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Automating retrosynthesis with artificial intelligence expedites organic chemistry research in digital laboratories. However, most existing deep-learning approaches are hard to explain, like a "black box" with few insights. Here, we propose RetroExplainer, formulizing the retrosynthesis task into a molecular assembly process, containing several retrosynthetic actions guided by deep learning. To guarantee a robust performance of our model, we propose three units: a multi-sense and multi-scale Graph Transformer, structure-aware contrastive learning, and dynamic adaptive multi-task learning. The results on 12 large-scale benchmark datasets demonstrate the effectiveness of RetroExplainer, which outperforms the state-of-the-art single-step retrosynthesis approaches. In addition, the molecular assembly process renders our model with good interpretability, allowing for transparent decision-making and quantitative attribution. When extended to multi-step retrosynthesis planning, RetroExplainer has identified 101 pathways, in which 86.9% of the single reactions correspond to those already reported in the literature. As a result, RetroExplainer is expected to offer valuable insights for reliable, high-throughput, and high-quality organic synthesis in drug development. Automating retrosynthesis prediction in organic chemistry is a major application of ML. Here the authors present RetroExplainer, which offers a high-performance, transparent and interpretable deep-learning framework providing valuable insights for drug development. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most malignant and challenging type of astrocytoma and also notoriously acknowledged as the most common primary brain tumor globally. Currently, chemotherapy is the most master therapy for tumor and is essential in clinical treatment for GBM. Nevertheless, the characterization of chemotherapy resistance seriously hinders clinical chemotherapy treatment. Accordingly, there are imperious demands for the exploitation of novel chemosensitizer to promote the efficacy of chemotherapy. Our current study was conducted to probe into the potential impacts of microRNA (miR)-640 on the chemosensitivity in GBM and the associated underlying mechanism. Initially, TargetScan software was utilized to predict the targeted genes of miR-640, and the target relationship between miR-640 and Bcl-2-modifying factor (BMF) was validated by double luciferase report assay. Additionally, to explore the role of miR-640/BMF in U251 cells, miR-640 inhibitor/BMF-siRNA was used. U251 cells were processed with 100 μM temozolomide (TMZ) and detected with CCK-8 kit. Eventually, RT-qPCR and Western blotting were used for evaluating Bcl-2, Bax mRNA, and protein expression level. Flow cytometry analysis was performed to measure cellular apoptosis. Initially, the results indicated that BMF was the target gene of miR-640. MiR-640 negatively regulated BMF expression in GBM cells. Besides, the findings revealed that miR-640 inhibition significantly inhibited U251 cell proliferation, promoted cell apoptosis, and increased the sensitivity of GBM cells to TMZ by targeting BMF. Moreover, BMF overexpression significantly suppressed U251 cell proliferation, induced cell apoptosis, and increased the sensitivity of GBM cells to TMZ. Inhibition of miR-640 expression enhances chemosensitivity of human GBM cells to TMZ by targeting BMF. [ABSTRACT FROM AUTHOR]

This research focuses on the position tracking control of the rotating barrel of large caliber artillery. Based on a nonlinear state-space model of the hydraulic-driven barrel servo system (HDBSS) with extensive non-linearities and uncertainties, a disturbance observer-based prescribed performance dynamic surface controller is proposed. The disturbance observer simultaneously estimates the mismatched and matched disturbances. The prescribed performance constraints predetermine the boundary of the output error. Inspired by the barrier Lyapunov function (BLF), conversion from the original constrained system into an an equivalent error-constrained system' is realized via a novel error transformation function, which efficiently avoids the calculation of the logarithmic part of the traditional prescribed performance controller. Furthermore, dynamic surface technology is applied in the last step of backstepping controller design to avoid the complexity of differential explosion. The stability and convergence of the closed-loop system are theoretically proven. The effectiveness of the proposed controller is verified by extensive comparative experimental results. [ABSTRACT FROM AUTHOR]

This article proposes a new control scheme by combining an improved quasi-continuous controller (IQCC) and sliding mode disturbance observer (SMDO) for automatic chain shell magazine (ACSM) position control. Unlike conventional quasi-continuous controller (QCC), the new IQCC switches between two formulas according to the value of the first derivative of sliding variable. The influence of parameters design in IQCC on the control effect is further discussed. By combining IQCC with SMDO, the design of controller gain is independent of the uncertainties bound. The close-loop stability of combined scheme is proved by a Lyapunov function. Compared with QCC, IQCC performs better in convergence rate and chattering restraining. The scheme could achieve satisfied control effects for nonlinear systems with uncertain disturbances. Simulation and experimental results verify the superiority of the proposed controller over QCC and proportional integral (PI). [ABSTRACT FROM AUTHOR]

CD8+CD103+ tissue-resident memory T cells (TRMs) are involved in tumor immune response and linked to favorable clinical outcome in human cancer. However, the distribution, phenotype, functional properties and clinical relevance of these cells in gastric cancer (GC) remain elusive. Here, our data show that, in comparison to non-tumor tissues, the percentages of CD8+CD103+ TRMs in tumors are significantly decreased. Most tumor-infiltrating CD8+CD103+ TRMs are CD45RA−CCR7− effector-memory cells with higher PD-1 and 4-1BB expression than those from non-tumor tissues. Further, tumor-infiltrating CD8+CD103+ TRMs show impaired cytolytic capacity due to decreased granzyme B and perforin expression. Moreover, ex vivo PD-1 blockade could restore the cytolytic capacity of tumor-infiltrating CD8+CD103+ TRMs, and such anti-PD-1-mediated reinvigoration of CD8+CD103+ TRMs could be further enhanced by 4-1BB co-stimulation. Finally, lower levels of Tumor-infiltrating CD8+CD103+ TRMs are positively correlated with GC progression and poor patients' survival. Our data suggest that restoring CD8+CD103+ TRM function by combining PD-1 blockade and 4-1BB co-stimulation may be a promising strategy for treating GC. [ABSTRACT FROM AUTHOR]

IL-22-producing CD4 T cells (IL-22CD4 T cells) and Th22 cells (IL-22IL-17IFN-γCD4 T cells) represent newly discovered T-cell subsets, but their nature, regulation, and clinical relevance in gastric cancer (GC) are presently unknown. In our study, the frequency of IL-22CD4 T cells in tumor tissues from 76 GC patients was significantly higher than that in tumor-draining lymph nodes, non-tumor, and peritumoral tissues. Most intratumoral IL-22CD4 T cells co-expressed IL-17 and IFN-γ and showed a memory phenotype. Locally enriched IL-22CD4 T cells positively correlated with increased CD14 monocytes and IL-6 and IL-23 detection ex vivo, and in vitro IL-6 and IL-23 induced the polarization of IL-22CD4 T cells in a dose-dependent manner and the polarized IL-22CD4 T cells co-expressed of IL-17 and IFN-γ. Moreover, IL-22CD4 T-cell subsets (IL-22IL-17CD4, IL-22IL-17CD4, IL-22IFN-γCD4, IL-22IFN-γCD4, and IL-22IL-17IFN-γCD4 T cells), and Th22 cells were also increased in tumors. Furthermore, higher intratumoral IL-22CD4 T-cell percentage and Th22-cell percentage were found in patients with tumor-node-metastasis stage advanced and predicted reduced overall survival. In conclusion, our data indicate that IL-22CD4 T cells and Th22 cells are likely important in establishing the tumor microenvironment for GC; increased intratumoral IL-22CD4 T cells and Th22 cells are associated with tumor progression and predict poorer patient survival, suggesting that tumor-infiltrating IL-22CD4 T cells and Th22 cells may be suitable therapeutic targets in patients with GC. [ABSTRACT FROM AUTHOR]

Background: CD8Foxp3 T lymphocytes have been detected in tumors. However, the distribution, phenotypic features, and regulation of these cells in gastric cancer remain unknown. Methods: The levels of CD8Foxp3 T lymphocytes in the peripheral blood, tumor-draining lymph nodes, non-tumor tissues, and tumor tissues of patients with gastric cancer were detected by flow cytometry. Foxp3 induction in CD8Foxp3 T cells was investigated in vitro. The suppressive function of CD8Foxp3 T lymphocytes was analyzed by their effect on CD4 T-cell proliferation and IFN-γ production. The percentages of CD8Foxp3 T lymphocytes were evaluated for the association with tumor stage. Results: The frequency of CD8Foxp3 T lymphocytes in tumor tissues was significantly higher than that in non-tumor tissues, and similar results were also observed in tumor-draining lymph nodes compared with peripheral blood. Most intratumoral CD8Foxp3 T lymphocytes were activated effector cells (CD45RACD27). TGF-β1 levels were positively correlated with the frequency of CD8Foxp3 T lymphocytes in tumor tissues, and in vitro TGF-β1 could induce the generation of CD8Foxp3 T lymphocytes in a dose-dependent manner. Furthermore, intratumoral CD8Foxp3 T lymphocytes suppressed the proliferation and IFN-γ production of CD4 T cells. Finally, intratumoral CD8Foxp3 T lymphocytes were significantly increased with tumor progression in terms of tumor-node-metastasis (TNM) stage. Conclusions: Our data have shown that increased intratumoral CD8Foxp3 T lymphocytes are associated with tumor stage and potentially influence CD4 T-cell functions, which may provide insights for developing novel immunotherapy protocols against gastric cancer. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are small endogenous RNAs molecules, approximately 21-23 nucleotides in length, which regulate gene expression by base-pairing with 3′ untranslated regions (UTRs) of target mRNAs. However, the functions of only a few miRNAs in organisms are known. Recently, the expression vector of artificial miRNA has become a promising tool for gene function studies. Here, a method for easy and rapid construction of eukaryotic miRNA expression vector was described. The cytoplasmic actin 3 (A3) promoter and flanked sequences of miRNA-9a (miR-9a) precursor were amplified from genomic DNA of the silkworm ( Bombyx mori) and was inserted into pCDNA3.0 vector to construct a recombinant plasmid. The enhanced green fluorescent protein (EGFP) gene was used as reporter gene. The Bombyx mori N (BmN) cells were transfected with recombinant miR-9a expression plasmid and were harvested 48 h post transfection. Total RNAs of BmN cells transfected with recombinant vectors were extracted and the expression of miR-9a was evaluated by reverse transcriptase polymerase chain reaction (RT-PCR) and Northern blot. Tests showed that the recombinant miR-9a vector was successfully constructed and the expression of miR-9a with EGFP was detected. [ABSTRACT FROM AUTHOR]

As one of the most abundant RNA post-transcriptional modifications, N6-methyladenosine (m6A) involves in a broad spectrum of biological and physiological processes ranging from mRNA splicing and stability to cell differentiation and reprogramming. However, experimental identification of m6A sites is expensive and laborious. Therefore, it is urgent to develop computational methods for reliable prediction of m6A sites from primary RNA sequences. In the current study, a new method called RAM-ESVM was developed for detecting m6A sites from Saccharomyces cerevisiae transcriptome, which employed ensemble support vector machine classifiers and novel sequence features. The jackknife test results show that RAM-ESVM outperforms single support vector machine classifiers and other existing methods, indicating that it would be a useful computational tool for detecting m6A sites in S. cerevisiae. Furthermore, a web server named RAM-ESVM was constructed and could be freely accessible at http://server.malab.cn/RAM-ESVM/. [ABSTRACT FROM AUTHOR]

The Dishevelled/EGL-10/Pleckstrin (DEP) domain-containing (DEPDC) proteins have seven members. However, whether this superfamily can be distinguished from other proteins based only on the amino acid sequences, remains unknown. Here, we describe a computational method to segregate DEPDCs and non-DEPDCs. First, we examined the Pfam numbers of the known DEPDCs and used the longest sequences for each Pfam to construct a phylogenetic tree. Subsequently, we extracted 188-dimensional (188D) and 20D features of DEPDCs and non-DEPDCs and classified them with random forest classifier. We also mined the motifs of human DEPDCs to find the related domains. Finally, we designed experimental verification methods of human DEPDC expression at the mRNA level in hepatocellular carcinoma (HCC) and adjacent normal tissues. The phylogenetic analysis showed that the DEPDCs superfamily can be divided into three clusters. Moreover, the 188D and 20D features can both be used to effectively distinguish the two protein types. Motif analysis revealed that the DEP and RhoGAP domain was common in human DEPDCs, human HCC and the adjacent tissues that widely expressed DEPDCs. However, their regulation was not identical. In conclusion, we successfully constructed a binary classifier for DEPDCs and experimentally verified their expression in human HCC tissues. [ABSTRACT FROM AUTHOR]

No vaccine against methicillin-resistant Staphylococcus aureus (MRSA) has been currently approved for use in humans. Staphylococcus enterotoxin B (SEB) is one of the most potent MRSA exotoxins. In the present study, we evaluated the efficacy and immunologic mechanisms of an SEB multiple B-cell epitope vaccine against MRSA infection. Synthetic overlapping peptide ELISA identified three novel B-cell immunodominant SEB epitopes (in addition to those previously known): SEB31-48, SEB133-150, and SEB193-210. Six B-cell immunodominant epitopes (amino acid residues 31-48, 97-114, 133-150, 193-210, 205-222, and 247-261) were sufficient to induce robust IgG1/IgG2b-specific protective responses against MRSA infection. Therefore, we constructed a recombinant MRSA SEB-specific multiple B-cell epitope vaccine Polypeptides by combining the six SEB immunodominant epitopes and demonstrated its ability to induce a robust SEB-specific IgG1 response to MRSA, as well as a Th2-directing isotype response. Moreover, Polypeptides-induced antisera stimulated synergetic opsonophagocytosis killing of MRSA. Most importantly, Polypeptides was more effective at clearing the bacteria in MRSA-infected mice than the whole SEB antigen, and was able to successfully protect mice from infection by various clinical MRSA isolates. Altogether, these results support further evaluation of the SEB multiple B-cell epitope-vaccine to address MRSA infection in humans. [ABSTRACT FROM AUTHOR]