Impaired immunity in patients with late-stage cancer is not limited to antitumor responses, as demonstrated by poor vaccination protection and high susceptibility to infection
. This has been largely ...attributed to chemotherapy-induced impairment of innate immunity, such as neutropenia
, whereas systemic effects of tumors on hematopoiesis and adoptive immunity remain incompletely understood. Here we observed anemia associated with severe deficiency of CD8
T cell responses against pathogens in treatment-naive mice bearing large tumors. Specifically, we identify CD45
erythroid progenitor cells (CD71
TER119
; EPCs) as robust immunosuppressors. CD45
EPCs, induced by tumor growth-associated extramedullary hematopoiesis, accumulate in the spleen to become a major population, outnumbering regulatory T cells (T
s) and myeloid-derived suppressor cells (MDSCs). The CD45
EPC transcriptome closely resembles that of MDSCs, and, like MDSCs, reactive oxygen species production is a major mechanism underlying CD45
EPC-mediated immunosuppression. Similarly, an immunosuppressive CD45
EPC population was detected in patients with cancer who have anemia. These findings identify a major population of immunosuppressive cells that likely contributes to the impaired T cell responses commonly observed in patients with advanced cancer.
Diamide resistant phenotypes have evolved in the field and the resistance has been attributed to target-site mutations in some lepidopteran pests. In this study, we documented the resistance status ...of Chilo suppressalis to chlorantraniliprole during 2016–2018 in seven provinces of China. To investigate the possible role of target-site mutations as known from lepidopterans, we sequenced respective domains of the RyR gene of C. suppressalis with different levels of diamide resistance. The results revealed that I4758M (corresponding to I4790M in P. xylostella), Y4667D/C (numbered according to C. suppressalis), G4915E (corresponding to G4946E in P. xylostella), and one novel Y4891F (numbered according to C. suppressalis) RyR target-site mutations were present. The contribution of these mutations was further investigated by diamide toxicity bioassays with eight genome modified Drosophila melanogaster lines. The study showed that genome modified flies bearing the Y4667D mutation (corresponding to the Y4667D and I4758M simultaneous mutation in C. suppressalis) exhibited high resistance ratios to chlorantraniliprole (1542.8-fold), cyantraniliprole (487.9-fold) and tetrachlorantraniliprole (290.1-fold). The M4758I and G4915E simultaneous mutations (corresponding to single G4915E mutation in C. suppressalis) showed high resistance ratios to chlorantraniliprole (153.1-fold) and cyantraniliprole (323.5-fold), and relatively low resistance to flubendiamide (28.9-fold) and tetrachlorantraniliprole (25.2-fold). These findings suggest that multiple point mutations in RyR confer diamide resistance of C. suppressalis. The results contribute to a better understanding of insect diamide resistance mechanisms and provide insights on the impact of RyR target-site mutations in insects.
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•Most of C. suppressalis field populations had developed high level of resistance to chlorantraniliprole.•Five mutations, I4758M, Y4667D, Y4667C, G4915E, and Y4891F are present in C. suppressalis populations.•Y4667D mutation confers very high resistance to chlorantraniliprole in Drosophila.•Double mutation, M4758I and G4915E, confers high chlorantraniliprole resistance in Drosophila.
Visualizing the location and dynamics of RNAs in live cells is key to understanding their function. Here, we identify two endonuclease-deficient, single-component programmable RNA-guided and ...RNA-targeting Cas13 RNases (dCas13s) that allow robust real-time imaging and tracking of RNAs in live cells, even when using single 20- to 27-nt-long guide RNAs. Compared to the aptamer-based MS2-MCP strategy, an optimized dCas13 system is user friendly, does not require genetic manipulation, and achieves comparable RNA-labeling efficiency. We demonstrate that the dCas13 system is capable of labeling NEAT1, SatIII, MUC4, and GCN4 RNAs and allows the study of paraspeckle-associated NEAT1 dynamics. Applying orthogonal dCas13 proteins or combining dCas13 and MS2-MCP allows dual-color imaging of RNAs in single cells. Further combination of dCas13 and dCas9 systems allows simultaneous visualization of genomic DNA and RNA transcripts in living cells.
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•Identification of CRISPR-dPspCas13b and -dPguCas13b for RNA imaging•Robust tracking of NEAT1 with dPspCas13b and single gRNAs in living cells•Tracking of NEAT1 reveals “kiss-and-run” and “fusion” models of paraspeckle dynamics•Simultaneous RNA-RNA/DNA labeling by orthogonal dCas13s or combined with dCas9
Yang et al. show that the dCas13 system is capable of labeling RNAs. Applying orthogonal dCas13s or combining with dCas9 allows simultaneous visualization of RNA-RNA and DNA-RNA in living cells. The dCas13 system is user friendly in real-time RNA imaging without requiring genetic manipulation.
Recently, non-fullerene-based organic solar cells (OSCs) have made great breakthroughs, and small structural differences can have dramatic impacts on the power conversion efficiency (PCE). We take ...ITIC and its isomers as examples to study their effects on the performance of OSCs. ITIC and NFBDT only differed in the side chain position, and they were used as models with the same donor molecule, PBDB-T, to investigate the main reasons for the difference in their performance in terms of theoretical methods. In this work, a detailed comparative analysis of the electronic structure, absorption spectra, open circuit voltage and interfacial parameters of the ITIC and NFBDT systems was performed mainly by combining the density functional theory/time-dependent density functional theory and molecular dynamics simulations. The results showed that the lowest excited state of the ITIC molecule possessed a larger ∆q and more hybrid FE/CT states, and PBDB-T/ITIC had more charge separation paths as well as a larger kCS and smaller kCR. The reason for the performance difference between PBDB-T/ITIC and PBDB-T/NFBDT was elucidated, suggesting that ITIC is a superior acceptor based on a slight modulation of the side chain and providing a guiding direction for the design of superior-performing small molecule acceptor materials.
Au nanoparticles (Au NPs) can be self-assembled in a bottom-up orderly manner at the oil–water interface, which is widely used as SERS platforms, but the stability of the Au NP interface needs to be ...improved due to shaking or shifting and the Brownian motion. The DNA structure with unique sequence specificity, excellent programmability, and flexible end-group modification capability owns good potential to precisely control the plasmonic structure’s distance. In this study, a large area of the SERS substrate is obtained from the DNA structure-stabilized self-assembled ordered Au NPs on the cyclohexane–water interface. Combining with the exonuclease III (exo III)-assisted DNA recycling amplification strategy, we construct a liquid-phase SERS biosensor for efficient detection of microRNA 155 (miRNA 155). Compared with the traditional randomly assembled Au NPs on the two-phase interface, the SERS signal is significantly enhanced and more stable. The detection limit of the SERS biosensor for miRNA 155 reached 1.45 fmol/L, which has a very wide linear range (100 fmol/L–5 nmol/L). This work gives an efficient approach to stabilize the self-assembly Au NPs on the liquid–liquid interface, which can broaden the application of SERS analysis.
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) variants continue to emerge and cocirculate in humans and wild animals. The factors driving the emergence and replacement of novel ...variants and recombinants remain incompletely understood. Herein, we comprehensively characterized the competitive fitness of SARS‐CoV‐2 wild type (WT) and three variants of concern (VOCs), Alpha, Beta and Delta, by coinfection and serial passaging assays in different susceptible cells. Deep sequencing analyses revealed cell‐specific competitive fitness: the Beta variant showed enhanced replication fitness during serial passage in Caco‐2 cells, whereas the WT and Alpha variant showed elevated fitness in Vero E6 cells. Interestingly, a high level of neutralizing antibody sped up competition and completely reshaped the fitness advantages of different variants. More importantly, single clone purification identified a significant proportion of homologous recombinants that emerged during the passage history, and immune pressure reduced the frequency of recombination. Interestingly, a recombination hot region located between nucleotide sites 22,995 and 28,866 of the viral genomes could be identified in most of the detected recombinants. Our study not only profiled the variable competitive fitness of SARS‐CoV‐2 under different conditions, but also provided direct experimental evidence of homologous recombination between SARS‐CoV‐2 viruses, as well as a model for investigating SARS‐CoV‐2 recombination.
Drug exposure impairs cortical plasticity and motor learning, which underlies the reduced behavioral flexibility in drug addiction. Physical exercise has been used to prevent relapse in drug ...rehabilitation program. However, the potential benefits and molecular mechanisms of physical exercise on drug-evoked motor-cortical dysfunctions are unknown. Here we report that 1-week treadmill training restores cocaine-induced synaptic deficits, in the form of improved in vivo spine formation, synaptic transmission, and spontaneous activities of cortical pyramidal neurons, as well as motor-learning ability. The synaptic and behavioral benefits relied on de novo protein synthesis, which are directed by the activation of the mechanistic target of rapamycin (mTOR)-ribosomal protein S6 pathway. These findings establish synaptic functional restoration and mTOR signaling as the critical mechanism supporting physical exercise training in rehabilitating the addicted brain.
Plenty of evidence has suggested that long noncoding RNAs (lncRNAs) play a vital role in competing endogenous RNA (ceRNA) networks. Poorly differentiated hepatocellular carcinoma (PDHCC) is a ...malignant phenotype. This paper aimed to explore the effect and the underlying regulatory mechanism of lncRNAs on PDHCC as a kind of ceRNA. Additionally, prognosis prediction was assessed. A total of 943 messenger RNAs (mRNAs), 86 miRNAs, and 468 lncRNAs that were differentially expressed between 137 PDHCCs and 235 well‐differentiated HCCs were identified. Thereafter, a ceRNA network related to the dysregulated lncRNAs was established according to bioinformatic analysis and included 29 lncRNAs, 9 miRNAs, and 96 mRNAs. RNA‐related overall survival (OS) curves were determined using the Kaplan‐Meier method. The lncRNA ARHGEF7‐AS2 was markedly correlated with OS in HCC (P = .041). Moreover, Cox regression analysis revealed that patients with low ARHGEF7‐AS2 expression were associated with notably shorter survival time (P = .038). In addition, the area under the curve values of the lncRNA signature for 1‐, 3‐, and 5‐year survival were 0.806, 0.741, and 0.701, respectively. Furthermore, a lncRNA nomogram was established, and the C‐index of the internal validation was 0.717. In vitro experiments were performed to demonstrate that silencing ARHGEF7‐AS2 expression significantly promoted HCC cell proliferation and migration. Taken together, our findings shed more light on the ceRNA network related to lncRNAs in PDHCC, and ARHGEF7‐AS2 may be used as an independent biomarker to predict the prognosis of HCC.
long noncoding RNAs (lncRNAs), interacting with microRNA to regulate target gene expression, have played a vital part in the networks of competing endogenous RNA (ceRNA). We firstly constructed a ceRNA network related to lncRNA in poorly differentiated hepatocellular carcinoma (HCC). We hope this study would shed more light on future tumor initiation as well as progression research in HCC.
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