Myogenic differentiation factor (MyoD) is a master transcription factor in muscle development and differentiation. Although several long non-coding RNAs (lncRNAs) linked to MyoD have been found to influence muscle development, the functions of many lncRNAs have not been explored. Here we utilized lncRNA and mRNA microarray analysis to identify potential lncRNAs regulated by MyoD in muscle cells. A total of 997 differentially expressed lncRNAs (335 up-regulated and 662 down-regulated) and 1,817 differentially expressed mRNAs (148 up-regulated and 1,669 down-regulated) were identified after MyoD knockdown in C2C12 cells. Functional predictions suggested that most lncRNAs are involved in the biological pathways related to muscle differentiation and cell cycle with co-expressed genes. To gain further insight into the MyoD-mediated lncRNA expression in muscle differentiation, tissue expression profiles and MyoD overexpression were performed, and we found one of the candidate lncRNAs-AK143003 was significantly regulated by MyoD. Further analyses showed its noncoding ability and cytoplasmic localisation. Silencing of AK143003 stimulated the accumulation of myogenic marker genes, whereas AK143003 overexpression led to their decreased synthesis. This study identified a multitude of MyoD-mediated lncRNAs for further investigation and identified a novel lncRNA, lnc-AK143003, which plays a role in controlling muscle differentiation.
Inhibition of aberrant Hedgehog (Hh) pathway had been proved to be a promising therapeutic intervention in cancers like basal cell carcinoma (BCC), medulloblastoma (MB), and so on. Two drugs (Vismodegib, Sonidegib) were approved to treat BCC and more inhibitors are in clinical investigation. However, the adverse effects and drug resistance restricted the use of Hh inhibitors. In the present study, 61 synthesized compounds containing central backbone of phthalazine or dimethylpyridazine were screened as candidates of new Hh signaling inhibitors by performing dual luciferase reporter assay. Among the compounds, L-4 exhibited an IC
50
value of 2.33 nM in the Shh-Light II assay. L-4 strongly inhibited the Hh pathway
in vitro
and blocked the Hh pathway by antagonizing the smoothened receptor (Smo). Remarkably, L-4 could significantly suppress the Hh pathway activity provoked by Smo mutant (D473H) which showed strong resistant properties to existing drugs such as Vismodegib. Orally administered L-4 exhibited prominent dose-dependent anti-tumor efficacy
in vivo
in Ptch+/-; p53-/- MB allograft model. Furthermore, L-4 showed good tolerance in acute toxicity test using ICR mice. These evidences indicated that L-4 was a potent, well-tolerated, orally active inhibitor of Hedgehog pathway, and might be a promising candidate in development of Hh-targeted anti-cancer drugs.
Background
Blowflies (Diptera: Calliphoridae) are the most commonly found entomological evidence in forensic investigations. Distinguished from other blowflies, Aldrichina grahami has some unique biological characteristics and is a species of forensic importance. Its development rate, pattern, and life cycle can provide valuable information for the estimation of the minimum postmortem interval.
Findings
Herein we provide a chromosome-level genome assembly of A. grahami that was generated by Pacific BioSciences sequencing platform and chromosome conformation capture (Hi-C) technology. A total of 50.15 Gb clean reads of the A. grahami genome were generated. FALCON and Wtdbg were used to construct the genome of A. grahami, resulting in an assembly of 600 Mb and 1,604 contigs with an N50 size of 1.93 Mb. We predicted 12,823 protein-coding genes, 99.8% of which was functionally annotated on the basis of the de novo genome (SRA: PRJNA513084) and transcriptome (SRA: SRX5207346) of A. grahami. According to the co-analysis with 11 other insect species, clustering and phylogenetic reconstruction of gene families were performed. Using Hi-C sequencing, a chromosome-level assembly of 6 chromosomes was generated with scaffold N50 of 104.7 Mb. Of these scaffolds, 96.4% were anchored to the total A. grahami genome contig bases.
Conclusions
The present study provides a robust genome reference for A. grahami that supplements vital genetic information for nonhuman forensic genomics and facilitates the future research of A. grahami and other necrophagous blowfly species used in forensic medicine.
The linear combination of multi-frequency carrier-phase and pseudorange observations can form the combined observations with special properties. The type and number of combined frequencies will directly affect the characteristics of the combined observations. BDS-2 and BDS-3 broadcast three and five signals, respectively, and the study of their linear combination is of great significance for precision positioning. In this contribution, the linear combination form of multi-frequency carrier-phase observations in cycles and meters is sorted out. Seven frequency combination modes are formed, and some special combinations for positioning are searched. Then, based on the principle of minimum combined noise, a simpler search method for the optimal real coefficients of ionosphere-free (IF) combination based on the least squares (LS) principle is proposed. The general analytical expressions of optimal real coefficients for multi-frequency geometry-based and ionosphere-free (GBIF), geometry-free and ionosphere-free (GFIF), and pseudorange multipath (PMP) combinations with the first-order ionosphere delay taken into account are derived. And the expression derivation process is given when both the first-order and second-order ionospheric delays are eliminated. Based on this, the characteristics of the optimal real coefficient combination in various modes are compared and discussed. The various combinations reflect that the accuracy of the combined observations from dual-frequency (DF) to five-frequency (FF) is gradually improving. The combination coefficient becomes significantly larger after taking the second-order ionospheric delay into account. In addition, the combined accuracy of BDS-3 is better than that of BDS-2. When only the first-order ionosphere is considered, the combination attribute of (B1C, B1I, B2a) is the best among the triple-frequency (TF) combinations of BDS-3. When both the first-order and second-order ionospheric delays are considered, the (B1C, B3I, B2a) combination is recommended.
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