Quantifying the frequency modulation in electrograms during simulated atrial fibrillation in 2D domains.

Atrial fibrillation (AF) affects millions of people in the world, causing increased morbidity and mortality. Treatment involves antiarrhythmic drugs and catheter ablation, showing high success for paroxysmal AF but challenges for persistent AF. Experimental evidence suggests reentrant waves and rotors contribute to AF substrates. Ablation procedures rely on electroanatomical maps and electrogram (EGM) signals; however, current methods used in clinical practice lack consideration for time-frequency varying EGM components. The fractional Fourier transform (FrFT) can be adopted to capture time-varying frequency components, thereby enhancing the comprehension of arrhythmogenic substrates during AF for improved ablation strategies. To this end, a FrFT-based algorithm is developed to characterize non-stationary components in EGM signals from simulated AF episodes. The proposed algorithm comprises a pre-processing step to enhance the coarser features of the EGM waveform, a windowing process for dynamic assessment of the EGM, and a FrFT order optimization stage that seeks compact signal representations in fractional Fourier domains. The resulting order is related to the rate of frequency change in the signal, making it a useful indicator for frequency-modulated components. The FrFT-based algorithm is implemented on EGM signals from AF simulations in 2D domains representing a region of the atrial tissue. Consequently, the computed optimum FrFT orders are used to build maps that are spatially correlated to the underlying propagation dynamics of the simulated AF episode. The results evince that the extreme values in the optimum orders map pinpoint the localization of fibrillatory mechanisms, generating EGM activation waveforms with varying frequency content over time.

Are Drivers Recurring or Ephemeral? Observations from Serial Mapping of Persistent Atrial Fibrillation.

RATIONALE: Rotational reentries and ectopic foci, or "drivers", are proposed mechanisms for persistent atrial fibrillation (persAF), but driver-based interventions have had mixed success in clinical trials. Selective targeting of drivers with multimonth stability may improve these interventions, but no prior work has investigated whether drivers can be stable on such a long timescale. OBJECTIVE: We hypothesized that drivers could recur even several months after initial observation. METHODS AND RESULTS: We performed serial electrophysiology studies on paced canines (n=18, 27-35 kg) at 1-, 3-, and 6-months post-initiation of continual persAF. Using a high-density 64-electrode catheter, we captured endocardial electrograms in the left atrium (LA) and right atrium (RA) to determine the presence of drivers at each major anatomical site. We defined drivers which were repeatedly observed across consecutive studies to be recurrent. Mean probability any driver would recur was 66% (LA: 73%, RA: 41%). We also found evidence of "multirecurring" drivers, i.e., those seen in all three studies. Multirecurring drivers constituted 53% of initially observed drivers with at least one found in 92% of animals, and we found more multirecurring drivers per animal than predicted by random chance (2.6±1.5 vs. 1.2±1.1, p<0.001). Driver sites showed more enhancement than non-drivers during late gadolinium enhancement-magnetic resonance imaging (p=0.04), but we observed no relationship between enhancement and driver recurrence type. CONCLUSIONS: We observed recurring drivers over a 6-month period at fixed locations, confirming our hypothesis. We also found drivers to be associated with fibrosis, implying a structural basis.

Effects of spatially dense adrenergic stimulation to rotor behaviour in simulated atrial sheets.

Sympathetic hyperactivity via spatially dense adrenergic stimulation may create pro-arrhythmic substrates even without structural remodelling. However, the effect of sympathetic hyperactivity on arrhythmic activity, such as rotors, is unknown. Using simulations, we examined the effects of gradually increasing the spatial density of adrenergic stimulation (AS) in atrial sheets on rotors. We compared their characteristics against rotors hosted in atrial sheets with increasing spatial density of minimally conductive (MC) elements to simulate structural remodelling due to injury or disease. We generated rotors using an S1-S2 stimulation protocol. Then, we created phase maps to identify phase singularities and map their trajectory over time. We measured each rotor's duration (s), angular speed (rad/s), and spatiotemporal organization. We demonstrated that atrial sheets with increased AS spatial densities could maintain rotors longer than with MC elements (2.6 ± 0.1 s vs. 1.5 ± 0.2 s, p<0.001). Moreover, rotors have higher angular speed (70 ± 7 rads/s vs. 60 ± 15 rads/s, p<0.05) and better spatiotemporal organization (0.56 ± 0.05 vs. 0.58 ± 0.18, p<0.05) in atrial sheets with less than 25% AS elements compared to MC elements. Our findings may help elucidate electrophysiological potential alterations in atrial substrates due to sympathetic hyperactivity, particularly among individuals with autonomic derangements caused by chronic distress.

Photodynamic therapy with Photoditazine increases microviscosity of cancer cells membrane in cellulo and in vivo.

Photodynamic therapy (PDT) is a minimally invasive method for cancer treatment, one of the effects of which is the oxidation of membrane lipids. However, changes in biophysical properties of lipid membranes during PDT have been poorly explored. In this work, we investigated the effects of PDT on membrane microviscosity in cancer cells in the culture and tumor xenografts. Membrane microviscosity was visualized using fluorescence lifetime imaging microscopy (FLIM) with a viscosity-sensitive rotor BODIPY2. It was found that PDT using chlorine e6-based photosensitizer Photoditazine caused a quick, steady elevation of membrane microviscosity both in cellulo and in vivo. The proposed mechanisms responsible for the increase in microviscosity was lipid peroxidation by reactive oxygen species that resulted in a decrease of phosphatidylcholine and the fraction of unsaturated fatty acids in the membranes. Our results suggest that the increased microviscosity is an important factor that contributes to tumor cell damage during PDT.

Aerodynamic Investigation on a Coaxial-Rotors Unmanned Aerial Vehicle of Bionic Chinese Parasol Seed.

Aerodynamic investigation of a bionic coaxial-rotors unmanned aerial vehicle (UAV) is performed. According to Chinese parasol seed features and flight requirements, the bionic conceptual design of a coaxial-rotors UAV is described. A solution procedure for the numerical simulation method, based on a multi-reference frame (MRF) model, is expressed, and a verification study is presented using the typical case. The aerodynamic design is conducted for airfoil, blade, and coaxial-rotors interference. The aerodynamic performance of the coaxial rotors is investigated by numerical simulation analysis. The rotor/motor integrated experiment verification is conducted to assess the performance of the coaxial-rotors UAV. The results indicate that the UAV has excellent aerodynamic performance and bionic configuration, allowing it to adapt to task requirements. The bionic UAV has a good cruise power load reach of 8.36 kg/kw, and the cruise flying thrust force is not less than 78 N at coaxial-rotor and rotor-balloon distance ratios of 0.39 and 1.12, respectively. It has the "blocks stability phenomenon" formed by the rotor downwash speed decreases and the balloon's additional negative pressure. The present method and the bionic configuration provide a feasible design and analysis strategy for coaxial-rotors UAVs.

Transition State Stabilizing Effects of Oxygen and Sulfur Chalcogen Bond Interactions.

Non-covalent chalcogen bond (ChB) interactions have found utility in many fields, including catalysis, organic semiconductors, and crystal engineering. In this study, the transition stabilizing effects of ChB interactions of oxygen and sulfur were experimentally measured using a series of molecular rotors. The rotors were designed to form ChB interactions in their bond rotation transition states. This enabled the kinetic influences to be assessed by monitoring changes in the rotational barriers. Despite forming weaker ChB interactions, the smaller chalcogens were able to stabilize transition states and had measurable kinetic effects on the rotational barriers. Sulfur stabilized the bond rotation transition state by as much as -7.2 kcal/mol without electron-withdrawing groups. The key was to design a system where the sulfur σ ${\sigma }$ -hole was aligned with the lone pairs of the chalcogen bond acceptor. Oxygen rotors also could form transition state stabilizing ChB interactions but required electron-withdrawing groups. For both oxygen and sulfur ChB interactions, a strong correlation was observed between transition state stabilizing abilities and electrostatic potential (ESP) of the chalcogen, providing a useful predictive parameter for the rational design of future ChB systems.

Spatially Confined Assembly and Immobilization of Hierarchical Nanoparticle Architectures inside Microdroplets in Magnetic Fields.

Magnetic field-directed colloidal interactions offer facile tools for assembly of structures that range from linear chains to multidimensional hierarchical architectures. While the field-driven assembly of colloidal particles has commonly been investigated in unbounded media, a knowledge gap remains concerning such assembly in confined microenvironments. Here, we investigate how confinement of ferromagnetic nanoparticles in microspheres directs their magnetic assembly into hierarchical architectures. Microdroplets from polydimethylsiloxane (PDMS) liquid precursor containing dispersed iron oxide magnetic nanoparticles (MNPs) were placed in a static magnetic field leading to the formation of organized assemblies inside the host droplets. By changing the MNP concentrations, we revealed a sequence of microstructures inside the droplets, ranging from linear chains at a low MNP loading, transitioning to a combination of chains and networked bundles, to solely 3D bundles at high MNP loading. These experimental results were analyzed with the aid of COMSOL simulations where we calculated the potential energy to identify the preferred assembly conformations. The chains at high MNP loading minimized their energy by aggregating laterally to form bundles with their MNP dipoles being out-of-registry. We cured these PDMS droplets to immobilize the assemblies by forming soft microbeads. These microbeads constitute an "interaction toolbox" with different magnetic macroscale responses, which are governed by the structuring of the MNPs and their magnetic polarizability. We show that thanks to their ability to rotate by field-induced torque under a rotating field, these microbeads can be employed in applications such as optical modulators and microrollers.

Core-Alkynylated Fluorescent Flippers: Altered Ultrafast Photophysics to Track Thick Membranes.

Fluorescent flippers have been introduced as small-molecule probes to image membrane tension in living systems. This study describes the design, synthesis, spectroscopic and imaging properties of flippers that are elongated by one and two alkynes inserted between the push and the pull dithienothiophene domains. The resulting mechanophores combine characteristics of flippers, reporting on physical compression in the ground state, and molecular rotors, reporting on torsional motion in the excited state, to take their photophysics to new level of sophistication. Intensity ratios in broadened excitation bands from differently twisted conformers of core-alkynylated flippers thus report on mechanical compression. Lifetime boosts from ultrafast excited-state planarization and lifetime drops from competitive intersystem crossing into triplet states report on viscosity. In standard lipid bilayer membranes, core-alkynylated flippers are too long for one leaflet and tilt or extend into disordered interleaflet space, which preserves rotor-like torsional disorder and thus weak, blue-shifted fluorescence. Flipper-like planarization occurs only in highly ordered membranes of matching leaflet thickness, where they light up and selectively report on these thick membranes with red-shifted, sharpened excitation maxima, high intensity and long lifetime.

Cy3-Based Nanoviscosity Determination of Mucus: Effect of Mucus Collection Methods and Antibiotics Treatment.

The integrity of the protective mucus layer as a primary defense against pathogen invasion and microbial leakage into the intestinal epithelium can be compromised by the effects of antibiotics on the commensal microbiome. Changes in mucus integrity directly affect the solvent viscosity in the immediate vicinity of the mucin network, that is, the nanoviscosity, which in turn affects both biochemical reactions and selective transport. To assess mucus nanoviscosity, a reliable readout via the viscosity-dependent fluorescence lifetime of the molecular rotor dye cyanine 3 is established and nanoviscosities from porcine and murine ex vivo mucus are determined. To account for different mucin concentrations due to the removal of digestive residues during mucus collection, the power law dependence of mucin concentration on viscosity is used. The impact of antibiotics combinations (meropenem/vancomycin, gentamycin/ampicillin) on ex vivo intestinal mucus nanoviscosity is presented. The significant increase in viscosity of murine intestinal mucus after treatment suggests an effect of antibiotics on the microbiota that affects mucus integrity. This method will be a useful tool to assess how drugs, directly or indirectly, affect mucus integrity. Additionally, the method can be utilized to analyze the role of mucus nanoviscosity in health and disease, as well as in drug development.

Directed Graph Mapping exceeds Phase Mapping for the detection of simulated 2D meandering rotors in fibrotic tissue with added noise.

Cardiac arrhythmias such as atrial fibrillation (AF) are recognised to be associated with re-entry or rotors. A rotor is a wave of excitation in the cardiac tissue that wraps around its refractory tail, causing faster-than-normal periodic excitation. The detection of rotor centres is of crucial importance in guiding ablation strategies for the treatment of arrhythmia. The most popular technique for detecting rotor centres is Phase Mapping (PM), which detects phase singularities derived from the phase of a signal. This method has been proven to be prone to errors, especially in regimes of fibrotic tissue and temporal noise. Recently, a novel technique called Directed Graph Mapping (DGM) was developed to detect rotational activity such as rotors by creating a network of excitation. This research aims to compare the performance of advanced PM techniques versus DGM for the detection of rotors using 64 simulated 2D meandering rotors in the presence of various levels of fibrotic tissue and temporal noise. Four strategies were employed to compare the performances of PM and DGM. These included a visual analysis, a comparison of F2-scores and distance distributions, and calculating p-values using the mid-p McNemar test. Results indicate that in the case of low meandering, fibrosis and noise, PM and DGM yield excellent results and are comparable. However, in the case of high meandering, fibrosis and noise, PM is undeniably prone to errors, mainly in the form of an excess of false positives, resulting in low precision. In contrast, DGM is more robust against these factors as F2-scores remain high, yielding F2≥0.931 as opposed to the best PM F2≥0.635 across all 64 simulations.

Controlled synchronization of three co-rotating exciters based on a circular distribution in a vibratory system.

In this article, an engineering problem of three co-rotating exciters with the circular distribution in a vibrating system is investigated. The dynamical model constructed by the motion differential equations is established. By introducing the small parameter averaged method in the dynamic equation, the synchronization and stability conditions of the electromechanical coupling dynamical model is derived. To illustrate the necessity of the controlling method, the self-synchronization of the vibrating system is firstly analyzed with the theory, numerical simulations and experiments. With the self-synchronization results, it is indicated that the ellipse trajectory which is needed in the industry can't be realizefd by the self-synchronization motion of the vibrating system. And then, a fuzzy PID controlling method based on the master-slave controlling strategy is introduced in the vibrating system to realize the controlled synchronization. The Lyapunov stability criterion is given to certify the stability of the controlling system. Through some simulations and experiments, the effectiveness of controlled synchronization is illustrated in the discussion. Finally, the present work illuminates the feasibility and practicality for designing some new types of vibrating screens in the industry.

Molecular Dynamics of Steroidal Rotors Probed by Theoretical, Spectroscopic and Dielectric Methods.

Our study focuses on molecular rotors with fast-moving rotators and their potential applications in the development of new amphidynamic crystals. Steroidal molecular rotors with a dipolar fluorine-substituted phenyl group as the rotator were synthesized and characterized. Three different rotors were investigated with varying numbers of fluorine atoms. A comprehensive analysis was performed using vibrational spectroscopy (Raman, FT-IR), electronic circular dichroism (ECD), and dielectric response to understand the behavior of the investigated model rotors. The results were supported by theoretical calculations using Density Functional Theory (DFT) methods. The angle-dependent polarized Raman spectra confirmed the crystallinity of the samples. Nearly frequency and temperature-independent permittivity suggest low-frequency librational motion of stators. An in-depth analysis of ECD spectra revealed high conformational flexibility in solution, resulting in low ECD effects, while in the solid-state with restricted rotation, significant ECD effects were observed. These findings shed light on the conformational behavior and potential applications of the studied steroidal molecular rotors.

Molecular Rotors for In Situ Viscosity Mapping during Evaporation of Confined Fluid Mixtures.

Numerous formulation processes of materials involve a drying step, during which evaporation of a solvent from a multicomponent liquid mixture, often confined in a thin film or in a droplet, leads to concentration and assembly of nonvolatile compounds. While the basic phenomena ruling evaporation dynamics are known, precise modeling of practical situations is hindered by the lack of tools for local and time-resolved mapping of concentration fields in such confined systems. In this article, the use of fluorescence lifetime imaging microscopy and of fluorescent molecular rotors is introduced as a versatile, in situ, and quantitative method to map viscosity and concentration fields in confined, evaporating liquids. More precisely, the cases of drying of a suspended liquid film and of a sessile droplet of mixtures of fructose and water are investigated. Measured viscosity and concentration fields allow characterization of drying dynamics, in agreement with simple modeling of the evaporation process.

Polymer network comprised of steroidal rotors as promising storage material.

In this paper, we report a new generation of polymeric networks as potential functional material based on changes in molecular dynamics in the solid state. The material is obtained by free radical polymerization of a diacrylate derivative bearing a steroid (stator) and a 1,4-diethynyl-phenylene-d4 fragment (rotator). Polymer research using the PALS technique complements the knowledge about nanostructural changes occurring in the system in the temperature range -115 °C - +190 °C. It indicates the presence of two types of free nanovolumes in the system and the occurrence of phase transitions. The polymer is characterized using 1 H NMR, 2 H Solid Echo NMR, ATR-FTIR and Raman spectroscopies, thermal analysis, and porosimetry. It is proved that the applied procedure leads to the formation of a novel porous organic material containing multiple molecular rotors.

Molecular Rotors: Fluorescent Sensors for Microviscosity and Conformation of Biomolecules.

The viscosity and crowding of biological environment are considered vital for the correct cellular function, and alterations in these parameters are known to underly a number of pathologies including diabetes, malaria, cancer and neurodegenerative diseases, to name a few. Over the last decades, fluorescent molecular probes termed molecular rotors proved extremely useful for exploring viscosity, crowding, and underlying molecular interactions in biologically relevant settings. In this review, we will discuss the basic principles underpinning the functionality of these probes and will review advances in their use as sensors for lipid order, protein crowding and conformation, temperature and non-canonical nucleic acid structures in live cells and other relevant biological settings.

A Photoelectromagnetic 3D Metal-Organic Framework from Flexible Tetraarylethylene-Backboned Ligand and Dynamic Copper-Based Coordination Chemistry.

Porous frameworks that display dynamic responsiveness are of interest in the fields of smart materials, information technology, etc. In this work, a novel copper-based dynamic metal-organic framework [Cu3TTBPE6(H2O)2] (H4TTBPE = 1,1,2,2-tetrakis(4″-(1H-tetrazol-5-yl)-[1,1″-biphenyl]-4-yl)ethane), denoted as HNU-1, is reported which exhibits modulable photoelectromagnetic properties. Due to the synergetic effect of flexible tetraarylethylene-backboned ligands and diverse copper-tetrazole coordination chemistries, a complex 3D tunneling network is established in this MOF by the layer-by-layer staggered assembly of triplicate monolayers, showing a porosity of 59%. These features further make it possible to achieve dynamic transitions, in which the aggregate-state MOF can be transferred to different structural states by changing the chemical environment or upon heating while displaying sensitive responsiveness in terms of light absorption, photoluminescence, and magnetic properties.

Wireless Magnetoelectrochemical Induction of Rotational Motion.

Electromagnetically induced rotation is a key process of many technological systems that are used in daily life, especially for energy conversion. In this context, the Lorentz force-induced deviation of charges is a crucial physical phenomenon to generate rotation. Herein, they combine the latter with the concept of bipolar electrochemistry to design a wireless magnetoelectrochemical rotor. Such a device can be considered as a wet analog of a conventional electric motor. The main driving force that propels this actuator is the result of the synergy between the charge-compensating ion flux along a bipolar electrode and an external magnetic field applied orthogonally to the surface of the object. The trajectory of the wirelessly polarized rotor can be controlled by the orientation of the magnetic field relative to the direction of the global electric field, producing a predictable clockwise or anticlockwise motion. Fine-tuning of the applied electric field allows for addressing conducting objects having variable characteristic lengths.

Cyanoarylporphyrazine dyes: multimodal compounds for personalised photodynamic therapy.

Photodynamic therapy is known as an effective primary and adjuvant anticancer treatment. Compounds with improved properties or additional modalities are still needed to create an 'ideal' photosensitizer. In this article, we review cyanoarylporphyrazine dyes for photodynamic (anticancer) therapy that we have synthesised to date. The review provides information on the chemistry of cyanoarylporphyrazines, photophysical properties, cellular uptake features and the use of various carriers for selective delivery of cyanoarylporphyrazines to the tumour. The potential of cyanoarylporphyrazines as photodynamic anti-tumour agents also has been evaluated. The most interesting feature of cyanoarylporphyrazines is the dependence of the fluorescence quantum yield and excited state lifetime on the viscosity of the medium, which makes it possible to use them as viscosity sensors in photodynamic therapy. In the future, we expect that the unique combination of photosensitizer and viscosity sensor properties of cyanoarylporphyrazines will provide a tool for dosimetry and tailoring treatment regimens in photodynamic therapy to the individual characteristics of each patient.

Correlation of Plasma Membrane Microviscosity and Cell Stiffness Revealed via Fluorescence-Lifetime Imaging and Atomic Force Microscopy.

The biophysical properties of cells described at the level of whole cells or their membranes have many consequences for their biological behavior. However, our understanding of the relationships between mechanical parameters at the level of cell (stiffness, viscoelasticity) and at the level of the plasma membrane (fluidity) remains quite limited, especially in the context of pathologies, such as cancer. Here, we investigated the correlations between cells' stiffness and viscoelastic parameters, mainly determined via the actin cortex, and plasma membrane microviscosity, mainly determined via its lipid profile, in cancer cells, as these are the keys to their migratory capacity. The mechanical properties of cells were assessed using atomic force microscopy (AFM). The microviscosity of membranes was visualized using fluorescence-lifetime imaging microscopy (FLIM) with the viscosity-sensitive probe BODIPY 2. Measurements were performed for five human colorectal cancer cell lines that have different migratory activity (HT29, Caco-2, HCT116, SW 837, and SW 480) and their chemoresistant counterparts. The actin cytoskeleton and the membrane lipid composition were also analyzed to verify the results. The cell stiffness (Young's modulus), measured via AFM, correlated well (Pearson r = 0.93) with membrane microviscosity, measured via FLIM, and both metrics were elevated in more motile cells. The associations between stiffness and microviscosity were preserved upon acquisition of chemoresistance to one of two chemotherapeutic drugs. These data clearly indicate that mechanical parameters, determined by two different cellular structures, are interconnected in cells and play a role in their intrinsic migratory potential.

Formation of Highly Emissive Anthracene Excimers for Aggregation-Induced Emission/Self-Assembly Directed (Bio)imaging.

AIEgens have emerged as a promising alternative to molecular rotors in bioimaging applications. However, transferring the concept of aggregation-induced emission (AIE) from solution to living systems remains a challenge. Given the highly heterogeneous nature and the compartmentalization of the cell, different approaches are needed to control the self-assembly within the crowded intricate cellular environment. Herein, we report for the first time the self-assembly mechanism of an anthracene-guanidine derivative (AG) forming the rare and highly emissive T-shaped dimer in breast cancer cell lines as a proof of concept. This process is highly sensitive to the local environment in terms of polarity, viscosity, and/or water quantity that should enable the use of the AG as a fluorescence lifetime imaging biosensor for intracellular imaging of cellular structures and the monitoring of intracellular state parameters. Different populations of the monomer and T-shaped and π-π dimers were observed in the cell membrane, cytoplasm, and nucleoplasm, related to the local viscosity and presence of water. The T-shaped dimer is formed preferentially in the nucleus because of the higher density and viscosity compared to the cytoplasm. The present results should serve as a precursor for the development of new design strategies for molecular systems for a wide range of applications such as cell viscosity, density, or temperature sensing and imaging.