Untargeted metabolomics reveals the mechanism of amantadine toxicity on Laminaria japonica.

The antiviral agent amantadine is frequently detected in seawater and marine organisms. Because of increasing concentrations, amantadine has become a contaminant of emerging concern. This compound has toxic effects on the brown algae Laminaria japonica. The effects of amantadine on the biological processes of L. japonica and the corresponding toxic mechanisms remain unclear. In this study, amantadine toxicity on L. japonica was investigated using histopathological and physiological characteristics combined with metabolomics analysis. Changes in metabolites were determined by untargeted metabolomics after exposure to 107 ng/L amantadine for 72 h. The catalase activity in the exposure group slightly increased, whereas the superoxide dismutase activity greatly decreased. An increase in the malondialdehyde concentration was observed after amantadine exposure, which suggested that lipid peroxidation and cell damage occurred. Metabolomics analysis showed that there were 406 differentially expressed metabolites after amantadine exposure. These were mainly phospholipids, amino acids, purines, and their derivatives. Inhibition of the glycerophospholipid metabolism affected the lipid bilayer and cell structure, which was aligned with changes in histological observation. Changes in amino acids led to perturbation of protein synthesis and induced oxidative stress through interference with glutathione metabolism and tyrosine metabolism. Amantadine also interfered with energy metabolism in L. japonica by disturbing the tricarboxylic acid cycle and purine metabolism. The results of this study provide new insights into the mechanism of amantadine toxicity on L. japonica.

Temporo-frontoparietal hypoconnectivity as a biomarker for isolated language impairment in mild cognitive impairment: A cross-cohort comparison.

INTRODUCTION: Whether brain functional connectivity (FC) is consistently disrupted in individuals with mild cognitive impairment (MCI) with isolated language impairment (ilMCI), and its potential to differentiate between MCI subtypes remains uncertain. METHODS: Cross-sectional data from 404 participants in two cohorts (the Chinese Preclinical Alzheimer's Disease Study and the Alzheimer's Disease Neuroimaging Initiative) were analyzed, including neuropsychological tests, resting-state functional magnetic resonance imaging (fMRI), cerebral amyloid positivity, and apolipoprotein E (APOE) status. RESULTS: Temporo-frontoparietal FC, particularly between the bilateral superior temporal pole and the left inferior frontal/supramarginal gyri, was consistently decreased in ilMCI compared to amnestic MCI (aMCI) and normal controls, which was correlated with semantic impairment. Using mean temporo-frontoparietal FC as a classifier could improve accuracy in identifying ilMCI subgroups with positive cerebral amyloid deposition and APOE risk alleles. DISCUSSION: Temporal-frontoparietal hypoconnectivity was observed in individuals with ilMCI, which may reflect semantic impairment and serve as a valuable biomarker to indicate potential mechanisms of underlying neuropathology. HIGHLIGHTS: Temporo-frontoparietal hypoconnectivity was observed in impaired language mild cognitive impairment (ilMCI). Temporo-frontoparietal hypoconnectivity may reflect semantic impairment. Temporo-frontoparietal functional connectivity can classify ilMCI subtypes.

Substituted indole derivatives as UNC-51-like kinase 1 inhibitors: Design, synthesis and anti-hepatocellular carcinoma activity.

The five-year survival rate for patients with hepatocellular carcinoma (HCC) is only 20 %, highlighting the urgent need to identify new therapeutic targets and develop potential therapeutic options to improve patient prognosis. One promising approach is inhibiting autophagy as a strategy for HCC treatment. In this study, we established a virtual docking conformation of the autophagy promoter ULK1 binding XST-14 derivatives. Based on this conformation, we designed and synthesized four series of derivatives. By evaluating their affinity and anti-HCC effects, we confirmed that these compounds exert anti-HCC activity by inhibiting ULK1. The structure-activity relationship was summarized, with derivative A4 showing 10 times higher activity than XST-14 and superior efficacy to sorafenib against HCC. A4 has excellent effect on reducing tumor growth and enhancing sorafenib activity in HepG2 and HCCLM3 cells. Moreover, we verified the therapeutic effect of A4 in sorafenib-resistant HCC cells both in vivo and in vitro. These results suggest that inhibiting ULK1 to regulate autophagy may become a new treatment method for HCC and that A4 will be used as a lead drug for HCC in further research. Overall, A4 shows good drug safety and efficacy, offering hope for prolonging the survival of HCC patients.

Dietary capsaicin attenuates cardiac injury after myocardial infarction in type 2 diabetic mice by inhibiting ferroptosis through activation of TRPV1 and Nrf2/HMOX1 pathway.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a major 21st-century epidemic. T2DM elevates the risk of myocardial infarction and heart failure while also reducinges survival rates. Recently Ferroptosis has been found to be involved in the development of various cardiovascular diseases. TRPV1 is also a potential therapeutic target for cardioprotection. This study explores whether capsaicin, a transient receptor potential vanilloid receptor 1 (TRPV1) agonist, can prevent diabetic myocardial infarction-induced injury by inhibiting ferroptosis. METHODS: T2DM model was induced by high-fat diet (HFD) feeding combined with streptozocin (STZ) injections, and the diabetic mice were treated with capsaicin(0.015 %) in their food. Myocardial infarction model was established as well. Mouse' general characteristics, cardiac function, and morphological histology were observed and analyzed. RNA-seq was used to investigate the possible mechanism of injury in AC16 cardiomyocytes cultured with high glucose and hypoxia. In addition, the potential mechanism of capsaicin against injury was further investigated in AC16 cardiomyocytes cultured with high glucose and hypoxia. RESULTS: The RNA-seq analysis revealed that ferroptosis was associated with cell death induced by high-glucose in combination with hypoxia, and CAP treatment could effectively inhibit ferroptosis to enhance cell survival. In vivo studies demonstrated that CAP treatment significantly improved post-MI cardiac function, attenuated myocardial inflammation and fibrosis. Furthermore, it was observed that CAP reduced ferroptosis levels by activating TRPV1 in the heart, upregulating Nrf2 expression, promoting Nrf2 nuclear translocation and increasing the expression of the Nrf2 downstream molecule Heme oxygenase-1 (HMOX1). CONCLUSIONS: Dietary capsaicin may inhibit cardiomyocyte ferroptosis through activation of myocardial TRPV1 and Nrf2/HMOX1 signaling pathway, which in turn exerts a protective effect on the myocardium after myocardial infarction in type 2 diabetic mice.

Red light-induced localized release of carbon monoxide for alleviating postoperative cognitive dysfunction.

Inflammation within the central nervous system (CNS), which may be triggered by surgical trauma, has been implicated as a significant factor contributing to postoperative cognitive dysfunction (POCD). The relationship between mitigating inflammation at peripheral surgical sites and its potential to attenuate the CNS inflammatory response, thereby easing POCD symptoms, remains uncertain. Notably, carbon monoxide (CO), a gasotransmitter, exhibits pronounced anti-inflammatory effects. Herein, we have developed carbon monoxide-releasing micelles (CORMs), a nanoparticle that safely and locally liberates CO upon exposure to 650 nm light irradiation. In a POCD mouse model, treatment with CORMs activated by light (CORMs + hv) markedly reduced the concentrations of interleukin (IL)-6, IL-1ß, and tumor necrosis factor-alpha (TNF-α) in both the peripheral blood and the hippocampus, alongside a decrease in ionized calcium-binding adapter molecule 1 in the hippocampal CA1 region. Furthermore, CORMs + hv treatment diminished Evans blue extravasation, augmented the expression of tight junction proteins zonula occludens-1 and occludin, enhanced neurocognitive functions, and fostered fracture healing. Bioinformatics analysis and experimental validation has identified Htr1b and Trhr as potential key regulators in the neuroactive ligand-receptor interaction signaling pathway implicated in POCD. This work offers new perspectives on the mechanisms driving POCD and avenues for therapeutic intervention.

Evolutionarily divergent Mycobacterium tuberculosis CTP synthase filaments are under selective pressure.

The final and rate-limiting enzyme in pyrimidine biosynthesis, CTP synthase (CTPS) , is essential for the viability of Mycobacterium tuberculosis and other mycobacteria. Its product, CTP, is critical for RNA, DNA, lipid and cell wall synthesis, and is involved in chromosome segregation. In various organisms across the tree of life, CTPS assembles into higher-order filaments, leading us to hypothesize that M. tuberculosis CTPS (mtCTPS) also forms higher-order structures. Here, we show that mtCTPS does assemble into filaments but with an unusual architecture not seen in other organisms. Through a combination of structural, biochemical, and cellular techniques, we show that polymerization stabilizes the active conformation of the enzyme and resists product inhibition, potentially allowing for the highly localized production of CTP within the cell. Indeed, CTPS filaments localize near the CTP-dependent complex needed for chromosome segregation, and cells expressing mutant enzymes unable to polymerize are altered in their ability to robustly form this complex. Intriguingly, mutants that alter filament formation are under positive selection in clinical isolates of M. tuberculosis, pointing to a critical role needed to withstand pressures imposed by the host and/or antibiotics. Taken together, our data reveal an unexpected mechanism for the spatially organized production of a critical nucleotide in M. tuberculosis, which may represent a vulnerability of the pathogen that can be exploited with chemotherapy.

Spock2 Functions as a Key Time-Series Gene of Endothelial Cells in Sepsis-Induced Cardiomyopathy.

ABSTRACT: The study aimed to investigate the pathogenesis of sepsis-induced cardiomyopathy, a leading cause of mortality in septic patients. Transcriptome data from cecal ligation and puncture-induced septic mice were analyzed at different time points (24, 48, and 72 hours) using GSE171546 data. Through weighted gene co-expression network analysis, time series, and differential expression analyses, key time-series differentially expressed genes were identified. In addition, single-cell sequencing data (GSE207363) were used for both differential and pseudotime analyses to pinpoint differentially expressed genes specific to endothelial cells. The study highlighted Spock2, S100a9, S100a8, and Xdh as differential genes specific to endothelial cells in a time-dependent manner. Immunofluorescence validation confirmed the increased expression of SPOCK2 in the endothelial cells of cecal ligation and puncture-induced septic mice. Furthermore, in vitrostudies showed that deletion of Spock2 significantly increased LPS-induced apoptosis and necrosis in human umbilical vein endothelial cells. In conclusion, SPOCK2 expression was increased in septic cardiac endothelial cells and LPS-induced human umbilical vein endothelial cells and may play a protective role.

Neighborhood structure-guided brain functional networks estimation for mild cognitive impairment identification.

The adoption and growth of functional magnetic resonance imaging (fMRI) technology, especially through the use of Pearson's correlation (PC) for constructing brain functional networks (BFN), has significantly advanced brain disease diagnostics by uncovering the brain's operational mechanisms and offering biomarkers for early detection. However, the PC always tends to make for a dense BFN, which violates the biological prior. Therefore, in practice, researchers use hard-threshold to remove weak connection edges or introduce l 1-norm as a regularization term to obtain sparse BFNs. However, these approaches neglect the spatial neighborhood information between regions of interest (ROIs), and ROI with closer distances has higher connectivity prospects than ROI with farther distances due to the principle of simple wiring costs in resent studies. Thus, we propose a neighborhood structure-guided BFN estimation method in this article. In detail, we figure the ROIs' Euclidean distances and sort them. Then, we apply the K-nearest neighbor (KNN) to find out the top K neighbors closest to the current ROIs, where each ROI's K neighbors are independent of each other. We establish the connection relationship between the ROIs and these K neighbors and construct the global topology adjacency matrix according to the binary network. Connect ROI nodes with k nearest neighbors using edges to generate an adjacency graph, forming an adjacency matrix. Based on adjacency matrix, PC calculates the correlation coefficient between ROIs connected by edges, and generates the BFN. With the purpose of evaluating the performance of the introduced method, we utilize the estimated BFN for distinguishing individuals with mild cognitive impairment (MCI) from the healthy ones. Experimental outcomes imply this method attains better classification performance than the baselines. Additionally, we compared it with the most commonly used time series methods in deep learning. Results of the performance of K-nearest neighbor-Pearson's correlation (K-PC) has some advantage over deep learning.

A de novo zwitterionic strategy of ultra-stable chemiluminescent probes: highly selective sensing of singlet oxygen in FDA-approved phototherapy.

Singlet oxygen (1O2), as a fundamental hallmark in photodynamic therapy (PDT), enables ground-breaking clinical treatment in ablating tumors and killing germs. However, accurate in vivo monitoring of 1O2 remains a significant challenge in probe design, with primary difficulties arising from inherent photo-induced side reactions with poor selectivity. Herein, we report a generalizable zwitterionic strategy for ultra-stable near-infrared (NIR) chemiluminescent probes that ensure a highly specific [2 + 2] cycloaddition between fragile electron-rich enolether units and 1O2 in both cellular and dynamic in vivo domains. Innovatively, zwitterionic chemiluminescence (CL) probes undergo a conversion into an inert ketone excited state with an extremely short lifetime through conical intersection (CI), thereby affording sufficient photostability and suppressing undesired photoreactions. Remarkably, compared with the well-known commercial 1O2 probe SOSG, the zwitterionic probe QMI exhibited an ultra-high signal-to-noise ratio (SNR, over 40-fold). Of particular significance is that the zwitterionic CL probes demonstrate excellent selectivity, high sensitivity, and outstanding photostability, thereby making a breakthrough in real-time tracking of the FDA-approved 5-ALA-mediated in vivo PDT process in living mice. This innovative zwitterionic strategy paves a new pathway for high-performance NIR chemiluminescent probes and high-fidelity feedback on 1O2 for future biological and medical applications.

Autonomous stabilization with programmable stabilized state.

Reservoir engineering is a powerful technique to autonomously stabilize a quantum state. Traditional schemes involving multi-body states typically function for discrete entangled states. In this work, we enhance the stabilization capability to a continuous manifold of states with programmable stabilized state selection using multiple continuous tuning parameters. We experimentally achieve 84.6% and 82.5% stabilization fidelity for the odd and even-parity Bell states as two special points in the manifold. We also perform fast dissipative switching between these opposite parity states within 1.8 µs and 0.9 µs by sequentially applying different stabilization drives. Our result is a precursor for new reservoir engineering-based error correction schemes.

Automated Droplet Ejection from a Digital Microfluidics Sample Pretreatment Device Enables Batch-Mode Chemiluminescence Immunoassay.

Digital microfluidics (DMF) features programmed manipulation of fluids in multiple steps, making it a valuable tool for sample pretreatment. However, the integration of sample pretreatment with its downstream reaction and detection requires transferring droplets from the DMF device to the outside world. To address this issue, the present study developed a modified DMF device that allows automated droplet ejection out of the chip, facilitated by a tailor-designed interface. A double-layered DMF microchip with an oil-filled medium was flipped over, with a liquid infusion port and a liquid expulsion port accommodated on the top working PCB plate and the bottom grounded ITO plate, respectively, to facilitate chip-to-world delivery of droplets. Using chemiluminescent immunoassay (CLIA) as an illustrative application, the sample pretreatment was programmed on the DMF device, and CLIA droplets were ejected from the chip for signal reading. In our workflow, CLIA droplets can be ejected from the DMF device through the chip-to-world interface, freeing up otherwise occupied electrodes for more sample pretreatment and enabling streamlined droplet microreactions and batch-mode operation for bioanalysis. Integrated with these interfacing portals, the DMF system achieved a single-channel throughput of 17 samples per hour, which can be further upscaled for more productive applications by parallelizing the DMF modules. The results of this study demonstrate that the droplet ejection function that is innovated in a DMF sample pretreatment microsystem can significantly improve analytical throughput, providing an approach to establishing an automated but decentralized biochemical sample preparation workstation for large-scale and continuous bioanalysis.

Electrically tunable layer-hybridized trions in doped WSe2 bilayers.

Doped van der Waals heterostructures host layer-hybridized trions, i.e. charged excitons with layer-delocalized constituents holding promise for highly controllable optoelectronics. Combining a microscopic theory with photoluminescence (PL) experiments, we demonstrate the electrical tunability of the trion energy landscape in naturally stacked WSe2 bilayers. We show that an out-of-plane electric field modifies the energetic ordering of the lowest lying trion states, which consist of layer-hybridized Λ -point electrons and layer-localized K-point holes. At small fields, intralayer-like trions yield distinct PL signatures in opposite doping regimes characterized by weak Stark shifts in both cases. Above a doping-asymmetric critical field, interlayer-like species are energetically favored and produce PL peaks with a pronounced Stark red-shift and a counter-intuitively large intensity arising from efficient phonon-assisted recombination. Our work presents an important step forward in the microscopic understanding of layer-hybridized trions in van der Waals heterostructures and paves the way towards optoelectronic applications based on electrically controllable atomically-thin semiconductors.

Talin1 promotes HCC progression by regulating NRG1/PI3K/AKT pathway.

OBJECTIVE OF THE STUDY: Hepatocellular carcinoma (HCC) stands as the third leading cause of cancer-related mortality globally. Metastasis, responsible for treatment failures, underscores the urgency to comprehend molecular drivers of invasion and migration. Central to the invasive and migratory processes underlying metastasis is the protein Talin1. However, the role and underlying mechanisms governing Talin1's involvement in HCC have remained elusive. METHODS: A total of 100 HCC specimens were collected from patients who underwent hepatectomy in our center. The expression level of talin1 was measured to evaluate the correlationship of talin1 and the development of HCC. In vitro and in vivo experiments were conducted to verify the characteristic of talin1 in HCC. RNA-seq and bioinformatics analysis were performed to identify the downstream signal pathway of talin1 and their impact on HCC development. RESULTS: Here, we reported elevated levels of Talin1 mRNA and protein in HCC tissues. Meanwhile, downregulation of Talin1 significantly reduced the HCC cell proliferation and metastasis in vitro and in vivo. Furthermore, elevating NRG-1, a downstream target of Talin1, enhanced metastasis of HCC cells. More importantly, attenuation of Talin1 inhibited HCC progression through decreasing the stabilization of NRG1 mRNA, consequently regulating the expression of NRG1 and its involvement in mediating the PI3K/AKT pathway. CONCLUSION: Taken together, Talin1 regulates cellular proliferation, metastasis, and invasiveness by modulating NRG1/PI3K/AKT axis, suggesting that Talin1 emerges as a promising candidate for treating HCC.

M2 macrophage-derived extracellular vesicles ameliorate Benzalkonium Chloride-induced dry eye.

Dry eye disease (DED) is a common ocular condition affecting a significant portion of the global population, yet effective treatment options remain elusive. This study investigates the therapeutic potential of M2 macrophage-derived extracellular vesicles (M2-EVs) in a mouse model of DED. The DED model was established using 0.2% benzalkonium chloride (BAC) eye drops, applied twice daily for a week. Post induction, the mice were categorized into 5 groups: PBS, Sodium Hyaluronate (HA, 0.1%), Fluoromethalone (FM, 0.1%), M0-EVs, and M2-EVs. The efficacy of M2-EVs was assessed through tear production, corneal fluorescein staining and HE staining. RNA sequencing (RNA-seq) was employed to investigate the mechanisms underlying the therapeutic effects of M2-EVs in DED. Notably, the M2-EVs treated group exhibited the highest tear secretion, indicating improved tear film stability and reduced corneal surface damage. Histological analysis revealed better corneal structure organization in the M2-EVs group, suggesting enhanced ocular surface repair and corneal preservation. Furthermore, M2-EVs treatment significantly decreased pro-inflammatory cytokine levels and showed unique enrichment of genes related to retinal development. These findings suggest that M2-EVs could serve as a promising noninvasive therapeutic approach for human DED, targeting ocular surface inflammation.

A feasibility study of tumor motion monitoring for SBRT of lung cancer based on 3D point cloud detection and stacking ensemble learning.

PURPOSE: To construct a tumor motion monitoring model for stereotactic body radiation therapy (SBRT) of lung cancer from a feasibility perspective. METHODS: A total of 32 treatment plans for 22 patients were collected, whose planning CT and the centroid position of the planning target volume (PTV) were used as the reference. Images of different respiratory phases in 4DCT were acquired to redefine the targets and obtain the floating PTV centroid positions. In accordance with the planning CT and CBCT registration parameters, data augmentation was accomplished, yielding 2130 experimental recordings for analysis. We employed a stacking multi-learning ensemble approach to fit the 3D point cloud variations of body surface and the change of target position to construct the tumor motion monitoring model, and the prediction accuracy was assess using root mean squared error (RMSE) and R-Square (R2). RESULTS: The prediction displacement of the stacking ensemble model shows a high degree of agreement with the reference value in each direction. In the first layer of model, the X direction (RMSE =0.019 ∼ 0.145mm, R2 =0.9793∼0.9996) and the Z direction (RMSE = 0.051 ∼ 0.168 mm, R2 = 0.9736∼0.9976) show the best results, while the Y direction ranked behind (RMSE = 0.088 ∼ 0.224 mm, R2 = 0.9553∼ 0.9933). The second layer model summarizes the advantages of unit models of first layer, and RMSE of 0.015 mm, 0.083 mm, 0.041 mm, and R2 of 0.9998, 0.9931, 0.9984 respectively for X, Y, Z were obtained. CONCLUSIONS: The tumor motion monitoring method for SBRT of lung cancer has potential application of non-ionization, non-invasive, markerless, and real-time.

Recent Progress of Functional Solvent-free Nanofluids: A Review.

Nanoparticles have aroused widespread interest because of their unique surface structure and nano effect, which presents novel characteristics like as sound, light, electricity, magnetism, and thermal properties. However, two critical defects have hindered their applications: (1) poor processability resulting from the high melting temperature (e.g., >1000 °C) for some inorganic nanoparticles; (2) the restriction of the nano effect caused by the easy aggregation of the nanoparticles. To solve those issues, solvent-free nanofluids (SNFs) with hard cores and flexible organic chains were successfully designed and fabricated at the beginning of the twenty-first century. The promising technology of SNFs not only solved the dispersion problem of nanomaterials but also imparted novel functionalization to nanoparticles. Up to now, many researchers have been devoted to developing diverse cores and flexible organic polymer chains to endow SNFs with particular functions, such as conductivity, fluorescence, lubricity, and so on. However, there are few review reports on the research progress in the fabrication and applications of functional SNFs. To gain a better understanding of SNFs, this paper presents an overall investigation into the development, fabrication, as well as the applications of functional SNFs.

Correlation between Anterior Mitral Annular Plane Systolic Excursion and Left Atrial Appendage Stasis in Patients with Nonvalvular Atrial Fibrillation.

Background: Atrial fibrillation (AF) can lead to a decline in left atrial appendage (LAA) function, potentially increasing the likelihood of LAA thrombus (LAAT) and spontaneous echo contrast (SEC). Measuring LAA flow velocity through transesophageal echocardiography (TEE) is currently the primary method for evaluating LAA function. This study aims to explore the potential correlation between anterior mitral annular plane systolic excursion (aMAPSE) and LAA stasis in patients with non-valvular atrial fibrillation (NVAF). Methods: A total of 465 patients with NVAF were enrolled between October 2018 and November 2021. Transthoracic echocardiography (TTE) and TEE were performed before scheduled electrical cardioversion. Propensity score matching (PSM) was used to balance confounders between the groups with and without LAAT/dense SEC. Results: Patients in the LAAT/dense SEC group showed increased left atrial (LA) diameter, LAA area, alongside reduced left ventricular ejection fraction (LVEF), LAA velocity, conjunction thickening ratio, aMAPSE, and LAA fraction area change (FAC) compared to those in the non-LAAT/dense SEC group. Multivariate logistic regression analysis identified aMAPSE and LAA FAC as independent predictors for LAAT/dense SEC. Specifically, an aMAPSE of < 6.76 mm and an LAA FAC of < 29.65% predicted LAAT/dense SEC with high diagnostic accuracy, demonstrated by an area under the curve (AUC) of 0.81 (sensitivity 0.81, specificity 0.80) for aMAPSE, and an AUC of 0.80 (sensitivity 0.70, specificity 0.84) for LAA FAC. Conclusions: Both aMAPSE and LAA FAC independently correlated with and accurately predict LAAT/dense SEC. Incorporating aMAPSE into routine TEE evaluations for LAA function alongside LAA flow velocity is recommended.

Efficacy and safety of transcutaneous auricular vagus nerve stimulation for frequent premature ventricular complexes: rationale and design of the TASC-V trial.

BACKGROUND: Premature Ventricular Complexes (PVCs) are very common in clinical practice, with frequent PVCs (more than 30 beats per hour) or polymorphic PVCs significantly increasing the risk of mortality. Previous studies have shown that vagus nerve stimulation improves ventricular arrhythmias. Stimulation of the auricular distribution of the vagus nerve has proven to be a simple, safe, and effective method to activate the vagus nerve. Transcutaneous au ricular vagus nerve stimulation (taVNS) has shown promise in both clinical and experimental setting for PVCs; however, high-quality clinical studies are lacking, resulting in insufficient evidence of efficacy. METHODS: The study is a prospective, randomized, parallel-controlled trial with a 1:1 ratio between the two groups. Patients will be randomized to either the treatment group (taVNS) or the control group (Sham-taVNS) with a 6-week treatment and a subsequent 12-week follow-up period. The primary outcome is the proportion of patients with a ≥ 50% reduction in the number of PVCs monitored by 24-hour Holter. Secondary outcomes include the proportion of patients with a ≥ 75% reduction in PVCs, as well as the changes in premature ventricular beats, total heartbeats, and supraventricular premature beats recorded by 24-hour Holter. Additional assessments compared score changes in PVCs-related symptoms, as well as the score change of self-rating anxiety scale (SAS), self-rating depression scale (SDS), and 36-item short form health survey (SF-36). DISCUSSION: The TASC-V trial will help to reveal the efficacy and safety of taVNS for frequent PVCs, offering new clinical evidence for the clinical practice. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04415203 (Registration Date: May 30, 2020).

Pre-existing immunity to influenza aids ferrets in developing stronger and broader H3 vaccine-induced antibody responses.

Influenza seasons occur annually, building immune history for individuals, but the influence of this history on subsequent influenza vaccine protection remains unclear. We extracted data from an animal trial to study its potential impact. The trial involved 80 ferrets, each receiving either one type of infection or a placebo before vaccination. We quantified the vaccine protection by evaluating hemagglutination inhibition (HAI) antibody titer responses. We tested whether hosts with different infection histories exhibited similar level of responses when receiving the same vaccine for all homologous and heterologous outcomes. We observed that different pre-existing immunities were generally beneficial to vaccine induced responses, but varied in magnitude. Without pre-immunity, post-vaccination HAI titers after the 1st dose of the vaccine were less likely to be above 1:40, and a booster shot was needed. Our study suggests that pre-existing immunity may strengthen and extend the homologous and heterologous vaccine responses.

N-Heterocyclic carbene catalytic 1,2-boron migrative acylation accelerated by photocatalysis.

The transformation of organoboron compounds plays an important role in synthetic chemistry, and recent advancements in boron-migration reactions have garnered considerable attention. Here, we report an unprecedented 1,2-boron migrative acylation upon photocatalysis-facilitated N-heterocyclic carbene catalysis. The design of a redox-active boronic ester substrate, serving as an excellent ß-boron radical precursor, is the linchpin to the success of this chemistry. With the established protocol, a wide spectrum of ß-boryl ketones has been rapidly synthesized, which could further undergo various C─B bond transformations to give multifunctionalized products. The robustness of this catalytic strategy is underscored by its successful application in late-stage modification of drug-derived molecules and natural products. Preliminary mechanistic investigations, including several control experiments, photochemistry measurements, and computational studies, shed light on the catalytic radical reaction mechanism.