Major depressive disorder has become a global public health problem of serious concern. Most of the clinical antidepressants are developed under the classic “monoamine hypothesis (strategy)”. These ...drugs generally have such deficiencies including slow onset and limited efficiency, cognitive impairment and suicidal tendency. Therefore, it is the direction to break through the classic monoamine strategy framework for developing antidepressants that have fast-acting, lower side effects, and cognitive enhancement, to satisfy the major clinical needs. In 2019, the launch of fast-acting antidepressants such as S-ketamine(S-Ket) and brexanolone into market by FDA has opened up new prospects for non-monoamine strategy mainly based on the N-methyl-d-aspartate (NMDA) and γ-aminobutyric acid type A (GABAA) receptors. There are two main trends in the development of fast-onset antidepressants: the optimized multi-target monoamine strategy (modern monoamine strategy) and the non-monoamine strategy based on glutamate(Glu)-GABA balance modulation. Based to the research conducted by foreign peers and our lab, we propose a hypothesis of “monoamine (5-HT)- Glu/GABA long neural circuit”, which holds the view that both monoaminergic mechanisms (such as 5-HT neurons located in raphe nucleus) and non-monoaminergic mechanisms (Glu/GABA neurons located in prefrontal cortex) are all part of the rapid-acting antidepressant mechanisms, and both of them form a long neural circuit mediating the fast synaptogenesis of the brain regions including prefrontal cortex. Based on this, it is proposed that fast launch and activation of this circuit may be an important mechanism for fast-onset of antidepressant, in which Glu/GABA (excitation/ inhibition, E/I) rebalance should be the critical rate-limiting step for the onset speed. Therefore, five potential strategies are proposed for fast-acting antidepressant based on this circuit: 1) Achieve the rapid E/I balance by relieving the inhibition of GABA interneurons on glutamatergic pyramidal neurons or directly activating pyramidal neurons; 2) Simultaneously modulate 5-HT neuronal activity and Glu/GABA balance by 5-HT transporter combining with some receptors such as 5-HT1A/1B (namely simultaneous enhancement of the 5-HT and Glu/GABA links); 3) Directly activate mammalian rapamycin target protein complex 1 (mTORC1) and rapidly enhance brain-derived neurotrophic factor (BDNF) -mTOR pathway; 4) Stimulate rapid release of BDNF in the brain; 5) Positive allosteric modulator of synaptic and extrasynaptic GABAA receptors. It is hoped that these ideas will provide possible strategies for the further development of a new generation of antidepressants and provide a useful reference for the further discovery of fast-onset antidepressant candidate targets.
With the deepening of cultural integration, people’s demand for English learning is also increasing rapidly. However, traditional teaching methods have certain limitations, and teaching conditions ...are limited by the slow development of information technology, oral English courses have been shelved and stopped for a long time. With the rapid development of technology, the era of artificial intelligence has arrived. Learning assistance systems based on artificial intelligence have emerged in an endless stream, which has also innovatively solved the problem of oral language learning. Natural language processing is a computing mode of deep learning by artificial intelligence, which can carry out deep learning and training according to the current goal and finally get the desired result. But relying only on the auxiliary learning system cannot fundamentally solve the problem of oral language learning. Therefore, we aim to update the current spoken English learning methods using natural language processing technology, and propose a natural language processing-based oral English teaching model. In this mode, natural language processing can match different teaching methods according to the spoken language characteristics of different students, and give constructive suggestions. Moreover, the spoken English teaching mode based on natural language processing can be continuously upgraded and adjusted to adapt to the changing and developing era in time. Experiments show that the oral English teaching mode based on natural language processing can improve students’ comprehensive ability of oral English. And it increased its comprehension by 19.7% year-on-year, and at the same time it also improved the enthusiasm for learning oral language by 33.3%.
To conquer the bottleneck of sluggish kinetics in cathodic oxygen reduction reaction (ORR) of metal‐air batteries, catalysts with dual‐active centers have stood out. Here, a “pre‐division metal ...clusters” strategy is firstly conceived to fabricate a N,S‐dual doped honeycomb‐like carbon matrix inlaid with CoN4 sites and wrapped Co2P nanoclusters as dual‐active centers (Co2P/CoN4@NSC‐500). A crystalline {CoII2} coordination cluster divided by periphery second organic layers is well‐designed to realize delocalized dispersion before calcination. The optimal Co2P/CoN4@NSC‐500 executes excellent 4e− ORR activity surpassing the benchmark Pt/C. Theoretical calculation results reveal that the CoN4 sites and Co2P nanoclusters can synergistically quicken the formation of *OOH on Co sites. The rechargeable Zn‐air battery (ZAB) assembled by Co2P/CoN4@NSC‐500 delivers ultralong cycling stability over 1742 hours (3484 cycles) under 5 mA cm−2 and can light up a 2.4 V LED bulb for ≈264 hours, evidencing the promising practical application potentials in portable devices.
A “pre‐division metal clusters” strategy is first conceived to fabricate dual‐active center catalysts (Co2P/CoN4@NSC‐500) with dispersed CoN4 and Co2P sites. The optimal catalyst executes superior ORR activity and was applied in ultralong Zn‐air batteries surpassing the benchmark 20 % Pt/C. Theoretical calculations demonstrate that the dual‐active sites synergistically quicken the formation of the *OOH intermediate, greatly boosting the performance.
Preoperative 5-fluorouracil- (5-FU-) based chemoradiotherapy is a standard treatment for locally advanced colorectal cancer (CRC). However, the effect of 5-FU-based chemoradiotherapy on CRC is ...limited due to the development of chemoradiation resistance (CRR), and the molecular mechanisms underlying this resistance are yet to be investigated. Recently, circular RNAs (circRNAs), which can function as microRNA sponges, were found to be involved in the development of several cancers. In this study, we focused on clarifying the modulation of the expression profiles of circRNAs in CRR. Microarray analysis identified 71 circRNAs differentially expressed in chemoradiation-resistant CRC cells. Among them, 47 were upregulated and 24 were downregulated by more than twofold. Furthermore, expression modulation of five representative circRNAs was validated by quantitative reverse transcription PCR (qRT-PCR). Moreover, these modulated circRNAs were predicted to interact with 355 miRNAs. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the most modulated circRNAs regulate several cancers and cancer-related pathways, and the possible mechanism underlying CRR was discussed. This is the first report revealing the circRNA modulations in 5-FU chemoradiation-resistant CRC cells by microarray. The study provided a useful database for further understanding CRR and presents potential targets to overcome CRR in CRC.
Visible light-induced difluoromethylation of N-arylacrylamides to afford difluoromethylated 2-oxindoles and quinoline-2,4-diones with difluoromethyl 2-pyridyl sulfones as radical precursors has been ...disclosed. This method provides convenient access to a variety of 2-oxindoles and quinoline-2,4-diones under mild conditions via a proposed tandem radical addition/cyclization process along with good tolerance to various functional groups. In addition, preliminary experimental studies have revealed that water is a key factor in difluoromethylation and the reaction involves an oxidative quenching cycle of the photocatalyst.
Aims
To evaluate the association between glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) and the risk of bone fracture in patients with type 2 diabetes mellitus (T2DM).
Materials and methods
We ...conducted a systematic literature search in PubMed, Embase, the Cochrane Library, and Web of Science from inception to 28 February 2018 and identified eligible randomized controlled trials. The following data were extracted from each study: first author, year of publication, sample size, patient characteristics, study design, intervention drug, control drug, follow‐up time, and incident bone fracture events. A meta‐analysis was conducted using Review Manager 5.3 software to calculate the odds ratio (OR) and 95% confidence intervals (CI) for dichotomous variables.
Results
A total of 38 studies with 39 795 patients with T2DM were included. There were 241 incident bone fracture cases (107 in the GLP‐1 RAs group and 134 in the control group). Compared with patients who received placebo and other anti‐diabetic drugs, those who received GLP‐1 RAs treatment showed a pooled OR of 0.71 (95% CI, 0.56‐0.91) for bone fracture. Subgroup analysis showed that treatments with liraglutide and lixisenatide were associated with significantly reduced risk of bone fractures (ORs, 0.56; 95% CI, 0.38‐0.81 and 0.55; 95% CI, 0.31‐0.97, respectively). However, other GLP‐1 RAs did not show superiority to placebo or other anti‐diabetic drugs. Moreover, these beneficial effects were dependent on the duration of GLP‐1 RAs treatment, only a GLP‐1 RAs treatment period of more than 52 weeks could significantly lower the risk of bone fracture in patients with T2DM (OR, 0.71; 95% CI, 0.56‐0.91).
Conclusions
Compared with placebo and other anti‐diabetic drugs, liraglutide and lixisenatide were associated with a significant reduction in the risk of bone fractures, and the beneficial effects were dependent on the duration of treatment.
With a proper energy management strategy (EMS), supercapacitor can be integrated into droop-controlled dc microgrid as an independent supercapacitor energy storage system (SCESS). The resulted ...microgrid could supply repeatedly quick bursts of electrical power due to load or source transients and improve power quality and lifetime of other distributed generations (DGs) or distributed energy storages. In this paper, a novel control strategy for SCESS is proposed. The method uses the virtual impedance loop to add a virtual resistor and a virtual capacitor connected in series between the converter and dc bus, which decouples power flow between SCESS and other DGs while ensuring the plug `n' play feature. The results show that the proposed EMS has a competing dynamic performance with excellent flexibility as compared to existing methods.
Spatially resolved (sub)millimeter polarization has been detected by Atacama Large Millimeter/submillimeter Array in an increasing number of disks. The majority of the observations show polarization ...patterns consistent with self scattering, especially at Band 7. The inferred sizes of the grains are typically of order 100 m, which is very different from the millimeter size commonly inferred from the dust opacity index β. In an effort to resolve this discrepancy, we first introduce the so-called "Coplanar Isotropic Radiation Field" approximation, which enables the computation of the (signed) polarization fraction semianalytically. With an oft-adopted dust composition, we find that models with big dust grains produce very small polarization with reversed orientation, which has not been observed. The semianalytic results are validated through Monte Carlo radiative transfer simulations. In these models, the "correct" polarization orientation and the small β index are mutually exclusive. To resolve this tension, we explore a wide range of dust models, parameterized by their complex refractive indices m = n + ik. We find that both the fraction and the orientation of the polarization depend on the refractive index in a complex way, and this dependence is mapped out on an n-k plane for a representative 3 mm size distribution and wavelength of 870 m. In particular, 3 mm-sized refractory organics grains produce reversed polarization, whereas grains made of absorptive carbonaceous materials produce a percent-level, nonreversed polarization; the latter may alleviate the aforementioned tension in grain size estimates. We conclude that scattering-induced polarization has the potential to also probe the grain compositions.
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