Quasi-Free Electron States Responsible for Single-Molecule Conductance Enhancement in Stable Radical

Stable organic radicals, which possess half-filled orbitals in the vicinity of the Fermi energy, are promising candidates for electronic devices. In this Letter, using a combination of scanning-tunneling-microscopy-based break junction (STM-BJ) experiments and quantum transport theory, a stable fluorene-based radical is investigated. We demonstrate that the transport properties of a series of fluorene derivatives can be tuned by controlling the degree of localization of certain orbitals. More specifically, radical has a delocalized half-filled orbital resulting in Breit-Wigner resonances, leading to an unprecedented conductance enhancement of 2 orders of magnitude larger than the neutral nonradical counterpart ( ). In other words, conversion from a closed-shell fluorene derivative to the free radical in opens an electron transport path which massively enhances the conductance. This new understanding of the role of radicals in single-molecule junctions opens up a novel design strategy for single-molecule-based spintronic devices

Enhanced RNA knockdown efficiency with engineered fusion guide RNAs that function with both CRISPR-CasRx and hammerhead ribozyme

Abstract Background CRISPR-Cas13 is a newly emerging RNA knockdown technology that is comparable to RNAi. Among all members of Cas13, CasRx degrades RNA in human cells with high precision and effectiveness. However, it remains unclear whether the efficiency of this technology can be further improved and applied to gene therapy. Results In this study, we fuse CasRx crRNA with an antisense ribozyme to construct a synthetic fusion guide RNA that can interact with both CasRx protein and ribozyme and tested the ability of this approach in RNA knockdown and cancer gene therapy. We show that the CasRx-crRNA-ribozyme system (CCRS) is more efficient for RNA knockdown of mRNAs and non-coding RNAs than conventional methods, including CasRx, shRNA, and ribozyme. In particular, CCRS is more effective than wild-type CasRx when targeting multiple transcripts simultaneously. We next use bladder cancer as a model to evaluate the anticancer effects of CCRS targeting multiple genes in vitro and in vivo. CCRS shows a higher anticancer effect than conventional methods, consistent with the gene knockdown results. Conclusions Thus, our study demonstrates that CCRS expands the design ideas and RNA knockdown capabilities of Cas13 technology and has the potential to be used in disease treatment

Long non-coding RNA DANCR promotes malignant phenotypes of bladder cancer cells by modulating the miR-149/MSI2 axis as a ceRNA

Abstract Background Accumulating evidences have indicated that long non-coding RNAs (lncRNAs) are potential biomarkers that play key roles in tumor development and progression. Differentiation antagonizing non-protein noding RNA (DANCR) is a novel lncRNA that acts as a potential biomarker and is involved in the development of cancers. However, the clinical significance and molecular mechanism of DANCR in bladder cancer is still unknown. Methods The relative expression level of DANCR was determined by Real-Time qPCR in a total of 106 patients with urothelial bladder cancer and in different bladder cancer cell lines. Loss-of-function experiments were performed to investigate the biological roles of DANCR on bladder cancer cell proliferation, migration, invasion and tumorigenicity. Comprehensive transcriptional analysis, RNA-FISH, dual-luciferase reporter assay and western blot were performed to explore the molecular mechanisms underlying the functions of DANCR. Results In this study, we found that DANCR was significantly up-regulated in bladder cancer. Moreover, increased DANCR expression was positively correlated with higher histological grade and advanced TNM stage. Further experiments demonstrated that knockdown of DANCR inhibited malignant phenotypes and epithelial-mesenchymal transition (EMT) of bladder cancer cells. Mechanistically, we found that DANCR was distributed mostly in the cytoplasm and DANCR functioned as a miRNA sponge to positively regulate the expression of musashi RNA binding protein 2 (MSI2) through sponging miR-149 and subsequently promoted malignant phenotypes of bladder cancer cells, thus playing an oncogenic role in bladder cancer pathogenesis. Conclusion This study is the first to demonstrate that DANCR plays a critical regulatory role in bladder cancer cell and DANCR may serve as a potential diagnostic biomarker and therapeutic target of bladder cancer

Complete Mitochondrial Genome Characterization of <i>Schrankia costaestrigalis</i> (Insecta: Erebidae: Hypenodinae) and Its Phylogenetic Implication

The pinion-streaked snout Schrankia costaestrigalis is a new potato pest that has recently been recorded in China. In this study, we analyzed the complete mitochondrial genome of S. costaestrigalis. The results revealed the mitogenome (GenBank: OQ181231) to occur as a circular DNA molecule of 16,376 bp with 51.001% AT content, including 13 protein-coding genes (PCGs), 22 transfer RNA (tRNA) genes, 2 ribosomal RNA (rRNA) genes, and 1 control region. Notably, the PCGs exhibited typical ATN (Met) start codons, including cox1, which deviated from the usual CGA start codon observed in other lepidopteran mitogenomes, and followed the conventional TAN stop codons. The 22 tRNA genes demonstrated the ability to form a cloverleaf structure, with the exception of trnS1-NCU, which lacked the DHU arm present in other Erebidae mitogenomes. Additionally, conserved motifs like “ATAGA + poly-T (19 bp) stretch” and five microsatellite-like elements (TA) were identified in the AT-rich region. The phylogenetic trees revealed that the Hypenodinae subfamily forms an independent lineage closely related to Erebinae and Catocalinae. The comprehensive mitogenome of S. costaestrigalis will greatly enhance future studies focused on the molecular classification and phylogenetic understanding of the Hypenodinae subfamily within the larger family Erebidae

Method to Probe Glass Transition Temperatures of Polymer Thin Films

A new methodology was developed to probe glass transition temperatures (<i>T</i>_gs) of polymer thin films supported on gold (Au) substrates and confined between two solid (silica and silver) surfaces based on the surface plasmon polariton (SFPP) signals generated by sum frequency generation (SFG) spectroscopy. The measured <i>T</i>_gs for polymer (poly­(methyl methacrylate), poly­(benzyl methacrylate) and poly­(ethyl methacrylate)) thin films supported on Au substrates showed similar thickness-dependent trend, that is, the <i>T</i>_g decreased as the thin film thickness decreased due to the free surface effect. However, the measured <i>T</i>_g of the (poly­(methyl methacrylate)) thin films confined between two solid surfaces increased significantly with respect to the bulk value, indicating the strong interfacial effect when the free surface was replaced by a buried interface. This method to measure the <i>T</i>_g can be applied to study different polymer thin films supported on metal surfaces or confined between two solid surfaces with different surface chemistries. More importantly, SFG has the unique selectivity and sensitivity to study surfaces and interfaces, providing the feasibility to develop SFG into a powerful tool to detect surface, interfacial, and bulk <i>T</i>_gs of a polymer thin film simultaneously in the future

A novel lncRNA uc.134 represses hepatocellular carcinoma progression by inhibiting CUL4A-mediated ubiquitination of LATS1

Abstract Background Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, and tumor recurrence and metastasis are major factors that contribute to the poor outcome of patients with HCC. Long noncoding RNAs (lncRNAs) are known to regulate different tumorigenic processes, and a growing body of evidence indicates that Hippo kinase signaling is inactivated in many cancers. However, the upstream lncRNA regulators of Hippo kinase signaling in HCC are poorly understood. Methods Using a lncRNA microarray, we identified a novel lncRNA, uc.134, whose expression was significantly decreased in the highly aggressive HCC cell line HCCLM3 compared with MHCC97L cells. Furthermore, we evaluated uc.134 expression in clinical samples using in situ hybridization (ISH) and quantitative real-time polymerase chain reaction (qRT-PCR) analysis. The full-length transcript of uc.134 was confirmed using rapid amplification of cDNA ends (RACE) analyses. To investigate the biological function of uc.134, we performed gain-of-function and loss-of-function studies both in vitro and in vivo. The underlying mechanisms of uc.134 in HCC were investigated using RNA pulldown, RNA immunoprecipitation, ubiquitination assays, Western blotting, mRNA microarray analyses, and qRT-PCR analyses. Results The ISH assay revealed that uc.134 expression was significantly decreased in 170 paraffin-embedded samples from patients with HCC compared with adjacent tissues and uc.134 expression directly correlated with patient prognosis. Furthermore, we defined a 1867-bp full-length transcript of uc.134 using 5′- and 3′-RACE analysis. The overexpression of uc.134 inhibited HCC cell proliferation, invasion, and metastasis in vitro and in vivo, whereas the knockdown of uc.134 produced the opposite results. Furthermore, we confirmed that uc.134 (1408–1867 nt) binds to CUL4A (592–759 aa region) and inhibits its nuclear export. Moreover, we demonstrated that uc.134 inhibits the CUL4A-mediated ubiquitination of LATS1 and increases YAPS127 phosphorylation to silence the target genes of YAP. Finally, a positive correlation between uc.134, LATS1, and pYAPS127 was confirmed in 90 paraffin-embedded samples by ISH and immunohistochemical staining. Conclusions Our study identifies that a novel lncRNA, uc.134, represses hepatocellular carcinoma progression by inhibiting the CUL4A-mediated ubiquitination of LATS1 and increasing YAPS127 phosphorylation. The use of this lncRNA may offer a promising treatment approach by inhibiting YAP and activating Hippo kinase signaling

Histone methyltransferase SETDB1 promotes cells proliferation and migration by interacting withTiam1 in hepatocellular carcinoma

Abstract Background SETDB1 is a histone H3K9 methyltransferase, which plays a significant role in the occurrence and progression of tumors. Previous studies have confirmed that T-lymphom invasion and metastasis gene (Tiam1) is a protein associated with the metastasis of hepatocellular carcinoma (HCC); however, we have not yet been successful in elucidating the specific mechanism of HCC. Methods Yeast two-hybrid test was conducted to screen proteins that interacted with Tiam1 gene. Glutathione-S-transferase (GST) pull-down and crosslinking-immunoprecipitation (CLIP) assays were performed to determine whether SETDB1 can interact with Tiam1 gene. A series of related experiments were performed to explore role of SETDB1 on cell proliferation, migration, and invasion in HCC. Recovery experiment was performed to investigate the effect of Tiam1 knockdown on cell proliferation and migration, which was caused by SETDB1 overexpression in HCC cells. The expression of SETDB1 was frequently upregulated in HCC tissues and positively correlated with Tiam1. Results GST pull-down and CLIP assays were performed to elucidate the interaction between SETDB1 and Tiam1. Cell proliferation, migration, and epithelial mesenchymal transformation (EMT) in HCC cells was promoted with the overexpression of SETDB1. Following the knockdown of Tiam1 gene, the effect of SETDB1 on cell proliferation and migration was reversed in HCC cells. The expression of SETDB1 was frequently up-regulated in HCC tissues, and it was positively correlated with Tiam1 gene. Conclusions Ours is the first study to prove that SETDB1 promotes the proliferation and migration of cells by forming SETDB1-Tiam1 compounds. We found that SETDB1-Tiam1 compounds were involved in a novel pathway, which regulated epigenetic modification of gene expression in HCC samples

Using microRNAs as Novel Predictors of Urologic Cancer Survival: An Integrated AnalysisResearch in Context

Background: MicroRNAs(miRNAs) are involved in the formation, maintenance, and metastasis of urologic cancer. Here, we aim to gather and evaluate all of the evidence regarding the potential role of miRNAs as novel predictors of urologic cancer survival. Methods: A systematic review was performed to identify and score all of the published studies that evaluated the prognostic effects of miRNAs in kidney (KCa), bladder (BCa) or prostate cancer (PCa). Where appropriate, the summary effects of miRNAs on urologic cancer were meta-analysed. The reliability of those results was then further validated by an integrated analysis of the TCGA cohort and miRNA panel. Results: Of 151 datasets, 80 miRNAs were enrolled in this systematic review. A meta-analysis of the prognostic qualities of each miRNA identified an objective association between miRNA and prognosis. miR-21 was identified as an unfavourable miRNA with the overall survival (HR:2.699, 1.76–4.14, P < 0.001) across various prognostic events. Our further meta-analyses, integrating a parallel TCGA analysis, confirmed these partial previous results and further revealed different summary effects, such as the moderate effect of miR-21 in BCa. The refined miRNA panel (KCa-6: miR-27b, −942, −497, −144, −141 and -27a) was more capable of predicting the overall survival than was any single miRNAs included in it (HR: 3.214, 1.971–5.240, P < 0.01). Conclusions: A miRNA panel may be able to determine the prognosis of urologic tumour more effectively and compensate for the unreliability of individual miRNA in estimating prognosis. More large-scale studies are therefore required to evaluate the unbiased prognostic value of miRNAs in urologic cancer effectively. Keywords: miRNAs, Urologic cancer, Prognosis, Biomarker, Bioinformatics analysis, miRNA pane