Chronic nicotine exposure is associated with electrophysiological and sympathetic remodeling in the intact rabbit heart.

Nicotine is the primary addictive component of tobacco products. Through its actions on the heart and autonomic nervous system, nicotine exposure is associated with electrophysiological changes and increased arrhythmia susceptibility. To assess the underlying mechanisms, we treated rabbits with transdermal nicotine (NIC, 21 mg/day) or control (CT) patches for 28 days before performing dual optical mapping of transmembrane potential (RH237) and intracellular Ca2+ (Rhod-2 AM) in isolated hearts with intact sympathetic innervation. Sympathetic nerve stimulation (SNS) was performed at the first to third thoracic vertebrae, and ß-adrenergic responsiveness was additionally evaluated following norepinephrine (NE) perfusion. Baseline ex vivo heart rate (HR) and SNS stimulation threshold were higher in NIC versus CT (P = 0.004 and P = 0.003, respectively). Action potential duration alternans emerged at longer pacing cycle lengths (PCL) in NIC versus CT at baseline (P = 0.002) and during SNS (P = 0.0003), with similar results obtained for Ca2+ transient alternans. SNS shortened the PCL at which alternans emerged in CT but not in NIC hearts. NIC-exposed hearts tended to have slower and reduced HR responses to NE perfusion, but ventricular responses to NE were comparable between groups. Although fibrosis was unaltered, NIC hearts had lower sympathetic nerve density (P = 0.03) but no difference in NE content versus CT. These results suggest both sympathetic hypoinnervation of the myocardium and regional differences in ß-adrenergic responsiveness with NIC. This autonomic remodeling may contribute to the increased risk of arrhythmias associated with nicotine exposure, which may be further exacerbated with long-term use.NEW & NOTEWORTHY Here, we show that chronic nicotine exposure was associated with increased heart rate, increased susceptibility to alternans, and reduced sympathetic electrophysiological responses in the intact rabbit heart. We suggest that this was due to sympathetic hypoinnervation of the myocardium and diminished ß-adrenergic responsiveness of the sinoatrial node following nicotine treatment. Though these differences did not result in increased arrhythmia propensity in our study, we hypothesize that prolonged nicotine exposure may exacerbate this proarrhythmic remodeling.

Sympathetic structural and electrophysiological remodeling in a rabbit model of reperfused myocardial infarction.

Chondroitin sulfate proteoglycans (CSPGs) inhibit sympathetic reinnervation in rodent hearts post myocardial infarction (MI), causing regional hypo-innervation that is associated with supersensitivity of ß-adrenergic receptors and increased arrhythmia susceptibility. To investigate the role of CSPGs and hypo-innervation in the heart of larger mammals, we used a rabbit model of reperfused MI and tested electrophysiological responses to sympathetic nerve stimulation (SNS). Innervated hearts from MI and sham rabbits were optically mapped using voltage and Ca2+-sensitive dyes. SNS was performed with electrical stimulation of the spinal cord and ß-adrenergic responsiveness was tested using isoproterenol. Sympathetic nerve density and CSPG expression were evaluated using immunohistochemistry. CSPGs were robustly expressed in the infarct region of all MI hearts, and the presence of CSPGs was associated with reduced sympathetic nerve density in the infarct vs. remote region. Action potential duration (APD) dispersion and susceptibility to ventricular tachycardia/fibrillation (VT/VF) were increased with SNS in MI hearts but not in sham. SNS decreased APD80 in MI but not sham hearts, while isoproterenol decreased APD80 in both groups. Isoproterenol also shortened Ca2+ transient duration (CaTD80) in both groups but to a greater extent in MI hearts. Our data suggest sympathetic remodeling post-MI is similar between rodents and rabbits, with CSPGs associated with sympathetic hypo-innervation. Despite a reduction in sympathetic nerve density, the infarct region of MI hearts remained responsive to both physiological SNS and isoproterenol, potentially through preserved or elevated ß-adrenergic responsiveness, which may underly increased APD dispersion and susceptibility for VT/VF.

Performance Evaluation Method for Intelligent Computing Components for Space Applications.

The computational performance requirements of space payloads are constantly increasing, and the redevelopment of space-grade processors requires a significant amount of time and is costly. This study investigates performance evaluation benchmarks for processors designed for various application scenarios. It also constructs benchmark modules and typical space application benchmarks specifically tailored for the space domain. Furthermore, the study systematically evaluates and analyzes the performance of NVIDIA Jetson AGX Xavier platform and Loongson platforms to identify processors that are suitable for space missions. The experimental results of the evaluation demonstrate that Jetson AGX Xavier performs exceptionally well and consumes less power during dense computations. The Loongson platform can achieve 80% of Xavier's performance in certain parallel optimized computations, surpassing Xavier's performance at the expense of higher power consumption.

Research on an Intelligent Mining Complete System of a Fully Mechanized Mining Face in Thin Coal Seam.

The mining environment of thin coal seam working faces is generally harsh, the labor intensity is high, and the production efficiency is low. Previous studies have shown that thin coal seam mining finds it difficult to follow machines, does not have complete sets of equipment, has a low degree of automation, and has difficult system co-control, which easily causes production safety accidents. In order to effectively solve the problems existing in thin coal seam mining, Binhu Coal Mine has established intelligent fully mechanized mining and actively explored automatic coal cutting, automatic support following, and intelligent control. The combination of an SAC electro-hydraulic control system and SAP pumping station control system has been applied in 16,108 intelligent fully mechanized coal mining faces, which realizes the automatic following of underground support and the control of adjacent support, partition support, and group operation; the automatic coal cutting of the shearer is realized by editing the automatic coal-cutting state of the shearer and adjusting the automatic parameters. A centralized control center is set up, which realizes the remote control and one-button start-stop of working face equipment. Through a comparative analysis of 16,108 intelligent fully mechanized mining faces and traditional fully mechanized mining faces, it is found that intelligent fully mechanized mining faces have obvious advantages in terms of equipment maintenance, equipment operation mode, and working face efficiency, which improve the equipment and technical mining level of thin coal seam. The application of intelligent mining in Binhu Coal Mine has a great and far-reaching impact on the development of thin coal seam mining technology in China.

Cardiac sympathetic nerve transdifferentiation reduces action potential heterogeneity after myocardial infarction.

Cardiac sympathetic nerves undergo cholinergic transdifferentiation following reperfused myocardial infarction (MI), whereby the sympathetic nerves release both norepinephrine (NE) and acetylcholine (ACh). The functional electrophysiological consequences of post-MI transdifferentiation have never been explored. We performed MI or sham surgery in wild-type (WT) mice and mice in which choline acetyltransferase was deleted from adult noradrenergic neurons [knockout (KO)]. Electrophysiological activity was assessed with optical mapping of action potentials (AP) and intracellular Ca2+ transients (CaT) in innervated Langendorff-perfused hearts. KO MI hearts had similar NE content but reduced ACh content compared with WT MI hearts (0.360 ± 0.074 vs. 0.493 ± 0.087 pmol/mg; KO, n = 6; WT, n = 4; P < 0.05). KO MI hearts also had higher basal ex vivo heart rates versus WT MI hearts (328.5 ± 35.3 vs. 247.4 ± 62.4 beats/min; KO, n = 8; WT, n = 6; P < 0.05). AP duration at 80% repolarization was significantly shorter in the remote and border zones of KO MI versus WT MI hearts, whereas AP durations (APDs) were similar in infarct regions. This APD heterogeneity resulted in increased APD dispersion in the KO MI versus WT MI hearts (11.9 ± 2.7 vs. 8.2 ± 2.3 ms; KO, n = 8; WT, n = 6; P < 0.05), which was eliminated with atropine. CaT duration at 80% and CaT alternans magnitude were similar between groups both with and without sympathetic nerve stimulation. These results indicate that cholinergic transdifferentiation following MI prolongs APD in the remote and border zone and reduces APD heterogeneity.NEW & NOTEWORTHY Cardiac sympathetic neurons undergo cholinergic transdifferentiation following myocardial infarction; however, the electrophysiological effects of corelease of norepinephrine and acetylcholine (ACh) have never been assessed. Using a mouse model in which choline acetyltransferase was deleted from adult noradrenergic neurons and optical mapping of innervated hearts, we found that corelease of ACh reduces dispersion of action potential duration, which may be antiarrhythmic.

Different paths, same destination: divergent action potential responses produce conserved cardiac fight-or-flight response in mouse and rabbit hearts.

KEY POINTS: Cardiac electrophysiology and Ca2+ handling change rapidly during the fight-or-flight response to meet physiological demands. Despite dramatic differences in cardiac electrophysiology, the cardiac fight-or-flight response is highly conserved across species. In this study, we performed physiological sympathetic nerve stimulation (SNS) while optically mapping cardiac action potentials and intracellular Ca2+ transients in innervated mouse and rabbit hearts. Despite similar heart rate and Ca2+ handling responses between mouse and rabbit hearts, we found notable species differences in spatio-temporal repolarization dynamics during SNS. Species-specific computational models revealed that these electrophysiological differences allowed for enhanced Ca2+ handling (i.e. enhanced inotropy) in each species, suggesting that electrophysiological responses are fine-tuned across species to produce optimal cardiac fight-or-flight responses. ABSTRACT: Sympathetic activation of the heart results in positive chronotropy and inotropy, which together rapidly increase cardiac output. The precise mechanisms that produce the electrophysiological and Ca2+ handling changes underlying chronotropic and inotropic responses have been studied in detail in isolated cardiac myocytes. However, few studies have examined the dynamic effects of physiological sympathetic nerve activation on cardiac action potentials (APs) and intracellular Ca2+ transients (CaTs) in the intact heart. Here, we performed bilateral sympathetic nerve stimulation (SNS) in fully innervated, Langendorff-perfused rabbit and mouse hearts. Dual optical mapping with voltage- and Ca2+ -sensitive dyes allowed for analysis of spatio-temporal AP and CaT dynamics. The rabbit heart responded to SNS with a monotonic increase in heart rate (HR), monotonic decreases in AP and CaT duration (APD, CaTD), and a monotonic increase in CaT amplitude. The mouse heart had similar HR and CaT responses; however, a pronounced biphasic APD response occurred, with initial prolongation (50.9 ± 5.1 ms at t = 0 s vs. 60.6 ± 4.1 ms at t = 15 s, P < 0.05) followed by shortening (46.5 ± 9.1 ms at t = 60 s, P = NS vs. t = 0). We determined the biphasic APD response in mouse was partly due to dynamic changes in HR during SNS and was exacerbated by ß-adrenergic activation. Simulations with species-specific cardiac models revealed that transient APD prolongation in mouse allowed for greater and more rapid CaT responses, suggesting more rapid increases in contractility; conversely, the rabbit heart requires APD shortening to produce optimal inotropic responses. Thus, while the cardiac fight-or-flight response is highly conserved between species, the underlying mechanisms orchestrating these effects differ significantly.

Diabetic hyperglycaemia activates CaMKII and arrhythmias by O-linked glycosylation.

Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is an enzyme with important regulatory functions in the heart and brain, and its chronic activation can be pathological. CaMKII activation is seen in heart failure, and can directly induce pathological changes in ion channels, Ca(2+) handling and gene transcription. Here, in human, rat and mouse, we identify a novel mechanism linking CaMKII and hyperglycaemic signalling in diabetes mellitus, which is a key risk factor for heart and neurodegenerative diseases. Acute hyperglycaemia causes covalent modification of CaMKII by O-linked N-acetylglucosamine (O-GlcNAc). O-GlcNAc modification of CaMKII at Ser 279 activates CaMKII autonomously, creating molecular memory even after Ca(2+) concentration declines. O-GlcNAc-modified CaMKII is increased in the heart and brain of diabetic humans and rats. In cardiomyocytes, increased glucose concentration significantly enhances CaMKII-dependent activation of spontaneous sarcoplasmic reticulum Ca(2+) release events that can contribute to cardiac mechanical dysfunction and arrhythmias. These effects were prevented by pharmacological inhibition of O-GlcNAc signalling or genetic ablation of CaMKIIδ. In intact perfused hearts, arrhythmias were aggravated by increased glucose concentration through O-GlcNAc- and CaMKII-dependent pathways. In diabetic animals, acute blockade of O-GlcNAc inhibited arrhythmogenesis. Thus, O-GlcNAc modification of CaMKII is a novel signalling event in pathways that may contribute critically to cardiac and neuronal pathophysiology in diabetes and other diseases.

Age-related changes in cardiac electrophysiology and calcium handling in response to sympathetic nerve stimulation.

KEY POINTS: Ageing results in changes to cardiac electrophysiology, Ca2+ handling, and ß-adrenergic responsiveness. Sympathetic neurodegeneration also occurs with age, yet detailed action potential and Ca2+ handling responses to physiological sympathetic nerve stimulation (SNS) in the aged heart have not been assessed. Optical mapping in mouse hearts with intact sympathetic innervation revealed reduced responsiveness to SNS in the aged atria (assessed by heart rate) and aged ventricles (assessed by action potentials and Ca2+ transients). Sympathetic nerve density and noradrenaline content were reduced in aged ventricles, but noradrenaline content was preserved in aged atria. These results demonstrate that reduced responsiveness to SNS in the atria may be primarily due to decreased ß-adrenergic receptor responsiveness, whereas reduced responsiveness to SNS in the ventricles may be primarily due to neurodegeneration. ABSTRACT: The objective of this study was to determine how age-related changes in sympathetic structure and function impact cardiac electrophysiology and intracellular Ca2+ handling. Innervated hearts from young (3-4 months, YWT, n = 10) and aged (20-24 months, AGED, n = 11) female mice (C57Bl6) were optically mapped using the voltage (Vm ,)- and calcium (Ca2+ )-sensitive indicators Rh237 and Rhod2-AM. Sympathetic nerve stimulation (SNS) was performed at the spinal cord (T1-T3). ß-Adrenergic responsiveness was assessed with isoproterenol (1 µM, ISO). Sympathetic nerve density and noradrenaline content were also quantified. Stimulation thresholds necessary to produce a defined increase in heart rate (HR) with SNS were higher in AGED vs. YWT hearts (5.4 ± 0.4 vs. 3.8 ± 0.4 Hz, P < 0.05). Maximal HR with SNS was lower in AGED vs. YWT (20.5 ± 3.41% vs. 73.0 ± 7.63% increase, P < 0.05). ß-Adrenergic responsiveness of the atria (measured as percentage increase in HR with ISO) was decreased in AGED vs. YWT hearts (75.3 ± 22.5% vs. 148.5 ± 19.8%, P < 0.05). SNS significantly increased action potential duration (APD) in YWT but not AGED. Ca2+ transient durations and rise times were unchanged by SNS, yet AGED hearts had an increased susceptibility to Ca2+ alternans and ventricular arrhythmias. ß-Adrenergic responsiveness of all ventricular parameters were similar between AGED and YWT. Sympathetic nerve density and noradrenaline content were decreased in the AGED ventricle, but not atria, compared to YWT. These data suggest that decreased responsiveness to SNS in the aged atria may be primarily due to decreased ß-adrenergic responsiveness, whereas decreased responsiveness to SNS in the aged ventricles may be primarily due to nerve degeneration.

Transient denervation of viable myocardium after myocardial infarction does not alter arrhythmia susceptibility.

Cardiac sympathetic nerves stimulate heart rate and force of contraction. Myocardial infarction (MI) leads to the loss of sympathetic nerves within the heart, and clinical studies have indicated that sympathetic denervation is a risk factor for arrhythmias and cardiac arrest. Two distinct types of denervation have been identified in the mouse heart after MI caused by ischemia-reperfusion: transient denervation of peri-infarct myocardium and sustained denervation of the infarct. Sustained denervation is linked to increased arrhythmia risk, but it is not known whether acute nerve loss in peri-infarct myocardium also contributes to arrhythmia risk. Peri-infarct sympathetic denervation requires the p75 neurotrophin receptor (p75NTR), but removal of p75NTR alters the pattern of sympathetic innervation in the heart and increases spontaneous arrhythmias. Therefore, we targeted the p75NTR coreceptor sortilin and the p75NTR-induced protease tumor necrosis factor-α-converting enzyme/A disintegrin and metalloproteinase domain 17 (TACE/ADAM17) to selectively block peri-infarct denervation. Sympathetic nerve density was quantified using immunohistochemistry for tyrosine hydroxylase. Genetic deletion of sortilin had no effect on the timing or extent of axon degeneration, but inhibition of TACE/ADAM17 with the protease inhibitor marimastat prevented the loss of axons from viable myocardium. We then asked whether retention of nerves in peri-infarct myocardium had an impact on cardiac electrophysiology 3 days after MI using ex vivo optical mapping of transmembrane potential and intracellular Ca2+. Preventing acute denervation of viable myocardium after MI did not significantly alter cardiac electrophysiology or Ca2+ handling, suggesting that transient denervation at this early time point has minimal impact on arrhythmia risk. NEW & NOTEWORTHY Sympathetic denervation after myocardial infarction is a risk factor for arrhythmias. We asked whether transient loss of nerves in viable myocardium contributed to arrhythmia risk. We found that targeting protease activity could prevent acute peri-infarct denervation but that it did not significantly alter cardiac electrophysiology or Ca2+ handling 3 days after myocardial infarction.

Myocardial Infarction Causes Transient Cholinergic Transdifferentiation of Cardiac Sympathetic Nerves via gp130.

Sympathetic and parasympathetic control of the heart is a classic example of norepinephrine (NE) and acetylcholine (ACh) triggering opposing actions. Sympathetic NE increases heart rate and contractility through activation of ß receptors, whereas parasympathetic ACh slows the heart through muscarinic receptors. Sympathetic neurons can undergo a developmental transition from production of NE to ACh and we provide evidence that mouse cardiac sympathetic nerves transiently produce ACh after myocardial infarction (MI). ACh levels increased in viable heart tissue 10-14 d after MI, returning to control levels at 21 d, whereas NE levels were stable. At the same time, the genes required for ACh synthesis increased in stellate ganglia, which contain most of the sympathetic neurons projecting to the heart. Immunohistochemistry 14 d after MI revealed choline acetyltransferase (ChAT) in stellate sympathetic neurons and vesicular ACh transporter immunoreactivity in tyrosine hydroxylase-positive cardiac sympathetic fibers. Finally, selective deletion of the ChAT gene from adult sympathetic neurons prevented the infarction-induced increase in cardiac ACh. Deletion of the gp130 cytokine receptor from sympathetic neurons prevented the induction of cholinergic genes after MI, suggesting that inflammatory cytokines induce the transient acquisition of a cholinergic phenotype in cardiac sympathetic neurons. Ex vivo experiments examining the effect of NE and ACh on rabbit cardiac action potential duration revealed that ACh blunted both the NE-stimulated decrease in cardiac action potential duration and increase in myocyte calcium transients. This raises the possibility that sympathetic co-release of ACh and NE may impair adaptation to high heart rates and increase arrhythmia susceptibility. SIGNIFICANCE STATEMENT: Sympathetic neurons normally make norepinephrine (NE), which increases heart rate and the contractility of cardiac myocytes. We found that, after myocardial infarction, the sympathetic neurons innervating the heart begin to make acetylcholine (ACh), which slows heart rate and decreases contractility. Several lines of evidence confirmed that the source of ACh was sympathetic nerves rather than parasympathetic nerves that are the normal source of ACh in the heart. Global application of NE with or without ACh to ex vivo hearts showed that ACh partially reversed the NE-stimulated decrease in cardiac action potential duration and increase in myocyte calcium transients. That suggests that sympathetic co-release of ACh and NE may impair adaptation to high heart rates and increase arrhythmia susceptibility.

Optical mapping of sarcoplasmic reticulum Ca2+ in the intact heart: ryanodine receptor refractoriness during alternans and fibrillation.

RATIONALE: Sarcoplasmic reticulum (SR) Ca(2+) cycling is key to normal excitation-contraction coupling but may also contribute to pathological cardiac alternans and arrhythmia. OBJECTIVE: To measure intra-SR free [Ca(2+)] ([Ca(2+)]SR) changes in intact hearts during alternans and ventricular fibrillation (VF). METHODS AND RESULTS: Simultaneous optical mapping of Vm (with RH237) and [Ca(2+)]SR (with Fluo-5N AM) was performed in Langendorff-perfused rabbit hearts. Alternans and VF were induced by rapid pacing. SR Ca(2+) and action potential duration (APD) alternans occurred in-phase, but SR Ca(2+) alternans emerged first as cycle length was progressively reduced (217±10 versus 190±13 ms; P<0.05). Ryanodine receptor (RyR) refractoriness played a key role in the onset of SR Ca(2+) alternans, with SR Ca(2+) release alternans routinely occurring without changes in diastolic [Ca(2+)]SR. Sensitizing RyR with caffeine (200 µmol/L) significantly reduced the pacing threshold for both SR Ca(2+) and APD alternans (188±15 and 173±12 ms; P<0.05 versus baseline). Caffeine also reduced the magnitude of spatially discordant SR Ca(2+) alternans, but not APD alternans, the pacing threshold for discordance, or threshold for VF. During VF, [Ca(2+)]SR was high, but RyR remained nearly continuously refractory, resulting in minimal SR Ca(2+) release throughout VF. CONCLUSIONS: In intact hearts, RyR refractoriness initiates SR Ca(2+) release alternans that can be amplified by diastolic [Ca(2+)]SR alternans and lead to APD alternans. Sensitizing RyR suppresses spatially concordant but not discordant SR Ca(2+) and APD alternans. Despite increased [Ca(2+)]SR during VF, SR Ca(2+) release was nearly continuously refractory. This novel method provides insight into SR Ca(2+) handling during cardiac alternans and arrhythmia.

Decreased inward rectifying K+ current and increased ryanodine receptor sensitivity synergistically contribute to sustained focal arrhythmia in the intact rabbit heart.

KEY POINTS: Heart failure leads to dramatic electrophysiological remodelling as a result of numerous cellular and tissue-level changes. Important cellular changes include increased sensitivity of ryanodine receptors (RyRs) to Ca(2+) release and down-regulation of the inward rectifying K(+) current (IK1), both of which contribute to triggered action potentials in isolated cells. We studied the role of increased RyR sensitivity and decreased IK1 in contributing to focal arrhythmia in the intact non-failing rabbit heart using optical mapping and pharmacological manipulation of RyRs and IK1. Neither increased RyR sensitivity or decreased IK1 alone led to significant increases in arrhythmia following local sympathetic stimulation; however, in combination, these two factors led to a significant increase in premature ventricular complexes and focal ventricular tachycardia. These results suggest synergism between increased RyR sensitivity and decreased IK1 in contributing to focal arrhythmia in the intact heart and may provide important insights into novel anti-arrhythmic treatments in heart failure. ABSTRACT: Heart failure (HF) results in dramatic electrophysiological remodelling, including increased sensitivity of ryanodine receptors (RyRs) and decreased inward rectifying K(+) current (IK1), which predisposes HF myocytes to delayed afterdepolarizations and triggered activity. Therefore, we sought to determine the role of increased RyR sensitivity and decreased IK1 in contributing to focal arrhythmia in the intact non-failing heart. Optical mapping of transmembrane potential and intracellular Ca(2+) was performed in Langendorff-perfused rabbit hearts (n = 15). Local ß-adrenergic receptor stimulation with noradrenaline (norepinephrine; NA, 50 µl, 250 µM) was applied to elicit focal activity (premature ventricular complexes (PVCs) or ventricular tachycardia (VT ≥ 3 beats)). NA was administered under control conditions (CTL) and following pretreatment with 50 µM BaCl2 to reduce IK1, or 200 µM caffeine (Caff) to sensitize RyRs, both alone and in combination. Local NA injection resulted in Ca(2+)-driven PVCs arising from the injection site in all hearts studied. No increase in NA-mediated PVCs was observed following pretreatment with either BaCl2 or Caff alone (CTL: 1.1 ± 0.7, BaCl2: 1.0 ± 0.7, Caff: 1.3 ± 0.8 PVCs/injection, P not significant). However, pretreatment with the combination of BaCl2 + Caff resulted in a significant increase in PVCs (2.3 ± 2.8 PVCs/injection, P < 0.05 vs. CTL, BaCl2, Caff). Additionally, pretreatment with BaCl2 + Caff led to sustained monomorphic VT arising from the NA application site in all hearts studied, which lasted up to 6 min following a single NA injection. VT was never observed under any other condition suggesting synergism between increased RyR sensitivity and decreased IK1 in contributing to focal activity. These findings may have important implications for the understanding and prevention of focal arrhythmia in HF.

Local ß-adrenergic stimulation overcomes source-sink mismatch to generate focal arrhythmia.

RATIONALE: ß-Adrenergic receptor stimulation produces sarcoplasmic reticulum Ca(2+) overload and delayed afterdepolarizations in isolated ventricular myocytes. How delayed afterdepolarizations are synchronized to overcome the source-sink mismatch and produce focal arrhythmia in the intact heart remains unknown. OBJECTIVE: To determine whether local ß-adrenergic receptor stimulation produces spatiotemporal synchronization of delayed afterdepolarizations and to examine the effects of tissue geometry and cell-cell coupling on the induction of focal arrhythmia. METHODS AND RESULTS: Simultaneous optical mapping of transmembrane potential and Ca(2+) transients was performed in normal rabbit hearts during subepicardial injections (50 µL) of norepinephrine (NE) or control (normal Tyrode's solution). Local NE produced premature ventricular complexes (PVCs) from the injection site that were dose-dependent (low-dose [30-60 µmol/L], 0.45±0.62 PVCs per injection; high-dose [125-250 µmol/L], 1.33±1.46 PVCs per injection; P<0.0001) and were inhibited by propranolol. NE-induced PVCs exhibited abnormal voltage-Ca(2+) delay at the initiation site and were inhibited by either sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase inhibition or reduced perfusate [Ca(2+)], which indicates a Ca(2+)-mediated mechanism. NE-induced PVCs were more common at right ventricular than at left ventricular sites (1.48±1.50 versus 0.55±0.89, P<0.01), and this was unchanged after chemical ablation of endocardial Purkinje fibers, which suggests that source-sink interactions may contribute to the greater propensity to right ventricular PVCs. Partial gap junction uncoupling with carbenoxolone (25 µmol/L) increased focal activity (2.18±1.43 versus 1.33±1.46 PVCs per injection, P<0.05), which further supports source-sink balance as a critical mediator of Ca(2+)-induced PVCs. CONCLUSIONS: These data provide the first experimental demonstration that localized ß-adrenergic receptor stimulation produces spatiotemporal synchronization of sarcoplasmic reticulum Ca(2+) overload and release in the intact heart and highlight the critical nature of source-sink balance in initiating focal arrhythmias.

A whale optimization algorithm based on atom-like structure differential evolution for solving engineering design problems.

The whale optimization algorithm has received much attention since its introduction due to its outstanding performance. However, like other algorithms, the whale optimization algorithm still suffers from some classical problems. To address the issues of slow convergence, low optimization precision, and susceptibility to local convergence in the whale optimization algorithm (WOA). Defining the optimization behavior of whale individuals as quantum mechanical behavior, a whale optimization algorithm based on atom-like structure differential evolution (WOAAD) is proposed. Enhancing the spiral update mechanism by introducing a sine strategy guided by the electron orbital center. Improving the random-walk foraging mechanism by applying mutation operations to both the electron orbital center and random individuals. Performing crossover operations between the newly generated individuals from the improved mechanisms and random dimensions, followed by a selection process to retain superior individuals. This accelerates algorithm convergence, enhances optimization precision, and prevents the algorithm from falling into local convergence. Finally, implementing a scouting bee strategy, where whale individuals progressively increase the number of optimization failures within a limited parameter L. When a threshold is reached, random initialization is carried out to enhance population diversity. Conducting simulation experiments to compare the improved algorithm with the whale optimization algorithm, other optimization algorithms, and other enhanced whale optimization algorithms. The experimental results indicate that the improved algorithm significantly accelerates convergence, enhances optimization precision, and prevents the algorithm from falling into local convergence. Applying the improved algorithm to five engineering design problems, the experimental results demonstrate that the improved algorithm exhibits good applicability.

The Effect of Different Factors on Poly(lactic-co-glycolic acid) Nanoparticle Properties and Drug Release Behaviors When Co-Loaded with Hydrophilic and Hydrophobic Drugs.

Poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) are versatile drug nanocarriers with a wide spectrum of applications owing to their extensive advantages, including biodegradability, non-toxic side effects, and low immunogenicity. Among the numerous nanoparticle preparation methods available for PLGA NPs (the hydrophobic polymer), one of the most extensively utilized preparations is the sonicated-emulsified solvent evaporation method, owing to its simplicity, speed, convenience, and cost-effectiveness. Nevertheless, several factors can influence the outcomes, such as the types of concentration of the surfactants and organic solvents, as well as the volume of the aqueous phase. The objective of this article is to explore the influence of these factors on the properties of PLGA NPs and their drug release behavior following encapsulation. Herein, PLGA NPs were fabricated using bovine serum albumin (BSA) as a surfactant to investigate the impact of influencing factors, including different water-soluble organic solvents such as propylene carbonate (PC), ethyl acetate (PA), and dichloromethane (DCM). Notably, the size of PLGA NPs was smaller in the EA group compared to that in the DCM group. Moreover, PLGA NPs showed excellent stability, ascribed to the presence of the BSA surfactant. Furthermore, PLGA NPs were co-loaded with varying concentrations of hydrophilic drugs (doxorubicin hydrochloride) and hydrophobic drugs (celecoxib), and exhibited pH-sensitive drug release behavior in PBS with pH 7.4 and pH 5.5.

Sympathetic structural and electrophysiological remodeling in a rabbit model of reperfused myocardial infarction.

Chondroitin sulfate proteoglycans (CSPGs) inhibit sympathetic reinnervation in rodent hearts post myocardial infarction (MI), causing regional hypo-innervation that is associated with supersensitivity of ß-adrenergic receptors and increased arrhythmia susceptibility. To investigate the role of CSPGs and hypo-innervation in the heart of larger mammals, we used a rabbit model of reperfused MI and tested electrophysiological responses to sympathetic nerve stimulation (SNS). Innervated hearts from MI and sham rabbits were optically mapped using voltage and Ca 2+ -sensitive dyes. SNS was performed with electrical stimulation of the spinal cord and ß-adrenergic responsiveness was tested using isoproterenol. Sympathetic nerve density and CSPG expression were evaluated using immunohistochemistry. CSPGs were robustly expressed in the infarct and border zone of all MI hearts, and the presence of CSPGs was associated with reduced sympathetic nerve density in the infarct vs. remote region. Action potential duration (APD) dispersion and susceptibility to ventricular tachycardia/fibrillation (VT/VF) were increased with SNS in MI hearts but not in sham. SNS decreased APD 80 in MI but not sham hearts, while isoproterenol decreased APD 80 in both groups. Isoproterenol also shortened Ca 2+ transient duration (CaTD 80 ) in both groups but to a greater extent in MI hearts. Our data suggest sympathetic remodeling post-MI is similar between species, with CSPGs associated with sympathetic hypo-innervation. Despite a reduction in sympathetic nerve density, the infarct region of MI hearts remained responsive to both physiological SNS and isoproterenol, potentially through preserved or elevated ß-adrenergic responsiveness, which may underly increased APD dispersion and susceptibility for VT/VF. NEW & NOTEWORTHY: Here we show that CSPGs are present in the infarcts of rabbit hearts with reperfused MI, where they are associated with reduced sympathetic nerve density. Despite hypo-innervation, sympathetic responsiveness is maintained or enhanced in MI rabbit hearts, which also demonstrate increased APD dispersion and tendency for arrhythmias following sympathetic modulation. Together, this study indicates that the mechanisms of sympathetic remodeling post-MI are similar between species, with hypo-innervation likely associated with enhanced ß-adrenergic sensitivity.

Sine Cosine Algorithm for Elite Individual Collaborative Search and Its Application in Mechanical Optimization Designs.

To address the shortcomings of the sine cosine algorithm such as the low search accuracy, slow convergence speed, and easily falling into local optimality, a sine cosine algorithm for elite individual collaborative search was proposed. Firstly, tent chaotic mapping was used to initialize the population and the hyperbolic tangent function was applied non-linearly to adjust the parameters of the sine cosine algorithm, which enhanced the uniformity of population distribution and balanced the global exploration and local exploitation ability. Secondly, the search method of the sine cosine algorithm was improved by combining the search strategy of the sine cosine algorithm, the m-neighborhood locally optimal individual-guided search strategy, and the global optimal individual-guided search strategy, and, then, the three search strategies were executed alternately, which achieved collaboration, improved the convergence accuracy, and prevented the algorithm from falling into local optima. Finally, a greedy selection strategy was employed to select the best individuals for the population, which accelerated the convergence speed of the sine cosine algorithm. The simulation results illustrated that the sine cosine algorithm for elite individual collaborative search demonstrated a better optimization performance than the sine cosine algorithm, the other improved sine cosine algorithms, the other chaos-based algorithms, and other intelligent optimization algorithms. In addition, the feasibility and applicability of the sine cosine algorithm for elite individual collaborative search were further demonstrated by two mechanical optimization design experiments.

Study of the mechanical characteristics of coal-serial sandstone after high temperature treatment under true triaxial loading.

In this study, a series of true triaxial loading tests were carried out on coal-measure sandstone after high temperature treatment by using a self-developed true triaxial test system combined with acoustic emission (AE) monitoring, and the mass loss, deformation characteristics and loss failure mode of sandstone before and after heat treatment were systematically studied. It is found that the true triaxial mechanical properties of sandstone after high temperature treatment are closely related to temperature, and the peak strength, maximum principal strain, volume strain, minimum fracture angle and elastic modulus, which all showed bimodal changes, and 800 °C is the threshold temperature of the first four parameters. The transition temperature of the elastic modulus is 400 °C. It is found that the test results of true triaxial high temperature sandstone are in good agreement with the existing true triaxial theory and test results. The failure forms of the samples at different temperatures show inverted "Y" or inverted "N" shapes. Shear failure occurs when the temperature is below 400 °C, and shear-tension failure occurs when the temperature is above 600 °C. At the same time, it is found that the AE signal has four periods, namely the quiet period, growth period, explosion period and decline period. The number of AE events corresponds to the deviatoric stress interval well. Experimental study of the mechanical properties of sandstone under the coupling effect of high temperature and true triaxial stress has guiding significance for the parameter selection and safety evaluation of roof sandstone in underground coal gasification.

Experimental Study on Mechanical and Damage Evolution Characteristics of Coal during True Triaxial Cyclic Loading and Unloading.

Research on the mechanical properties and damage evolution of coal during true triaxial cyclic loading and unloading is of great significance for maintaining the long-term safety and stability of underground engineering structures in coal mines. In this paper, firstly, the deformation, strength and fracturing characteristics of coal during true triaxial loading and true triaxial cyclic loading and unloading were analyzed. Then, the residual strain characteristics, energy distribution and evolution of coal were systematically studied. Additionally, the damage evolution laws of coal during cyclic loading and unloading were quantitatively analyzed from the perspectives of residual strain and energy dissipation, respectively. The damage evolution law based on residual strain showed that when the intermediate principal stress was high, the damage to coal was directional. With the increase in cyclic load, the coal damage variables in the directions of σ1 and σ3 increased exponentially, while that in the direction of σ2 increased quadratically. The damage evolution law based on energy dissipation showed that the coal damage variable increased exponentially with the increase in cyclic load. With the increase in σ2, the increasing speed of coal damage variable decreased first and then increased. The damage variables established based on residual strain and energy dissipation can both reveal the damage deterioration mechanism of coal during true triaxial cyclic loading and unloading, which is of great theoretical and engineering significance for scientifically evaluating the stability of underground coal and rock engineering and preventing the occurrence of major geological disasters.

Developing a Novel Enamel Adhesive with Amorphous Calcium Phosphate and Silver Nanoparticles to Prevent Demineralization during Orthodontic Treatment.

During fixed orthodontic treatment, white spot lesions are prevalent issues associated with cariogenic bacteria. This study aims to construct an orthodontic adhesive containing nanoparticles of amorphous calcium phosphate-polydopamine-Ag (NPA) fillers to combat white spot lesions. The NPA fillers were prepared and characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS). The biocompatibility of the fillers was evaluated. A colony counting test evaluated the antibacterial property of the fillers against Streptococcus mutans (S. mutans). NPA fillers were mixed with orthodontic adhesive (Transbond XT) at different weight ratios (0, 0.1, 0.2, 0.3, and 0.5 wt.%). The shear bond strength and antibacterial properties were then further investigated. The results showed that NPA was prepared successfully, with good antibacterial properties. The cell survival rate of all groups of fillers was higher than 70%, showing good biocompatibility. Moreover, the shear bond strength of the orthodontic adhesive with 0.2 wt.% NPA fillers was 11.89 ± 1.27 MPa, meeting the minimal clinical bond strength requirements of 7.8 MPa. Furthermore, the orthodontic adhesive resin blocks and the extract displayed good antibacterial properties, with the number of colonies decreasing significantly (p < 0.001). Taken together, we think that an orthodontic adhesive with NPA may have a good application potential for the prevention and treatment of white spot lesions.