Hyperactivation of ATF4/TGF-ß1 signaling contributes to the progressive cardiac fibrosis in Arrhythmogenic cardiomyopathy caused by DSG2 Variant.

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiomyopathy characterized with progressive cardiac fibrosis and heart failure. However, the exact mechanism driving the progression of cardiac fibrosis and heart failure in ACM remains elusive. This study aims to investigate the underlying mechanisms of progressive cardiac fibrosis in ACM caused by newly identified Desmoglein-2 (DSG2) variation. METHODS: We identified homozygous DSG2F531C variant in a family with 8 ACM patients using whole-exome sequencing and generated Dsg2F536C knock-in mice. Neonatal and adult mouse ventricular myocytes isolated from Dsg2F536C knock-in mice were used. We performed functional, transcriptomic and mass spectrometry analyses to evaluate the mechanisms of ACM caused by DSG2F531C variant. RESULTS: All eight patients with ACM were homozygous for DSG2F531C variant. Dsg2F536C/F536C mice displayed cardiac enlargement, dysfunction, and progressive cardiac fibrosis in both ventricles. Mechanistic investigations revealed that the variant DSG2-F536C protein underwent misfolding, leading to its recognition by BiP within the endoplasmic reticulum, which triggered endoplasmic reticulum stress, activated the PERK-ATF4 signaling pathway and increased ATF4 levels in cardiomyocytes. Increased ATF4 facilitated the expression of TGF-ß1 in cardiomyocytes, thereby activating cardiac fibroblasts through paracrine signaling and ultimately promoting cardiac fibrosis in Dsg2F536C/F536C mice. Notably, inhibition of the PERK-ATF4 signaling attenuated progressive cardiac fibrosis and cardiac systolic dysfunction in Dsg2F536C/F536C mice. CONCLUSIONS: Hyperactivation of the ATF4/TGF-ß1 signaling in cardiomyocytes emerges as a novel mechanism underlying progressive cardiac fibrosis in ACM. Targeting the ATF4/TGF-ß1 signaling may be a novel therapeutic target for managing ACM.

Halide Anions Tuning of Lead-Free Perovskite-Type Ferroelectric Semiconductors with Inverse High-Temperature Symmetry Breaking.

There is a noticeable gap in the literature regarding research on halogen-substitution-regulated ferroelectric semiconductors featuring multiple phase transitions. Here, a new category of 1D perovskite ferroelectrics (DFP)2SbX5 (DFP+ = 3,3-difluoropyrrolidium, X- = I-, Br-, abbreviated as I-1 and Br-2) with twophase transitions (PTs) is reported. The first low-temperature PT is a mmmFmm2 ferroelectric PT, while the high-temperature PT is a counterintuitive inverse temperature symmetry-breaking PT. By the substitution of iodine with bromine, the Curie temperature (Tc) significantly increases from 348 K of I-1 to 374 K of Br-2. Their ferroelectricity and pyroelectricity are improved (Ps value from 1.3 to 4.0 µC cm-2, pe value from 0.2 to 0.48 µC cm-2 K-1 for I-1 and Br-2), while their optical bandgaps increased from 2.1 to 2.7 eV. A critical slowing down phenomenon is observed in the dielectric measurement of I-1 while Br-2 exhibits the ferroelastic domain. Structural and computational analyses elucidate that the order-disorder movement of cations and the distortion of the chain perovskite [SbX5]2- anions skeleton lead to PT. The semiconductor properties are determined by [SbX5]2- anions. The findings contribute to the development of ferroelectric semiconductors and materials with multiple PTs and provide materials for potential applications in the optoelectronic field.

Mid-term outcome of catheter ablation of idiopathic non-outflow tract ventricular arrhythmias.

BACKGROUND: Catheter ablation is recommended in patients with frequent and symptomatic ventricular arrhythmias (VAs) in an otherwise normal heart. Right or left outflow tract (OT) are the most common origins, and catheter ablation is highly effective with low complication rates. However, outcome of catheter ablation of VAs other than the OT (non-OTVAs) is limited. The aim of this single-center study was to assess the safety and mid-term outcome of catheter ablation for non-OTVAs. METHOD AND RESULTS: From 2013 to 2018, 251 patients who underwent catheter ablation for idiopathic non-OTVAs were enrolled and grouped according to the origins including His-Purkinje system (HPS, n = 108), papillary muscle / moderator band (PM/MB, n = 47), tricuspid annulus (TA, n = 70), and mitral annulus (MA, n = 26), 244 (97.2%) had acute elimination of VAs. The time of VAs recurrence of the single procedure was 1.69 (0.12,9.72) months, with 66% occurring within the first 3 months. The recurrence rate was significantly higher in the PM/MB group than in the TA (p = 0.025) and MA groups (p = 0.023). The single procedure success rate in all patients was 70.1%, in which 66.7%, 59.6%, 80%, and 76.9% were achieved in the HPS, PM/MB, TA, and MA groups, respectively (p = 0.284). After multiple procedures, the total success rate was 76.5% at the follow-up of 4.38 ± 2.42 years. The rate was significantly lower in the PM/MB group than in the TA group (p = 0.035). In subgroup analysis, no significant difference was observed in the recurrence rate of single procedure in patients with different VA origins within the PM/MB (log-rank test, p = 0.546). CONCLUSION: Despite a certain percentage of recurrences observed in the mid-term follow-up, catheter ablation remained feasible and effective for idiopathic non-OTVAs.

Association between brominated flame retardants (PBDEs and PBB153) exposure and hypertension in U.S. adults: results from NHANES 2005-2016.

BACKGROUND: Brominated Flame Retardants (BFRs) have attracted widespread concern due to their environmental persistence and potential toxicity. This study aims to examine the association between BFRs exposure and hypertension. METHODS: We used data from the National Health and Nutrition Examination Survey (NHANES) spanning 2005 to 2016 for the cross-sectional analysis. To evaluate the individual and combined impacts of BFRs exposure on hypertension, we utilized multivariate models, including generalized additive models, weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR) models. RESULTS: 9882 individuals (48% male) aged ≥ 20 were included in the final analysis, of whom 4114 had hypertension. After controlling for potential covariates, higher serum concentrations of PBDE100 (OR: 1.26; 95% CI: 1.01, 1.57) and PBDE153 (OR: 1.50; 95% CI: 1.18, 1.88) were significantly associated with hypertension. A nonlinear relationship between PBDE28 and hypertension was observed (P = 0.03). Moreover, BFRs mixture were positively associated with the prevalence of hypertension in both the WQS (ß:1.09; 95% CI: 1.02, 1.17; P = 0.02) and BKMR models. CONCLUSION: Our study suggested that BFRs exposure is positively associated with hypertension in the general population. To confirm this association and elucidate the mechanisms, further research is required.

Novel algorithm for diagnosis of Arrhythmogenic cardiomyopathy and dilated cardiomyopathy: Key gene expression profiling using machine learning.

BACKGROUND: It is difficult to distinguish between arrhythmogenic cardiomyopathy (ACM) and dilated cardiomyopathy (DCM) because of their similar clinical manifestations. This study aimed to develop a novel diagnostic algorithm for distinguishing ACM from DCM. METHODS: Two public datasets containing human ACM and DCM myocardial samples were used. Consensus clustering, non-negative matrix factorization and principal component analysis were applied. Weighted gene co-expression network analysis and machine learning methods, including random forest and the least absolute shrinkage and selection operator, were used to identify candidate genes. Receiver operating characteristic curves and nomograms were performed to estimate diagnostic efficacy, and Spearman's correlation analysis was used to assess the correlation between candidate genes and cardiac function indices. RESULTS: Both ACM and DCM showed highly similar gene expression patterns in the clustering analyses. Hub gene modules associated with cardiomyopathy were obtained using weighted gene co-expression network analysis. Thirteen candidate genes were selected using machine learning algorithms, and their combination showed a high diagnostic value (area under the ROC curve = 0.86) for distinguishing ACM from DCM. In addition, TATA-box binding protein associated factor 15 showed a negative correlation with cardiac index (R = -0.54, p = 0.0054) and left ventricular ejection fraction (R = -0.48, p = 0.0015). CONCLUSIONS: Our study revealed an effective diagnostic model with key gene signatures, which indicates a potential tool to differentiate between ACM and DCM in clinical practice. In addition, we identified several genes that are highly related to cardiac function, which may contribute to our understanding of ACM and DCM.

Piezo-Activated Atomic-Thin Molybdenum Disulfide/MXene Nanoenzyme for Integrated and Efficient Tumor Therapy via Ultrasound-Triggered Schottky Electric Field.

Monolayer molybdenum disulfide (MoS2 ) nanoenzymes exhibit a piezoelectric polarization, which generates reactive oxygen species to inactivate tumors under ultrasonic strain. However, its therapeutic efficiency is far away from satisfactory, due to stackable MoS2 , quenching of piezo-generated charges, and monotherapy. Herein, chitosan-exfoliated monolayer MoS2 (Ch-MS) is composited with atomic-thin MXene, Ti3 C2 (TC), to self-assemble a multimodal nanoplatform, Ti3 C2 -Chitosan-MoS2 (TC@Ch-MS), for tumor inactivation. TC@Ch-MS not only inherits piezoelectricity from monolayer MoS2 , but also maintains remarkable stability. Intrinsic metallic MXene combines with MoS2 to construct an interfacial Schottky heterojunction, facilitating the separation of electron-hole pairs and endowing TC@Ch-MS increase-sensitivity magnetic resonance imaging responding. Schottky interface also leads to peroxidase mimetics with excellent catalytic performance toward H2 O2 in the tumor microenvironment under mechanical vibration. TC@Ch-MS possesses the superior photothermal conversion efficiency than pristine TC under near-infrared ray illumination, attributed to its enhanced interlaminar conductivity. Meanwhile, TC@Ch-MS realizes optimized efficiency on tumor apoptosis with immunotherapy. Therefore, TC@Ch-MS achieves an integrated diagnosis and multimodal treatment nanoplatform, whereas the toxicity to normal tissue cells is negligible. This work may shed fresh light on optimizing the piezoelectric materials in biological applications, and also give prominence to the significance of intrinsic metallicity in MXene.

Effect of Prolonged Use of Dronedarone on Recurrence in Patients with Non-Paroxysmal Atrial Fibrillation After Radiofrequency Ablation (DORIS): Rationale and Design of a Randomized Multicenter, Double-Blinded Placebo-Controlled Trial.

BACKGROUND: Prolonged use of anti-arrhythmic drugs (AAD) beyond the post-ablation blanking period to maintain sinus rhythm has been adopted in clinical practice but without sufficient evidence. Dronedarone is an AAD valid for maintaining sinus rhythm with fewer side effects than other AAD for long-term use. OBJECTIVE: We sought to investigate the effect of prolonged use of dronedarone on the recurrence of non-paroxysmal AF patients beyond 3 months within the first year after ablation. METHODS: Non-paroxysmal AF patients will receive dronedarone for 3 months after radiofrequency ablation. Patients without drug side effects and atrial tachyarrhythmia (AT) recurrence will then be randomly divided into dronedarone and placebo groups and followed up until 1 year after ablation. The primary endpoint is the cumulative nonrecurrence rate post 3 months to 1 year after ablation. Patients will receive 7-day Holter monitoring (ECG patch) at 6, 9, and 12 months after ablation to evaluate AT recurrence. Secondary endpoints include dronedarone withdrawal due to side effects or intolerance of AT recurrence, time to the first recurrence, repeat ablation, electrical cardioversion, unscheduled emergency room visit, or re-hospitalization. CONCLUSION: This trial will evaluate whether prolonged use of dronedarone effectively reduces the recurrence rate after ablation in non-paroxysmal AF patients. The result of this trial will provide evidence for optimizing post-ablation anti-arrhythmic therapy. TRIAL REGISTRATION: ClinicalTrials.gov ; NCT05655468, 19-December-2022.

An analysis of antithrombotic therapy in elderly patients with atrial fibrillation undergoing percutaneous coronary interventions.

As a result of large, randomized trials and updates to clinical guidelines, antithrombotic therapy following percutaneous coronary intervention (PCI) has changed in recent years for patients with nonvalvular atrial fibrillation (NVAF). The purpose of this study was to investigate the real-world data of antithrombotic regimens at discharge and their evolving trends, as well as compare the effect of different therapies on the incidence of major cardiovascular and cerebrovascular ischemic events (MACCEs) and bleeding events in elderly patients. An analysis of 6298 stent implantation patients from 2016 to 2018 was carried out retrospectively. Atrial fibrillation (AF) patients ages 65 and older were divided into two groups according to the antithrombotic regimens prescribed at hospital discharge: dual antiplatelet aggregation treatment group (DAPT) and anticoagulant treatment and antiplatelet aggregation treatment group (ATT). Baseline characteristics, efficacy endpoints (MACCEs/cerebrovascular ischemic events) and safety endpoints (bleeding events) were analysed and compared between the different antithrombotic regiments. During 2016 to 2018, the use of oral anticoagulants (OAC) increased from 16.3% to 54.1% (p trend <0.01). Since the introduction of non-vitamin K antagonist oral anticoagulants (NOACs), warfarin usage has decreased from 100% to 41.7%, and NOACs have rapidly replaced warfarin. The rate of persistent AF in the ATT group was significantly higher than the rate in the DAPT group (79.6% vs 59.7%, p = 0.01), and the ATT group used more proton pump inhibitors (PPI) than the DAPT group (23.3% vs 11.8%, p = 0.01). A significant decrease was observed in MACCEs (10.7% vs 26.0%, p < 0.01) and cerebrovascular ischemic events (2.9% vs 11.8%, p = 0.01) in the ATT group compared with the DAPT group. According to the ATT subgroup analysis, there was a significant difference in the incidence of overall bleeding between the triple anticoagulant therapy group and the dual anticoagulant therapy group (DT) (18.0% vs 2.4%, p = 0.02). MACCEs were predicted independently by ATT and CHA2 DS2 -VASc (congestive heart failure, hypertension, age ≥75 years, diabetes, stroke or transient ischemic attack, vascular disease, age 65 to 74 years, sex category) scores, whereas bleeding was predicted independently by PPI use and HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol) scores. As a result of NOAC introduction and use, the combination of antithrombotic regimens at discharge for elderly patients with AF after PCI has changed rapidly over the past few years toward a higher use of ATTs, whereas patients with AF undergoing PCI still rarely receive an appropriate antithrombotic regimen. It is essential to conduct ATT in elderly patients who are undergoing PCI, and further DT may be more appropriate.

Association between urinary metabolites of volatile organic compounds and cardiovascular disease in the general population from NHANES 2011-2018.

BACKGROUND: Volatile organic compounds (VOCs) contain hundreds of chemicals and human exposure to VOCs is pervasive. However, most studies have considered only a single chemical or a class of similar chemicals. OBJECTIVE: We aimed to investigate the association between urinary volatile organic compound metabolites (mVOCs) and the risk of cardiovascular disease (CVD) in the general population. METHODS: The data in this study were collected from the National Health and Nutrition Examination Survey in 2011-2018. Eligible patients were aged ≥20 years for whom complete data for 20 types of urinary mVOCs and CVD outcomes were available. Multivariate logistic regression models were used to elucidate the association between mVOCs and CVD. Generalized additive models were used to examine the nonlinear relationships between mVOCs and CVD. RESULTS: 6814 indiviuals were included in the final analysis, of whom 508 had CVD. Higher urinary concentrations of N-acetyl-S-(2-carboxyethyl)-L-cysteine (CEMA) and N-Acetyl-S-(2-cyanoethyl)-l-cysteine (CYMA) and a lower urinary concentration of 2-aminothiazoline-4-carboxylic acid (ATCA) were associated with CVD outcomes after the adjustment for potential confounding factors. A nonlinear relationship and a threshold effect were only observed between N-acetyl-S-(N-methylcarbamoyl)-l-cysteine (AMCC) and CVD among 20 types of mVOCs. There was a significantly positive correlation between AMCC and CVD when AMCC concentration was >2.32 g/mL. CONCLUSION: The findings of this study suggested a significant correlation between urinary VOC metabolites and CVD. Urinary mVOCs may indicate hazardous exposure or distinct metabolic traits in patients with CVD.

Bone marrow-derived naïve B lymphocytes improve heart function after myocardial infarction: a novel cardioprotective mechanism for empagliflozin.

The role of adaptive immunity in myocardial recovery post myocardial infarction (MI), particularly the immune response by B lymphocytes, remains elusive. Bone marrow immune microenvironment in response to MI is remotely regulated by the hypothalamic pituitary adrenal (HPA) axis. We utilized the cardioprotective actions of SGLT2 inhibitor to identify and characterize bone marrow B cell subsets that respond to myocardial injury. Initially, we preformed ligation of left anterior descendant (LAD) coronary artery in male C57BL/6J mice to monitor the dynamic changes of immune cells across tissues. Mechanistic insights from mouse models demonstrated arrest of bone marrow B cell maturation and function 24 h post MI. A secondary MI model (twice MIs) in mice was established for the first time to evaluate the dosage-dependent cardioprotection of empagliflozin (EMPA). Single-cell RNA-Seq further demonstrated that EMPA restored bone marrow naïve B cell (B220+CD19+CD43-IgM+IgD+) counts and function. Additionally, we recruited 14 acute MI patients with single LAD disease, and profiled B cells post percutaneous coronary intervention (PCI) (compared to 18 matched no-MI controls). We revealed a positive correlation of increased B cell counts with enhanced ejection fraction in MI patients with PCI while lymphopenia was associated with patients with heart failure. Mechanistically, MI triggers the release of glucocorticoids from neuroendocrine system, inducing NHE1-mediated autophagic death of bone marrow B cells while repressing B cell progenitor proliferation and differentiation. Infusion of B cells derived from bone marrow significantly improved cardiac function and diminished infarct size post MI. These findings provide new mechanistic insights into regulation of adaptive immune response post MI, and support targeting bone marrow B cell development for improved ventricular remodeling and reduced heart failure after MI.

Bipolar catheter ablation strategies for outflow tract ventricular arrhythmias refractory to unipolar ablation.

INTRODUCTION: Conventional unipolar catheter ablation (UA) is generally effective for the treatment of outflow tract ventricular arrhythmias (OT-VAs). However, deep foci refractory to UA remains a clinical challenge. The present study evaluated the efficacy and safety of bipolar ablation (BA) in the treatment of OT-VAs refractory to UA. METHODS: A total of 1022 consecutive patients with antiarrhythmic drugs resistant OT-VAs were screened for inclusion in this study, from 1643 VAs cases who underwent catheter ablation in two centers from October 2014 to May 2019. BA was performed after failed sequential UA. The pair of catheters used for BA was positioned on opposing surfaces of the earliest activation (EA) sites or on adjacent anatomical structures. RESULTS: Twelve patients (seven males, mean age 33.3 ± 16.2 years) who met the inclusion criteria were recruited: one patient suffered sustained monomorphic ventricular tachycardia (VT), six patients had frequent premature ventricular contractions (PVCs), and nonsustained VT (NSVT), and five patients had PVCs only. The 24-hPVC/NSVT burden was 36.9 ± 21.7%. The mean distance between two ablation catheters during BA was 11.1 ± 4.3 mm (range 6.5-23.9 mm). The "rS" morphology of the unipolar electrogram was recorded simultaneously in both EA regions in seven cases (58.3%). Acute eradication of VAs was obtained in 10 (83.3%) cases. At a median follow-up of 58 months, 10 patients (83.3%) remained free from VAs. CONCLUSION: BA was highly effective and safe for the treatment of OT-VAs refractory to UA.

NIR-Activated Multimodal Photothermal/Chemodynamic/Magnetic Resonance Imaging Nanoplatform for Anticancer Therapy by Fe(II) Ions Doped MXenes (Fe-Ti3 C2 ).

2D MXene, Ti3 C2 (TC), has displayed enormous potential in applications in photothermal therapy (PTT), attributing to its biocompatibility and outstanding photothermal conversion capability. However, some tumor ablations are difficult to be realized completely by monotherapy due to the essential defects of monotherapy and intricate tumor microenvironment (TME). In this work, the appropriate doped Fe2+ ions are anchored into the layers of 2D ultrathin TC nanosheets (TC NSs) to synthesize a novel multifunctional nanoshell of Fe(II)-Ti3 C2 (FTC) through interlayer electrostatic adsorption. FTC possesses superior photothermal conversion efficiency (PTCE) than TC NSs, attributing to the enhanced conductivity promoted by interlaminar ferrous ion-channels. Moreover, Fenton reaction based on ferrous ions endows FTC the abilities of reactive oxide species (ROS) releasing and glutathione (GSH) suppression triggered by near-infrared (NIR) laser, featuring splendid biocompatibility and curative effect in hypoxic TME. Meanwhile, magnetic resonance imaging (MRI) responding in FTC reveals the potential as an integrated diagnosis and treatment nanoplatform. FTC could provide new insights into the development of multimoded synergistic nanoplatform for biological applications, especially breaking the shackles of MXenes merely used as a photo-thermal agent (PTA), adopting it to bioimaging sensor and drug loading.

Gastrodin pretreatment alleviates myocardial ischemia/reperfusion injury through promoting autophagic flux.

Gastrodin (GAS), a monomeric component exacted from the herb Gastrodia elata Bl, may have cardioprotective effects during injury caused by myocardial ischemia/reperfusion (I/R). For the significant role of autophagy in I/R process, we targeted to explore whether autophagy was contributing to the GAS-induced protective effects during I/R procedure. Male C57BL/6 mice were subjected to reversible left coronary artery ligation and cultured neonatal rat cardiomyocytes (NRCs) exposed to hypoxia were preconditioned with GAS prior to ischemia or hypoxia, following reperfusion for 2 h or re-oxygennation for 3 h respectively. Our results demonstrated that GAS pretreatment increased autophagy and reduced apoptosis during I/R, this effect was weakened by co-treatment with the autophagic flux inhibitor chloroquine (Cq). Compared to mice subjected solely to I/R, GAS-pretreated mice had a notably smaller heart infarct size and an elevation in cardiac function. In GAS-pretreated NRCs, WB data showed that autophagy was promoted (expression of p62 was inhibited and LC3II was increased). In addition, tandem fluorescent mRFP-GFP-LC3 assays illustrated that autophagosomes were degraded duo to an increase in autophagic flux. Co-administration of Cq blocked the autophagic flux. Furthermore, GAS pretreatment increased the mitochondrial membrane potential of NRCs with subjected to H/R and increased the cardiomyocyte survival rate. These protective effects were reversed with Cq. Besides, GAS-induced the enhaucement of autophagy may correlated with activating AMP-activated protein kinase (AMPK) phosphorylation and reduced Mammalian target of rapamycin (mTOR) phosphorylation, which was abrogated by Compound C (Com C, AMPK-specific inhibitor). Our results establish that GAS pretreatment attenuates myocardial I/R injury by increasing autophagic flux aimed at eliminating dysfunctional mitochondria, therefore protecting neighbouring mitochondria and cardiomyocytes.

Growth of Wide-Bandgap Monolayer Molybdenum Disulfide for a Highly Sensitive Micro-Displacement Sensor.

Two-dimensional (2D) piezoelectric semiconductor materials are garnering significant attention in applications such as intelligent sensing and energy harvesting due to their exceptional physical and chemical properties. Among these, molybdenum disulfide (MoS2), a 2D wide-bandgap semiconductor, exhibits piezoelectricity in odd-layered structures due to the absence of an inversion symmetry center. In this study, we present a straightforward chemical vapor deposition (CVD) technique to synthesize monolayer MoS2 on a Si/SiO2 substrate, achieving a lateral size of approximately 50 µm. Second-harmonic generation (SHG) characterization confirms the non-centrosymmetric crystal structure of the wide-bandgap MoS2, indicative of its piezoelectric properties. We successfully transferred the triangular MoS2 to a polyethylene terephthalate (PET) flexible substrate using a wet-transfer method and developed a wide-bandgap MoS2-based micro-displacement sensor employing maskless lithography and hot evaporation techniques. Our testing revealed a piezoelectric response current of 5.12 nA in the sensor under a strain of 0.003% along the armchair direction of the monolayer MoS2. Furthermore, the sensor exhibited a near-linear relationship between the piezoelectric response current and the strain within a displacement range of 40-100 µm, with a calculated response sensitivity of 1.154 µA/%. This research introduces a novel micro-displacement sensor, offering potential for advanced surface texture sensing in various applications.

The significance of heart rate variability in patients with frequent premature ventricular complex originating from the ventricular outflow tract.

BACKGROUND: As an indicator of cardiac autonomic nervous activity, heart rate variability (HRV) is closely linked to premature ventricular complexes (PVCs). However, its role in patients with frequent PVCs originating from the ventricular outflow tract remains unclear. HYPOTHESIS: Here, we hypothesize that there may be alterations in HRV among patients with frequent PVCs originating from the ventricular outflow tract, which could play significant roles in the management of such patients. METHODS: A retrospective study was conducted, including 106 patients with frequent outflow tract PVCs and 106 healthy participants as controls. HRV was assessed based on the 24-hour Holter recording. The originating foci of PVCs were identified during radiofrequency catheter ablation. RESULTS: Patients with frequent outflow tract PVCs exhibited decreased levels of high frequency (HF), standard deviation of all NN intervals, and standard deviation of the average NN intervals, but increased ratios of low frequency to HF (LF/HF ratio), even after propensity score-matched analysis. Further investigation revealed that patients with PVCs originating from right ventricular outflow tract (RVOT) had much higher LF/HF ratios. Multivariate logistic regression analysis demonstrated that the LF/HF ratio was independently associated with PVCs originating from RVOT. Receiver operating characteristics curve indicated that the LF/HF ratio effectively determined the origin of PVCs (the area under the curve = 0.75, p < .001). CONCLUSIONS: Patients with frequent outflow tract PVCs exhibited impaired HRV. Additionally, the LF/HF ratio played a significant role in determining the origin of outflow tract PVCs.

On-demand drug delivery bioelectronics through a water-processable low dimensional highly conductive MXene layer.

On-demand drug delivery holds great promise to optimize pharmaceutical efficacy while minimizing the side effects. However, existing on-demand drug delivery systems often require complicated manufacturing processes that preclude their wide implementation of a broad range of drugs. In this work, we demonstrate the introduction of MXene-coated microneedles (MNs) into bioelectronics for digitally controllable gate-valve drug delivery. MXenes, featuring high electronic conductivity, excellent biocompatibility, and solution processibility, enable low-cost scalability for printable bioelectronics. In an electrolytic state (e.g., body fluid), the coated MXene is oxidized and desorbed due to redox reactions caused by electrical bias, allowing the underlying drug to be controllably released. The MXene-incorporated drug delivery system not only demonstrates excellent biocompatibility and operational stability, but also features low-cost construction and sustainable usage. Besides, these MXene-coated MNs allow both on-demand transformation and local-region customization, further increasing the structural versatility and capability of multidrug delivery systems.

Piezoelectricity in wide bandgap semiconductor 2D crystal GaN nanosheets.

Gallium nitride (GaN) exhibits various potential applications in optics and optoelectronics due to its outstanding physical characteristics, including a wide direct bandgap, strong deep-ultraviolet emission, and excellent electron transport properties. However, research on the piezoelectric and related properties of GaN nanosheets are scarce, as previous small-scale GaN investigations have mainly concentrated on nanowires and nanotubes. Here, we report a strategy for growing 2D GaN nanosheets using chemical vapor deposition on Ga/W liquid-phase substrates. Additionally, utilizing scanning probe techniques, it has been observed that 700 nm-thick GaN nanosheets demonstrate a piezoelectric constant of deff33 = 1.53 ± 0.21 pm V-1 and possess the capability to effectively modulate the Schottky barrier. The piezoelectric characteristics of 2D GaN are offering new options for innovative applications in various fields, including energy harvesting, electronics, sensing, and communications.

Highly Stretchable, Tissue-like Ag Nanowire-Enhanced Ionogel Nanocomposites as an Ionogel-Based Wearable Sensor for Body Motion Monitoring.

The development of wearable electronic devices for human health monitoring requires materials with high mechanical performance and sensitivity. In this study, we present a novel transparent tissue-like ionogel-based wearable sensor based on silver nanowire-reinforced ionogel nanocomposites, P(AAm-co-AA) ionogel-Ag NWs composite. The composite exhibits a high stretchability of 605% strain and a moderate fracture stress of about 377 kPa. The sensor also demonstrates a sensitive response to temperature changes and electrostatic adsorption. By encapsulating the nanocomposite in a polyurethane transparent film dressing, we address issues such as skin irritation and enable multidirectional stretching. Measuring resistive changes of the ionogel nanocomposite in response to corresponding strain changes enables its utility as a highly stretchable wearable sensor with excellent performance in sensitivity, stability, and repeatability. The fabricated pressure sensor array exhibits great proficiency in stress distribution, capacitance sensing, and discernment of fluctuations in both external electric fields and stress. Our findings suggest that this material holds promise for applications in wearable and flexible strain sensors, temperature sensors, pressure sensors, and actuators.

Bifunctional TRPV1 Targeted Magnetothermal Switch to Attenuate Osteoarthritis Progression.

Transient receptor potential vanilloid family member 1 (TRPV1) has been revealed as a therapeutic target of osteoarthritis (OA), the most common deteriorating whole joint disease, by impeding macrophagic inflammation and chondrocytes ferroptosis. However, the clinical application for capsaicin as the TRPV1 agonist is largely limited by its chronic toxicity. To address this issue, we developed a bifunctional controllable magnetothermal switch targeting TRPV1 for the alleviation of OA progression by coupling of magnetic nanoparticles (MNPs) to TRPV1 monoclonal antibodies (MNPs-TRPV1). Under the alternating magnetic field (AMF) stimulation, MNPs-TRPV1 locally dissipated heat, which was sufficient to trigger the opening and activation of TRPV1, and effectively impeded macrophagic inflammation and chondrocyte ferroptosis. This magnetothermal modulation of TRPV1 simultaneously attenuated synovitis and cartilage degeneration in mice incurred by destabilization of medial meniscus surgery, indicating the delayed OA progression. Furthermore, MNPs-TRPV1 with AMF exposure remarkably reduced knee pain sensitivity, alleviated the crippled gait, and improved spontaneous ambulatory activity performance in the mice OA model. Overall, this work provides a potential pathogenesis-based precise OA therapy with temporally and spatially magnetothermal modulation of TRPV1 in a controllable manner.

Achilles tendinopathy treatment via circadian rhythm regulation.

INTRODUCTION: Achilles tendinopathy (AT) is a prevalent musculoskeletal disorder closely linked to oxidative stress. Existing evidence suggests a potential link between circadian clock rhythms and oxidative stress. However, the precise role of the circadian clock in the progression and treatment of AT remains unclear. OBJECTIVE: The purpose of this study was to investigate the role of the Achilles tendon circadian clock in AT pathology and explore the potential use of biomaterials for modulating the circadian clock in the treatment of AT. METHODS: We utilized in vivo and in vitro models to investigate the alterations of the circadian clock within the Achilles tendon during the progression of AT, as well as its impact on disease development. Additionally, we fabricated Nb2C@CeO2 composites featuring a Schottky heterojunction for regulating the circadian rhythm and validated its therapeutic efficacy and molecular mechanism of AT through both in vivo and in vitro experiments. RESULTS: The Achilles tendon functioned as a peripheral oscillator with an independent and self-sustained time-keeping system. The rhythm of the Achilles tendon clock was disrupted during the development of AT, as indicated by the decreased amplitude of Bmal1 and Nrf2 rhythm expression. Mechanistically, the knockdown of Bmal1 disrupted the Achilles tendon clock, thereby destroying the Bmal1-Nrf2 axis dependent molecular defense mechanism, and exacerbating the inflammatory response, whereas overexpression of Bmal1 had a protective effect. Nb2C@CeO2 composites with Schottky heterojunctions enhance intercellular electrical signaling, boosting Bmal1 expression and mitigating AT's pathological changes. Importantly, enhancing Bmal1 expression during its peak, rather than its trough, was more effective. CONCLUSION: This study identified the protective role of the circadian clock against oxidative stress and inflammation in the Achilles tendon. Achilles tendon circadian clock-targeted therapy represents a promising strategy for AT treatment.