Drug-drug interactions prediction based on deep learning and knowledge graph: A review.

Drug-drug interactions (DDIs) can produce unpredictable pharmacological effects and lead to adverse events that have the potential to cause irreversible damage to the organism. Traditional methods to detect DDIs through biological or pharmacological analysis are time-consuming and expensive, therefore, there is an urgent need to develop computational methods to effectively predict drug-drug interactions. Currently, deep learning and knowledge graph techniques which can effectively extract features of entities have been widely utilized to develop DDI prediction methods. In this research, we aim to systematically review DDI prediction researches applying deep learning and graph knowledge. The available biomedical data and public databases related to drugs are firstly summarized in this review. Then, we discuss the existing drug-drug interactions prediction methods which have utilized deep learning and knowledge graph techniques and group them into three main classes: deep learning-based methods, knowledge graph-based methods, and methods that combine deep learning with knowledge graph. We comprehensively analyze the commonly used drug related data and various DDI prediction methods, and compare these prediction methods on benchmark datasets. Finally, we briefly discuss the challenges related to drug-drug interactions prediction, including asymmetric DDIs prediction and high-order DDI prediction.

Transcriptome and Metabolomics Integrated Analysis Reveals MdMYB94 Associated with Esters Biosynthesis in Apple (Malus × domestica).

Volatile esters are major aromas contributing to the organoleptic quality of apple fruit. However, the molecular mechanisms underlying the regulation of volatile ester biosynthesis in apple remain elusive. This study investigated the volatile profiles and transcriptomes of 'Qinguan' (QG) apple fruit during development and/or postharvest storage. Although the constitution of volatiles varied widely between the peel and flesh, the volatile profiles of the peel and flesh of ripening QG fruit were dominated by volatile esters. WGCNA results suggested that 19 genes belonging to ester biosynthesis pathways and 11 hub transcription factor genes potentially participated in the biosynthesis and regulation of esters. To figure out key regulators of ester biosynthesis, correlation network analysis, dual-luciferase assays, and yeast one-hybrid assay were conducted and suggested that MdMYB94 trans-activated the MdAAT2 promoter and participated in the regulation of ester biosynthesis. This study provides a framework for understanding ester biosynthesis and regulation in apple.

A novel three-dimensional Ag nanoparticles/reduced graphene oxide microtubular field effect transistor sensor for NO2 detections.

A novel three-dimensional (3D) microtubular NO2 field effect transistor (FET) sensor has been fabricated from 2D reduced graphene oxide (rGO) nanosheets decorated with Ag nanoparticles, by applying the self-roll-up technique. The electrical properties of 2D and 3D Ag NP/rGO FET sensors have been investigated and compared. Finally, the performance of the 3D sensors has been demonstrated, where the preliminary results show that our 3D Ag NP/rGO FET NO2 sensor exhibits a relatively fast response (response time of 116 s) to 20 parts per million NO2 with a response of 4.92% at room temperature at zero bias voltage and 2 V source-drain bias voltage. Moreover, characteristics of our 3D Ag NP/rGO FET sensors, e.g. response, response and recovery times, have been demonstrated to be tuned by adjusting the applied source-drain and gate biases. Compared to the 2D geometry, our 3D geometry occupies less device area, but with the same sensing area. This study provides a new way to optimize sensing device performance, and promotes its development for miniaturized and integrated gas-sensing applications for indoor health and safety detection, outdoor environmental monitoring, industrial pollution monitoring and beyond.

A Novel Three-Dimensional Ag nanoparticles/rGO Microtubular Field Effect Transistor Sensor for NO2Detections.

Abstract：A novel three-dimensional (3D) microtubular NO2FET sensor has been fabricated from the two-dimensional (2D) reduced graphene oxide (rGO) nanosheets decorated with Ag nanoparticles, by applying the self-roll up technique. The electrical properties of 2D and 3D FET Ag NPs/rGO sensors have been investigated and compared. Finally, the performance of the 3D sensors has been demonstrated, where the preliminary results shown that our 3D FET Ag NPs/rGO NO2sensor exhibit a relative fast response (response time of 116 s) to 20 part per million (ppm) NO2with a response of 4.92 % at room temperature at zero bias voltage and 2 V source-drain bias voltage. Moreover, the characteristics of our 3D FET Ag NPs/rGO sensors, e.g. response, response and recovery times have been demonstrated to be tuned by adjusting the applied source-drain and gate biases. Compared to 2D geometry, our 3D geometry occupied less device area, but with the same sensing area. This study would provide a new way to optimize sensing devices performance, and promote its developments for miniaturized and integrated gas sensing applications for indoor health and safety detections, outdoor environmental monitoring, industrial pollution monitoring and beyond.

High sensitivity ultraviolet detection based on three-dimensional graphene field effect transistors decorated with TiO2 NPs.

A three-dimensional (3D) ultraviolet (UV) photodetector was fabricated by decorating a tubular graphene field-effect transistor (GFET) with titanium dioxide (TiO2) nanoparticles (NPs). The unique tubular architecture not only provides a natural 3D optical resonant microcavity to enhance the optical field inside it, but also increases the light-matter interaction area. Strong UV absorption in the TiO2 NPs creates a number of electron-hole pairs, where the electrons are transferred to graphene, while the holes are trapped within the TiO2 NPs, leading to a strong photogating effect on the graphene channel conductance. The photoresponsivity of our 3D GFET photodetector decorated with TiO2 NPs was demonstrated up to 475.5 A W-1 at 325 nm, which is about 2 orders of magnitude higher than that of a 3D GFET photodetector without the TiO2 NP decoration (1 A W-1), and over 3 orders of magnitude higher than that of a recently reported UV photodetector based on the graphene/vertical Ga2O3 nanowire array heterojunction (0.185 A W-1). Moreover, the photoresponsivity and photoresponse speed of the device can be easily tuned by applying a small gate bias (≤3 V) and/or changing the source-drain bias. These results indicate that the photoresponsivities of graphene-based photodetectors can be significantly improved by exploiting 3D graphene structures and integrating graphene with semiconducting light harvesters simultaneously.

Single-cell RNA-Seq analysis identifies a noncoding interleukin 4 (IL-4) RNA that post-transcriptionally up-regulates IL-4 production in T helper cells.

High-throughput sequencing has revealed a tremendous complexity of cellular transcriptomes, which is partly due to the generation of multiple alternative transcripts from a single gene locus. Because alternative transcripts often have low abundance in bulk cells, the functions of most of these transcripts and their relationship with their canonical counterparts remain unclear. Here we applied single-cell RNA-Seq to analyze the transcriptome complexity of in vitro-differentiated, murine type 2 T helper (Th2) cells. We found that cytokine gene transcripts contribute most of the intercellular heterogeneity, with a group of universal cytokines, including interleukins 1a, 2, 3, and 16, being bimodally expressed. At the single-cell level, use of alternative promoters prevalently generated alternative transcripts. For instance, although undetectable in bulk cells, a noncoding RNA isoform of IL-4 (IL4nc), which was driven by an intronic promoter in the IL-4 locus, was predominantly expressed in a subset of Th2 cells. IL4nc displayed distinct temporal expression patterns compared with the canonical IL-4 mRNA and post-transcriptionally promoted the production of IL-4 protein in Th2 cells. In conclusion, our findings reveal a mechanism whereby minor noncanonical transcripts post-transcriptionally regulate expression of their cognate canonical genes.

Iron Drives T Helper Cell Pathogenicity by Promoting RNA-Binding Protein PCBP1-Mediated Proinflammatory Cytokine Production.

Iron deposition is frequently observed in human autoinflammatory diseases, but its functional significance is largely unknown. Here we showed that iron promoted proinflammatory cytokine expression in T cells, including GM-CSF and IL-2, via regulating the stability of an RNA-binding protein PCBP1. Iron depletion or Pcbp1 deficiency in T cells inhibited GM-CSF production by attenuating Csf2 3' untranslated region (UTR) activity and messenger RNA stability. Pcbp1 deficiency or iron uptake blockade in autoreactive T cells abolished their capacity to induce experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis. Mechanistically, intracellular iron protected PCBP1 protein from caspase-mediated proteolysis, and PCBP1 promoted messenger RNA stability of Csf2 and Il2 by recognizing UC-rich elements in the 3' UTRs. Our study suggests that iron accumulation can precipitate autoimmune diseases by promoting proinflammatory cytokine production. RNA-binding protein-mediated iron sensing may represent a simple yet effective means to adjust the inflammatory response to tissue homeostatic alterations.

Tim-3 signaling in peripheral NK cells promotes maternal-fetal immune tolerance and alleviates pregnancy loss.

Pregnancy loss occurs in about 15% of clinically recognized pregnancies, and defective maternal-fetal immune tolerance contributes to more than 50% of these events. We found that signaling by the type I membrane protein T cell immunoglobulin and mucin-containing protein 3 (Tim-3) in natural killer (NK) cells had an essential protective role during early pregnancy. Tim-3 on peripheral NK (pNK) cells was transiently increased in abundance during the first trimester of pregnancy, which depended on interleukin-4 (IL-4)-signal transducer and activator of transcription 6 (STAT6) and progesterone signaling. Tim-3+ pNK cells displayed immunosuppressive activities, including the production of anti-inflammatory cytokines and the induction of regulatory T cells (Tregs) in a transforming growth factor-ß1 (TGF-ß1)-dependent manner. Tim-3 on pNK cells was stimulated by its ligand galectin-9 (Gal-9), leading to signaling by the kinases c-Jun N-terminal kinase (JNK) and AKT. In recurrent miscarriage (RM) patients, Tim-3 abundance on pNK cells was reduced and the immunosuppressive activity of Tim-3+ pNK cells was impaired. Compared to Tim-3+ pNK cells from donors with normal pregnancies, RM patient Tim-3+ pNK cells exhibited changes in DNA accessibility in certain genetic loci, which were reversed by inhibiting accessible chromatin reader proteins. Furthermore, Tim-3+ pNK cells, but not Tim-3- pNK cells, reduced fetal loss in abortion-prone and NK cell-deficient mice. Together, our findings reveal a critical role for Tim-3-Gal-9 signaling-mediated immunoregulation by pNK cells in maternal-fetal immune tolerance and suggest that Tim-3 abundance on pNK cells is a potential biomarker for RM diagnosis.

Targeted AID-mediated mutagenesis (TAM) enables efficient genomic diversification in mammalian cells.

A large number of genetic variants have been associated with human diseases. However, the lack of a genetic diversification approach has impeded our ability to interrogate functions of genetic variants in mammalian cells. Current screening methods can only be used to disrupt a gene or alter its expression. Here we report the fusion of activation-induced cytidine deaminase (AID) with nuclease-inactive clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (dCas9) for efficient genetic diversification, which enabled high-throughput screening of functional variants. Guided by single guide (sg)RNAs, dCas9-AID-P182X (AIDx) directly changed cytidines or guanines to the other three bases independent of AID hotspot motifs, generating a large repertoire of variants at desired loci. Coupled with a uracil-DNA glycosylase inhibitor, dCas9-AIDx converted targeted cytidines specifically to thymines, creating specific point mutations. By targeting BCR-ABL with dCas9-AIDx, we efficiently identified known and new mutations conferring imatinib resistance in chronic myeloid leukemia cells. Thus, targeted AID-mediated mutagenesis (TAM) provides a forward genetic tool to screen for gain-of-function variants at base resolution.

Effect of reactions in small eddies on biomass gasification with eddy dissipation concept - Sub-grid scale reaction model.

Large-eddy simulation (LES) approach is used for gas turbulence, and eddy dissipation concept (EDC)-sub-grid scale (SGS) reaction model is employed for reactions in small eddies. The simulated gas molar fractions are in better agreement with experimental data with EDC-SGS reaction model. The effect of reactions in small eddies on biomass gasification is emphatically analyzed with EDC-SGS reaction model. The distributions of the SGS reaction rates which represent the reactions in small eddies with particles concentration and temperature are analyzed. The distributions of SGS reaction rates have the similar trend with those of total reactions rates and the values account for about 15% of the total reactions rates. The heterogeneous reaction rates with EDC-SGS reaction model are also improved during the biomass gasification process in bubbling fluidized bed.