A simulation study on the antiarrhythmic mechanisms of established agents in myocardial ischemia and infarction.

Patients with myocardial ischemia and infarction are at increased risk of arrhythmias, which in turn, can exacerbate the overall risk of mortality. Despite the observed reduction in recurrent arrhythmias through antiarrhythmic drug therapy, the precise mechanisms underlying their effectiveness in treating ischemic heart disease remain unclear. Moreover, there is a lack of specialized drugs designed explicitly for the treatment of myocardial ischemic arrhythmia. This study employs an electrophysiological simulation approach to investigate the potential antiarrhythmic effects and underlying mechanisms of various pharmacological agents in the context of ischemia and myocardial infarction (MI). Based on physiological experimental data, computational models are developed to simulate the effects of a series of pharmacological agents (amiodarone, telmisartan, E-4031, chromanol 293B, and glibenclamide) on cellular electrophysiology and utilized to further evaluate their antiarrhythmic effectiveness during ischemia. On 2D and 3D tissues with multiple pathological conditions, the simulation results indicate that the antiarrhythmic effect of glibenclamide is primarily attributed to the suppression of efflux of potassium ion to facilitate the restitution of [K+]o, as opposed to recovery of IKATP during myocardial ischemia. This discovery implies that, during acute cardiac ischemia, pro-arrhythmogenic alterations in cardiac tissue's excitability and conduction properties are more significantly influenced by electrophysiological changes in the depolarization rate, as opposed to variations in the action potential duration (APD). These findings offer specific insights into potentially effective targets for investigating ischemic arrhythmias, providing significant guidance for clinical interventions in acute coronary syndrome.

3D Carbon Fiber Skeleton Film Modified with Gradient Cu Nanoparticles as Auxiliary Anode Regulates Dendrite-Free, Bottom-Up Zinc Deposition.

Achieving stable Zn plating/stripping under high current density and large area capacity remains a major challenge for metal Zn anodes. To address this issue, common filter paper is utilized to construct 3D carbon fiber skeleton film modified with gradient Cu nanoparticles (CFF@Cu). The original zincophobic hydrophilic CFF is transformed into gradient zincophilic and reversed gradient hydrophilic composite, due to the gradient distribution of Cu nanoparticles. When CFF@Cu is placed above Zn foil as an auxiliary anode, Zn foil anode exhibits stable, reversible, and dendrite-free Zn plating/stripping for 1200 h at 10 mA cm-2 and 2 mAh cm-2, 2000 h at 2 mA cm-2 and 2 mAh cm-2, 340 h at 10 mA cm-2 and 10 mAh cm-2. Additionally, nucleation barrier of Zn, Zn2+ transport and deposition kinetics are improved. The deposits on the Zn foil anode become homogeneous, dense, and fine. Side reactions and by-products are effectively inhibited. The excellent performance is mainly attributed to the gradient zincophilic field in 3D CFF. A portion of Zn2+ is captured by Cu and deposited within CFF@Cu from bottom to top, which reduces and homogenizes Zn2+ flux on Zn foil, as well as weakens and homogenizes electric field on Zn foil.

Bismuth-Antimony Alloy Nanoparticles Embedded in 3D Hierarchical Porous Carbon Skeleton Film for Superior Sodium Storage.

A composite film that features bismuth-antimony alloy nanoparticles uniformly embedded in a 3D hierarchical porous carbon skeleton is synthesized by the polyacrylonitrile-spreading method. The dissolved polystyrene is used as a soft template. The average diameter of the bismuth-antimony alloy nanoparticles is ~34.5 nm. The content of the Bi-Sb alloy has an impact on the electrochemical performance of the composite film. When the content of the bismuth-antimony alloy is 45.27%, the reversible capacity and cycling stability of the composite film are the best. Importantly, the composite film outperforms the bismuth-antimony alloy nanoparticles embedded in dense carbon film and the cube carbon nanobox in terms of specific capacity, cycling stability, and rate capability. The composite film can provide a discharge capacity of 322 mAh g-1 after 500 cycles at 0.5 A g-1, 292 mAh g-1 after 500 cycles at 1 A g-1, and 185 mAh g-1 after 2000 cycles at 10 A g-1. The carbon film prepared by the spreading method presents a unique integrated composite structure that significantly improves the structural stability and electronic conductivity of Bi-Sb alloy nanoparticles. The 3D hierarchical porous carbon skeleton structure further enhances electrolyte accessibility, promotes Na+ transport, increases reaction kinetics, and buffers internal stress.

Nanocapsule of MnS Nanopolyhedron Core@CoS Nanoparticle/Carbon Shell@Pure Carbon Shell as Anode Material for High-Performance Lithium Storage.

MnS has been explored as an anode material for lithium-ion batteries due to its high theoretical capacity, but low electronic conductivity and severe volume change induce low reversible capacity and poor cycling performance. In this work, the nanocapsule consisting of MnS nanopolyhedrons confined in independent, closed and conductive hollow polyhedral nanospheres is prepared by embedding MnCO3 nanopolyhedrons into ZIF-67, followed by coating of RF resin and gaseous sulfurization/carbonization. Benefiting from the unique nanocapsule structure, especially inner CoS/C shell and outer pure C shell, the MnS@CoS/C@C composite as anode material presents excellent cycling performance (674 mAh g-1 at 1 A g-1 after 300 cycles; 481 mAh g-1 at 5 A g-1 after 300 cycles) and superior rate capability (1133.3 and 650.6 mAh g-1 at 0.1 and 4 A g-1), compared to the control materials (MnS and MnS@CoS/C) and other MnS composites. Kinetics measurements further reveal a high proportion of the capacitive effect and low reaction impedance of MnS@CoS/C@C. SEM and TEM observation on the cycled electrode confirms superior structural stability of MnS@CoS/C@C during long-term cycles. Excellent lithium storage performance and the convenient synthesis strategy demonstrates that the MnS@CoS/C@C nanocapsule is a promising high-performance anode material.

Constructing zigzag-like hollow mesoporous nanospheres MoO2/C with superior lithium storage performance.

Hollow mesoporous nanospheres MoO2/C are successfully constructed through metal chelating reaction between molybdenum acetylacetone and glycerol as well as the Kirkendall effect induced by diammonium hydrogen phosphate. MoO2nanoparticles coupled by amorphous carbon are assembled to unique zigzag-like hollow mesoporous nanosphere with large specific surface area of 147.7 m2g-1and main pore size of 8.7 nm. The content of carbon is 9.1%. As anode material for lithium-ion batteries, the composite shows high specific capacity and excellent cycling performance. At 0.2 A g-1, average discharge capacity stabilizes at 1092 mAh g-1. At 1 A g-1after 700 cycles, the discharge capacity still reaches 512 mAh g-1. Impressively, the composite preserves intact after 700 cycles. Even at 5 A g-1, the discharge capacity can reach 321 mAh g-1, exhibiting superior rate capability. Various kinetics analyses demonstrate that in electrochemical reaction, the proportion of the surface capacitive effect is higher, and the composite has relatively high diffusion coefficient of Li ions and fast faradic reaction kinetics. Excellent lithium storge performance is attributed to the synergistic effect of zigzag-like hollow mesoporous nanosphere and amorphous carbon, which improves reaction kinetics, structure stability and electronic conductivity of MoO2. The present work provides a new useful structure design strategy for advanced energy storage application of MoO2.

Heart failure-induced atrial remodelling promotes electrical and conduction alternans.

Heart failure (HF) is associated with an increased propensity for atrial fibrillation (AF), causing higher mortality than AF or HF alone. It is hypothesized that HF-induced remodelling of atrial cellular and tissue properties promotes the genesis of atrial action potential (AP) alternans and conduction alternans that perpetuate AF. However, the mechanism underlying the increased susceptibility to atrial alternans in HF remains incompletely elucidated. In this study, we investigated the effects of how HF-induced atrial cellular electrophysiological (with prolonged AP duration) and tissue structural (reduced cell-to-cell coupling caused by atrial fibrosis) remodelling can have an effect on the generation of atrial AP alternans and their conduction at the cellular and one-dimensional (1D) tissue levels. Simulation results showed that HF-induced atrial electrical remodelling prolonged AP duration, which was accompanied by an increased sarcoplasmic reticulum (SR) Ca2+ content and Ca2+ transient amplitude. Further analysis demonstrated that HF-induced atrial electrical remodelling increased susceptibility to atrial alternans mainly due to the increased sarcoplasmic reticulum Ca2+-ATPase (SERCA) Ca2+ reuptake, modulated by increased phospholamban (PLB) phosphorylation, and the decreased transient outward K+ current (Ito). The underlying mechanism has been suggested that the increased SR Ca2+ content and prolonged AP did not fully recover to their previous levels at the end of diastole, resulting in a smaller SR Ca2+ release and AP in the next beat. These produced Ca2+ transient alternans and AP alternans, and further caused AP alternans and Ca2+ transient alternans through Ca2+→AP coupling and AP→Ca2+ coupling, respectively. Simulation of a 1D tissue model showed that the combined action of HF-induced ion channel remodelling and a decrease in cell-to-cell coupling due to fibrosis increased the heart tissue's susceptibility to the formation of spatially discordant alternans, resulting in an increased functional AP propagation dispersion, which is pro-arrhythmic. These findings provide insights into how HF promotes atrial arrhythmia in association with atrial alternans.

Mechanism underlying impaired cardiac pacemaking rhythm during ischemia: A simulation study.

Ischemia in the heart impairs function of the cardiac pacemaker, the sinoatrial node (SAN). However, the ionic mechanisms underlying the ischemia-induced dysfunction of the SAN remain elusive. In order to investigate the ionic mechanisms by which ischemia causes SAN dysfunction, action potential models of rabbit SAN and atrial cells were modified to incorporate extant experimental data of ischemia-induced changes to membrane ion channels and intracellular ion homeostasis. The cell models were incorporated into an anatomically detailed 2D model of the intact SAN-atrium. Using the multi-scale models, the functional impact of ischemia-induced electrical alterations on cardiac pacemaking action potentials (APs) and their conduction was investigated. The effects of vagal tone activity on the regulation of cardiac pacemaker activity in control and ischemic conditions were also investigated. The simulation results showed that at the cellular level ischemia slowed the SAN pacemaking rate, which was mainly attributable to the altered Na+-Ca2+ exchange current and the ATP-sensitive potassium current. In the 2D SAN-atrium tissue model, ischemia slowed down both the pacemaking rate and the conduction velocity of APs into the surrounding atrial tissue. Simulated vagal nerve activity, including the actions of acetylcholine in the model, amplified the effects of ischemia, leading to possible SAN arrest and/or conduction exit block, which are major features of the sick sinus syndrome. In conclusion, this study provides novel insights into understanding the mechanisms by which ischemia alters SAN function, identifying specific conductances as contributors to bradycardia and conduction block.

Drug-Target Binding Affinity Prediction in a Continuous Latent Space Using Variational Autoencoders.

Accurate prediction of Drug-Target binding Affinity (DTA) is a daunting yet pivotal task in the sphere of drug discovery. Over the years, a plethora of deep learning-based DTA models have emerged, rendering promising results in predicting the binding affinities between drugs and their target proteins. However, in contrast to the conventional approach of modeling binding affinity in vector spaces, we propose a more nuanced modeling process in a continuous space to account for the diversity of input samples. Initially, the drug is encoded using the Simplified Molecular Input Line Entry System (SMILES), while the target sequences are characterized via a pretrained language model. Subsequently, highly correlative information is extracted utilizing residual gated convolutional neural networks. In a departure from existing deep learning-based models, our model learns the hidden representations of the drugs and targets jointly. Instead of employing two vectors, our hidden representations consist of two Gaussian distributions. To validate the effectiveness of our proposal, we conducted evaluations on commonly utilized benchmark datasets. The experimental outcomes corroborated that our method surpasses the state-of-the-art vectorial representation methods in terms of performance. This approach, therefore, offers potential enhancements in the precision of DTA predictions, potentially contributing to more efficient drug discovery processes.

MRI-Based Clinical-Imaging-Radiomics Nomogram Model for Discriminating Between Benign and Malignant Solid Pulmonary Nodules or Masses.

RATIONALE AND OBJECTIVES: Pulmonary nodules or masses are highly prevalent worldwide, and differential diagnosis of benign and malignant lesions remains difficult. Magnetic resonance imaging (MRI) can provide functional and metabolic information of pulmonary lesions. This study aimed to establish a nomogram model based on clinical features, imaging features, and multi-sequence MRI radiomics to identify benign and malignant solid pulmonary nodules or masses. MATERIALS AND METHODS: A total of 145 eligible patients (76 male; mean age, 58.4 years ± 13.7 [SD]) with solid pulmonary nodules or masses were retrospectively analyzed. The patients were randomized into two groups (training cohort, n = 102; validation cohort, n = 43). The nomogram was used for predicting malignant pulmonary lesions. The diagnostic performance of different models was evaluated by receiver operating characteristic (ROC) curve analysis. RESULTS: Of these patients, 95 patients were diagnosed with benign lesions and 50 with malignant lesions. Multivariate analysis showed that age, DWI value, LSR value, and ADC value were independent predictors of malignant lesions. Among the radiomics models, the multi-sequence MRI-based model (T1WI+T2WI+ADC) achieved the best diagnosis performance with AUCs of 0.858 (95%CI: 0.775, 0.919) and 0.774 (95%CI: 0.621, 0.887) for the training and validation cohorts, respectively. Combining multi-sequence radiomics, clinical and imaging features, the predictive efficacy of the clinical-imaging-radiomics model was significantly better than the clinical model, imaging model and radiomics model (all P < 0.05). CONCLUSION: The MRI-based clinical-imaging-radiomics model is helpful to differentiate benign and malignant solid pulmonary nodules or masses, and may be useful for precision medicine of pulmonary diseases.

Confining Co1.11Te2 nanoparticles within mesoporous hollow carbon combination sphere for fast and ultralong sodium storage.

Co1.11Te2 nanoparticles are in-situ uniformly grown within mesoporous hollow carbon combination sphere (MHCCS@Co1.11Te2) using a hard-template and spray drying process, solution impregnation and pyrolysis tellurization. Material characterizations reveal that Co1.11Te2, with a diameter of âˆ¼ 20 nm, is attached to the internal walls of the unit spheres or embedded in the mesopore shells of the unit spheres, presenting a distinctive "ships-in-combination-bottles" nanoencapsulation structure. In sodium-ion half-cells, MHCCS@Co1.11Te2 exhibits excellent cycling stability, achieving reversible capacities of 257 mAh/g at 0.5 A/g after 250 cycles, 235 mAh/g at 1.0 A/g after 300 cycles and 161 mAh/g at 10.0 A/g after 1900 cycles. Electrochemical kinetic analyses and ex-situ characterizations reveal rapid electron/Na+ transport kinetics, prominent surface pseudocapacitive behavior, robust nanocomposite structure, and multi-step conversion reactions of sodium polytellurides. In sodium-ion full-cells, MHCCS@Co1.11Te2 still demonstrates stable cycling performance at 1.0 and 5.0 A/g and excellent rate capability. The superior electrochemical performance is associated with the nanoencapsulation structure based on mesoporous hollow carbon combination spheres, which promotes electron conduction and Na+ transport. The space-confined effect maintains the high electrochemical activity and cycling stability of Co1.11Te2.