that AMPK is involved in the DNA damage response (DDR), but the mechanisms remain unclear. Herein, we demonstrate that AMPK promotes classic non-homologous end joining (c-NHEJ) in double-strand break (DSB) repair through recruiting a key chromatin-based mediator named p53-binding protein 1 (53BP1), which facilitates the end joining of distal DNA ends during DDR. We find that the interaction of AMPK and 53BP1 spatially occurs under DSB stress. In the context of DSBs, AMPK directly phosphorylates 53BP1 at Ser1317 and promotes 53BP1 recruitment during DDR for an efficient c-NHEJ, thus maintaining genomic stability and diversity of the immune repertoire. Taken together, our study demonstrates that AMPK is a regulator of 53BP1 and controls c-NHEJ choice by phospho-regulation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Both somatic hypermutation (SHM) and class switch recombination (CSR) are initiated by activation-induced cytidine deaminase (AID). Dysregulation of these processes has been linked to B cell lymphomagenesis. Here we performed an in-depth analysis of diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) genomes. We characterized seven genomic mutational signatures, including two B cell tumor-specific signatures, one of which is novel and associated with aberrant SHM. We further identified two major mutational signatures (K1 and K2) of clustered mutations (kataegis) resulting from the activities of AID or error-prone DNA polymerase η, respectively. K1 was associated with the immunoglobulin (Ig) switch region mutations/translocations and the ABC subtype of DLBCL, whereas K2 was related to the Ig variable region mutations and the GCB subtype of DLBCL and FL. Similar patterns were also observed in chronic lymphocytic leukemia subtypes. Thus, alterations associated with aberrant CSR and SHM activities can be linked to distinct developmental paths for different subtypes of B cell lymphomas., Competing Interests: Disclosures: The authors declare no competing interests exist., (© 2020 Ye et al.)

The adaptive immune system can diversify the antigen receptors to eliminate various pathogens through programmed DNA lesions at antigen receptor genes. In immune diversification, general DNA repair machineries are applied to transform the programmed DNA lesions into gene mutation or recombination events with common and unique features. Here we focus on antibody class switch recombination (CSR), and review the initiation of base damages, the conversion of damaged base to DNA double-strand break, and the ligation of broken ends. With an emphasis on the unique features in CSR, we discuss recent advances in the understanding of DNA repair/replication coordination, and ERCC6L2-mediated deletional recombination. We further elaborate the application of CSR in end-joining, resection and translesion synthesis assays. In the time of the COVID-19 pandemic, we hope it help to understand the generation of therapeutic antibodies., Competing Interests: Conflict of interestThe authors declare no competing financial interests., (© Shenzhen University School of Medicine; Fondazione Istituto FIRC di Oncologia Molecolare 2021.)

Telomeres at the ends of eukaryotic chromosomes are essential for genome integrality and stability. In order to identify genes that sustain telomere maintenance independently of telomerase recruitment, we have exploited the phenotype of over-long telomeres in the cells that express Cdc13-Est2 fusion protein, and examined 195 strains, in which individual non-essential gene deletion causes telomere shortening. We have identified 24 genes whose deletion results in dramatic failure of Cdc13-Est2 function, including those encoding components of telomerase, Yku, KEOPS and NMD complexes, as well as quite a few whose functions are not obvious in telomerase activity regulation. We have characterized Swc4, a shared subunit of histone acetyltransferase NuA4 and chromatin remodeling SWR1 (SWR1-C) complexes, in telomere length regulation. Deletion of SWC4, but not other non-essential subunits of either NuA4 or SWR1-C, causes significant telomere shortening. Consistently, simultaneous disassembly of NuA4 and SWR1-C does not affect telomere length. Interestingly, inactivation of Swc4 in telomerase null cells accelerates both telomere shortening and senescence rates. Swc4 associates with telomeric DNA in vivo, suggesting a direct role of Swc4 at telomeres. Taken together, our work reveals a distinct role of Swc4 in telomere length regulation, separable from its canonical roles in both NuA4 and SWR1-C., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide severe coronavirus disease 2019 (COVID-19) pandemic since December 2019. There is a great demand for effective therapies for the prevention and treatment of COVID-19. Developing therapeutic neutralizing antibodies (NAbs), which could block viral infection, is such a promising approach, as NAbs have been successfully applied to the treatment of other viral infections. The recent advances of antibody technology have greatly accelerated the discovery of SARS-CoV-2 NAbs, and many of which are now actively tested in clinical trials. Here, we review the approaches applied for SARS-CoV-2 NAb development, and discuss the emerging technologies underlining the antibody discovery. We further summarize the common features of these antibodies including the shared neutralizing epitopes and sequence features., (© The Author(s) (2020). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS.)

Since Takahashi and Yamanaka reported the generation of induced pluripotent stem cells (iPSCs) in 2006, the field of pluripotent stem cells has entered an unprecedented state of development. It plays an important role in disease modeling, drug discovery and cell therapy, and promotes the development of cell biology and regenerative medicine. At present, iPSC technology has become an important tool for studying of pathological mechanisms. New drugs screened by iPSC technology are being developed, and the number of clinical trials using iPSC-derived cells is gradually increasing. The latest research progress of iPSCs, combined with gene editing technology and 3D organoid methodology, promotes the further applications of iPSCs in disease research. In this review, we introduce the innovation of reprogramming methods in recent years, analyze the advantages and disadvantages of four reprogramming methods: integrated virus vector system, integrated non-viral vector system, non-integrated virus vector system and non-integrated non virus vector system. At the same time, we summarize the latest research progress on iPSCs in disease modeling and clinical treatment strategies, so as to provide a reference for further in-depth research in various fields of iPSCs.

Endogenous DNA double-strand breaks (DSBs) formation and repair in neural stem/progenitor cells (NSPCs) play fundamental roles in neurogenesis and neurodevelopmental disorders. NSPCs exhibit heterogeneity in terms of lineage fates and neurogenesis activity. Whether NSPCs also have heterogeneous regulations on DSB formation and repair to accommodate region-specific neurogenesis has not been explored. Here, we identified a regional regulator Filia, which is predominantly expressed in mouse hippocampal NSPCs after birth and regulates DNA DSB formation and repair. On one hand, Filia protects stalling replication forks and prevents the replication stress-associated DNA DSB formation. On the other hand, Filia facilitates the homologous recombination-mediated DNA DSB repair. Consequently, Filia -/- mice had impaired hippocampal NSPC proliferation and neurogenesis and were deficient in learning, memory, and mood regulations. Thus, our study provided the first proof of concept demonstrating the region-specific regulations of DSB formation and repair in subtypes of NSPCs., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)