N‐Trifluoromethyl azoles are valuable targets in medicinal chemistry, but their synthesis is challenging. Classical preparation of N‐CF3 azoles relies on the functional group interconversions but ...suffers from tedious N‐pre‐functionalization and unfriendly agents. Introduction of the CF3 onto the nitrogen of heterocycles provides a direct route to such motifs, but the N‐trifluoromethylation remains underdeveloped. Reported here is an alternative and scalable cyclization strategy based on NCF3‐containing synthons for constructing N‐CF3 azoles. The approach involves the N‐trifluoromethylation of nitriles followed by a 3+2 cyclization between resulting N‐CF3 nitrilium derivatives and 1,3‐dipoles. PhICF3Cl was an effective CF3 source for the transformation. As a result, a generic platform is established to divergently synthesize N‐trifluoromethylated tetrazoles, imidazoles, and 1,2,3‐triazoles by using sodium azide, activated methylene isocyanides, and diazo compounds as dipoles.
A scalable N‐trifluoromethylative cyclization strategy is reported to construct N‐CF3 tetrazoles/imidazoles/1,2,3‐triazoles. N‐CF3 nitrilium derivatives are obtained via the N‐trifluoromethylation of nitriles and well used as NCF3‐containing synthons in 1,3‐dipolar cyclizations for the first time. A generic platform for accessing diverse N‐CF3 azoles is thus provided.
For steganalysis, many studies showed that convolutional neural network (CNN) has better performances than the two-part structure of traditional machine learning methods. Existing CNN architectures ...use various tricks to improve the performance of steganalysis, such as fixed convolutional kernels, the absolute value layer, data augmentation and the domain knowledge. However, some designing of the network structure were not extensively studied so far, such as different convolutions (inception, xception, etc.) and variety ways of pooling(spatial pyramid pooling, etc.). In this paper, we focus on designing a new CNN network structure to improve detection accuracy of spatial-domain steganography. First, we use 3×3 kernels instead of the traditional 5 × 5 kernels and optimize convolution kernels in the preprocessing layer. The smaller convolution kernels are used to reduce the number of parameters and model the features in a small local region. Next, we use separable convolutions to utilize channel correlation of the residuals, compress the image content and increase the signal-to-noise ratio (between the stego signal and the image signal). Then, we use spatial pyramid pooling (SPP) to aggregate the local features and enhance the representation ability of features by multi-level pooling. Finally, data augmentation is adopted to further improve network performance. The experimental results show that the proposed CNN structure is significantly better than other five methods such as SRM, Ye-Net, Xu-Net, Yedroudj-Net and SRNet, when it is used to detect three spatial algorithms such as WOW, S-UNIWARD and HILL with a wide variety of datasets and payloads.
Objective: The health action process approach (HAPA) is a social-cognitive model specifying motivational and volitional determinants of health behavior. A meta-analysis of studies applying the HAPA ...in health behavior contexts was conducted to estimate the size and variability of correlations among model constructs, test model predictions, and test effects of past behavior and moderators (behavior type, sample type, measurement lag, study quality) on model relations. Method: A literature search identified 95 studies meeting inclusion criteria with 108 independent samples. Averaged corrected correlations among HAPA constructs and multivariate tests of model predictions were computed using conventional meta-analysis and meta-analytic structural equation modeling, with separate models estimated in each moderator group. Results: Action and maintenance self-efficacy and outcome expectancies had small-to-medium sized effects on health behavior, with effects of outcome expectancies and action self-efficacy mediated by intentions, and action and coping planning. Effects of risk perceptions and recovery self-efficacy were small by comparison. Past behavior attenuated the intention-behavior relationship. Few variations in model effects were observed across moderator groups. Effects of action self-efficacy on intentions and behavior were larger in studies on physical activity compared with studies on dietary behaviors, whereas effects of volitional self-efficacy on behavior were larger in studies on dietary behaviors. Conclusions: Findings highlight the importance of self-efficacy in predicting health behavior in motivational and volitional action phases. The analysis is expected to catalyze future research including experimental studies targeting change in individual HAPA constructs, and longitudinal research to examine change and reciprocal effects among constructs in the model.
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CEKLJ, FFLJ, NUK, ODKLJ, PEFLJ
Development of fluorometric chemosensors for the detection of hypochlorous acid.
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•The development and application of HOCl fluorescent probes were summarized.•These HOCl probes were ...divided according to various recognition groups.•Many large challenges still remain in the application of HOCl fluorescent probes for imaging in vivo.
As one of the reactive oxygen species, hypochlorous acid (HOCl) may be associated with various diseases. To understand the roles of HOCl in living organism, fluorescent probes for imaging HOCl in living systems have been developed fast in recent years owing to their high selectivity, excellent sensitivity and spectral resolution. In this review, we summarized and highlighted the recent advances in the development and application of HOCl fluorescent probes. This review is focused on the detection mechanisms of probes for HOCl. According to the various recognition groups, we divided the HOCl fluorescence probes into five parts and discussed detection mechanisms, respectively.
Baicalin, which is isolated from Radix Scutellariae, possesses strong biological activities including an anti-inflammation property. Recent studies have shown that the anti-inflammatory effect of ...baicalin is linked to toll-like receptor 4 (TLR4), which participates in pathological changes of central nervous system diseases such as depression. In this study, we explored whether baicalin could produce antidepressant effects via regulation of TLR4 signaling in mice and attempted to elucidate the underlying mechanisms.
A chronic unpredictable mild stress (CUMS) mice model was performed to explore whether baicalin could produce antidepressant effects via the inhibition of neuroinflammation. To clarify the role of TLR4 in the anti-neuroinflammatory efficacy of baicalin, a lipopolysaccharide (LPS) was employed in mice to specially activate TLR4 and the behavioral changes were determined. Furthermore, we used LY294002 to examine the molecular mechanisms of baicalin in regulating the expression of TLR4 in vivo and in vitro using western blot, ELISA kits, and immunostaining. In the in vitro tests, the BV2 microglia cell lines and primary microglia cultures were pretreated with baicalin and LY292002 for 1 h and then stimulated 24 h with LPS. The primary microglial cells were transfected with the forkhead transcription factor forkhead box protein O 1 (FoxO1)-specific siRNA for 5 h and then co-stimulated with baicalin and LPS to investigate whether FoxO1 participated in the effect of baicalin on TLR4 expression.
The administration of baicalin (especially 60 mg/kg) dramatically ameliorated CUMS-induced depressive-like symptoms; substantially decreased the levels of interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) in the hippocampus; and significantly decreased the expression of TLR4. The activation of TLR4 by the LPS triggered neuroinflammation and evoked depressive-like behaviors in mice, which were also alleviated by the treatment with baicalin (60 mg/kg). Furthermore, the application of baicalin significantly increased the phosphorylation of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and FoxO1. The application of baicalin also promoted FoxO1 nuclear exclusion and contributed to the inhibition of the FoxO1 transactivation potential, which led to the downregulation of the expression of TLR4 in CUMS mice or LPS-treated BV2 cells and primary microglia cells. However, prophylactic treatment of LY294002 abolished the above effects of baicalin. In addition, we found that FoxO1 played a vital role in baicalin by regulating the TLR4 and TLR4-mediating neuroinflammation triggered by the LPS via knocking down the expression of FoxO1 in the primary microglia.
Collectively, these results demonstrate that baicalin ameliorated neuroinflammation-induced depressive-like behaviors through the inhibition of TLR4 expression via the PI3K/AKT/FoxO1 pathway.
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•The ultrathin RhIr NSs/NF was prepared by a simple and mild one-pot aqueous strategy at room temperature.•The unique sheet-like architectures provided large ECSA and exposed ...high-density active sites.•The self-supported RhIr NSs/NF had excellent HER activity and stability for the HER over a wide pH range.
The development of low-cost and high-efficiency electrocatalysts is very important for electrocatalytic hydrogen evolution reaction (HER) in water splitting system. Herein, ultrathin rhodium-iridium nanosheets were facilely in-situ grown on nickel foam (RhIr NSs/NF) by a one-pot aqueous strategy at room temperature. The sheet-like structures with the film thickness of 78 nm were identified by scanning electron microscopy and transmission electron microscopy. The catalyst showed greatly high HER features in both 1.0 M KOH and 0.5 M H2SO4 with the overpotentials of 15 and 14 mV to achieve 10 mA cm−2, respectively, surpassing most Pt-free catalysts. Also, the RhIr NSs/NF exhibited amazing catalytic stability during the long-term operation. This study offers a facile and rational pathway for design and synthesis of advanced HER electrocatalysts for energy conversion devices.
•The prevalence of anxiety and depression symptom was 7.7% and 12.2%, respectively.•Having confirmed and suspected cases in family members or relatives was associated with the higher risk of ...depression symptom.•Self-reported health condition was strongly associated with risk of anxiety and depression symptom.
: Although studies have suggested experiencing the epidemic of severe infectious diseases increased the prevalence of mental health problems, the association between COVID-19 epidemic and risk of anxiety and depression symptom in college students in China was unclear.
: A large cross-sectional online survey with 44,447 college students was conducted in Guangzhou, China. The Zung's Self-rating Anxiety Scale (SAS) and the Center for Epidemiologic Studies Depression Scale (CES-D Scale) were used to define the anxiety and depression symptom, respectively. Multivariable logistic regression models were used to analyze the association between COVID-19 epidemic and risk of anxiety and depression symptom.
: The prevalence of anxiety and depression symptom was 7.7% (95% confidence interval CI: 7.5%, 8.0%) and 12.2% (95%CI: 11.9%, 12.5%), respectively. Compared with students who reported have not infected or suspected cases in family members and relatives, students who reported having confirmed (OR=4.06; 95%CI: 1.62, 10.19; P = 0.003), and suspected (OR=2.11; 95%CI: 1.11, 4.00; P = 0.023) cases in family members and relatives had higher risk of depression symptom. Additionally, the proportions of students with anxiety and depression symptom reported more demand of psychological knowledge and interventions than those without (P<0.001).
: All the data in this study was collected through online questionnaire, and we did not evaluate the reliability and validity.
: The prevalence of anxiety and depression symptom was relatively low in college students, but the COVID-19 epidemic-related factors might be associated with higher depression symptom risk.
Nanoparticles (NPs) have emerged as an effective means to deliver therapeutic drugs for cancer treatment, as they can preferentially accumulate at tumor site through the enhanced permeability and ...retention effect. Various forms of NPs including liposomes, polymeric micelles, and inorganic particles have been used for therapeutic applications. However, the therapeutic benefits of nanomedicines are suboptimal. Although many possible reasons may account for the compromised therapeutic efficacy, the inefficient tumor penetration can be a vital obstacle. Tumor develops characteristic pathological environment, such as abnormal vasculature, elevated interstitial fluid pressure, and dense extracellular matrix, which intrinsically hinder the transport of nanomedicines in the tumor parenchyma. The physicochemical properties of the NPs such as size, shape, and surface charge have profound effect on tumor penetration. In this review, we will highlight the factors that affect the transport of NPs in solid tumor, and then elaborate on designing strategies to improve NPs' penetration and uniform distribution inside the tumor interstitium.
This article is categorized under:
Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Advanced designing strategies can be exploited to improve tumor penetration and therapeutic efficacy of cancer nanomedicines.
Tools for GPCR drug discovery Zhang, Ru; Xie, Xin
Acta pharmacologica Sinica,
03/2012, Volume:
33, Issue:
3
Journal Article
Peer reviewed
Open access
G-protein-coupled receptors （GPCRs） mediate many important physiological functions and are considered as one of the most success- ful therapeutic targets for a broad spectrum of diseases. The design ...and implementation of high-throughput GPCR assays that allow the cost-effective screening of large compound libraries to identify novel drug candidates are critical in early drug discovery. Early functional GPCR assays depend primarily on the measurement of G-protein-mediated 2nd messenger generation. Taking advantage of the continuously deepening understanding of GPCR signal transduction, many G-protein-independent pathways are utilized to detect the activity of GPCRs, and may provide additional information on functiona~ selectivity of candidate compounds. With the combination of automated imaging systems and label-free detection systems, such assays are now suitable for high-throughput screening （HTS）. In this review, we summarize the most widely used GPCR assays and recent advances in HTS technologies for GPCR drug discovery.
Cultivating college students' computational thinking is an important teaching plan in computer basic teaching in university stage. Teachers should integrate the teaching content according to the ...level of computer basic knowledge and ability of college students, classify the basic teaching contents of college computer scientifically and increase the part of experimental teaching in the college computer teaching classroom. Using scientific computer teaching methods can improve students' computational thinking effectively, so that the comprehensive ability of college students can be improved.
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