Comparative analysis of the effect of electromyogram to bispectral index and 95% spectral edge frequency under remimazolam and propofol anesthesia: a prospective, randomized, controlled clinical trial.

Background: Bispectral index (BIS), an index used to monitor the depth of anesthesia, can be interfered with by the electromyogram (EMG) signal. The 95% spectral edge frequency (SEF95) also can reflect the sedation depth. Remimazolam in monitored anesthesia care results in higher BIS values than propofol, though in the same sedation level assessed by Modified Observers Assessment of Alertness and Sedation (MOAA/S). Our study aims to illustrate whether EMG is involved in remimazolam causing higher BIS value than propofol preliminarily and to explore the correlations among BIS, EMG, and SEF95 under propofol and remimazolam anesthesia. Patients and methods: Twenty-eight patients were randomly divided into propofol (P) and remimazolam (RM) groups. Patients in the two groups received alfentanil 10 µg/kg, followed by propofol 2 mg/kg and remimazolam 0.15 mg/kg. Blood pressure (BP), heart rate (HR), and oxygen saturation (SpO2) were routinely monitored. The BIS, EMG, and SEF95 were obtained through BIS VISTATM. The primary outcomes were BIS, EMG, and the correlation between BIS and EMG in both groups. Other outcomes were SEF95, the correlation between BIS and SEF95, and the correlation between EMG and SEF95. And all the statistical and comparative analysis between these signals was conducted with SPSS 26.0 and GraphPad Prism 8. Results: BIS values, EMG, and SEF95 were significantly higher in the RM group than in the P group (all p < 0.001). There was a strong positive correlation between BIS and EMG in the RM group (r = 0.416). Nevertheless, the BIS in the P group showed a weak negative correlation with EMG (r = -0.219). Both P (r = 0.787) and RM group (r = 0.559) had a reasonably significant correlation coefficient between BIS and SEF95. SEF95 almost did not correlate with EMG in the RM group (r = 0.101). Conclusion: Bispectral index can be interfered with high EMG intensity under remimazolam anesthesia. However, EMG can hardly affect the accuracy of BIS under propofol anesthesia due to low EMG intensity and a weak negative correlation between EMG and BIS. Moreover, SEF95 may have a great application prospect in predicting the sedation condition of remimazolam.

Discovery of novel non-nucleoside inhibitors with high potency and selectivity for DNA methyltransferase 3A.

DNA methyltransferases (DNMTs) are important epigenetic regulatory enzymes involved in gene expression corresponding to many diseases including cancer. As one of the major enzymatically active mammalian DNMTs, DNMT3A has been regarded as an attractive target for the treatment of cancer particularly in hematological malignancy. Discovery of promising inhibitors toward this target with low toxicity, adequate activity and target selectivity is therefore pivotal in the development of novel cancer therapy and the inhibitory mechanism investigation. In this study, a multistep structure-based virtual screening and in vitro bioassays were conducted to search for potent novel DNMT3A inhibitors. Compound DY-46 was then identified as a promising new scaffold candidate (IC50 = 1.3 ± 0.22 µM) that can occupy both the SAM-cofactor pocket and the cytosine pocket of DNMT3A. Further similarity searching led to the discovery of compound DY-46-2 with IC50 of 0.39 ± 0.23 µM, which showed excellent selectivity against DNMT1 (33.3-fold), DNMT3B (269-fold) and G9a (over 1000-fold). These potent compounds significantly inhibited cancer cell proliferation and showed low cytotoxicity in peripheral blood mononuclear cells. This study provides a promising scaffold for the further development of DNMT3A inhibitors, and the possibility to design proper analogs with broad or specific selectivity.

A Two-Stream Graph Convolutional Network Based on Brain Connectivity for Anesthetized States Analysis.

Investigating neural mechanisms of anesthesia process and developing efficient anesthetized state detection methods are especially on high demand for clinical consciousness monitoring. Traditional anesthesia monitoring methods are not involved with the topological changes between electrodes covering the prefrontal-parietal cortices, by investigating electrocorticography (ECoG). To fill this gap, a framework based on the two-stream graph convolutional network (GCN) was proposed, i.e., one stream for extracting topological structure features, and the other one for extracting node features. The two-stream graph convolutional network includes GCN Model 1 and GCN Model 2. For GCN Model 1, brain connectivity networks were constructed by using phase lag index (PLI), representing different structure features. A common adjacency matrix was founded through the dual-graph method, the structure features were expressed on nodes. Therefore, the traditional spectral graph convolutional network can be directly applied on the graphs with changing topological structures. On the other hand, the average of the absolute signal amplitudes was calculated as node features, then a fully connected matrix was constructed as the adjacency matrix of these node features, as the input of GCN Model 2. This method learns features of both topological structure and nodes of the graph, and uses a dual-graph approach to enhance the focus on topological structure features. Based on the ECoG signals of monkeys, results show that this method which can distinguish awake state, moderate sedation and deep sedation achieved an accuracy of 92.75% in group-level experiments and mean accuracy of 93.50% in subject-level experiments. Our work verifies the excellence of the graph convolutional network in anesthesia monitoring, the high recognition accuracy also shows that the brain network may carry neurological markers associated with anesthesia.

Brain Connectivity Analysis in Anesthetized and Awake States: an ECoG Study in Monkeys.

Increasingly, studies have shown that changes in brain network topology accompany loss of consciousness such that the functional connectivity of the prefrontal-parietal network differs significantly in anesthetized and awake states. In this work, anesthetized and awake segments of electrocorticography were selected from two monkeys. Using phase lag index, functional connectivity matrices were built in multiple frequency bands. Quantifying topological changes in brain network through graph-theoretic properties revealed significant differences between the awake and anesthetized states. Compared to the awake state, there were distinct increases in overall and Delta prefrontal-frontal connectivity, and decreases in Alpha, Beta1 and Beta2 prefrontal-frontal connectivity during the anesthetized state, which indicate a change in the topology of the small-world network. Using functional connectivity features we achieved a satisfactory classification accuracy (93.68%). Our study demonstrates that functional connectivity features are of sufficient power to distinguish awake versus anesthetized state.Clinical Relevance- This explores the brain network topology in awake and anesthetized states, and provides new ideas for clinical depth of anesthesia monitoring.

DNA methyltransferases: emerging targets for the discovery of inhibitors as potent anticancer drugs.

DNA methyltransferases (DNMTs) are a conserved family of cytosine methylases with crucial roles in epigenetic regulation. They have been considered as promising therapeutic targets for the epigenetic treatment of cancer. Therefore, DNMT inhibitors (DNMTis) have attracted considerable interest in recent years for the modulation of the aberrant DNA methylation pattern in a reversible way. In this review, we provide a structure-based overview of the therapeutic importance of DNMTs against different cancer types, and then summarize recently investigated DNMTis as well as their inhibitory mechanisms, focusing on recent advances in the development of DNMTis with specificity and/or selectivity using computational approaches.

Insight into the selective binding mechanism of DNMT1 and DNMT3A inhibitors: a molecular simulation study.

DNA methyltransferases (DNMTs), responsible for the regulation of DNA methylation, have been regarded as promising drug targets for cancer therapy. However, high structural conservation of the catalytic domains of DNMTs poses a big challenge to design selective inhibitors for a specific DNMT isoform. In this study, molecular dynamics (MD) simulations, end-point free energy calculations and umbrella sampling (US) simulations were performed to reveal the molecular basis of the binding selectivity of three representative DNMT inhibitors towards DNMT1 and DNMT3A, including SFG (DNMT1 and DNMT3A dual inhibitors), DC-05 (DNMT1 selective inhibitor) and GSKex1 (DNMT3A selective inhibitor). The binding selectivity of the studied inhibitors reported in previous experiments is reproduced by the MD simulation and binding free energy prediction. The simulation results also suggest that the driving force to determine the binding selectivity of the studied inhibitors stems from the difference in the protein-inhibitor van der Waals interactions. Meanwhile, the per-residue free energy decomposition reveals that the contributions from several non-conserved residues in the binding pocket of DNMT1/DNMT3A, especially Val1580/Trp893, Asn1578/Arg891 and Met1169/Val665, are the key factors responsible for the binding selectivity of DNMT inhibitors. In addition, the binding preference of the studied inhibitors was further validated by the potentials of mean force predicted by the US simulations. This study will provide valuable information for the rational design of novel selective inhibitors targeting DNMT1 and DNMT3A.