[Identification of Q-markers for Schisandrae Sphenantherae Fructus in treating drug-induced liver injury based on network pharmacology, fingerprint and quantitative analysis].

This study aims to establish the ultra-performance liquid chromatography(UPLC) fingerprint and multi-indicator quantitative analysis method for Schisandrae Sphenantherae Fructus(SSF) and to screen out the potential quality markers(Q-markers) of hepatoprotection based on network pharmacology. The similarity analysis was performed using the Chinese Medicine Chromatographic Fingerprint Similarity Evaluation System, which showed that the similarity of the fingerprints of 15 samples from different regions ranged from 0.981 to 0.998. Eighteen common components were identified, from which 3 differential components were selected by cluster analysis and principal component analysis. The "component-target-pathway" network was built to predict the core components related to the hepatoprotective effects. Fourteen core components were screened by network pharmacology. They acted on the targets such as AKT1, CCND1, CYP1A1, CYP3A4, MAPK1, MAPK3, NOS2, NQO1, and PTGS2 to regulate the signaling pathways of lipid metabolism and atherosclerosis, hepatitis B, interleukin-17, and tumor necrosis factor. Considering the chemical measurability, characteristics, and validity, schisantherin A, anwulignan, and schisandrin A were identified as the Q-markers. The content of schisantherin A, anwulignan, and schisandrin A in the test samples were 0.20%-0.57%, 0.13%-0.33%, and 0.42%-0.70%, respectively. Combining the fingerprint, network pharmacology, and content determination, this study predicted that schisantherin A, anwulignan, and schisandrin A were the Q-markers for the hepatoprotective effect of SSF. The results can provide reference for improving the quality evaluation standard and exploring the hepatoprotective mechanism of SSF.

A social network analysis: mental health scales used during the COVID-19 pandemic.

Introduction: The focus on psychological issues during COVID-19 has led to the development of large surveys that involve the use of mental health scales. Numerous mental health measurements are available; choosing the appropriate measurement is crucial. Methods: A rule-based named entity recognition was used to recognize entities of mental health scales that occur in the articles from PubMed. The co-occurrence networks of mental health scales and Medical Subject Headings (MeSH) terms were constructed by Gephi. Results: Five types of MeSH terms were filtered, including research objects, research topics, research methods, countries/regions, and factors. Seventy-eight mental health scales were discovered. Discussion: The findings provide insights on the scales used most often during the pandemic, the key instruments used to measure healthcare workers' physical and mental health, the scales most often utilized for assessing maternal mental health, the tools used most commonly for assessing older adults' psychological resilience and loneliness, and new COVID-19 mental health scales. Future studies may use these findings as a guiding reference and compass.

Calcium-Sensitive Receptors Alters Intestinal Microbiota Metabolites Especially SCFAs and Ameliorates Intestinal Barrier Damage in Neonatal Rat Endotoxemia.

Purpose: The calcium-sensing receptor (CaSR) acts as a major modulator of tissue responses related to calcium homeostasis and expresses highly in the mammalian intestine. Endotoxemia tends to impair intestinal barrier function and poses significant obstacles in clinical treatment. This work is designed to decipher whether CaSR can protect lipopolysaccharide (LPS)-induced intestinal barrier dysfunction in neonatal rats by targeting intestinal metabolites. Patient and Methods: In this study, we utilized gas chromatography (GC) combined with liquid chromatography-mass spectrometry (LC-MS) to quantitatively analyze SCFAs and metabolites in fecal samples of 24 neonatal rats with LPS induced endotoxemia. Results: Our results showed that CaSR alleviated endotoxin damage to the intestinal tight junction structure and upregulated the levels of butyric acid, propionic acid, valeric acid, and isovaleric acid in short-chain fatty acids (SCFAs). Non-targeted metabolomics analysis indicated that CaSR improved intestinal metabolic disorders by regulating glycerophospholipid metabolism, α-linolenic acid metabolism, as well as sphingolipids metabolism. Conclusion: CaSR can alter intestinal microbiota metabolites, especially SCFAs, and improve intestinal barrier damage in neonatal rat endotoxemia.

Evolution of Public Attitudes and Opinions Regarding COVID-19 Vaccination During the Vaccine Campaign in China: Year-Long Infodemiology Study of Weibo Posts.

BACKGROUND: Monitoring people's perspectives on the COVID-19 vaccine is crucial for understanding public vaccination hesitancy and developing effective, targeted vaccine promotion strategies. Although this is widely recognized, studies on the evolution of public opinion over the course of an actual vaccination campaign are rare. OBJECTIVE: We aimed to track the evolution of public opinion and sentiment toward COVID-19 vaccines in online discussions over an entire vaccination campaign. Moreover, we aimed to reveal the pattern of gender differences in attitudes and perceptions toward vaccination. METHODS: We collected COVID-19 vaccine-related posts by the general public that appeared on Sina Weibo from January 1, 2021, to December 31, 2021; this period covered the entire vaccination process in China. We identified popular discussion topics using latent Dirichlet allocation. We further examined changes in public sentiment and topics during the 3 stages of the vaccination timeline. Gender differences in perceptions toward vaccination were also investigated. RESULTS: Of 495,229 crawled posts, 96,145 original posts from individual accounts were included. Most posts presented positive sentiments (positive: 65,981/96,145, 68.63%; negative: 23,184/96,145, 24.11%; neutral: 6980/96,145, 7.26%). The average sentiment scores were 0.75 (SD 0.35) for men and 0.67 (SD 0.37) for women. The overall trends in sentiment scores showed a mixed response to the number of new cases and significant events related to vaccine development and important holidays. The sentiment scores showed a weak correlation with new case numbers (R=0.296; P=.03). Significant sentiment score differences were observed between men and women (P<.001). Common and distinguishing characteristics were found among frequently discussed topics during the different stages, with significant differences in topic distribution between men and women (January 1, 2021, to March 31, 2021: χ23=3030.9; April 1, 2021, to September 30, 2021: χ24=8893.8; October 1, 2021, to December 31, 2021: χ25=3019.5; P<.001). Women were more concerned with side effects and vaccine effectiveness. In contrast, men reported broader concerns around the global pandemic, the progress of vaccine development, and economics affected by the pandemic. CONCLUSIONS: Understanding public concerns regarding vaccination is essential for reaching vaccine-induced herd immunity. This study tracked the year-long evolution of attitudes and opinions on COVID-19 vaccines according to the different stages of vaccination in China. These findings provide timely information that will enable the government to understand the reasons for low vaccine uptake and promote COVID-19 vaccination nationwide.

p85S6K sustains synaptic GluA1 to ameliorate cognitive deficits in Alzheimer's disease.

BACKGROUND: Ribosomal protein S6 kinase 1 (S6K1) is a serine-threonine kinase that has two main isoforms: p70S6K (70-kDa isoform) and p85S6K (85-kDa isoform). p70S6K, with its upstream mammalian target of rapamycin (mTOR), has been shown to be involved in learning and memory and participate in the pathophysiology of Alzheimer's disease (AD). However, the function of p85S6K has long been neglected due to its high similarity to p70S6k. The role of p85S6K in learning and memory is still largely unknown. METHODS: We fractionated the postsynaptic densities to illustrate the differential distribution of p85S6K and p70S6K. Coimmunoprecipitation was performed to unveil interactions between p85S6K and the GluA1 subunit of AMPA receptor. The roles of p85S6K in synaptic targeting of GluA1 and learning and memory were evaluated by specific knockdown or overexpression of p85S6K followed by a broad range of methodologies including immunofluorescence, Western blot, in situ proximity ligation assay, morphological staining and behavioral examination. Further, the expression level of p85S6K was measured in brains from AD patients and AD model mice. RESULTS: p85S6K, but not p70S6K, was enriched in the postsynaptic densities. Moreover, knockdown of p85S6K resulted in defective spatial and recognition memory. In addition, p85S6K could interact with the GluA1 subunit of AMPA receptor through synapse-associated protein 97 and A-kinase anchoring protein 79/150. Mechanistic studies demonstrated that p85S6K could directly phosphorylate GluA1 at Ser845 and increase the amount of GluA1 in synapses, thus sustaining synaptic function and spine densities. Moreover, p85S6K was found to be specifically decreased in the synaptosomal compartment in the brains of AD patients and AD mice. Overexpression of p85S6K ameliorated the synaptic deficits and cognitive impairment in transgenic AD model mice. CONCLUSIONS: These results strongly imply a significant role for p85S6K in maintaining synaptic and cognitive function by interacting with GluA1. The findings provide an insight into the rational targeting of p85S6K as a therapeutic potential for AD.

A novel framework-based meta-analysis for in-depth characterization of microplastic pollution and associated ecological risks in Chinese Bays.

Among aquatic ecosystems, bays are ubiquitously contaminated with microplastics (MPs, size <5 mm), but a comprehensive understanding of their pollution characterization in Chinese Bays is largely elusive. The current study aims to systematically highlight factors intricating MP contamination as well as their geographic distribution, interactions, risk evaluation, and abundance prediction in bays. MPs' abundance was varied in different bays, at concentrations ranging between 0.26 ± 0.14-89, 500 ± 20, 600 items/m3 in water, 15 ± 6-6433.5 items/kg dry weight in sediment and 0.21 ± 0.10-103.5 items/individual in biota. Redundancy analysis, Permannova, and GeoDetector model revealed that the sampling and extraction/identification methods, and geographical locations were the major drivers affecting MP distribution and characteristics. The Mantel test highlighted that the MP characteristics changed with geographic distance, higher in water than that in sediment and biota. ANOSIM results showed that the different environmental media exhibit significant differences in MP characteristics (e.g., color, shape, and polymer). The ARIMA model predicted that Sanggou Bay and Hangzhou Bay have a higher potential for significantly increasing MP contamination in the future. The highest hazard index (HI) values for water, sediment, and biota were respectively reported at Jiaozhou Bay (18,844.16), Bohai Bay (11,485.37), and Dongshan Bay (48,485.11). The highest values for the ecological risk index (RI) in water, sediment, and biota were detected at Beibu Gulf (6,129,559.02), Haikou Bay (2229.14), and Dongshan Bay (561,563.05), respectively. Overall, this framework can be used at different scales and in different environments, which makes it useful for understanding and controlling MP pollution in the ecosystem.

Rapid identification of chemical constituents in Xuezhikang Capsule by UPLC-Q-TOF/MSE combined with the establishment of UNIFI MS database / 药学学报

An UPLC-Q-TOF/MSE technology coupled with UNIFI database was used to develop a rapid, high coverage, accurate and efficient chemical composition qualitative method for Xuezhikang Capsule. A UNIFI database was established utilizing compound name, formula, structure, following automatic matching with high-resolution mass numbers, isotope distributions, mass deviations, fragment ion matching, and chromatographic retention features in UNIFI database to achieve the qualitative results of natural products in Xuezhikang Capsules. Combined with manual confirmation, 82 chemical components were identified in Xuezhikang Capsules, and the MS2 fragmentation pathway of typical organic acids, flavonoids, monacrines, and monascus were analyzed to ensure accuracy of the LC-MS workflow. This study clarified the chemical substance basis of Xuezhikang Capsules by LC-MS technology, providing experimental data support for the identification of key quality attributes, quality control and consistency evaluation in the manufacturing process of Xuezhikang Capsules.

Genetic variation within the pri-let-7f-2 in the X chromosome predicting stroke risk in a Chinese Han population from Liaoning, China: From a case-control study to a new predictive nomogram.

Background and objectives: Stroke is the most common cause of disability and the second cause of death worldwide. Therefore, there is a need to identify patients at risk of developing stroke. This case-control study aimed to create and verify a gender-specific genetic signature-based nomogram to facilitate the prediction of ischemic stroke (IS) risk using only easily available clinical variables. Materials and methods: A total of 1,803 IS patients and 1,456 healthy controls from the Liaoning province in China (Han population) were included which randomly divided into training cohort (70%) and validation cohort (30%) using the sample function in R software. The distribution of the pri-let-7f-2 rs17276588 variant genotype was analyzed. Following genotyping analysis, statistical analysis was used to identify relevant features. The features identified from the multivariate logistic regression, the least absolute shrinkage and selection operator (LASSO) regression, and univariate regression were used to create a multivariate prediction nomogram model. A calibration curve was used to determine the discrimination accuracy of the model in the training and validation cohorts. External validity was also performed. Results: The genotyping analysis identified the A allele as a potential risk factor for IS in both men and women. The nomogram identified the rs17276588 variant genotype and several clinical parameters, including age, diabetes mellitus, body mass index (BMI), hypertension, history of alcohol use, history of smoking, and hyperlipidemia as risk factors for developing IS. The calibration curves for the male and female models showed good consistency and applicability. Conclusion: The pri-let-7f-2 rs17276588 variant genotype is highly linked to the incidence of IS in the northern Chinese Han population. The nomogram we devised, which combines genetic fingerprints and clinical data, has a lot of promise for predicting the risk of IS within the Chinese Han population.

Application of Telemedicine in COVID-19: A Bibliometric Analysis.

Background: Telemedicine as a tool that can reduce potential disease spread and fill a gap in healthcare has been increasingly applied during the COVID-19 pandemic. Many studies have summarized telemedicine's technologies or the diseases' applications. However, these studies were reviewed separately. There is a lack of a comprehensive overview of the telemedicine technologies, application areas, and medical service types. Objective: We aimed to investigate the research direction of telemedicine at COVID-19 and to clarify what kind of telemedicine technology is used in what diseases, and what medical services are provided by telemedicine. Methods: Publications addressing telemedicine in COVID-19 were retrieved from the PubMed database. To extract bibliographic information and do a bi-clustering analysis, we used Bicomb and gCLUTO. The co-occurrence networks of diseases, technology, and healthcare services were then constructed and shown using R-studio and the Gephi tool. Results: We retrieved 5,224 research papers on telemedicine at COVID-19 distributed among 1460 journals. Most articles were published in the Journal of Medical Internet Research (166/5,224, 3.18%). The United States published the most articles on telemedicine. The research clusters comprised 6 clusters, which refer to mental health, mhealth, cross-infection control, and self-management of diseases. The network analysis revealed a triple relation with diseases, technologies, and health care services with 303 nodes and 5,664 edges. The entity "delivery of health care" was the node with the highest betweenness centrality at 6,787.79, followed by "remote consultation" (4,395.76) and "infection control" (3,700.50). Conclusions: The results of this study highlight widely use of telemedicine during COVID-19. Most studies relate to the delivery of health care and mental health services. Technologies were primarily via mobile devices to deliver health care, remote consultation, control infection, and contact tracing. The study assists researchers in comprehending the knowledge structure in this sector, enabling them to discover critical topics and choose the best match for their survey work.

Fracture Behavior of Steel Slag Powder-Cement-Based Concrete with Different Steel-Slag-Powder Replacement Ratios.

The influence of different replacement ratios of steel-slag powder as cement-replacement material on the fracture performance of concrete is studied in this paper. A three-point bending fracture test is carried out on slag powder-cement-based concrete (SPC)-notched beams with steel-slag powder as cementitious materials, partially replacing cement (0%, 5%, 10%, 15%, and 20%). Load-deflection curves and load-crack-opening displacement curves of SPC-notched beams with five different replacement ratios of steel-slag powder were obtained. The effects of different steel-slag-powder replacement ratios on the fracture properties (fracture energy, fracture toughness, and double-K fracture parameters) of the SPC were analyzed and discussed. The results showed that the incorporation of appropriate steel-slag powder can affect the fracture performance of SPC. Compared with concrete without steel-slag powder, adding appropriate steel-slag powder can effectively improve the bond performance between aggregate and matrix because the steel-slag powder contains hydration activity substances such as calcium oxide and aluminium trioxide. The fracture energy and fracture toughness of SPC increased and then decreased with the increase in steel-slag-powder replacement ratios, and the SPC concrete showed best fracture performance with a 5% steel slag powder replacement ratio. Its fracture energy increases by 13.63% and fracture toughness increases by 53.22% compared with NC.

Calorimetric effect and thermokinetics in the formation process of a deep eutectic solvent.

For the first time, we report the calorimetric effect and thermokinetics in the formation process of a model deep eutectic solvent (DES), ChCl:urea. Mixing of a 1-to-2 molar ratio of choline chloride and urea shows a rapid endothermic process under stirring. The rate constants and reaction orders are determined by analyzing the thermokinetic curves at several constant temperatures. Low activation energy and activation parameters demonstrate that the formation of this DES is a rapid process. Other thermodynamic parameters are also estimated.

HIF-1α promotes the proliferation and migration of pulmonary arterial smooth muscle cells via activation of Cx43.

The proliferation of pulmonary artery smooth muscle cells (PASMCs) is an important cause of pulmonary vascular remodelling in hypoxia-induced pulmonary hypertension (HPH). However, its underlying mechanism has not been well elucidated. Connexin 43 (Cx43) plays crucial roles in vascular smooth muscle cell proliferation in various cardiovascular diseases. Here, the male Sprague-Dawley (SD) rats were exposed to hypoxia (10% O2 ) for 21 days to induce rat HPH model. PASMCs were treated with CoCl2 (200 µM) for 24 h to establish the HPH cell model. It was found that hypoxia up-regulated the expression of Cx43 and phosphorylation of Cx43 at Ser 368 in rat pulmonary arteries and PASMCs, and stimulated the proliferation and migration of PASMCs. HIF-1α inhibitor echinomycin attenuated the CoCl2 -induced Cx43 expression and phosphorylation of Cx43 at Ser 368 in PASMCs. The interaction between HIF-1α and Cx43 promotor was also identified using chromatin immunoprecipitation assay. Moreover, Cx43 specific blocker (37,43 Gap27) or knockdown of Cx43 efficiently alleviated the proliferation and migration of PASMCs under chemically induced hypoxia. Therefore, the results above suggest that HIF-1α, as an upstream regulator, promotes the expression of Cx43, and the HIF-1α/Cx43 axis regulates the proliferation and migration of PASMCs in HPH.

Deep eutectic solvent-assisted synthesis of porous Ni2CO3(OH)2/SiO2 nanosheets for ultra-efficient removal of anionic dyes from water.

Wastewater treatment is a severe environment issue, especially the discharge of excessive synthetic dyestuffs in the aquatic environment. In this study, a facile binary deep eutectic solvothermal process plus silica surface modification was successfully applied for preparation of porous nanosheet Ni2CO3(OH)2/SiO2 composites. The composites show powerful anionic dyes removal ability due to the high specific surface areas, hydrogen bond connection, coordination effect and strong electrostatic interactions with anionic dyes. A maximum adsorption capacity of 2637 mg g-1 at neutral pH (ca.7) and 303 K was achieved for Ni2CO3(OH)2/SiO2 composite to adsorb Congo red, a representative anionic dye. Moreover, the composite has an excellent specificity for anionic dyes and could maintain above 95% removal efficiency after 5 cycles. Therefore, the as-prepared nanocomposites could be qualified as candidates for industrial environmental remedy. Furthermore, the proposed material preparation strategy could be extended to fabricate various advanced energy and environmental materials.

Thermal properties and cold crystallization kinetics of deep eutectic solvents confined in nanopores.

Herein, the phase behaviors of both bulk and confined deep eutectic solvents in controlled pore glasses were first investigated. Glass transition, cold crystallization and melting behaviors alter significantly in the nanopores due to the size effect and interfacial interactions. Kinetic analysis of the crystallization reveals increased effective activation energies and pre-exponential factors under nanoconfinement.

Exosomal connexin 43 regulates the resistance of glioma cells to temozolomide.

Glioblastoma is the most common and aggressive brain tumor and it is characterized by a high mortality rate. Temozolomide (TMZ) is an effective chemotherapy drug for glioblastoma, but the resistance to TMZ has come to represent a major clinical problem, and its underlying mechanism has yet to be elucidated. In the present study, the role of exosomal connexin 43 (Cx43) in the resistance of glioma cells to TMZ and cell migration was investigated. First, higher expression levels of Cx43 were detected in TMZ­resistant U251 (U251r) cells compared with those in TMZ­sensitive (U251s) cells. Exosomes from U251s or U251r cells (sExo and rExo, respectively) were isolated. It was found that the expression of Cx43 in rExo was notably higher compared with that in sExo, whereas treatment with rExo increased the expression of Cx43 in U251s cells. Additionally, exosomes stained with dioctadecyloxacarbocyanine (Dio) were used to visualized exosome uptake by glioma cells. It was observed that the uptake of Dio­stained rExo in U251s cells was more prominent compared with that of Dio­stained sExo, while 37,43Gap27, a gap junction mimetic peptide directed against Cx43, alleviated the rExo uptake by cells. Moreover, rExo increased the IC50 of U251s to TMZ, colony formation and Bcl­2 expression, but decreased Bax and cleaved caspase­3 expression in U251s cells. 37,43Gap27 efficiently inhibited these effects of rExo on U251s cells. Finally, the results of the wound healing and Transwell assays revealed that rExo significantly enhanced the migration of U251s cells, whereas 37,43Gap27 significantly attenuated rExo­induced cell migration. Taken together, these results indicate the crucial role of exosomal Cx43 in chemotherapy resistance and migration of glioma cells, and suggest that Cx43 may hold promise as a therapeutic target for glioblastoma in the future.

CO2 switchable deep eutectic solvents for reversible emulsion phase separation.

The concept of CO2 switchable deep eutectic solvents (DESs) was proposed and a series of CO2 switchable imidazole-based deep eutectic solvents (DESs) was designed. The CO2 switch mechanism was investigated and the system was used for easy emulsion separation of olive oil from DESs. The benign CO2 switchable DESs have great potential applications in dissolution and easy separation.

Highly Efficient Cleavage of Ether Bonds in Lignin Models by Transfer Hydrogenolysis over Dual-Functional Ruthenium/Montmorillonite.

Cleavage of ether bonds is a crucial but challenging step for lignin valorization. To efficiently realize this transformation, the development of robust catalysts or catalytic systems is required. In this study, montmorillonite (MMT)-supported Ru (denoted as Ru/MMT) is fabricated as a dual-functional heterogeneous catalyst to cleave various types of ether bonds through transfer hydrogenolysis without using any additional acids or bases. The prepared Ru/MMT material is found to efficiently catalyze the cleavage of various lignin models and lignin-derived phenols; cyclohexanes (fuels) and cyclohexanols (key intermediates) are the main products. The synergistic effect between electron-enriched Ru and the acidic sites on MMT contributes to the excellent performance of Ru/MMT. Systematic studies reveal that the reaction proceeds through two possible reaction pathways, including the direct cleavage of ether bonds and the formation of intermediates with one hydrogenated benzene ring, for all examined types of ether bonds, namely, 4-O-5, α-O-4, and ß-O-4.

Tributyltin impaired spermatogenesis and reproductive behavior in male zebrafish.

Tributyltin (TBT) was reported to affect sexual behavior and gametogenesis in fish. However, the modes of action involved are largely unclear. In order to elucidate the toxicological mechanisms of TBT in reproduction, zebrafish (Danio rerio) males were exposed to TBT at concentrations of 100 and 500 ng/L for 28 days. After exposure, the sperm count of the treated fish was sharply decreased though the testis weight and gonadosomatic index remained unchanged. Moreover, reduced number of spermatogonia and spermatozoa and increased spermatocytes were observed in TBT-treated fish by histological observation and PCNA-immunostaining. Increased number of apoptotic-positive spermatocytes was also present in TBT-treated fish, indicating an enhanced apoptosis in these cells. Consistent to decreased number of spermatogonia, down-regulated expressions of genes responsible for germ cell proliferation (cyclind1 and pcna) were observed in TBT-treated fish. In contrast, TBT elevated the expressions of genes involved in meiotic entry and maintenance (aldhla2, sycp3 and dmc1) while suppressed the mRNA level of gene responsible for terminus of meiotic entry (cyp26a1), in agreement with arrested meiosis and reduced sperm count. Furthermore, TBT significantly elevated the ratios of bax/bcl-2 and tnfrsf1a/tnfrsf1b in testis, which are markers for intrinsic- and extrinsic-apoptotic pathways, consistent with the enhanced TUNEL positive signals in spermatocytes. Moreover, TBT also significantly affected the parameter of reproductive behaviors in treated fish (reflected by decreased frequency of meeting, visits and time spent in spawning area). Consistently, the expressions of genes responsible for the modulation of reproductive behaviors in brain (such as cyp19a1b, kiss2, gnrh3 and ompb) were significantly down-regulated in treated-fish. Interestingly, disrupted reproductive behaviors of untreated female fish were also observed in the present study. The present study indicated that TBT might affect the reproduction of zebrafish male by disrupting the spermatogenesis and reproductive behavior of the fish.

PKC and Ras are Involved in M1 Muscarinic Receptor-Mediated Modulation of AMPA Receptor GluA1 Subunit.

M1 muscarinic acetylcholine receptors (M1 mAChRs) have long been an attractive target for the treatment of Alzheimer's disease (AD), the most common cause of dementia in the elderly. M1 mAChR agonists show desirably preclinical activities; however, most have not gone further into late clinical trials due to ineffectiveness or side effects. Thus, to understand the signaling pathways involved in M1 mAChR-mediated memory improvement may be important for design of biased agonists with on-target therapeutic effects. M1 mAChRs are classically coupled to Gαq or ectopically to Gαs to activate multiple kinases such as protein kinase C (PKC), Ras and protein kinase A (PKA). Our previous studies have found that M1 mAChRs could improve learning and memory through modulating AMPA receptor GluA1 subunit via PKA-PI3K-Akt signaling. Here, we further investigated whether PKC and Ras were involved in M1 mAChR-mediated modulation of GluA1. We demonstrated the role of PKC and Ras in the signaling pathway, as both PKC inhibitors Ro-31-8425 or Gö6983 and Ras inhibitor salirasib abolished the membrane insertion of GluA1 and enhancement of its phosphorylation at Ser845 induced by M1 mAChRs in the primary cultured neurons and hippocampus in vivo. We further showed that PKC and Ras modulated PKA-PI3K-Akt signaling since the increases of PKA, Akt and mTOR activities by M1 mAChR activation were blocked by PKC and Ras inhibitors. These data demonstrated the detailed mechanism underlying M1 mAChR-mediated modulation of GluA1 through Gαq/11 coupling, broadening the knowledge of the downstream signaling after M1 mAChR-Gαq/11 coupling.

"Inverted" Deep Eutectic Solvents Based on Host-Guest Interactions.

Herein, the concept of "inverted" (the mode "molecules mainly interact with cations") deep eutectic solvents (DESs) is proposed. A strategy to form inverted DESs by host-guest interactions was developed, and thus numerous DESs could be designed and formed by a combination of host and guest molecules. These liquids are expected to be used as nonaqueous electrolytes in potassium-ion batteries or other fields for further exploration.