Deep learning modeling m6A deposition reveals the importance of downstream cis-element sequences.

The N6-methyladenosine (m6A) modification is deposited to nascent transcripts on chromatin, but its site-specificity mechanism is mostly unknown. Here we model the m6A deposition to pre-mRNA by iM6A (intelligent m6A), a deep learning method, demonstrating that the site-specific m6A methylation is primarily determined by the flanking nucleotide sequences. iM6A accurately models the m6A deposition (AUROC = 0.99) and uncovers surprisingly that the cis-elements regulating the m6A deposition preferentially reside within the 50 nt downstream of the m6A sites. The m6A enhancers mostly include part of the RRACH motif and the m6A silencers generally contain CG/GT/CT motifs. Our finding is supported by both independent experimental validations and evolutionary conservation. Moreover, our work provides evidences that mutations resulting in synonymous codons can affect the m6A deposition and the TGA stop codon favors m6A deposition nearby. Our iM6A deep learning modeling enables fast paced biological discovery which would be cost-prohibitive and unpractical with traditional experimental approaches, and uncovers a key cis-regulatory mechanism for m6A site-specific deposition

Co2N nanoparticles embedded N-doped mesoporous carbon as efficient electrocatalysts for oxygen reduction reaction

Co-N-C electrocatalysts have attracted great attention in electrocatalytic ORR (oxygen reduction reaction) field. In this work, we propose to prepare Co 2 N nanoparticles embedded N-doped mesoporous carbon by a facile method including in situ copolymerization and pyrolysis under NH 3 atmosphere. The results show that more N atoms can be doped in carbon framework by NH 3 pyrolysis, it is also found that pyrolysis temperature and Co content can influence the ORR performance of samples. The sample prepared by adding Co precursor and pyrolysis at 700 °C has high N content (11.86 at.%) and relative large specific surface area (362 m 2 g −1 ), and it also exhibited superior electrocatalytic ORR performance in terms of E onset (−0.038 V vs. SCE), E 1/2 (−0.126 V vs. SCE) and large current density (5.22 mA cm −2 ). Additionally, the sample also shows better stability and resistance to methanol poisoning than Pt/C catalyst. The synergistic effect of Co-N active centers and hierarchical porous structures contribute the excellent electrocatalytic activity, which are considering as alternative catalysts for ORR in full cells

EPCFormer: Expression Prompt Collaboration Transformer for Universal Referring Video Object Segmentation

Audio-guided Video Object Segmentation (A-VOS) and Referring Video Object Segmentation (R-VOS) are two highly-related tasks, which both aim to segment specific objects from video sequences according to user-provided expression prompts. However, due to the challenges in modeling representations for different modalities, contemporary methods struggle to strike a balance between interaction flexibility and high-precision localization and segmentation. In this paper, we address this problem from two perspectives: the alignment representation of audio and text and the deep interaction among audio, text, and visual features. First, we propose a universal architecture, the Expression Prompt Collaboration Transformer, herein EPCFormer. Next, we propose an Expression Alignment (EA) mechanism for audio and text expressions. By introducing contrastive learning for audio and text expressions, the proposed EPCFormer realizes comprehension of the semantic equivalence between audio and text expressions denoting the same objects. Then, to facilitate deep interactions among audio, text, and video features, we introduce an Expression-Visual Attention (EVA) mechanism. The knowledge of video object segmentation in terms of the expression prompts can seamlessly transfer between the two tasks by deeply exploring complementary cues between text and audio. Experiments on well-recognized benchmarks demonstrate that our universal EPCFormer attains state-of-the-art results on both tasks. The source code of EPCFormer will be made publicly available at https://github.com/lab206/EPCFormer.Comment: The source code will be made publicly available at https://github.com/lab206/EPCForme

Molecular mechanisms on how FABP5 inhibitors promote apoptosis-induction sensitivity of prostate cancer cells.

Previous work showed that FABP5 inhibitors suppressed the malignant progression of prostate cancer cells, and this suppression might be achieved partially by promoting apoptosis. But the mechanisms involved were not known. Here, we investigated the effect of inhibitors on apoptosis and studied the relevant mechanisms. WtrFABP5 significantly reduced apoptotic cells in 22Rv1 and PC3 by 18% and 42%, respectively. In contrast, the chemical inhibitor SB-FI-26 produced significant increases in percentages of apoptotic cells in 22Rv1 and PC3 by 18.8% (±4.1) and 4.6% (±1.1), respectively. The bio- inhibitor dmrFABP5 also did so by 23.1% (±2.4) and 15.8% (±3.0), respectively, in these cell lines. Both FABP5 inhibitors significantly reduced the levels of the phosphorylated nuclear fatty acid receptor PPARγ, indicating that these inhibitors promoted apoptosis-induction sensitivity of the cancer cells by suppressing the biological activity of PPARγ. Thus, the phosphorylated PPARγ levels were reduced by FABP5 inhibitors, the levels of the phosphorylated AKT and activated nuclear factor kapper B (NFκB) were coordinately altered by additions of the inhibitors. These changes eventually led to the increased levels of cleaved caspase-9 and cleaved caspase-3; and thus, increase in the percentage of cells undergoing apoptosis. In untreated prostate cancer cells, increased FABP5 suppressed the apoptosis by increasing the biological activity of PPARγ, which, in turn, led to a reduced apoptosis by interfering with the AKT or NFκB signaling pathway. Our results suggested that the FABP5 inhibitors enhanced the apoptosis-induction of prostate cancer cells by reversing the biological effect of FABP5 and its related pathway

FABP5 can substitute for androgen receptor in malignant progression of prostate cancer cells.

Fatty acid‑binding protein 5 (FABP5) and androgen receptor (AR) are critical promoters of prostate cancer. In the present study, the effects of knocking out the FABP5 or AR genes on malignant characteristics of prostate cancer cells were investigated, and changes in the expression of certain key proteins in the FABP5 (or AR)‑peroxisome proliferator activated receptor‑γ (PPARγ)‑vascular endothelial growth factor (VEGF) signaling pathway were monitored. The results obtained showed that FABP5‑ or AR‑knockout (KO) led to a marked suppression of the malignant characteristics of the cells, in part, through disrupting this signaling pathway. Moreover, FABP5 and AR are able to interact with each other to regulate this pathway, with FABP5 controlling the dominant AR splicing variant 7 (ARV7), and AR, in return, regulates the expression of FABP5. Comparisons of the RNA profiles revealed the existence of numerous differentially expressed genes (DEGs) comparing between the parental and the FABP5‑ or AR‑KO cells. The six most abundant changes in DEGs were found to be attributable to the transition from androgen‑responsive to androgen‑unresponsive, castration‑resistant prostate cancer (CRPC) cells. These findings have provided novel insights into the complex molecular pathogenesis of CRPC cells, and have demonstrated that interactions between FABP5 and AR contribute to the transition of prostate cancer cells to an androgen‑independent state. Moreover, gene enrichment analysis revealed that the most highly enriched biological processes associated with the DEGs included those responsive to fatty acids, cholesterol and sterol biosynthesis, as well as to lipid and fatty acid transportation. Since these pathways regulated by FABP5 or AR may be crucial in terms of transducing signals for cancer cell progression, targeting FABP5, AR and their associated pathways, rather than AR alone, may provide a new avenue for the development of therapeutic strategies geared towards suppressing the malignant progression to CRPC cells

Experimental treatment efficacy of dmrFABP5 on prostate cancer singly or in combination with drugs in use.

Enzalutamide is a drug used to treat prostate cancer (PC) and docetaxel is a drug for chemotherapeutic treatment of diverse cancer types, including PC. The effectiveness of these drugs in treating castration-resistant prostate cancer (CRPC) is poor and therefore CRPC is still largely incurable. However, the bio-inhibitor of fatty acid-binding protein 5 (FABP5), dmrFABP5, which is a mutant form of FABP5 incapable of binding to fatty acids, has been shown recently to be able to suppress the tumorigenicity and metastasis of cultured CRPC cells. The present study investigated the possible synergistic effect of dmrFABP5 combined with either enzalutamide or docetaxel on suppressing the tumorigenic properties of PC cells, including cell viability, migration, invasion and colony proliferation in soft agar. A highly significant synergistic inhibitory effect on these properties was observed when dmrFABP5 was used in combination with enzalutamide on androgen-responsive PC 22RV1 cells. Moreover, a highly significant synergistic inhibitory effect was also observed when dmrFABP5 was combined with docetaxel, and added to 22RV1 cells and to the highly malignant, androgen-receptor (AR)-negative Du145 cells. DmrFABP5 alone failed to produce any suppressive effect when added to the FABP5-negative cell line LNCaP, although enzalutamide could significantly suppress LNCaP cells when used as a single agent. These synergistic inhibitory effects of dmrFABP5 were produced by interrupting the FABP5-related signal transduction pathway in PC cells. Thus, dmrFABP5 appears to be not only a potential single therapeutic agent, but it may also be used in combination with existing drugs to suppress both AR-positive and AR-negative PC

Correction: Inhibitor SBFI26 suppresses the malignant progression of castration-resistant PC3-M cells by competitively binding to oncogenic FABP5.

[This corrects the article DOI: 10.18632/oncotarget.16055.]