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microRNAs (miRNAs) are small noncoding RNAs that play important regulatory roles in plants, animals and viruses. Measuring miRNA activity in vivo remains a big challenge. Here, using an miRNA-mediated single guide RNA (sgRNA)-releasing strategy and dCas9–VPR to drive a transgene red fluorescent protein, we create an miRNA sensor that can faithfully measure miRNA activity at cellular levels and use it to monitor differentiation status of stem cells. Furthermore, by designing sgRNAs to target endogenous loci, we adapted this system to control the expression of endogenous genes or mutate specific DNA bases upon induction by cell-type-specific miRNAs. Finally, by miRNA sensor library screening, we discover a previously undefined layer of heterogeneity associated with miR-21a activity in mouse embryonic stem cells. Together, these results highlight the utility of an miRNA-induced CRISPR–Cas9 system as miRNA sensors and cell-type-specific genome regulation tools. Wang et al. developed an inducible CRISPR–Cas9 system, in which guide RNA release is controlled by specific microRNAs, and demonstrated its application as a microRNA sensor and cell-type-specific genome regulator.

This study aimed to determine the levels of health-related behaviours (physical activity, screen exposure and sleep status) among Chinese students from primary, secondary and high schools during the pandemic of COVID-19, as well as their changes compared with their status before the pandemic. A cross-sectional online survey of 10,933 students was conducted among 10 schools in Guangzhou, China, between 8th and 15th March, 2020. After getting the informed consent from student’s caregivers, an online questionnaire was designed and used to obtain time spending on health-related behaviours during the pandemic of COVID-19, as well as the changes compared with 3 months before the pandemic, which was completed by students themselves or their caregivers. Students were stratified by regions (urban, suburban, exurban), gender (boys and girls), and grades (lower grades of primary school, higher grades of primary schools, secondary schools and high schools). Data were expressed as number and percentages and Chi-square test was used to analyse difference between groups. Overall, the response rate of questionnaire was 95.3% (10,416/10,933). The median age of included students was 13.0 (10.0, 16.0) years and 50.1% (n = 5,219) were boys. 41.4%, 53.6% and 53.7% of total students reported less than 15 min per day in light, moderate and vigorous activities and 58.7% (n = 6,113) reported decreased participation in physical activity compared with the time before pandemic. Over 5 h of screen time spending on online study was reported by 44.6% (n = 4,649) of respondents, particular among high school students (81.0%). 76.9% of students reported increased screen time compared with the time before pandemic. Inadequate sleep was identified among 38.5% of students and the proportion was highest in high school students (56.9%). Our study indicated that, during the COVID-19 pandemic, the school closure exerted tremendous negative effects on school-aged children’s health habits, including less physical activity, longer screen exposure and irregular sleeping pattern.

The production of double P -wave heavy quarkonia is studied systematically within the framework of non-relativistic quantum chromodynamics at the exclusive process of the electron–positron collision annihilation at the CM energy s = 91.1876 GeV of the Z 0 pole, i.e., double P -wave charmonia, double P -wave B c mesons, and double P -wave bottomonia in e + e - → γ ∗ / Z 0 → | ( Q Q ′ ¯ ) [ n ] ⟩ + | ( Q ′ Q ¯ ) [ n ′ ] ⟩ ( Q / Q ′ = c - or b -quarks) at a future super Z factory, where [ n ] or [ n ′ ] stands for the color-singlet [ 1 P 1 ] and [ 3 P J ] ( J = 0 , 1 , 2 ) Fock states. As an improved trace technology is useful for calculating the complicated double P -wave channels, the analytical result can be obtained at the amplitude level. According to our study, the generation rates for the double P -wave heavy quarkonia at the future super Z factory are considerable. The values obtained for the total cross sections of the double P -wave charmonium for σ ( | ( c c ¯ ) [ 1 ] ⟩ + | ( c c ¯ ) [ 1 ] ⟩ ) = 4 . 191 - 0.498 + 0.489 × 10 - 3 f b , the total cross sections of the double P -wave B c mesons for σ ( | ( c b ¯ ) [ 1 ] ⟩ + | ( b c ¯ ) [ 1 ] ⟩ ) = 0 . 2045 - 0.0080 + 0.0084 f b , and the total cross sections of the double P -wave bottomonium for σ ( | ( b b ¯ ) [ 1 ] ⟩ + | ( b b ¯ ) [ 1 ] ⟩ ) = 5 . 244 - 0.136 + 0.134 × 10 - 3 f b . The main uncertainties come from the mass of heavy quarkonia and the corresponding first-derivative radial wave functions at the origin under the Buchmüller–Tye (BT) potential. The number of events in the production of double P -wave charmonium, B c -meson, and bottomonium states via e - e + → γ ∗ / Z 0 → | ( Q Q ¯ ′ ) [ n ] ⟩ + | ( Q ′ Q ¯ ) [ n ′ ] ⟩ at the integrated luminosity L ≈ 10 34 c m - 2 s - 1 at the super Z factory is almost unobservable.

Long noncoding RNAs (lncRNAs) have emerged as important components of gene regulatory network in embryonic stem cells (ESCs). However, the function and molecular mechanism of lncRNAs are still largely unknown. Here we identifies Trincr1 ( TR IM71 i nteracting long n on c oding R NA 1 ) lncRNA that regulates the FGF/ERK signaling and self-renewal of ESCs. Trincr1 is exported by THOC complex to cytoplasm where it binds and represses TRIM71, leading to the downregulation of SHCBP1 protein. Knocking out Trincr1 leads to the upregulation of phosphorylated ERK and ERK pathway target genes and the decrease of ESC self-renewal, while knocking down Trim71 completely rescues the defects of Trincr1 knockout. Furthermore, ectopic expression of Trincr1 represses FGF/ERK signaling and the self-renewal of neural progenitor cells (NPCs). Together, this study highlights lncRNA as an important player in cell signaling network to coordinate cell fate specification. FGF signaling through ERK is known to promote the differentiation of embryonic stem cells (ES cells). Here, the authors demonstrate that the lncRNA Trincr1 binds and represses TRIM71 in ES cells, leading to downregulation of SHCBP1 protein, the reduction of FGF/ERK signaling and the promotion of self-renewal.

Some long noncoding RNAs (lncRNAs) play important roles in the regulation of gene expression by acting as competing endogenous RNAs (ceRNAs). However, the roles of lncRNA associated-ceRNAs in oncogenesis are not fully understood. Here, based on lncRNA microarray data of gastric cancer, bioinformatic algorithm miRcode and microRNA (miRNA) targets database TarBase, we first constructed an lncRNA-miRNA-mRNA network. Then, we confirmed it by data of six types of other cancer including head and neck squamous cell carcinoma, prostate cancer, papillary thyroid carcinoma, pituitary gonadotrope tumors, ovarian cancer and chronic lymphocytic leukemia. The results showed a clear cancer-associated ceRNA network. Eight lncRNAs (AC009499.1, GACAT1, GACAT3, H19, LINC00152, AP000288.2, FER1L4 and RP4-620F22.3) and nine miRNAs (miR-18a-5p, miR-18b-5p, miR-19a-3p, miR-20b-5p, miR-106a-5p, miR-106b-5p, miR-31-5p, miR-139-5p and miR-195-5p) were involved. For instance, through its miRNA response elements (MREs) to compete for miR-106a-5p, lncRNA-FER1L4 regulates the expression of PTEN, RB1, RUNX1, VEGFA, CDKN1A, E2F1, HIPK3, IL-10 and PAK7. Furthermore, cellular experimental results indicated that FER1L4-small interfering RNA (siRNA) simultaneously suppressed FER1L4 and RB1 mRNA level. These results suggest that lncRNAs harbor MREs and play important roles in post-transcriptional regulation in cancer.

Efficient clearance of dying cells (efferocytosis) is an evolutionarily conserved process for tissue homeostasis. Genetic enhancement of efferocytosis exhibits therapeutic potential for inflammation resolution and tissue repair. However, pharmacological approaches to enhance efferocytosis remain sparse due to a lack of targets for modulation. Here, we report the identification of columbamine (COL) which enhances macrophage‐mediated efferocytosis and attenuates intestinal inflammation in a murine colitis model. COL enhances efferocytosis by promoting LC3‐associated phagocytosis (LAP), a non‐canonical form of autophagy. Transcriptome analysis and pharmacological characterization revealed that COL is a biased agonist that occupies a part of the ligand binding pocket of formyl peptide receptor 2 (FPR2), a G‐protein coupled receptor involved in inflammation regulation. Genetic ablation of the Fpr2 gene or treatment with an FPR2 antagonist abolishes COL‐induced efferocytosis, anti‐colitis activity and LAP. Taken together, our study identifies FPR2 as a potential target for modulating LC3‐associated efferocytosis to alleviate intestinal inflammation and highlights the therapeutic value of COL, a natural and biased agonist of FPR2, in the treatment of inflammatory bowel disease. Synopsis Enhancement of efferocytosis has been regarded as an emerging strategy for inflammatory diseases, while pharmacological approaches to modulate efferocytosis are poorly defined. Our study identified a natural compound, columbamine (COL), that can activate LC3‐associated efferocytosis and attenuate DSS‐induced colitis by biasedly targeting FPR2 on macrophages. This study provides a novel therapeutic strategy for inflammatory diseases, including colitis, via enhancing FPR2‐mediated efferocytosis. COL has been identified as a novel efferocytosis enhancer that ameliorates mouse colitis. COL binds to and biasedly activates FPR2, leading to enhanced efferocytosis in macrophages. FPR2 emerges as a promising therapeutic target for the treatment of inflammatory diseases through modulating LC3‐associated efferocytosis in macrophages. Graphical Abstract Enhancement of efferocytosis has been regarded as an emerging strategy for inflammatory diseases, while pharmacological approaches to modulate efferocytosis are poorly defined. Our study identified a natural compound, columbamine (COL), that can activate LC3‐associated efferocytosis and attenuate DSS‐induced colitis by biasedly targeting FPR2 on macrophages. This study provides a novel therapeutic strategy for inflammatory diseases, including colitis, via enhancing FPR2‐mediated efferocytosis.

Long non-coding RNAs are identified using a high-throughput paired-guide RNA genomic deletion screen. CRISPR–Cas9 screens have been widely adopted to analyze coding-gene functions, but high-throughput screening of non-coding elements using this method is more challenging because indels caused by a single cut in non-coding regions are unlikely to produce a functional knockout. A high-throughput method to produce deletions of non-coding DNA is needed. We report a high-throughput genomic deletion strategy to screen for functional long non-coding RNAs (lncRNAs) that is based on a lentiviral paired-guide RNA (pgRNA) library. Applying our screening method, we identified 51 lncRNAs that can positively or negatively regulate human cancer cell growth. We validated 9 of 51 lncRNA hits using CRISPR–Cas9-mediated genomic deletion, functional rescue, CRISPR activation or inhibition and gene-expression profiling. Our high-throughput pgRNA genome deletion method will enable rapid identification of functional mammalian non-coding elements.

The current severe situation of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has not been reversed and posed great threats to global health. Therefore, there is an urgent need to find out effective antiviral drugs. The 3-chymotrypsin-like protease (3CLpro) in SARS-CoV-2 serve as a promising anti-virus target due to its essential role in the regulation of virus reproduction. Here, we report an improved integrated approach to identify effective 3CLpro inhibitors from effective Chinese herbal formulas. With this approach, we identified the 5 natural products (NPs) including narcissoside, kaempferol-3-O-gentiobioside, rutin, vicenin-2 and isoschaftoside as potential anti-SARS-CoV-2 candidates. Subsequent molecular dynamics simulation additionally revealed that these molecules can be tightly bound to 3CLpro and confirmed effectiveness against COVID-19. Moreover, kaempferol-3-o-gentiobioside, vicenin-2 and isoschaftoside were first reported to have SARS-CoV-2 3CLpro inhibitory activity. In summary, this optimized integrated strategy for drug screening can be utilized in the discovery of antiviral drugs to achieve rapid acquisition of drugs with specific effects on antiviral targets.

Sorafenib is one a first‐line therapeutic drugs for advanced hepatocellular carcinoma (HCC). However, only 30% of patients benefit from sorafenib due to drug resistance. We and other groups have revealed that nuclear factor I B (NFIB) regulates liver regeneration and carcinogenesis, but its role in drug resistance is poorly known. We found that NFIB was more upregulated in sorafenib‐resistant SMMC‐7721 cells compared to parental cells. NFIB knockdown not only sensitized drug‐resistant cells to sorafenib but also inhibited the proliferation and invasion of these cells. Meanwhile, NFIB promoted the proliferation and invasion of HCC cells in vitro and facilitated tumor growth and metastasis in vivo. Knocking down NFIB synergetically inhibited tumor growth with sorafenib. Mechanically, gene expression profiling and subsequent verification experiments proved that NFIB could bind with the promoter region of a complex I inhibitor NDUFA4L2 and promote its transcription. Transcriptional upregulation of NDUFA4L2 by NFIB could thus inhibit the sorafenib‐induced reactive oxygen species accumulation. Finally, we found that NFIB was highly expressed in HCC tissues, and high NFIB expression level was associated with macrovascular invasion, advanced tumor stage, and poor prognosis of HCC patients (n = 156). In summary, we demonstrated that NFIB could transcriptionally upregulate NDUFA4L2 to enhance both intrinsic and acquired sorafenib resistance of HCC cells by reducing reactive oxygen species induction. NFIB could directly promote transcription of NDUFA4L2 to reduce sorafenib‐induced ROS accumulation. High NFIB expression was associated with poor prognosis of HCC patients.

DNA double-strand breaks （DSBs） are highly cytotoxic lesions and pose a major threat to genome stability if not properly repaired. We and others have previously shown that a class of DSB-induced small RNAs （diRNAs） is produced from sequences around DSB sites. DiRNAs are associated with Argonaute （Ago） proteins and play an im- portant role in DSB repair, though the mechanism through which they act remains unclear. Here, we report that the role of diRNAs in DSB repair is restricted to repair by homologous recombination （HR） and that it specifically relies on the effector protein Ago2 in mammalian cells. Interestingly, we show that Ago2 forms a complex with RadS1 and that the interaction is enhanced in cells treated with ionizing radiation. We demonstrate that RadS1 accumulation at DSB sites and HR repair depend on catalytic activity and small RNA-binding capability of Ago2. In contrast, DSB resection as well as RPA and Mrell loading is unaffected by Ago2 or Dicer depletion, suggesting that Ago2 very likely functions directly in mediating RadS1 accumulation at DSBs. Taken together, our findings suggest that guided by diRNAs, Ago2 can promote RadS1 recruitment and/or retention at DSBs to facilitate repair by HR.