Copper-Catalyzed Tunable Oxygenative Rearrangement of Tetrahydrocarbazoles.

Herein, we report a general copper-catalyzed method for the tunable oxygenative rearrangement of tetrahydrocarbazoles to cyclopentyl-bearing spiroindolin-2-ones and spiroindolin-3-ones. The method demonstrates excellent chemoselectivity, regioselectivity, and product control simply by using the H2O and O2 as oxygen source, respectively. This open-flask method is safe and simple to operate, and no other chemical oxidants are required. Besides, inspired from the unique pathway of 1, 2-migration rearrangement, a highly controllable hydroxylation of indoles for the construction of C3a-hydroxyl iminium indolines was also developed. Mechanistic experiments suggest that a single-electron transfer-induced oxidation process is responsible for the tunable selectivity control.

Direct synthesis of N-functionalized indoles through isomerization of azomethine ylides.

An unexpected isomerization of azomethine ylides generated in situ from isatin with indoline-2-carboxylic acid has been disclosed, providing direct access to N-functionalized indole scaffolds. This protocol has good functional group tolerance and provides various 3-(1H-indol-1-yl)indolin-2-one derivatives in moderate to high yields simply by using alcohol as the solvent, with no additional additive being required.

Application of arterial spin labeling techniques in autism spectrum disorder with or without global developmental delay / 实用放射学杂志

Objective To measure and compare the cerebral blood flow(CBF)of children with autism spectrum disorder(ASD),global developmental delay(GDD),and ASD with GDD groups via arterial spin labeling(ASL)technique,and to evaluate the diag-nostic value of CBF values.Methods ASL images of ASD,GDD,and ASD with GDD groups of children were firstly acquired,and the CBF values of frontal lobe,temporal lobe,parietal lobe,occipital lobe,striatum and thalamus region of interest(ROI)were fur-ther measured,respectively.One-way analysis of variance or Kruskal-Wallis H test was used to compare the differences in CBF values among these three groups,and the receiver operating characteristic(ROC)curve was used to analyze the efficacy of CBF values in distinguishing ASD with GDD from without GDD.Results ASD with GDD had significantly lower CBF values in the left and right frontal lobes than those with ASD or GDD alone,and the differences were statistically significant(P<0.05).The CBF values in the left and right frontal lobes effectively distinguished ASD with GDD from without GDD[area under the curve(AUC)>0.7].Conclusion ASL technique can noninvasively assess CBF in children with or without GDD,helping to understand the pathophysiology of ASD with GDD and improving diagnostic accuracy.

Reduced expression of semaphorin 3A in osteoclasts causes lymphatic expansion in a Gorham-Stout disease (GSD) mouse model / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Gorham-Stout disease (GSD) is a sporadic chronic disease characterized by progressive bone dissolution, absorption, and disappearance along with lymphatic vessel infiltration in bone-marrow cavities. Although the osteolytic mechanism of GSD has been widely studied, the cause of lymphatic hyperplasia in GSD is rarely investigated. In this study, by comparing the RNA expression profile of osteoclasts (OCs) with that of OC precursors (OCPs) by RNA sequencing, we identified a new factor, semaphorin 3A (Sema3A), which is an osteoprotective factor involved in the lymphatic expansion of GSD. Compared to OCPs, OCs enhanced the growth, migration, and tube formation of lymphatic endothelial cells (LECs), in which the expression of Sema3A is low compared to that in OCPs. In the presence of recombinant Sema3A, the growth, migration, and tube formation of LECs were inhibited, further confirming the inhibitory effect of Sema3A on LECs in vitro. Using an LEC-induced GSD mouse model, the effect of Sema3A was examined by injecting lentivirus-expressing Sema3A into the tibiae in vivo. We found that the overexpression of Sema3A in tibiae suppressed the expansion of LECs and alleviated bone loss, whereas the injection of lentivirus expressing Sema3A short hairpin RNA (shRNA) into the tibiae caused GSD-like phenotypes. Histological staining further demonstrated that OCs decreased and osteocalcin increased after Sema3A lentiviral treatment, compared with the control. Based on the above results, we propose that reduced Sema3A in OCs is one of the mechanisms contributing to the pathogeneses of GSD and that expressing Sema3A represents a new approach for the treatment of GSD.

Electrochemical bromocyclization enables 3,5-diversification of heterocyclic indolines.

Electrophilic bromocyclization reactions are widely used as key steps in the synthesis of diverse functionalized tetrahydrofuroindolines and hexahydropyrroloindolines. However, the direct dibromination variants of these reactions for the synthesis of 3,5-dibromoindolines remain undeveloped. Here, we report a protonic-acid-promoted electrooxidative protocol for the dearomative C3,C5-dibromocyclizations of tryptophol and tryptamine derivatives. This electrosynthetic approach, which enables direct selective construction of heterocyclic 3a,5a-dibromoindolines with inexpensive, non-hazardous NaBr as both the electrolyte and Br source, provides a convenient, practical method for the late-stage 3,5-diversification of heterocyclic indolines.

Copper-Catalyzed Aerobic Selective Oxidation of Tetrahydrocarbolines.

We report a safe and convenient open-flask copper-catalyzed selective oxidation/functionalization methodology for tetrahydrocarbolines and tetrahydro-ß-carbolines that employs atmospheric O2 as the terminal oxidant. The system is applicable to oxidative rearrangement of tetrahydro-ß-carbolines, tetrahydrocarboline oxidation to α-alkoxy carbazoles and spirooxindoles, and Witkop oxidation. Mechanistic experiments indicated that a single-electron oxidation process is responsible for the tunable selectivity control. This copper-catalysis protocol represents a significant advance in the field of indole oxidation.

Copper-Catalyzed Selective Oxidative Cross-Coupling of Tryptophols and Tryptamines To Access Heterocyclic 3a,3a'-Bisindolines.

The first example of cyclization cross-coupling of tryptophols and tryptamines has been realized by copper catalysis with air or oxone as the terminal oxidant, resulting in the direct construction of a new class of heterocyclic 3a,3a'-bisindolines in moderate to good yields with high chemoselectivities. A series of mechanistic control experiments were also conducted, indicating that the copper catalyst selectively coordinates with the nitrogen moiety of the tryptamine to initiate the oxidation, and a nucleophilic-alkylation process is proposed for the carbon-carbon bond-forming in the reaction. The novel synthetic strategies and molecular skeletons outlined in this work provide new ideas and concepts for the design of other useful reaction and potential drugs.

Copper-Catalyzed Cyclization/Dimerization of Tryptamines with O2/Air as the Sole Oxidant: Direct Access to Complex Bispyrrolidino[2,3-b]indoline.

The first transition metal catalytic one-step synthesis of the 3a, 3a'-bispyrrolidino [2,3-b] indoline scaffold via tandem cyclization/dimerization of tryptamines has been realized with the environmentally friendly O2/air as the sole oxidant. Different from the traditional direct oxidation of indole "N-H" group by excess amount of metal salts, a copper-catalyzed oxidative cyclization reaction is developed for the formation of the radical pyrrolidinoindoline intermediate in the current strategy. The robustness and practicality of this methodology is demonstrated by the step-economic, divergent total synthesis of natural products (±)-folicanthine and meso-folicanthine.

Copper-catalyzed aerobic oxidative radical alkoxycyclization of tryptamines to access 3-alkoxypyrroloindolines.

We report a copper-catalyzed alkoxycyclization of tryptamine derivatives with O2 as the sole oxidant, leading to a variety of C3a-alkoxypyrroloindolines in good yields with high diastereoselectivities. This reaction involves an interesting double catalytic cycle in which copper-catalyzed carboamination cyclization is favored to form the C-3 radical pyrrolidinoindoline intermediate, then a copper-catalytic radical alkoxylation reaction proceeds smoothly.

Classification of Non-Severe Traumatic Brain Injury from Resting-State EEG Signal Using LSTM Network with ECOC-SVM.

Traumatic brain injury (TBI) is one of the common injuries when the human head receives an impact due to an accident or fall and is one of the most frequently submitted insurance claims. However, it is often always misused when individuals attempt an insurance fraud claim by providing false medical conditions. Therefore, there is a need for an instant brain condition classification system. This study presents a novel classification architecture that can classify non-severe TBI patients and healthy subjects employing resting-state electroencephalogram (EEG) as the input, solving the immobility issue of the computed tomography (CT) scan and magnetic resonance imaging (MRI). The proposed architecture makes use of long short term memory (LSTM) and error-correcting output coding support vector machine (ECOC-SVM) to perform multiclass classification. The pre-processed EEG time series are supplied to the network by each time step, where important information from the previous time step will be remembered by the LSTM cell. Activations from the LSTM cell is used to train an ECOC-SVM. The temporal advantages of the EEG were amplified and able to achieve a classification accuracy of 100%. The proposed method was compared to existing works in the literature, and it is shown that the proposed method is superior in terms of classification accuracy, sensitivity, specificity, and precision.

Detection of Moderate Traumatic Brain Injury from Resting-State Eye-Closed Electroencephalography.

Traumatic brain injury (TBI) is one of the injuries that can bring serious consequences if medical attention has been delayed. Commonly, analysis of computed tomography (CT) or magnetic resonance imaging (MRI) is required to determine the severity of a moderate TBI patient. However, due to the rising number of TBI patients these days, employing the CT scan or MRI scan to every potential patient is not only expensive, but also time consuming. Therefore, in this paper, we investigate the possibility of using electroencephalography (EEG) with computational intelligence as an alternative approach to detect the severity of moderate TBI patients. EEG procedure is much cheaper than CT or MRI. Although EEG does not have high spatial resolutions as compared with CT and MRI, it has high temporal resolutions. The analysis and prediction of moderate TBI from EEG using conventional computational intelligence approaches are tedious as they normally involve complex preprocessing, feature extraction, or feature selection of the signal. Thus, we propose an approach that uses convolutional neural network (CNN) to automatically classify healthy subjects and moderate TBI patients. The input to this computational intelligence system is the resting-state eye-closed EEG, without undergoing preprocessing and feature selection. The EEG dataset used includes 15 healthy volunteers and 15 moderate TBI patients, which is acquired at the Hospital Universiti Sains Malaysia, Kelantan, Malaysia. The performance of the proposed method has been compared with four other existing methods. With the average classification accuracy of 72.46%, the proposed method outperforms the other four methods. This result indicates that the proposed method has the potential to be used as a preliminary screening for moderate TBI, for selection of the patients for further diagnosis and treatment planning.

Arrangements of Resting State Electroencephalography as the Input to Convolutional Neural Network for Biometric Identification.

Biometric is an important field that enables identification of an individual to access their sensitive information and asset. In recent years, electroencephalography- (EEG-) based biometrics have been popularly explored by researchers because EEG is able to distinct between two individuals. The literature reviews have shown that convolutional neural network (CNN) is one of the classification approaches that can avoid the complex stages of preprocessing, feature extraction, and feature selection. Therefore, CNN is suggested to be one of the efficient classifiers for biometric identification. Conventionally, input to CNN can be in image or matrix form. The objective of this paper is to explore the arrangement of EEG for CNN input to investigate the most suitable input arrangement of EEG towards the performance of EEG-based identification. EEG datasets that are used in this paper are resting state eyes open (REO) and resting state eyes close (REC) EEG. Six types of data arrangement are compared in this paper. They are matrix of amplitude versus time, matrix of energy versus time, matrix of amplitude versus time for rearranged channels, image of amplitude versus time, image of energy versus time, and image of amplitude versus time for rearranged channels. It was found that the matrix of amplitude versus time for each rearranged channels using the combination of REC and REO performed the best for biometric identification, achieving validation accuracy and test accuracy of 83.21% and 79.08%, respectively.

Angiopoietin-like 4 stimulates STAT3-mediated iNOS expression and enhances angiogenesis to accelerate wound healing in diabetic mice.

Impaired wound healing is a major source of morbidity in diabetic patients. Poor outcome has, in part, been related to increased inflammation, poor angiogenesis, and deficiencies in extracellular matrix components. Despite the enormous impact of these chronic wounds, effective therapies are lacking. Here, we showed that the topical application of recombinant matricellular protein angiopoietin-like 4 (ANGPTL4) accelerated wound reepithelialization in diabetic mice, in part, by improving angiogenesis. ANGPTL4 expression is markedly elevated upon normal wound injury. In contrast, ANGPTL4 expression remains low throughout the healing period in diabetic wounds. Exogenous ANGPTL4 modulated several regulatory networks involved in cell migration, angiogenesis, and inflammation, as evidenced by an altered gene expression signature. ANGPTL4 influenced the expression profile of endothelial-specific CD31 in diabetic wounds, returning its profile to that observed in wild-type wounds. We showed ANGPTL4-induced nitric oxide production through an integrin/JAK/STAT3-mediated upregulation of inducible nitric oxide synthase (iNOS) expression in wound epithelia, thus revealing a hitherto unknown mechanism by which ANGPTL4 regulated angiogenesis via keratinocyte-to-endothelial-cell communication. These data show that the replacement of ANGPTL4 may be an effective adjunctive or new therapeutic avenue for treating poor healing wounds. The present finding also confirms that therapeutic angiogenesis remains an attractive treatment modality for diabetic wound healing.