High-κ perovskite membranes as insulators for two-dimensional transistors.

The scaling of silicon metal-oxide-semiconductor field-effect transistors has followed Moore's law for decades, but the physical thinning of silicon at sub-ten-nanometre technology nodes introduces issues such as leakage currents1. Two-dimensional (2D) layered semiconductors, with an atomic thickness that allows superior gate-field penetration, are of interest as channel materials for future transistors2,3. However, the integration of high-dielectric-constant (κ) materials with 2D materials, while scaling their capacitance equivalent thickness (CET), has proved challenging. Here we explore transferrable ultrahigh-κ single-crystalline perovskite strontium-titanium-oxide membranes as a gate dielectric for 2D field-effect transistors. Our perovskite membranes exhibit a desirable sub-one-nanometre CET with a low leakage current (less than 10-2 amperes per square centimetre at 2.5 megavolts per centimetre). We find that the van der Waals gap between strontium-titanium-oxide dielectrics and 2D semiconductors mitigates the unfavourable fringing-induced barrier-lowering effect resulting from the use of ultrahigh-κ dielectrics4. Typical short-channel transistors made of scalable molybdenum-disulfide films by chemical vapour deposition and strontium-titanium-oxide dielectrics exhibit steep subthreshold swings down to about 70 millivolts per decade and on/off current ratios up to 107, which matches the low-power specifications suggested by the latest International Roadmap for Devices and Systems5.

Manganese Increases the Sensitivity of the cGAS-STING Pathway for Double-Stranded DNA and Is Required for the Host Defense against DNA Viruses.

Manganese (Mn) is essential for many physiological processes, but its functions in innate immunity remain undefined. Here, we found that Mn2+ was required for the host defense against DNA viruses by increasing the sensitivity of the DNA sensor cGAS and its downstream adaptor protein STING. Mn2+ was released from membrane-enclosed organelles upon viral infection and accumulated in the cytosol where it bound directly to cGAS. Mn2+ enhanced the sensitivity of cGAS to double-stranded DNA (dsDNA) and its enzymatic activity, enabling cGAS to produce secondary messenger cGAMP in the presence of low concentrations of dsDNA that would otherwise be non-stimulatory. Mn2+ also enhanced STING activity by augmenting cGAMP-STING binding affinity. Mn-deficient mice showed diminished cytokine production and were more vulnerable to DNA viruses, and Mn-deficient STING-deficient mice showed no increased susceptibility. These findings indicate that Mn is critically involved and required for the host defense against DNA viruses.

Orphan nuclear receptors-induced ALT-associated PML bodies are targets for ALT inhibition.

Orphan nuclear receptors (NRs), such as COUP-TF1, COUP-TF2, EAR2, TR2 and TR4, are implicated in telomerase-negative cancers that maintain their telomeres through the alternative lengthening of telomeres (ALT) mechanism. However, how telomere association of orphan NRs is involved in ALT activation remains unclear. Here, we demonstrate that telomeric tethering of orphan NRs in human fibroblasts initiates formation of ALT-associated PML bodies (APBs) and features of ALT activity, including ALT telomere DNA synthesis, telomere sister chromatid exchange, and telomeric C-circle generation, suggesting de novo ALT induction. Overexpression of orphan NRs exacerbates ALT phenotypes in ALT cells, while their depletion limits ALT. Orphan NRs initiate ALT via the zinc finger protein 827, suggesting the involvement of chromatin structure alterations for ALT activation. Furthermore, we found that orphan NRs and deficiency of the ALT suppressor ATRX-DAXX complex operate in concert to promote ALT activation. Moreover, PML depletion by gene knockout or arsenic trioxide treatment inhibited ALT induction in fibroblasts and ALT cancer cells, suggesting that APB formation underlies the orphan NR-induced ALT activation. Importantly, arsenic trioxide administration abolished APB formation and features of ALT activity in ALT cancer cell line-derived mouse xenografts, suggesting its potential for further therapeutic development to treat ALT cancers.

Neuronal activity-induced, equilibrative nucleoside transporter-dependent, somatodendritic adenosine release revealed by a GRAB sensor.

The purinergic signaling molecule adenosine (Ado) modulates many physiological and pathological functions in the brain. However, the exact source of extracellular Ado remains controversial. Here, utilizing a newly optimized genetically encoded GPCR-Activation-Based Ado fluorescent sensor (GRABAdo), we discovered that the neuronal activity-induced extracellular Ado elevation is due to direct Ado release from somatodendritic compartments of neurons, rather than from the axonal terminals, in the hippocampus. Pharmacological and genetic manipulations reveal that the Ado release depends on equilibrative nucleoside transporters but not the conventional vesicular release mechanisms. Compared with the fast-vesicular glutamate release, the Ado release is slow (~40 s) and requires calcium influx through L-type calcium channels. Thus, this study reveals an activity-dependent second-to-minute local Ado release from the somatodendritic compartments of neurons, potentially serving modulatory functions as a retrograde signal.

Self-Trapped Exciton Emission in Highly Polar 0D Hybrid Ammonium/Hydronium-Based Perovskites Triggered by Antimony Doping.

Various monovalent cations are employed to construct metal halide perovskites with various structures and functionalities. However, perovskites based on highly polar A-site cations have seldom been reported. Here, a novel hybrid 0D (NH4)x(OH3)3-xInCl6 perovskite with highly polar hydronium OH3+ cations is introduced in this study. Upon doping with Sb3+, hybrid 0D (NH4)x(OH3)3-xInCl6 single crystals exhibited highly efficient broadband yellowish-green (550 nm) and red (630 nm) dual emissions with a PLQY of 86%. The dual emission arises due to Sb3+ occupying two sites within the crystal lattice that possess different polarization environments, leading to distinct Stokes shift energies. The study revealed that lattice polarity plays a significant role in the self-trapped exciton emission of Sb3+-doped perovskites, contributing up to 25% of the Stokes shift energy for hybrid 0D (NH4)x(OH3)3-xInCl6:Sb3+ as a secondary source, in addition to the Jahn-Teller deformation. These findings highlight the potential of Sb3+-doped perovskites for achieving tunable broadband emission and underscore the importance of lattice polarity in determining the emission properties of perovskite materials.

Epigenetic silencing of LDHB promotes hepatocellular carcinoma by remodeling the tumor microenvironment.

Lactate dehydrogenase B (LDHB) reversibly catalyzes the conversion of pyruvate to lactate or lactate to pyruvate and expressed in various malignancies. However, the role of LDHB in modulating immune responses against hepatocellular carcinoma (HCC) remains largely unknown. Here, we found that down-regulation of lactate dehydrogenase B (LDHB) was coupled with the promoter hypermethylation and knocking down the DNA methyltransferase 3A (DNMT 3A) restored LDHB expression levels in HCC cell lines. Bioinformatics analysis of the HCC cohort from The Cancer Genome Atlas revealed a significant positive correlation between LDHB expression and immune regulatory signaling pathways and immune cell infiltrations. Moreover, immune checkpoint inhibitors (ICIs) have shown considerable promise for HCC treatment and patients with higher LDHB expression responded better to ICIs. Finally, we found that overexpression of LDHB suppressed HCC growth in immunocompetent but not in immunodeficient mice, suggesting that the host immune system was involved in the LDHB-medicated tumor suppression. Our findings indicate that DNMT3A-mediated epigenetic silencing of LDHB may contribute to HCC progression through remodeling the tumor immune microenvironment, and LDHB may become a potential prognostic biomarker and therapeutic target for HCC immunotherapy.

Elimination of Intragrain Defect to Enhance the Performance of FAPbI3 Perovskite Solar Cells by Ionic Liquid.

Ionic liquids have been widely used to improve the efficiency and stability of perovskite solar cells (PSCs), and are generally believed to passivate defects on the grain boundaries of perovskites. However, few studies have focused on the relevant effects of ionic liquids on intragrain defects in perovskites which have been shown to be critical for the performance of PSCs. In this work, the effect of ionic liquid 1-hexyl-3-methylimidazolium iodide (HMII) on intragrain defects of formamidinium lead iodide (FAPbI3) perovskite is investigated. Abundant {111}c intragrain planar defects in pure FAPbI3 grains are found to be significantly reduced by the addition of the ionic liquid HMII, shown by using ultra-low-dose selected area electron diffraction. As a result, longer charge carrier lifetimes, higher photoluminescence quantum yield, better charge carrier transport properties, lower Urbach energy, and current-voltage hysteresis are achieved, and the champion power conversion efficiency of 24.09% is demonstrated. These observations suggest that ionic liquids significantly improve device performance resulting from the elimination of {111}c intragrain planar defects.

Pseudouridine synthase 1 promotes hepatocellular carcinoma through mRNA pseudouridylation to enhance the translation of oncogenic mRNAs.

BACKGROUND AND AIMS: Pseudouridine is a prevalent RNA modification and is highly present in the serum and urine of patients with HCC. However, the role of pseudouridylation and its modifiers in HCC remains unknown. We investigated the function and underlying mechanism of pseudouridine synthase 1 (PUS1) in HCC. APPROACH AND RESULTS: By analyzing the TCGA data set, PUS1 was found to be significantly upregulated in human HCC specimens and positively correlated with tumor grade and poor prognosis of HCC. Knockdown of PUS1 inhibited cell proliferation and the growth of tumors in a subcutaneous xenograft mouse model. Accordingly, increased cell proliferation and tumor growth were observed in PUS1-overexpressing cells. Furthermore, overexpression of PUS1 significantly accelerates tumor formation in a mouse HCC model established by hydrodynamic tail vein injection, while knockout of PUS1 decreases it. Additionally, PUS1 catalytic activity is required for HCC tumorigenesis. Mechanistically, we profiled the mRNA targets of PUS1 by utilizing surveying targets by apolipoprotein B mRNA-editing enzyme 1 (APOBEC1)-mediated profiling and found that PUS1 incorporated pseudouridine into mRNAs of a set of oncogenes, thereby endowing them with greater translation capacity. CONCLUSIONS: Our study highlights the critical role of PUS1 and pseudouridylation in HCC development, and provides new insight that PUS1 enhances the protein levels of a set of oncogenes, including insulin receptor substrate 1 (IRS1) and c-MYC, by means of pseudouridylation-mediated mRNA translation.

Associations of sleep disorders with serum neurofilament light chain levels in Parkinson's disease.

BACKGROUND: Sleep disorders are a prevalent non-motor symptom of Parkinson's disease (PD), although reliable biological markers are presently lacking. OBJECTIVES: To explore the associations between sleep disorders and serum neurofilament light chain (NfL) levels in individuals with prodromal and early PD. METHODS: The study contained 1113 participants, including 585 early PD individuals, 353 prodromal PD individuals, and 175 healthy controls (HCs). The correlations between sleep disorders (including rapid eye movement sleep behavior disorder (RBD) and excessive daytime sleepiness (EDS)) and serum NfL levels were researched using multiple linear regression models and linear mixed-effects models. We further investigated the correlations between the rates of changes in daytime sleepiness and serum NfL levels using multiple linear regression models. RESULTS: In baseline analysis, early and prodromal PD individuals who manifested specific behaviors of RBD showed significantly higher levels of serum NfL. Specifically, early PD individuals who experienced nocturnal dream behaviors (ß = 0.033; P = 0.042) and movements of arms or legs during sleep (ß = 0.027; P = 0.049) showed significantly higher serum NfL levels. For prodromal PD individuals, serum NfL levels were significantly higher in individuals suffering from disturbed sleep (ß = 0.038; P = 0.026). Our longitudinal findings support these baseline associations. Serum NfL levels showed an upward trend in early PD individuals who had a higher total RBDSQ score (ß = 0.002; P = 0.011) or who were considered as probable RBD (ß = 0.012; P = 0.009) or who exhibited behaviors on several sub-items of the RBDSQ. In addition, early PD individuals who had a high total ESS score (ß = 0.001; P = 0.012) or who were regarded to have EDS (ß = 0.013; P = 0.007) or who exhibited daytime sleepiness in several conditions had a trend toward higher serum NfL levels. CONCLUSION: Sleep disorders correlate with higher serum NfL, suggesting a link to PD neuronal damage. Early identification of sleep disorders and NfL monitoring are pivotal in detecting at-risk PD patients promptly, allowing for timely intervention. Regular monitoring of NfL levels holds promise for tracking both sleep disorders and disease progression, potentially emerging as a biomarker for evaluating treatment outcomes.

New Insights for Biosensing: Lessons from Microbial Defense Systems.

Microorganisms have gained defense systems during the lengthy process of evolution over millions of years. Such defense systems can protect them from being attacked by invading species (e.g., CRISPR-Cas for establishing adaptive immune systems and nanopore-forming toxins as virulence factors) or enable them to adapt to different conditions (e.g., gas vesicles for achieving buoyancy control). These microorganism defense systems (MDS) have inspired the development of biosensors that have received much attention in a wide range of fields including life science research, food safety, and medical diagnosis. This Review comprehensively analyzes biosensing platforms originating from MDS for sensing and imaging biological analytes. We first describe a basic overview of MDS and MDS-inspired biosensing platforms (e.g., CRISPR-Cas systems, nanopore-forming proteins, and gas vesicles), followed by a critical discussion of their functions and properties. We then discuss several transduction mechanisms (optical, acoustic, magnetic, and electrical) involved in MDS-inspired biosensing. We further detail the applications of the MDS-inspired biosensors to detect a variety of analytes (nucleic acids, peptides, proteins, pathogens, cells, small molecules, and metal ions). In the end, we propose the key challenges and future perspectives in seeking new and improved MDS tools that can potentially lead to breakthrough discoveries in developing a new generation of biosensors with a combination of low cost; high sensitivity, accuracy, and precision; and fast detection. Overall, this Review gives a historical review of MDS, elucidates the principles of emulating MDS to develop biosensors, and analyzes the recent advancements, current challenges, and future trends in this field. It provides a unique critical analysis of emulating MDS to develop robust biosensors and discusses the design of such biosensors using elements found in MDS, showing that emulating MDS is a promising approach to conceptually advancing the design of biosensors.

Identification of Sulfur-Containing Chlorinated Paraffin Structural Analogues in Human Serum: Origination from Biotransformation or Bioaccumulation?

Chlorinated paraffins (CPs) are manufactured and used in high quantities and have diverse structural analogues. It is generally recognized that sulfur-containing structural analogues of CPs are mainly derived from sulfate-conjugated phase II metabolism. In this study, we non-targeted identified three classes of sulfur-containing CP structural analogues (CPs-S) in human serum, including 44 CP sulfates (CPs-SO4H/CPs-SO4H-OH), 14 chlorinated benzene sulfates (CBs-SO4H), and 19 CP sulfite esters (CPs-SO3/CPs-S2O6), which were generated during the production of commercial mixtures of CPs and, thus, bioaccumulated via environmental exposures. We first wrote a program to screen CPs-S, which were baseline-separated from CPs according to their polar functional groups. Then, mass spectral analyses of alkalization-acidification liquid-liquid extracts of serum samples and Orbitrap mass spectrometry analyses in the presence and absence of tetraphenylphosphonium chloride (Ph4PCl), respectively, were performed to determine the ionization forms ([M + Cl]- or [M - H]-) of CPs-S. The presence of fragment ions (SO4H-, SO3-, SO2Cl-, and HSO3-) revealed the structures of CPs-S, which were validated by their detections in commercial mixtures of CPs. The estimated total concentrations of CPs-S in the human serum samples were higher than the concentrations of medium- and long-chain CPs. The profiles of CPs-S in human serum were similar to those detected in CP commercial mixtures and rats exposed to the commercial mixtures, but CPs-S were not detected in human liver S9 fractions or rat tissues after exposure to CP standards. These results, together with the knowledge of the processes used to chemically synthesize CPs, demonstrate that CPs-S in humans originates from environmental bioaccumulation.

Analgesic Effects of Intraperitoneal Lidocaine in Adults Undergoing Surgery: A Systematic Review and Meta-Analysis with Trial Sequential Analysis.

OBJECTIVE: The administration of local anaesthesia in intraperitoneal space as part of the multi-modal analgesic regimen has shown to be effective in reducing postoperative pain. Recent studies demonstrated that intraperitoneal lidocaine may provide analgesic effects. Primary objective was to determine the impact of intraperitoneal lidocaine on postoperative pain scores at rest. DESIGN: We carried out a systematic review and meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). METHODS: Databases of MEDLINE, EMBASE, and CENTRAL were searched from their inception date until May 2023. Randomized clinical trials (RCT) comparing intraperitoneal lidocaine and placebo in adults undergoing surgery were included. RESULTS: Our systematic review included 24 RCTs (n = 1,824). The intraperitoneal lidocaine group was significantly associated with lower postoperative pain scores at rest (MD: -0.87, 95% CI: -1.04 to -0.69) and at movement (MD: -0.50, 95% Cl: -0.93 to -0.08) among adult patients after surgery. Its administration also significantly decreased morphine consumption (MD: -6.42 mg, 95% Cl: -11.56 to -1.27), lowered the incidence of needing analgesia (OR: 0.22, 95% Cl: 0.14 to 0.35). Intraperitoneal lidocaine statistically reduced time to resume regular diet (MD: 0.16 days; 95% Cl: -0.31 to -0.01), and lowered postoperative incidence of nausea and vomiting (OR: 0.54, 95% Cl: 0.39 to 0.75). CONCLUSIONS: In this review, our findings should be interpreted with caution. Future studies are warranted to determine the optimal dose of administering intraperitoneal lidocaine among adult patients undergoing surgery.

Comparison of blended learning and traditional lecture method on learning outcomes in the evidence-based medicine course: a comparative study.

BACKGROUND: Blended learning comprised with flipped classroom (FC) and "internet plus" is a new learning strategy that reverses the position of teacher and students in class, and provides abundant learning resources before and after class. This study aimed to assess the impact of blended learning on learning outcomes in evidence-based medicine course, and compare with traditional learning method. METHODS: The participants of the two groups were from two difference cohorts in Air force medical university in China. The two groups toke the same pre-test before class and then were given the teaching of same chapters of evidence-based medicine with two different learning strategy. In the blended learning group, the participants were required to create a debriefing slide about their learning outcomes and the answers of questions given in advance after study the learning material sent by teacher a week before class, and the teacher gave a detailed summary based on the common problems, and distributed multimedia resources for review. After the experiment was carried out, learning outcomes including mastering knowledge, learning satisfaction, and self-evaluation were compared. RESULTS: 37 and 39 participants were enrolled to blended learning and traditional learning groups, respectively, and no statistically significant difference were found in baseline information and pre-test grades. Statistically significant differences were found in learning outcomes including post-test score (t = 2.90, p = 0.005), changes of scores between pre-test and post-test (t = 2.49, p = 0.022), learning satisfaction (t = 12.41, p = 0.001), and self-evaluation of the two groups (t = 7.82, p = 0.001). Especially, the changes of scores between pre-test and post-test of blended learning and traditional learning groups were 4.05 (4.26), and 2.00 (2.85), respectively. CONCLUSIONS: This study showed that compared with traditional learning strategy, blended learning can effectively enhanced participants' acquisition of knowledge, learning satisfaction, and self-evaluation in evidence-based medicine. Using blended learning method including "internet plus" and flipped classroom is recommended in the teaching of evidence-based medicine course.

Fibroblast growth factor 5 expression predicts the progression of oral squamous cell carcinoma.

BACKGROUND/PURPOSE: Fibroblast growth factor (FGF) 5 is a member of the FGF family that functions as a regulator of tissue growth and regeneration. Aberrant FGF5 expression has been previously associated with the progression of a number of different malignancies. However, its potential role in oral cancer remains unclear. In this study, we explored the relationship between the expression of FGF5 protein in oral squamous cell carcinomas (OSCCs) and the clinicopathological parameters of OSCCs and whether the expression of FGF5 protein in OSCCs could be a prognostic factor for OSCC patients. METHODS: The FGF5 protein expression was examined in 64 OSCC and 34 normal oral mucosal specimens by immunohistochemical staining. Stress induced upregulation and intracellular redistribution of FGF5 were verified using xenograft animal model and OSCC cell lines. RESULTS: The mean FGF5 protein labelling index was significantly higher in OSCC than in normal oral mucosal samples, with high FGF5 protein labelling index (>58%) being correlated with advanced stage and poor survival of OSCC patients. Apart from the peri-cytoplasmic staining pattern characteristic of paracrine growth factors, FGF5 protein was localized as distinct punctate structures in the cytoplasm of advanced stage or stressed-induced cells. This redistribution and upregulation of FGF5 protein could be sustained after termination of the stress induction in cell line and xenograft animal models. CONCLUSION: FGF5 can be induced by cellular stress and risk factors of OSCC, where high expression levels of FGF5 is potentially a useful parameter for predicting OSCC progression and patient survival.

Paramedian versus midline approach of spinal anesthesia: a systematic review and meta-analysis with trial sequential analysis.

PURPOSE: Midline approach of spinal anesthesia has been widely used for patients undergoing surgical procedures. However, it might not be effective for obstetric patients and elderly with degenerative spine changes. Primary objective was to examine the success rate at the first attempt between the paramedian and midline spinal anesthesia in adults undergoing surgery. METHODS: Databases of MEDLINE, EMBASE, and CENTRAL were searched from their starting date until February 2023. Randomized clinical trials (RCTs) comparing the paramedian versus midline approach of spinal anesthesia were included. The primary outcome was the success rate at the first attempt of spinal anesthesia. RESULTS: Our review included 36 RCTs (n = 5379). Compared to the midline approach, paramedian approach may increase success rate at the first attempt but the evidence is very uncertain (OR: 0.47, 95% CI 0.27-0.82, ρ = 0.007, level of evidence:very low). Our pooled data indicates that the paramedian approach likely reduced incidence of post-spinal headache (OR: 2.07, 95% CI 1.51-2.84, ρ < 0.00001, level of evidence:moderate). The evidence suggests that the paramedian approach may result in a reduction in the occurrence of paresthesia (OR: 1.61, 95% CI 1.06-2.45, ρ = 0.03, level of evidence:low). CONCLUSIONS: Our meta-analysis of 36 RCTs showed that paramedian approach may result in little to no difference in success rate at the first attempt owing to its very low level of evidence. However, given the low level of evidence and studies with small sample sizes, these findings need to be interpreted with caveat. CLINICAL TRIAL REGISTRATION NUMBER: CRD42023397781.

Depression and anxiety between nurses and nursing assistants working in long-term care facilities during the COVID-19 pandemic.

AIM: This study investigated the levels of depression and anxiety in nurses and nursing assistants working in long-term care facilities during the COVID-19 pandemic. We also explored the potential causes of depression and anxiety in nurses and nursing assistants working in long-term care facilities during the pandemic. BACKGROUND: The COVID-19 pandemic has had a considerable impact on long-term care facilities. The high infection and mortality rates for COVID-19 have resulted in an increased workload for caregivers. INTRODUCTION: The COVID-19 pandemic exposed caregivers working in long-term care facilities to higher risks of anxiety and depression. Additionally, the high risk of infection in the work environment and concerns about spreading COVID-19 to family members and long-term care facility residents led to various forms of stress among caregivers. METHODS: The present study was a cross-sectional study. Questionnaires were used to investigate depression and anxiety among regarding nurses and nursing assistants working in long-term care facilities during the pandemic. RESULTS: The depression and anxiety levels of the nurses were higher than nursing assistants, but had no statistically significant difference (p = 0.551). The factors influencing levels of depression and anxiety in nurses contained facility affiliation and experience working. In terms of nursing assistants, age, marital status, and facility affiliation were correlated with the levels of depression and anxiety. DISCUSSION: The pandemic has severely impacted caregivers. In the process of implementing pandemic prevention measures and providing care for COVID-19 patients, safeguarding the psychological health of caregivers is also essential. CONCLUSION: The levels of depression and anxiety in nurses were higher than in nursing assistants working in long-term care facilities during the pandemic. IMPLICATION FOR NURSING AND HEALTH POLICY: Long-term care facilities managers are recommended to enhance the education and training process for caregivers. Managers are also recommended to ensure provision of sufficient amounts of pandemic prevention equipment and resources.

[Mechanism of bulleyaconitine A in inhibiting bone destruction of rheumatoid arthritis via Src/PI3K/Akt signaling pathway].

Based on the sarcoma receptor coactivator(Src)/phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt) signaling pathway, the mechanism of action of bulleyaconitine A in the treatment of bone destruction of experimental rheumatoid arthritis(RA) was explored. Firstly, key targets of RA bone destruction were collected through GeneCards, PharmGKB, and OMIM databa-ses. Potential targets of bulleyaconitine A were collected using SwissTargetPrediction and PharmMapper databases. Next, intersection targets were obtained by the Venny 2.1.0 platform. Protein-protein interaction(PPI) network and topology analysis were managed by utilizing the STRING database and Cytoscape 3.8.0. Then, Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses were conducted in the DAVID database. AutoDock Vina was applied to predict the molecular docking and binding ability of bulleyaconitine A with key targets. Finally, a receptor activator of nuclear factor-κB(RANKL)-induced osteoclast differentiation model was established in vitro. Quantitative real-time polymerase chain reaction(qRT-PCR) was used to detect the mRNA expression levels of related targets, and immunofluorescence and Western blot were adopted to detect the protein expression level of key targets. It displayed that there was a total of 29 drug-disease targets, and Src was the core target of bulleyaconitine A in anti-RA bone destruction. Furthermore, KEGG enrichment analysis revealed that bulleyaconitine A may exert an anti-RA bone destruction effect by regulating the Src/PI3K/Akt signaling pathway. The molecular docking results showed that bulleyaconitine A had better bin-ding ability with Src, phosphatidylinositol-4,5-diphosphate 3-kinase(PIK3CA), and Akt1. The result of the experiment indicated that bulleyaconitine A not only dose-dependently inhibited the mRNA expression levels of osteoclast differentiation-related genes cathepsin K(CTSK) and matrix metalloproteinase-9(MMP-9)(P<0.01), but also significantly reduced the expression of p-c-Src, PI3K, as well as p-Akt in vitro osteoclasts(P<0.01). In summary, bulleyaconitine A may inhibit RA bone destruction by regulating the Src/PI3K/Akt signaling pathway. This study provides experimental support for the treatment of RA bone destruction with bulleyaconitine A and lays a foundation for the clinical application of bulleyaconitine A.

Binding FSI- to Construct a Self-Healing SEI Film for Li-Metal Batteries by In situ Crosslinking Vinyl Ionic Liquid.

The solid electrolyte interphase (SEI) membrane on the Li metal anode tends to breakdown and undergo reconstruction during operation, causing Li metal batteries to experience accelerated decay. Notably, an SEI membrane with self-healing characteristics can help considerably in stabilizing the Li-electrolyte interface; however, uniformly fixing the repairing agent onto the anode remains a challenging task. By leveraging the noteworthy film-forming attributes of bis(fluorosulfonyl)imide (FSI-) anions and the photopolymerization property of the vinyl group, the ionic liquid 1-vinyl-3-methylimidazolium bis(fluorosulfonyl)imide (VMI-FSI) was crosslinked with polyethylene oxide (PEO) in this study to form a self-healing film fixing FSI- groups as the repairing agent. When they encounter lithium metal, the FSI- groups are chemically decomposed into LiF & Li3N, which assist forming SEI membrane on lithium sheet and repairing SEI membrane in the cracks lacerated by lithium dendrite. Furthermore, the FSI- anions exchanged from film are electrochemically decomposed to generate inorganic salts to strengthen the SEI membrane. Benefiting from the self-healing behavior of the film, Li/LiCoO2 cells with the loading of 16.3 mg cm-2 exhibit the initial discharge capacities of 183.0 mAh ⋅ g-1 and are stably operated for 500 cycles with the retention rates of 81.4 % and the average coulombic efficiency of 99.97 %, operated between 3.0-4.5 V vs. Li+/Li. This study presents a new design approach for self-healing Li metal anodes and durable lithium metal battery.

Shell Modulation of Hollow Metal Sulfide Nanocomposite for Stable Potassium Storage at Room and High Temperature.

The large size of K-ion makes the pursuit of stable high-capacity anodes for K-ion batteries (KIBs) a formidable challenge, particularly for high temperature KIBs as the electrode instability becomes more aggravated with temperature climbing. Herein, we demonstrate that a hollow ZnS@C nanocomposite (h-ZnS@C) with a precise shell modulation can resist electrode disintegration to enable stable high-capacity potassium storage at room and high temperature. Based on a model electrode, we identify an interesting structure-function correlation of the h-ZnS@C: with an increase in the shell thickness, the cyclability increases while the rate and capacity decrease, shedding light on the design of high-performance h-ZnS@C anodes via engineering the shell thickness. Typically, the h-ZnS@C anode with a shell thickness of 60 nm can deliver an impressive comprehensive performance at room temperature; the h-ZnS@C with shell thickness increasing to 75 nm can achieve an extraordinary stability (88.6 % capacity retention over 450 cycles) with a high capacity (450 mAh g-1) and a superb rate even at an extreme temperature of 60 °C, which is much superior than those reported anodes. This contribution envisions new perspectives on rational design of functional metal sulfides composite toward high-performance KIBs with insights into the significant structure-function correlation.

Circ_0000052/miR-382-3p axis induces PD-L1 expression and regulates cell proliferation and immune evasion in head and neck squamous cell carcinoma.

A better understanding of the mechanisms underlying PD-L1 aberrant expression in head and neck squamous cell carcinoma (HNSCC) will help reveal predictive biomarkers and overcome resistance to treatment. In this study, the prognostic significance of PD-L1 in forty-five HNSCC archival samples was determined by qRT-PCR. The biological function associated with malignant behaviour was assessed by PD-L1 depletion, miR-382-3p re-expression and regulation of circ_0000052. The interactions of PD-L1-miRNA and miRNA-circRNA were determined by qRT-PCR, Western blot analysis, dual-luciferase reporter assays and RNA immunoprecipitation assays. PD-L1 was highly expressed in patient samples and cancer cell lines. Higher levels of PD-L1 were associated with patient recurrences and play a pivotal role in regulating cell proliferation, migration, invasion, clonogenicity and apoptosis. In addition to demonstrating that the IFN-γ/JAK2/STAT1 signalling pathway can induce PD-L1 overexpression in HNSCC, a novel mechanism by which upregulated circ_0000052 mediates PD-L1 overexpression was also demonstrated. To do this, circ_0000052 competitively binds to miR-382-3p and alleviates its repression of PD-L1. This leads to overexpression of PD-L1, causing the aggressiveness of the cells. Our data demonstrate that circ_0000052 is oncogenic, and the circ_0000052/miR-382-3p/PD-L1 axis is critical in HNSCC progression. The manipulation of circRNAs/miRNAs in combination with anti-PD-L1 therapy may improve personalized disease management.