Aqueous rechargeable zinc‐ion batteries (ZIBs) have attracted considerable attention as a promising candidate for low‐cost and high‐safety electrochemical energy storage. However, the advancement of ...ZIBs is strongly hindered by the sluggish ionic diffusion and structural instability of inorganic metal oxide cathode materials during the Zn2+ insertion/extraction. To address these issues, a new organic host material, poly(2,5‐dihydroxy‐1,4‐benzoquinonyl sulfide) (PDBS), has been designed and applied for zinc ion storage due to its elastic structural factors (tunable space and soft lattice). The aqueous Zn‐organic batteries based on the PDBS cathode show outstanding cycling stability and rate capability. The coordination moieties (O and S) display the strong electron donor character during the discharging process and can act as the coordination arms to host Zn2+. Also, under the electrochemical environment, the malleable polymer structure of PDBS permits the rotation and bending of polymer chains to facilitate the insertion/extraction of Zn2+, manifesting the superiority and uniqueness of organic electrode materials in the polyvalent cation storage. Finally, quasi‐solid‐state batteries based on aqueous gel electrolyte demonstrate highly stable capacity under different bending conditions.
A new organic polymer has been identified as a cathode material for efficient zinc ion storage due to its elastic structural factors. The coordination moieties (O and S) display strong electron donor character during the charging process and can act as the coordination arms to synergistically host Zn2+, manifesting the superiority and uniqueness of organic electrode materials in the multi‐valence cation storage.
Topoisomerases introduce transient DNA breaks to relax supercoiled DNA, remove catenanes and enable chromosome segregation. Human cells encode six topoisomerases (TOP1, TOP1mt, TOP2α, TOP2β, TOP3α ...and TOP3β), which act on a broad range of DNA and RNA substrates at the nuclear and mitochondrial genomes. Their catalytic intermediates, the topoisomerase cleavage complexes (TOPcc), are therapeutic targets of various anticancer drugs. TOPcc can also form on damaged DNA during replication and transcription, and engage specific repair pathways, such as those mediated by tyrosyl-DNA phosphodiesterase 1 (TDP1) and TDP2 and by endonucleases (MRE11, XPF-ERCC1 and MUS81). Here, we review the roles of topoisomerases in mediating chromatin dynamics, transcription, replication, DNA damage repair and genomic stability, and discuss how deregulation of topoisomerases can cause neurodegenerative diseases, immune disorders and cancer.
Small-molecule inhibitors of PARP are thought to mediate their antitumor effects as catalytic inhibitors that block repair of DNA single-strand breaks (SSB). However, the mechanism of action of PARP ...inhibitors with regard to their effects in cancer cells is not fully understood. In this study, we show that PARP inhibitors trap the PARP1 and PARP2 enzymes at damaged DNA. Trapped PARP-DNA complexes were more cytotoxic than unrepaired SSBs caused by PARP inactivation, arguing that PARP inhibitors act in part as poisons that trap PARP enzyme on DNA. Moreover, the potency in trapping PARP differed markedly among inhibitors with niraparib (MK-4827) > olaparib (AZD-2281) >> veliparib (ABT-888), a pattern not correlated with the catalytic inhibitory properties for each drug. We also analyzed repair pathways for PARP-DNA complexes using 30 genetically altered avian DT40 cell lines with preestablished deletions in specific DNA repair genes. This analysis revealed that, in addition to homologous recombination, postreplication repair, the Fanconi anemia pathway, polymerase β, and FEN1 are critical for repairing trapped PARP-DNA complexes. In summary, our study provides a new mechanistic foundation for the rational application of PARP inhibitors in cancer therapy.
: Increasing evidence demonstrates that melatonin has an anti‐inflammatory effect. Nevertheless, the molecular mechanisms remain obscure. In this study, we investigated the effect of melatonin on ...toll‐like receptor 4 (TLR4)‐mediated molecule myeloid differentiation factor 88 (MyD88)‐dependent and TRIF‐dependent signaling pathways in lipopolysaccharide (LPS)‐stimulated macrophages. RAW264.7 cells were incubated with LPS (2.0 μg/mL) in the absence or presence of melatonin (10, 100, 1000 μm). As expected, melatonin inhibited TLR4‐mediated tumor necrosis factor alpha (TNF‐α), interleukin (IL)‐1β, IL‐6, IL‐8, and IL‐10 in LPS‐stimulated macrophages. In addition, melatonin significantly attenuated LPS‐induced upregulation of cyclooxygenase (COX)‐2 and inducible nitric oxide synthase (iNOS) in macrophages. Further analysis showed that melatonin inhibited the expression of MyD88 in LPS‐stimulated macrophages. Although it had no effect on TLR4‐mediated phosphorylation of c‐Jun N‐terminal kinase (JNK), p38, and extracellular regulated protein kinase (ERK), melatonin significantly attenuated the activation of nuclear factor kappa B (NF‐κB) in LPS‐stimulated macrophages. In addition, melatonin inhibited TLR4‐mediated Akt phosphorylation in LPS‐stimulated macrophages. Moreover, melatonin significantly attenuated the elevation of interferon (IFN)‐regulated factor‐3 (IRF3), which was involved in TLR4‐mediated TRIF‐dependent signaling pathway, in LPS‐stimulated macrophages. Correspondingly, melatonin significantly alleviated LPS‐induced IFN‐β in macrophages. In conclusion, melatonin modulates TLR4‐mediated inflammatory genes through MyD88‐dependent and TRIF‐dependent signaling pathways.
Topoisomerase II (TOP2) relieves torsional stress by forming transient cleavage complex intermediates (TOP2ccs) that contain TOP2-linked DNA breaks (DSBs). While TOP2ccs are normally reversible, they ...can be “trapped” by chemotherapeutic drugs such as etoposide and subsequently converted into irreversible TOP2-linked DSBs. Here, we have quantified etoposide-induced trapping of TOP2ccs, their conversion into irreversible TOP2-linked DSBs, and their processing during DNA repair genome-wide, as a function of time. We find that while TOP2 chromatin localization and trapping is independent of transcription, it requires pre-existing binding of cohesin to DNA. In contrast, the conversion of trapped TOP2ccs to irreversible DSBs during DNA repair is accelerated 2-fold at transcribed loci relative to non-transcribed loci. This conversion is dependent on proteasomal degradation and TDP2 phosphodiesterase activity. Quantitative modeling shows that only two features of pre-existing chromatin structure—namely, cohesin binding and transcriptional activity—can be used to predict the kinetics of TOP2-induced DSBs.
Display omitted
•TOP2 binding and cleavage complex (TOP2cc) formation is dependent on cohesin•Transcription facilitates the processing of TOP2cc to DSBs that drives translocation•TOP2cc processing is rapid, while commitment to processing is rate-limiting•Cohesin and transcription levels predict TOP2-mediated breakage and translocation
TOP2 induces DNA breaks to relieve DNA torsional stress. When not resolved, these DNA lesions can turn into long-lived breaks that can give rise to oncogenic chromosomal translocations. Canela et al. determine that cohesin is required for TOP2 localization and activity, whereas transcription increases genome instability.
We developed a cost‐effective cobalt‐catalyzed electrochemical annulation to generate diversified novel complex dihydroisoquinolin derivatives from amides and alkenes in a simple and maneuverable ...undivided cell. The reaction proceeded C−H/N−H activation, and the catalyst was regenerated by anodic oxidation. Notably, the strategy of electrocatalysis avoided the consumption of stoichiometric chemical oxidants.
•The appropriate features of news are analyzed for training models.•The ensemble learning model for fake news detection is proposed in the paper.•The weights of the ensemble learning model are ...optimized in the paper.•The cross-domain intractability issue is investigated in the paper.
In general, the features of fake news are almost the same as those of real news, so it is not easy to identify them. In this paper, we propose a fake news detection system using a deep learning model. First, news articles are preprocessed and analyzed based on different training models. Then, an ensemble learning model combining four different models called embedding LSTM, depth LSTM, LIWC CNN, and N-gram CNN is proposed for fake news detection. Besides, to achieve higher accuracy in fake news detection, the optimized weights of the ensemble learning model are determined using the Self-Adaptive Harmony Search (SAHS) algorithm. In the experiments, we verify that the proposed model is superior to the state-of-the-art methods, with the highest accuracy of 99.4%. Furthermore, we also investigate the cross-domain intractability issue and achieve the highest accuracy of 72.3%. Finally, we believe there is still room for improving the ensemble learning model in addressing the cross-domain intractability issue.
Cyberbullying, as a serious kind of repeated, intentional, and harmful aggressive behavior, cannot be ignored. In light of the limited studies and inconsistent findings on the matter, this study ...explores cyberbullying’s frequency and other factors (gender, academic achievement, types of technologies used, and anonymity) relevant to both the issue itself and the East Asian context. The interrelationship of different roles (bullies, victims, and bystanders) in cyberbullying is also examined. A survey was conducted with 545 Taiwan junior high school students. The results indicate that male students were more likely to bully others in cyberspace and that cyberbullying was not affected by one’s level of academic achievement. Regarding the various technologies and various country-specific cyberbullying forms pertinent to technology users, instant messenger (IM) users experienced significantly more cyberbullying than users of other technologies. The survey results also indicate that the anonymity of cyberbullying was not a pertinent factor. The study found that the dominant attitude toward cyberbullying was indifference, raising alarms about the lack of cyberbullying prevention. Peers, who were the people most teenagers would likely turn to when experiencing cyberbullying, usually took no action because of their tendency to avoid conflicts and to maintain group harmony. In its interpretation of the findings, this study emphasizes Taiwan’s context, including Confucian philosophy.
Anti-PARP drugs were initially developed as catalytic inhibitors to block the repair of DNA single-strand breaks. We recently reported that several PARP inhibitors have an additional cytotoxic ...mechanism by trapping PARP-DNA complexes, and that both olaparib and niraparib act as PARP poisons at pharmacologic concentrations. Therefore, we have proposed that PARP inhibitors should be evaluated based both on catalytic PARP inhibition and PARP-DNA trapping. Here, we evaluated the novel PARP inhibitor, BMN 673, and compared its effects on PARP1 and PARP2 with two other clinical PARP inhibitors, olaparib and rucaparib, using biochemical and cellular assays in genetically modified chicken DT40 and human cancer cell lines. Although BMN 673, olaparib, and rucaparib are comparable at inhibiting PARP catalytic activity, BMN 673 is ∼100-fold more potent at trapping PARP-DNA complexes and more cytotoxic as single agent than olaparib, whereas olaparib and rucaparib show similar potencies in trapping PARP-DNA complexes. The high level of resistance of PARP1/2 knockout cells to BMN 673 demonstrates the selectivity of BMN 673 for PARP1/2. Moreover, we show that BMN 673 acts by stereospecific binding to PARP1 as its enantiomer, LT674, is several orders of magnitude less efficient. BMN 673 is also approximately 100-fold more cytotoxic than olaparib and rucaparib in combination with the DNA alkylating agents methyl methane sulfonate (MMS) and temozolomide. Our study demonstrates that BMN 673 is the most potent clinical PARP inhibitor tested to date with the highest efficiency at trapping PARP-DNA complexes.
PDF
