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.

[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.

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.

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.

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.

M1 muscarinic receptors regulate the phosphorylation of AMPA receptor subunit GluA1 via a signaling pathway linking cAMP-PKA and PI3K-Akt.

M1 muscarinic acetylcholine receptors are highly expressed in key areas that control cognition, such as the cortex and hippocampus, representing one potential therapeutic target for cognitive dysfunctions of Alzheimer's disease and schizophrenia. We have reported that M1 receptors facilitate cognition by promoting membrane insertion of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor AMPA receptor subunit 1 (GluA1) through phosphorylation at Ser845. However, the signaling pathway is still unclear. Here we showed that adenylyl cyclase inhibitor 2',5'-dideoxyadenosine and PKA inhibitor KT5720 inhibited enhancement of phosphorylation of Ser845 and membrane insertion of GluA1 induced by M1 receptor activation. Furthermore, PI3K inhibitor LY294002 and protein kinase B (Akt) inhibitor IV blocked the effects of M1 receptors as well. Remarkably, the increase of the activity of PI3K-Akt signaling induced by M1 receptor activation could be abolished by cAMP-PKA inhibitors. Moreover, inhibiting the mammalian target of rapamycin (mTOR) complex 1, an important downstream effector of PI3K-Akt, by short-term application of rapamycin attenuated the effects of M1 receptors on GluA1. Furthermore, such effect was unrelated to possible protein synthesis promoted by mTOR. Taken together, these data demonstrate that M1 receptor activation induces membrane insertion of GluA1 via a signaling linking cAMP-PKA and PI3K-Akt-mTOR pathways but is irrelevant to protein synthesis.-Zhao, L.-X., Ge, Y.-H., Li, J.-B., Xiong, C.-H., Law, P.-Y., Xu, J.-R., Qiu, Y., Chen, H.-Z. M1 muscarinic receptors regulate the phosphorylation of AMPA receptor subunit GluA1 via a signaling pathway linking cAMP-PKA and PI3K-Akt.

M1 muscarinic receptor facilitates cognitive function by interplay with AMPA receptor GluA1 subunit.

M1 muscarinic acetylcholine receptors (M1 mAChRs) are the most abundant muscarinic receptors in the hippocampus and have been shown to have procognitive effects. AMPA receptors (AMPARs), an important subtype of ionotropic glutamate receptors, are key components in neurocognitive networks. However, the role of AMPARs in procognitive effects of M1 mAChRs and how M1 mAChRs affect the function of AMPARs remain poorly understood. Here, we found that basal expression of GluA1, a subunit of AMPARs, and its phosphorylation at Ser845 were maintained by M1 mAChR activity. Activation of M1 mAChRs promoted membrane insertion of GluA1, especially to postsynaptic densities. Impairment of hippocampus-dependent learning and memory by antagonism of M1 mAChRs paralleled the reduction of GluA1 expression, and improvement of learning and memory by activation of M1 mAChRs was accompanied by the synaptic insertion of GluA1 and its increased phosphorylation at Ser845. Furthermore, abrogation of phosphorylation of Ser845 residue of GluA1 ablated M1 mAChR-mediated improvement of learning and memory. Taken together, these results show a functional correlation of M1 mAChRs and GluA1 and the essential role of GluA1 in M1 mAChR-mediated cognitive improvement.-Zhao, L.-X., Ge, Y.-H., Xiong, C.-H., Tang, L., Yan, Y.-H., Law, P.-Y., Qiu, Y., Chen, H.-Z. M1 muscarinic receptor facilitates cognitive function by interplay with AMPA receptor GluA1 subunit.

[Identification and pathogenicity prediction of a novel GLB1 variant c.101T>C (p.Ile34Thr) in an infant with GM1 gangliosidosis].

GM1 gangliosidosis is an autosomal recessive disorder caused by galactosidase beta1 (GLB1) gene variants which affect the activity of ß-galactosidase (GLB). GLB dysfunction causes abnormalities in the degradation of GM1 and its accumulation in lysosome. This article reports the clinical and genetic features of a child with GM1 gangliosidosis. The girl, aged 2 years and 5 months, was referred to the hospital due to motor developmental regression for more than one year. Physical examination showed binocular deflection and horizontal nystagmus, but no abnormality was found on fundoscopy. The girl had increased muscular tone of the extremities, limitation of motion of the elbow, knee, and ankle joints, and hyperactive patellar tendon reflex. Blood biochemical examination showed a significant increase in aspartate aminotransferase. The 24-hour electroencephalographic monitoring detected frequent seizure attacks and diffuse θ wave activity, especially in the right hemisphere. Head magnetic resonance imaging showed thinner white matter in the periventricular region and diffuse high T2WI signal with unclear boundary. Three-dimensional reconstruction of white matter fiber tracts by diffusion tensor imaging showed smaller and thinner white matter fiber tracts, especially in the right hemisphere. Genetic analysis showed that the girl had compound heterozygous mutations of c.446C>T (p.Ser149Phe) and c.101T>C (p.Ile34Thr) in the GLB1 gene from her parents, among which c.101T>C (p.Ile34Thr) had not been reported in the literatures. The girl was finally diagnosed with GM1 gangliosidosis. Her conditions were not improved after antiepileptic treatment and rehabilitation training for 2 months.

Thermochromic Magnetic Ionic Liquids from Cationic Nickel(II) Complexes Exhibiting Intramolecular Coordination Equilibrium.

Among the various thermochromic materials, liquid thermochromic materials are comparatively rare. To produce functional thermochromic liquids, we have designed ionic liquids based on cationic nickel complexes with ether side chains, [Ni(acac)(Me2 NC2 H4 NR1 R2 )]Tf2 N ([1]Tf2 N: R1 =C3 H6 OEt, R2 =Me; [2]Tf2 N: R1 =C3 H6 OMe, R2 =Me; [3]Tf2 N: R1 =R2 =C3 H6 OMe), where acac=acetylacetonate and Tf2 N=(F3 CSO2 )2 N- . The side chains (R1 , R2 ) can moderately coordinate to the metal center, enabling temperature-dependent coordination equilibria in the liquid state. [1]Tf2 N is a liquid at room temperature. [2]Tf2 N is obtained as a solid (Tm =352.7 K) but remains liquid at room temperature after melting. [3]Tf2 N is a solid with a high melting point (Tm =422.3 K). These salts display thermochromism in the liquid state, appearing red at high temperatures and orange, light-blue, or bluish-green at lower temperatures, and exhibiting concomitant changes in their magnetic properties. This phenomenon is based on temperature-dependent equilibrium between a square-planar diamagnetic species and a paramagnetic species with intramolecular ether coordination.

Chromoblastomycosis due to Fonsecaea monophora in a man with nephritic syndrome.

Chromoblastomycosis is a chronic subcutaneous mycosis caused by dematiaceous fungi. Fonsecaea monophora, a new species segregated from F. pedrosoi, may be the most prevalent pathogen of chromoblastomycosis in southern China. Herein, we report a rare case of chromoblastomycosis in a man with nephritic syndrome. He presented with an asymptomatic red plaque on the back of his left wrist that had appeared and enlarged over a period of 1.5 years, without any prior trauma. He was initially diagnosed with sporotrichosis. However, he did not respond to a 6-month course of potassium iodide treatment. The lesion slowly enlarged and became verrucous instead. Concurrently, a similar maculopapule appeared on his left forearm. Histopathological examination of a biopsy specimen indicated the presence of sclerotic bodies in the dermis. The fungus was identified as Fonsecaea spp. based on the results of a slide culture; in addition, the agent was confirmed to be F. monophora by using molecular methods. The patient demonstrated marked improvement after receiving appropriate antifungal therapy for 3 months. To our knowledge, this is the first case of chromoblastomycosis caused by F. monophora in an immunosuppressed patient. The identification of the agent by molecular techniques is important for epidemiological purposes. Thus, we believe that combination therapy with itraconazole and terbinafine would be a suitable option for infections caused by F. monophora.

In vitro and in vivo activities of pterostilbene against Candida albicans biofilms.

Pterostilbene (PTE) is a stilbene-derived phytoalexin that originates from several natural plant sources. In this study, we evaluated the activity of PTE against Candida albicans biofilms and explored the underlying mechanisms. In 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) reduction assays, biofilm biomass measurement, confocal laser scanning microscopy, and scanning electron microscopy, we found that ≤16 µg/ml PTE had a significant effect against C. albicans biofilms in vitro, while it had no fungicidal effect on planktonic C. albicans cells, which suggested a unique antibiofilm effect of PTE. Then we found that PTE could inhibit biofilm formation and destroy the maintenance of mature biofilms. At 4 µg/ml, PTE decreased cellular surface hydrophobicity (CSH) and suppressed hyphal formation. Gene expression microarrays and real-time reverse transcription-PCR showed that exposure of C. albicans to 16 µg/ml PTE altered the expression of genes that function in morphological transition, ergosterol biosynthesis, oxidoreductase activity, and cell surface and protein unfolding processes (heat shock proteins). Filamentation-related genes, especially those regulated by the Ras/cyclic AMP (cAMP) pathway, including ECE1, ALS3, HWP1, HGC1, and RAS1 itself, were downregulated upon PTE treatment, indicating that the antibiofilm effect of PTE was related to the Ras/cAMP pathway. Then, we found that the addition of exogenous cAMP reverted the PTE-induced filamentous growth defect. Finally, with a rat central venous catheter infection model, we confirmed the in vivo activity of PTE against C. albicans biofilms. Collectively, PTE had strong activities against C. albicans biofilms both in vitro and in vivo, and these activities were associated with the Ras/cAMP pathway.

Didymocarpuspingyuanensis (Gesneriaceae), a new species endemic to Danxia landscape from Guangdong Province, China, and two new combinations in Didymocarpus.

Didymocarpuspingyuanensis, endemic to the Danxia landscape in Pingyuan County, Guangdong, China, is described and illustrated here. This species can be distinguished from other members of Didymocarpussect.Heteroboea by its calyx deeply 5-lobed to about three quarters of its length. The phylogenetic position of the new species within Didymocarpus was examined using nuclear ribosomal internal transcribed spacer (ITS) sequences. Based on phylogenetics analysis and morphological evidence, we propose two new combinations, elevating the two varieties to species level, namely D.yinzhengii and D.gamosepalus.

Fluconazole assists berberine to kill fluconazole-resistant Candida albicans.

It was found in our previous study that berberine (BBR) and fluconazole (FLC) used concomitantly exhibited a synergism against FLC-resistant Candida albicans in vitro. The aim of the present study was to clarify how BBR and FLC worked synergistically and the underlying mechanism. Antifungal time-kill curves indicated that the synergistic effect of the two drugs was BBR dose dependent rather than FLC dose dependent. In addition, we found that BBR accumulated in C. albicans cells, especially in the nucleus, and resulted in cell cycle arrest and significant change in the transcription of cell cycle-related genes. Besides BBR, other DNA intercalators, including methylene blue, sanguinarine, and acridine orange, were all found to synergize with FLC against FLC-resistant C. albicans. Detection of intracellular BBR accumulation by fluorescence measurement showed that FLC played a role in increasing intracellular BBR concentration, probably due to its effect in disrupting the fungal cell membrane. Similar to the case with FLC, other antifungal agents acting on the cell membrane were able to synergize with BBR. Interestingly, we found that the efflux of intracellular BBR was FLC independent but strongly glucose dependent and associated with the drug efflux pump Cdr2p. These results suggest that BBR plays a major antifungal role in the synergism of FLC and BBR, while FLC plays a role in increasing the intracellular BBR concentration.

ECM17-dependent methionine/cysteine biosynthesis contributes to biofilm formation in Candida albicans.

Candida albicans has become the fourth leading pathogen of nosocomial bloodstream infections largely due to biofilm formation on implanted medical devices. Previous microarray data indicated that almost all genes in methionine (Met)/cysteine (Cys) biosynthesis pathway were up-regulated during biofilm formation, especially during the adherence period. In this work, we studied the role of Met/Cys biosynthesis pathway by disrupting ECM17, a gene encoding sulfite reductase in C. albicans. It was found that the ecm17Δ/Δ mutant failed to catalyze the biochemical reaction from sulfite to H(2)S and hardly grew in media lacking Met and Cys. NaSH, the donor of H(2)S, dose-dependently improved the growth of ecm17Δ/Δ in media lacking a sulfur source. Sufficient Met/Cys supply inhibited the expression of ECM17 in a dose-dependent manner. These results validated the important role of ECM17 in Met/Cys biosynthesis. Interestingly, the ecm17Δ/Δ mutant showed diminished ability to form biofilm, attenuated adhesion on abiotic substrate and decreased filamentation on solid SLD medium, especially under conditions lacking Met/Cys. Further results indicated that ECM17 affected the expressions of ALS3, CSH1, HWP1 and ECE1, and that the cAMP-protein kinase A (PKA) pathway was associated with ECM17 and Met/Cys biosynthesis pathway. These results provide new insights into the role of Met/Cys biosynthesis pathway in regulating cAMP-PKA pathway and benefiting biofilm formation.

Using Galleria mellonella-Candida albicans infection model to evaluate antifungal agents.

Candida albicans is the most common fungal pathogen. Galleria mellonella is widely used as an infection model host. Nevertheless, the G. mellonella-C. albicans infection model had not been optimized for drug evaluation before this study. In this work, we revealed that 5 × 10(5) colony forming unit (CFU)/larva was a suitable inoculum to optimize the G. mellonella-C. albicans infection model in order to evaluate antifungal agents. Using our optimized model, the antifungal effect of fluconazole, amphotericin B and flucytosine, and the synergy between amphotericin B and flucytosine were successfully verified. Thus, this study provides a rapid, inexpensive and reliable way to evaluate antifungals in vivo.

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.

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.

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.

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.