Multiple sequence alignment-based RNA language model and its application to structural inference.

Compared with proteins, DNA and RNA are more difficult languages to interpret because four-letter coded DNA/RNA sequences have less information content than 20-letter coded protein sequences. While BERT (Bidirectional Encoder Representations from Transformers)-like language models have been developed for RNA, they are ineffective at capturing the evolutionary information from homologous sequences because unlike proteins, RNA sequences are less conserved. Here, we have developed an unsupervised multiple sequence alignment-based RNA language model (RNA-MSM) by utilizing homologous sequences from an automatic pipeline, RNAcmap, as it can provide significantly more homologous sequences than manually annotated Rfam. We demonstrate that the resulting unsupervised, two-dimensional attention maps and one-dimensional embeddings from RNA-MSM contain structural information. In fact, they can be directly mapped with high accuracy to 2D base pairing probabilities and 1D solvent accessibilities, respectively. Further fine-tuning led to significantly improved performance on these two downstream tasks compared with existing state-of-the-art techniques including SPOT-RNA2 and RNAsnap2. By comparison, RNA-FM, a BERT-based RNA language model, performs worse than one-hot encoding with its embedding in base pair and solvent-accessible surface area prediction. We anticipate that the pre-trained RNA-MSM model can be fine-tuned on many other tasks related to RNA structure and function.

Tfcancer: a manually curated database of transcription factors associated with human cancers.

SUMMARY: Transcription factors (TFs) are critical regulation elements and its dysregulation can lead to a variety of cancers. However, currently, there are no such online resources for large-scale collection, storage and analysis of TF-cancer associations in those cancers. To fill this gap, we present a database called TFcancer (http://lcbb.swjtu.edu.cn/tfcancer/), which contains 3136 experimentally supported associations between 364 TFs and 33 TCGA cancers by manually curating more than 1800 literature. TFcancer mainly concentrates on four aspects: TF expression, molecular alteration, regulatory relationships between TFs and target genes, and biological processes and signaling pathways of TFs in cancers. TFcancer not only provides a user-friendly interface for browsing and searching but also allows flexible data downloading and user data submitting. It is believed that TFcancer is a helpful and valuable resource for researchers who seek to understand the functions and molecular mechanisms of TFs involved in human cancers. AVAILABILITY AND IMPLEMENTATION: The TFcancer are freely available at http://lcbb.swjtu.edu.cn/tfcancer/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

EnhFFL: A database of enhancer mediated feed-forward loops for human and mouse.

Feed-forward loops (FFLs) are thought to be one of the most common and important classes of transcriptional network motifs involved in various diseases. Enhancers are cis-regulatory elements that positively regulate protein-coding genes or microRNAs (miRNAs) by recruiting DNA-binding transcription factors (TFs). However, a comprehensive resource to identify, store, and analyze the FFLs of typical enhancer and super-enhancer FFLs is not currently available. Here, we present EnhFFL, an online database to provide a data resource for users to browse and search typical enhancer and super-enhancer FFLs. The current database covers 46 280/7000 TF-enhancer-miRNA FFLs, 9997/236 enhancer-miRNA-gene FFLs, 3 561 164/3 193 182 TF-enhancer-gene FFLs, and 1259/235 TF-enhancer feed-back loops (FBLs) across 91 tissues/cell lines of human and mouse, respectively. Users can browse loops by selecting species, types of tissue/cell line, and types of FFLs. EnhFFL supports searching elements including name/ID, genomic location, and the conservation of miRNA target genes. We also developed tools for users to screen customized FFLs using the threshold of q value as well as the confidence score of miRNA target genes. Disease and functional enrichment analysis showed that master miRNAs that are widely engaged in FFLs including TF-enhancer-miRNAs and enhancer-miRNA-genes are significantly involved in tumorigenesis. Database URL:http://lcbb.swjtu.edu.cn/EnhFFL/.

[The crystalline polymorph control and selection of gabapentin with polymer heteronuclei].

The pharmaceutical properties, including the physical and chemical properties, and the bioavailability are greatly influenced by their polymorphism. In this paper the polymer heteronuclei were used to produce the gabapentin polymorphs that were characterized by X-ray powder diffraction, FT-IR and DSC. The results indicated that the polymer heteronuclei are an effective method to control and select the gabapentin polymorphism. One new polymorph of gabapentin was found besides all known gabapentin polymorphs.

miR­1 reverses multidrug resistance in gastric cancer cells via downregulation of sorcin through promoting the accumulation of intracellular drugs and apoptosis of cells.

Gastric cancer (GC) is one of the most common cancers worldwide and results in the second greatest rate of cancer­associated mortality globally. Multidrug resistance (MDR) often develops during the chemotherapy, resulting in the failure of treatment. To investigate the molecular mechanism of MDR, the roles of microRNA (miR)­1 were studied in GC. Reverse transcription­quantitative polymerase chain reaction and western blotting were used to investigate the expression levels of miR­1 and sorcin in SGC7901/ADM and SGC7901/VCR cell lines. The effect of miR­1 on the half maximal inhibitory concentration (IC50), cell apoptosis rates and drug accumulation was uncovered by MTT assay and flow cytometric analysis. Furthermore, dual­luciferase assay and western blotting were used to determine the target of miR­1 in GC. It was demonstrated that miR­1 was highly downregulated in MDR GC cell lines, including SGC7901/ADM and SGC7901/VCR. Overexpression of miR­1 in MDR GC cells decreased IC50, but increased the cell apoptosis rates and promoted the drug accumulation in cancer cells. Dual­luciferase activity assay indicated that sorcin was the target of miR­1 in GC. In addition, overexpression of sorcin could partially reverse the effect of miR­1 in MDR GC cells. The role of miR­1 in MDR GC cells makes it a potential therapeutic target for a successful clinical outcome.

A collagen-based multicellular tumor spheroid model for evaluation of the efficiency of nanoparticle drug delivery.

Targeted drug delivery systems, especially those that use nanoparticles, have been the focus of research into cancer therapy during the last decade, to improve the bioavailability and delivery of anticancer drugs to specific tumor sites, thereby reducing the toxicity and side effects to normal tissues. However, the positive antitumor effects of these nanocarriers observed in conventional monolayer cultures frequently fail in vivo, due to the lack of physical and biological barriers resembling those seen in the actual body. Therefore, the collagen-based 3-D multicellular culture system, to screen new nanocarriers for drug delivery and to obtain more adequate and better prediction of therapeutic outcomes in preclinical experiments, was developed. This 3-D culture model was successfully established using optimized density of cells. Our result showed that 3-D cell colonies were successfully developed from 95-D, U87 and HCT116 cell lines respectively, after a seven-day culture in the collagen matrix. The coumarin-conjugated nanoparticles were able to penetrate the matrix gel to reach the tumor cells. The model is supposedly more accurate in reflecting/predicting the dynamics and therapeutic outcomes of candidates for drug transport in vivo, and/or investigation of tumor biology, thus speeding up the pace of discovery of novel drug delivery systems for cancer therapy.

Identification and characteristic analysis of enhancer-miRNA regulatory pairs in hepatic carcinoma / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To explore the regulatory relationship between enhancer and miRNA and the characteristics of the enhancers that regulate miRNA in hepatic carcinoma and normal hepatic tissues, and to screen the differentially expressed miRNAs regulated by enhancers as well as their association with the treatment targets in liver cancer. Methods: Based on the TCGA and FANTOM5 databases, Co-expression and 3D genomic analysis were performed on 417 samples of enhancers and miRNAs in liver cancer and normal liver tissues. The difference in signal value of the enhancer that regulates miRNA was analyzed by ChIP-seq data of histone modification and transcription factor in liver cancer and normal liver tissues in ENCODE database. The differentially expressed miRNAs regulated by enhancers were screened out, and the correlation analysis was performed on the patient's survival and treatment targets. Results: 93 and 40 pairs of enhancer-miRNA were identified in liver cancer and normal liver tissues, respectively. ChIP-seqdata comparison analysis found that the signal of H3K27ac, H3K4me1 and sH3K4me3 histone modification in the region of enhancers regulating miRNA was significantly higher than that in the region of enhancers not regulating miRNA (|rho|>0.3, P<0.05). Moreover, the enrichment of multiple transcription factors in liver cancer-related enhancers was significantly lower than that in normal liver tissue-realted enhancers (|rho|>0.3, P<0.05). Differential expression analysis of enhancer-regulated miRNAs identified 6 miRNAs related to the survival of liver cancer patients(hsa-miR-4664, hsa-miR-5003,hsa-miR-1915,hsa-miR-3619,hsa-miR-4745, hsa-miR-6728),and found that these miRNAs were significantly associated with 87 genes for targeted therapy and 8 tumor immune checkpoint genes (|rho|>0.1, FDR<0.05). Conclusion: The enhancer-miRNA regulatory pairs and the characteristics of the enhancer that regulates miRNA were successfully identified in liver cancer. The miRNAs regulated by enhancers and related to the therapeutic targets and survival of patients with liver cancer were also screened out. It provides a valuable preliminary basis for future in-depth basic and clinical research in hepatic carcinoma.

An investigation of antitumor efficiency of novel sustained and targeted 5-fluorouracil nanoparticles.

Traditional chemotherapeutic drugs remain the major treatment for advanced colorectal cancer. However, due to the lack of tumor specificity these drug also destroy healthy tissue and organs, which has been the main reason for treatment failure and mortality. Folate-based drug delivery systems for improving nanoparticle endocytosis have been used to address these problems. Here, folic acid (FA) conjugated mPEG-b-P(CABCL-co-ACL) diblock copolymers were synthesized and characterized by TEM and NMR. Drug loaded nanoparticles were prepared using dialysis method and was obtained with a mean diameter of 45.2 nm with sustained in vitro release profile. In vitro cytotoxicity assay indicated that the cytotoxicity of folate modified nanoparticles were significantly increased compared to free drug and non-folate nanoparticles. In addition, results of hemolytic and histopathologic study suggested that the non-loaded nanoparticle (NL/NP) was non-toxic and biocompatible at the testing concentration. Moreover, in vivo results showed that FA/5-FU/NP effectively inhibited growth of HCT-8 cell-based xenograft tumors in BALB/c mice and revealed stronger antitumor efficacy than other treated groups. Thus, both in vitro and in vivo results exhibited that the folate conjugated mPEG-b-P(CABCL-co-ACL) copolymers have great potential to be used as sustainable and specific colon cancer targeting delivery system for anticancer agents.

Overcoming multidrug resistance in 2D and 3D culture models by controlled drug chitosan-graft poly(caprolactone)-based nanoparticles.

The principal limitations of chemotherapy are dose-limiting systemic toxicity and the development of multidrug-resistant phenotypes. The aim of this study was to investigate the efficiency of a new sustained drug delivery system based on chitosan and ε-caprolactone to overcome multidrug resistance in monolayer and drug resistance associated with the three-dimensional (3D) tumor microenvironment in our established 3D models. The 5-fluorouracil (5-FU)-loaded nanoparticles (NPs) were characterized by transmission electron microscope and dynamic light scattering, and its released property was determined at different pH values. 5-FU/NPs exhibited well-sustained release properties and markedly enhanced the cytotoxicity of 5-FU against HCT116/L-OHP or HCT8/VCR MDR cells in two-dimensional (2D) and its parental cells in 3D collagen gel culture with twofold to threefold decrease in the IC50 values, as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, Hoechst/propidium iodide staining and flow cytometry analysis. Furthermore, the possible mechanism was explored by high-performance liquid chromatography and rhodamine 123 accumulation experiment. Overall, the results demonstrated that 5-FU/NPs increase intracellular concentration of 5-FU and enhance its anticancer efficiency by inducing apoptosis. It was suggested that this novel NPs are a promising carrier to decrease toxic of 5-FU and has the potential to reverse the forms of both intrinsic and acquired drug resistance in 2D and 3D cultures.