Photo-Controlled Nano-Supramolecular Size and Reversible Luminescent Behaviors Based on Cucurbit[7]uril Cascaded Assembly.

Supramolecular luminescent material with switchable behavior and photo-induced aggregation with emission enhancement is a current research hot spot. Herein, a size-tunable nano-supramolecular assembly with reversible photoluminescent behavior was constructed by noncovalent polymerization of diarylethene-bridged bis(coumarin) derivative (DAE-CO), cucurbit[7]uril (CB[7]), and ß-cyclodextrin-grafted hyaluronic acid (HACD). Benefiting from the macrocyclic confinement effect, the guest molecule DAE-CO was included into the cavity of CB[7] to give enhanced fluorescence emission of the resulting DAE-CO⊂CB[7]2 with longer lifetime at 432 nm to 1.43 ns, thereby further enhancing fluorescence output and lifetime (1.46 ns) when further assembled with HACD, compared with the free DAE-CO (0.95 ns). In addition, DAE-CO, DAE-CO⊂CB[7]2, and DAE-CO⊂CB[7]2&HACD all possessed characteristics of aggregation-induced emission and reversible photo-switched structural interconversion, exhibiting an obvious photophysical activation phenomenon of self-aggregation into larger nanoparticles with increase in fluorescence emission intensity, lifetime, and size after irradiation, which could be increased step by step with the alternating irradiation of 254 nm (5 min) or >600 nm (30 s) repeated 7 times. These supramolecular assemblies were successfully used in the tumor cells' targeted imaging and anti-counterfeiting because of the capability of HACD for recognizing specific receptors overexpressed on the surface of tumor cells and the excellent photo-regulated switch ability of DAE-CO, providing an approach of constructing photo-induced emission-enhanced luminescent materials.

Integrated mRNA sequence optimization using deep learning.

The coronavirus disease of 2019 pandemic has catalyzed the rapid development of mRNA vaccines, whereas, how to optimize the mRNA sequence of exogenous gene such as severe acute respiratory syndrome coronavirus 2 spike to fit human cells remains a critical challenge. A new algorithm, iDRO (integrated deep-learning-based mRNA optimization), is developed to optimize multiple components of mRNA sequences based on given amino acid sequences of target protein. Considering the biological constraints, we divided iDRO into two steps: open reading frame (ORF) optimization and 5' untranslated region (UTR) and 3'UTR generation. In ORF optimization, BiLSTM-CRF (bidirectional long-short-term memory with conditional random field) is employed to determine the codon for each amino acid. In UTR generation, RNA-Bart (bidirectional auto-regressive transformer) is proposed to output the corresponding UTR. The results show that the optimized sequences of exogenous genes acquired the pattern of human endogenous gene sequence. In experimental validation, the mRNA sequence optimized by our method, compared with conventional method, shows higher protein expression. To the best of our knowledge, this is the first study by introducing deep-learning methods to integrated mRNA sequence optimization, and these results may contribute to the development of mRNA therapeutics.

A Meta-Analysis on the Impact of Prenatal and Early Childhood Antimicrobial Use on Autism Spectrum Disorders.

OBJECTIVE: To investigate the impact of prenatal and early childhood antimicrobial use on autism spectrum disorders (ASD). DATA SOURCES: We searched PubMed and Embase databases for relevant studies from inception to August 2022. STUDY SELECTION AND DATA EXTRACTION: Peer-reviewed, observational studies were all acceptable. Raw data were extracted into a predefined worksheet and quality analysis was performed using the Newcastle-Ottawa Scale. DATA SYNTHESIS: Nineteen studies were identified in the meta-analysis. Prenatal antimicrobial exposure was not associated with ASD (P = 0.06 > 0.05), whereas early childhood antimicrobial exposure was associated with an increased odds ratio of ASD (OR = 1.17, 95% CI = [1.08-1.27], P value < 0.001). The sibling-matched analysis, with a very limited sample size, suggested that neither prenatal (P = 0.47 > 0.05) nor early childhood (P = 0.13 > 0.05) antimicrobial exposure was associated with ASD. Medical professionals may need to take the possible association into consideration when prescribing an antimicrobial in children. CONCLUSIONS: Early childhood antimicrobial exposure could increase the incidence of ASD. In future studies, it would be necessary to control for confounding factors, such as genetic factors, parenteral age at birth, or low birthweight, to further validate the association.

AFINet: Attentive Feature Integration Networks for image classification.

Convolutional Neural Networks (CNNs) have achieved tremendous success in a number of learning tasks including image classification. Residual-like networks, such as ResNets, mainly focus on the skip connection to avoid gradient vanishing. However, the skip connection mechanism limits the utilization of intermediate features due to simple iterative updates. To mitigate the redundancy of residual-like networks, we design Attentive Feature Integration (AFI) modules, which are widely applicable to most residual-like network architectures, leading to new architectures named AFI-Nets. AFI-Nets explicitly model the correlations among different levels of features and selectively transfer features with a little overhead. AFI-ResNet-152 obtains a 1.24% relative improvement on the ImageNet dataset while decreases the FLOPs by about 10% and the number of parameters by about 9.2% compared to ResNet-152.

Electroacupuncture at Zusanli ameliorates the autistic-like behaviors of rats through activating the Nrf2-mediated antioxidant responses.

OBJECTIVE: Emerging evidence suggests that acupuncture plays a neuroprotective role in autism. This study aimed to explore the effect of electroacupuncture at Zusanli (ST36) on autistic-like behaviors and the underlying mechanism. METHOD: Pregnant rats were administered with valproic acid (VPA) on gestational day 12.5 to induce an autism spectrum disorder (ASD) model. The pups were given electroacupuncture at ST36 daily from postnatal day (PND) 28-48. On PND28, the adenoviral vector containing small interfering RNA Nrf2 (Ad-siRNA-Nrf2) was injected into the prefrontal cortex of rats. The behavioral analysis was performed on PND 44-48. On PND48, the animals were euthanized and the brains were collected for further detection. Nissl staining was performed to detect neuronal viability. The biochemical markers of oxidative stress were subsequently measured. RESULT: Electroacupuncture at ST36 ameliorated the locomotor activity, social behavior, spatial learning and memory and repetitive behavior compared with ASD rats. It was notable that the electroacupuncture decreased oxidative stress markers in the tissues of prefrontal cortex, enhanced translocation of nuclear factor erythroid2-related factor2 (Nrf2) from cytoplasm to nucleus, and up-regulated the levels of NADP(H) quinone oxidoreductase (NQO1) and heme oxygenase (HO-1). However, these effects induced by electroacupuncture at ST36 were abolished after injection of Ad-siRNA-Nrf2. CONCLUSION: These data suggested that electroacupuncture at ST36 protected nerve function in ASD rats through Nrf2 activation and the antioxidant response.

Acupuncture at ST36 Alleviates the Behavioral Disorder of Autistic Rats by Inhibiting TXNIP-Mediated Activation of NLRP3.

Autism is a common neurodevelopmental disorder that severely affects patients' quality of life. We aimed to investigate whether acupuncture at Zusanli (ST36) could alleviate the behavior disorder of autistic rats by inhibiting thioredoxin-interacting protein (TXNIP)-mediated activation of NLRP3. An autism model was induced by intraperitoneal injection of pregnant rats with valproic acid (VPA). The pups' behaviors were analyzed using hot plate, open field, Morris water maze, and 3-chamber social interaction tests. Nissl staining was used to visualize neurons in prefrontal cortex. Levels of TXNIP, NLRP3, interleukin (IL)-1ß, and caspase were determined by Western blot or quantitative real-time PCR. After ST36 acupuncture, pain sensitivity, autonomous activity, sociability index, sociability preference index, and learning and memory were improved in the autism model rats. Levels of TXNIP, NLRP3, IL-1ß, and caspase 1 were decreased after acupuncture. Interference with TXNIP alleviated the behavior disorders and inhibited NLRP3, caspase 1, and IL-1ß levels. In summary, ST36 acupuncture reduced TXNIP expression, inhibited the activation of the NLRP3 inflammasome, and alleviated the behavior disorder related to the prefrontal cortex of the autistic rats. These results point to a potential mechanism for acupuncture-induced improvement of autistic behavioral disorders.

Novel Porous Rhodium Metal-Organic Aerogel for Efficient Removal of Organic Dyes and Catalysis of Si-H Insertion Reactions.

Metal-organic gels (MOGs) are attracting increasing attention for removal of organic dyes from aqueous solution and for catalysis of Si-H insertion reactions. Herein, we report that a reaction of porphyrin derivative 1 with Rh2(OAc)4 generates stable metal-organic gels and subsequent subcritical carbon dioxide drying affords metal-organic aerogels. Owing to their micro- and mesoporosity, the aerogels adsorbed dyes. Moreover, aerogel I catalyzed Si-H insertion reactions to give organosilicon compounds in high yields.

Codon optimization with deep learning to enhance protein expression.

Heterologous expression is the main approach for recombinant protein production ingenetic synthesis, for which codon optimization is necessary. The existing optimization methods are based on biological indexes. In this paper, we propose a novel codon optimization method based on deep learning. First, we introduce the concept of codon boxes, via which DNA sequences can be recoded into codon box sequences while ignoring the order of bases. Then, the problem of codon optimization can be converted to sequence annotation of corresponding amino acids with codon boxes. The codon optimization models for Escherichia Coli were trained by the Bidirectional Long-Short-Term Memory Conditional Random Field. Theoretically, deep learning is a good method to obtain the distribution characteristics of DNA. In addition to the comparison of the codon adaptation index, protein expression experiments for plasmodium falciparum candidate vaccine and polymerase acidic protein were implemented for comparison with the original sequences and the optimized sequences from Genewiz and ThermoFisher. The results show that our method for enhancing protein expression is efficient and competitive.

Reversible Emitting Anti-Counterfeiting Ink Prepared by Anthraquinone-Modified ß-Cyclodextrin Supramolecular Polymer.

Intelligent fluorescent materials have been paid more and more attention due to their wide application in information encryption and anti-counterfeiting materials. Herein, a supramolecular polymer is constructed through the host-guest interaction of anthraquinone-modified ß-cyclodextrin (AQ-ß-CD) in aqueous solution. Thanks to the hydrophobic microenvironment of the cyclodextrin cavity and the shielding effect on oxygen molecules, the anthraquinone group, as the guest molecule, can rapidly produce 9,10-anthracenediol (QH2) with strong fluorescence by photoreduction. Interestingly, the generated anthracenediol group is still sensitive to oxygen and can be converted to anthraquinone by oxygen. Significantly, aqueous solution of AQ-ß-CD supermolecular polymer is used as emitting ink, which decrypts the information by ultraviolet light and encrypts the information in the air.

Polysaccharide-Based Nanoparticles for Two-Step Responsive Release of Antitumor Drug.

A novel two-step in situ method for targeted antitumor drug release by supramolecular assembly (Fc-CPT@HACD) was constructed using camptothecin prodrug (Fc-CPT) and ß-cyclodextrin (ß-CD)-modified hyaluronic acid (HACD). Benefiting from the overexpressed H2O2 and glutathione (GSH) in tumor cells, Fc-CPT@HACD can be disassembled by oxidation of ferrocene (Fc) to Fc+, leading to an efficient release of the anticancer drug camptothecin (CPT) to induce tumor cell apoptosis without affecting normal cells. The in vivo experiment results also demonstrated that Fc-CPT@HACD possessed higher anticancer efficiency than free CPT, accompanied by negligible side effects.

Photo-controlled chirality transfer and FRET effects based on pseudo[3]rotaxane.

The use of light to regulate the chirality of supramolecular assemblies in a non-invasive manner remains a challenge. Herein, we report a novel photochromic pseudo[3]rotaxane based on a (R/S)-2,2'-binaphthyl secondary ammonium salt guest (2) and anthracene-bridged bis(dibenzo-24-crown-8) (1), which features a chirality transfer and fluorescence resonance energy transfer (FRET) from 2 to 1. Benefiting from the photo-oxidation of anthracene, the induced circular dichroism (ICD) signals of (R/S)-2@1 can be switched off/on by irradiation with 365 nm UV light and heating. This noncovalent supramolecular assembly strategy provides us with unique opportunities to design and construct further smart photo-responsive chiral molecular switches.

Multistimuli-Responsive and Photocontrolled Supramolecular Luminescent Gels Constructed by Anthracene-Bridged Bis(dibenzo-24-crown-8) with Secondary Ammonium Salt Polymer.

A novel multistimuli-responsive and photcontrolled supramolecular luminescent gel is fabricated from anthracene-bridged bis(dibenzo-24-crown-8) (1) and secondary ammonium salt-functionalized graft polymer (3). X-ray crystallographic analysis reveals that the dibenzo-24-crown-8 (DB24C8) ring is located at the opposite site of 1, which will greatly hinder the mutual intermolecular π-π stacking between anthracene groups. By taking advantage of the controllable binding of 1 with 3, the unique gel-sol transition could occur under different temperatures, pH, and competitive guest bindings. Benefiting from the photo-oxygenation of anthracene, the luminescence behavior of the supramolecular gel could be switched off and on under UV light (365 nm) and heating treatment, which provides a new approach for constructing photocontrolled supramolecular luminescent gel.

A tumor-targeting Ru/polysaccharide/protein supramolecular assembly with high photodynamic therapy ability.

Supramolecular assembly with tumor-targeting properties or photodynamic therapy (PDT) ability has recently become a focus of interest in biomaterial field because of its high therapeutic efficacy against tumor cells. Herein, we reported a new type of targeted supramolecular nanoparticles for photodynamic therapy of tumor cells constructed using adamantane-functionalized transferrin protein (Ad-TRF) and a ß-cyclodextrin-functionalized ruthenium complex (Ru-HOP-CD), wherein Ad-TRFs acted as the targeted sites for tumor cells, the coordinated Ru(ii) centers acted as the PDT active sites, and the biocompatible polysaccharide ß-cyclodextrins acted as the non-covalent linkers. Significantly, the resultant Ru/polysaccharide/protein exhibited not only specific targeting properties towards tumor cells but also high PDT ability under the irradiation of visible light. Furthermore, the assembly showed selective killing towards tumor cells along with negligible toxicity towards normal cells.

Capsule Networks Showed Excellent Performance in the Classification of hERG Blockers/Nonblockers.

Capsule networks (CapsNets), a new class of deep neural network architectures proposed recently by Hinton et al., have shown a great performance in many fields, particularly in image recognition and natural language processing. However, CapsNets have not yet been applied to drug discovery-related studies. As the first attempt, we in this investigation adopted CapsNets to develop classification models of hERG blockers/nonblockers; drugs with hERG blockade activity are thought to have a potential risk of cardiotoxicity. Two capsule network architectures were established: convolution-capsule network (Conv-CapsNet) and restricted Boltzmann machine-capsule networks (RBM-CapsNet), in which convolution and a restricted Boltzmann machine (RBM) were used as feature extractors, respectively. Two prediction models of hERG blockers/nonblockers were then developed by Conv-CapsNet and RBM-CapsNet with the Doddareddy's training set composed of 2,389 compounds. The established models showed excellent performance in an independent test set comprising 255 compounds, with prediction accuracies of 91.8 and 92.2% for Conv-CapsNet and RBM-CapsNet models, respectively. Various comparisons were also made between our models and those developed by other machine learning methods including deep belief network (DBN), convolutional neural network (CNN), multilayer perceptron (MLP), support vector machine (SVM), k-nearest neighbors (kNN), logistic regression (LR), and LightGBM, and with different training sets. All the results showed that the models by Conv-CapsNet and RBM-CapsNet are among the best classification models. Overall, the excellent performance of capsule networks achieved in this investigation highlights their potential in drug discovery-related studies.

Effect of dexmedetomidine on cerebral ischemia-reperfusion rats by activating mitochondrial ATP-sensitive potassium channel.

The aim of the study reported here was to evaluate whether the mitochondrial ATP-sensitive potassium (mitoKATP) channel could participate in the effect of dexmedetomidine on cerebral ischemia-reperfusion (I/R) rats. Forty rats were randomly assigned into 5 groups: sham operation (S) group; cerebral I/R group; dexmedetomidine (D) group; 5-hydroxydecanoate (5-HD) group; 5-HD + D group. The cerebral I/R were produced by 2 h right middle cerebral artery occlusion followed by 24 h reperfusion. Dexmedetomidine (50µg/kg) was injected intraperitoneally before ischemia and after the onset of reperfusion. 5-HD (30 mg/kg) was injected intraperitoneally at 1 h before ischemia. The neurological deficit score (NDS) and the levels of super oxide dismutase (SOD), malondialdehyde (MDA), myeloperoxidase (MPO), Interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) were evaluated. Compared to group S, NDS and the levels of MDA, MPO, IL-6 and TNF-α were significantly higher, and SOD levels were significantly lower in the other groups (P < 0.05). Compared to group I/R,NDS and the levels of MDA, MPO, IL-6 and TNF-α were significantly lower, and SOD level was significantly higher in group D (P < 0.05). Compared to group D, NDS and the levels of MDA, MPO, IL-6 and TNF-α were significantly higher, and SOD level was significantly lower in group5-HD + D (P < 0.05). The activation of the mitoKATP channel could contribute to the protective effect of dexmedetomidine on rats induced by focal cerebral ischemia-reperfusion injury.

Enantioselective Intramolecular C-H Insertion of Donor and Donor/Donor Carbenes by a Nondiazo Approach.

The first enantioselective intramolecular C-H insertion and cyclopropanation reactions of donor- and donor/donor-carbenes by a nondiazo approach are reported. The reactions were conducted in a one-pot manner without slow addition and provided the desired dihydroindole, dihydrobenzofuran, tetrahydrofuran, and tetrahydropyrrole derivatives with up to 99 % ee and 100 % atom efficiency.

Dexmedetomidine-fentanyl versus propofol-fentanyl in flexible bronchoscopy: A randomized study.

The aim of the present study was to evaluate the effect of a combination of dexmedetomidine and fentanyl on peripheral oxygen saturation (SpO2) and hemodynamic stability in patients undergoing flexible bronchoscopy. One hundred patients undergoing elective flexible bronchoscopy were randomized into either a propofol-fentanyl group (PF group; n=50) or a dexmedetomidine-fentanyl group (DF group; n=50). SpO2 values, heart rate (HR), systolic and diastolic blood pressure (SBP and DBP), patients' cough scores and discomfort scores as determined by patients and bronchoscopists, levels of sedation, number of times that additional lidocaine was required, elapsed time until recovery, and adverse events were recorded. The mean SpO2 values in the DF group were significantly higher than those in the PF group (P<0.01), and HR, SBP and DBP were significantly lower in the DF group than in the PF group (P<0.05). There were no statistically significant differences between the two groups in terms of cough scores or discomfort scores, sedation levels, or number of times that additional lidocaine was required (P>0.05). Elapsed time until recovery in the DF group was significantly longer than in the PF group (P=0.002). The incidence of hypoxemia was significantly lower in the DF group than in the PF group (P=0.027), but the incidence of bradycardia was significantly higher in the DF group than in the PF group (P=0.037). Dexmedetomidine-fentanyl was superior to propofol-fentanyl in providing satisfactory SpO2. Furthermore, dexmedetomidine-fentanyl attenuated hemodynamic responses during bronchoscopy and maintained hemodynamic stability in the early stage of the procedure.

Dual Catalysis: Proton/Metal-Catalyzed Tandem Benzofuran Annulation/Carbene Transfer Reaction.

An efficient proton/metal-catalyzed tandem benzofuran annulation/carbene transfer reaction for the synthesis of various benzofuryl-substituted cyclopropanes and cycloheptatrienes has been developed. The reaction was proposed to proceed through two key intermediates, o-quinone methide (o-QM) and benzofuryl carbene. The DFT-based computational studies indicated that the reaction was initiated through the dehydration of o-HBA via a Brønsted acid mediated proton shuttle transition state, forming the key intermediate o-QM.

Impact of CYP2D6 Polymorphisms on Postoperative Fentanyl Analgesia in Gastric Cancer Patients.

BACKGROUND: This study investigated the influence of human cytochrome P450 2D6 (CYP2D6) gene polymorphism in gastric cancer (GC) patients to understand the pharmacogenomic basis for patient response to postoperative fentanyl analgesia. METHODS: The prospective study design contained 212 patients recovering from radical gastrectomy. Peripheral blood samples were collected after general anesthesia, and CYP2D6 genotypes were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. After providing adequate instructions to operate the analgesia pump, patients self-administered fentanyl via patient controlled intravenous analgesia. The cumulative amount of fentanyl self-administered and the associated adverse effects were recorded at 6, 12, 24, and 48 h postoperatively. RESULTS: Five patients, out of the 212 patients recruited to this study, failed to complete the study. The remaining 207 patients were classified into three groups based on their genotypes: W/W group (n=44), M/W group (n=112), and M/M group (n=51). Our results demonstrated that the cumulative amount of fentanyl consumption significantly increased in the M/M group at 6, 12, and 24 h postoperatively, compared with the W/W group (p<0.05). In addition, visual analogue scale (VAS) score in the M/M group was significantly higher than the W/W group in the analepsia period after general anesthesia and at 6 h postoperatively (p<0.05). No significant adverse effects were observed in all the groups (p>0.05). CONCLUSION: CYP2D6 polymorphism influenced patient response to postoperative fentanyl analgesia in GC patients.