Utility of noninvasive electrocardiographic imaging in the localization of nonpulmonary vein triggers of atrial fibrillation determined by pacing common trigger sites.

INTRODUCTION: Identifying the origin of nonpulmonary vein atrial fibrillation (AF) triggers (NPVTs) after pulmonary vein isolation (PVI) can be challenging. We aimed to determine if noninvasive electrocardiographic imaging (ECGi) could localize pacing from common NPVT sites. ECGi combines measured body surface potentials with heart-torso geometry acquired from computed tomography (CT) to generate an activation map. METHODS: In 12 patients with AF undergoing first time ablation, the ECGi vest was fitted for preprocedural CT scan and worn during the procedure. After PVI, we performed steady-state pacing from 15 typical anatomic NPVT sites at a cycle length of 700-800 ms. We co-registered the invasive anatomic map with the CT-based ECGi epicardial activation map to compare ECGi predicted to true pacing origin. RESULTS: In the study cohort (67% male, 58% persistent AF, and 67% with left atrial dilation), 148 (82%) pacing sites had both capture and adequate anatomy acquired from the three-dimensional mapping system to co-register with ECGi activation map. Median distance between true pacing sites and point of earliest epicardial activation derived from the ECGi maps for all sites was 17 mm (interquartile range, 10-22 mm). Assuming paced sites treated as regions with a radius of 2.5 cm, the earliest activation site on ECGi map falls within the region with 94% accuracy. CONCLUSION: ECGi can approximate the origin of paced beats from common NPVT sites to within a median distance of 17 mm. A rapidly identified region may then be the focus of more detailed catheter-based mapping techniques to facilitate successful localization and ablation of NPVTs.

Supramolecular Aggregation of Carbon Nanodots.

Supramolecular aggregation has provided the archetype concept to understand the variants in an emerging systems property. Herein, we have achieved the supramolecular assembly of carbon nanodots (CDs) for the first time and employ supramolecular aggregation to understand their alteration in photophysical properties. In detail, we have employed the CDs as a block to construct the supramolecular assembly of aggregates in the CDs' antisolvent of ethanol. The CD-based aggregates exhibit complex and organized morphologies with another long-wavelength excitation-dependent emission band. The experimental results and density functional theoretical calculations reveal that the supramolecular assembly of CDs can decrease the energy gap between the ground and excited states, contributing to the new long-wavelength excitation-dependent emission. The supramolecular aggregation can be employed as one universal strategy to manipulate and understand the luminescence of CDs. These findings cast new light to build the emerging systems and understand the light emission of CDs through supramolecular chemistry.

In Situ Confining Citric Acid-Derived Carbon Dots for Full-Color Room-Temperature Phosphorescence.

Room-temperature phosphorescence has received much attention owing to its potential applications in information encryption and bioelectronics. However, the preparation of full-color single-component-derived phosphorescent materials remains a challenge. Herein, a facile in situ confining strategy is proposed to achieve full-color phosphorescent carbon dots (CDs) through rapid microwave-assisted carbonization of citric acid in NaOH. By tuning the mass ratio of citric acid and NaOH, the obtained CDs exhibit tunable phosphorescence wavelengths ranging from 483 to 635 nm and alterable lifetimes from 58 to 389 ms with a synthesis yield of up to 83.7% (>30 g per synthesis). Theoretical calculations and experimental results confirm that the formation of high-density ionic bonds between cations and CDs leads to efficient afterglow emission via the dissociation of CD arrangement, and the evolution of the aggregation state of CDs results in redshifted phosphorescence. These findings provide a strategy for the synthesis of new insights into achieving and manipulating room-temperature phosphorescent CDs, and prospect their applications in labeling and information encryption.

Brighten Triplet Excitons of Carbon Nanodots for Multicolor Phosphorescence Films.

Triplet excitons usually do not emit light under ambient conditions due to the spin-forbidden transition rule, thus they are called dark excitons. Herein, triplet excitons in carbon nanodots (CNDs) are brightened by embedding the CNDs into poly(vinyl alcohol) (PVA) films; flexible multicolor phosphorescence films are thus demonstrated. PVA chains can isolate the CNDs, and excited state electron or energy transfer induced triplet exciton quenching is thus reduced; while the formed hydrogen bonds between the CNDs and PVA can restrict vibration/rotation of the CNDs, thus further protecting the triplet excitons from nonradiative recombination. The lifetimes of the flexible multicolor phosphorescence films can reach 567, 1387, 726, and 311 ms, and the longest-lasting phosphorescence film can be observed by naked eyes for nearly 15 s even after bending 5000 times. The phosphorescence films can be processed into various patterns, and a dynamic optical signature concept has been proposed and demonstrated based on the phosphorescence films.

Cavity Quantum Electrodynamics Effects with Nitrogen Vacancy Center Spins Coupled to Room Temperature Microwave Resonators.

Cavity quantum electrodynamics (CQED) effects, such as Rabi splitting, Rabi oscillations, and superradiance, have been demonstrated with nitrogen vacancy (NV) center spins in diamond coupled to microwave resonators at cryogenic temperature. In this Letter, we explore the possibility to realize strong collective coupling and CQED effects with ensembles of NV spins at room temperature. Our calculations show that thermal excitation of the individual NV spins leads to population of collective Dicke states with low symmetry and a reduced collective coupling to the microwave resonators. Optical pumping can be applied to counteract the thermal excitation of the NV centers and to prepare the spin ensemble in Dicke states with high symmetry. The resulting strong coupling with high-quality resonators enables the study of intriguing CQED effects across the weak-to-strong coupling regime, and may have applications in quantum sensing and quantum information processing.

Excitation-independent deep-blue emitting carbon dots with 62% emission quantum efficiency and monoexponential decay profile for high-resolution fingerprint identification.

Reaching emissive nanomaterials at short wavelengths with a high quantum efficiency (QE) is an attractive task for researchers. This is more demanding in carbon dots (CDs) with diverse applications that usually emit photons at wavelengths around 450-620 nm. In this study, deep blue-emissive doped-CDs (d-CDs) with high photoluminescence (PL) QE up to 62% and excitation-independent properties were prepared via a short-time microwave irradiation method. The prepared CDs showed simultaneous amorphous and crystalline features, with average sizes of 4.75 nm and bright emission color located at 422 nm. It was found that the presence of sulfur-related dopant levels plays a key role in emission properties in such a way that the PL signal drops significantly in the absence of N-acetyl-l-cysteine (NAC) as a dopant source. On the other hand, the trisodium citrate dihydrate (TSC) was selected as a carbon source to form the main carbon skeleton without it no emission was recorded. Monoexponential-fitted recombination trend with an average lifetime of about 10 ns also confirmed excellent PL emission properties with uniform energy levels and minimized defect-contributing recombinations. The practical use of the as-prepared N, S-doped CDs was assessed in fingerprint detection indicating a bright and clear scheme for both core and termination regions of the fingerprint. Simplicity, cost-effectiveness, high-product yield, low toxicity, along with high/stable PL quantum efficiency in deep-blue wavelengths, and demonstrated ability for fingerprint purposes, support the prospective application of these dual doped-CDs for sensing and bioimaging applications.

Severe dyspnea and uncontrolled seizures following meperfluthrin poisoning: a case report.

BACKGROUND: Meperfluthrin is a novel sanitary cyhalothrin insecticide invented in China and has increasingly been used to produce liquid mosquito repellents. Oral meperfluthrin poisoning in human has rarely been reported. Here, we reported a case of meperfluthrin poisoning by ingestion of a meperfluthrin-based liquid mosquito repellent in a 16-month-old infant. CASE PRESENTATION: A 16-month-old boy with a history of accident ingestion of meperfluthrin was admitted to our hospital's emergency department. He exhibited severe dyspnea, and lung radiograph showed multiple patchy and cord-like high-density shadows bilaterally in a short time. He also suffered 35 min of seizures which were finally controlled by the intravenous infusion of propofol. He was diagnosed with meperfluthrin poisoning, status epilepticus and severe pneumonia. After treated with methylprednisolone, aerosolized beclomethasone dipropionate, anti-infection, and some critical supportive therapy, the patient was in good health and showed no symptoms during 12 months of follow-up. CONCLUSIONS: Meperfluthrin poisoning is rare. Oral meperfluthrin poisoning shows neurotoxic effects and pulmonary toxicity. Controlling seizures rapidly and ensuring an adequate oxygen supply are critical to the successful treatment.

Mapping and Ablation of Ventricular Fibrillation Associated With Early Repolarization Syndrome.

BACKGROUND: We conducted a multicenter study to evaluate mapping and ablation of ventricular fibrillation (VF) substrates or VF triggers in early repolarization syndromes (ERS) or J-wave syndrome (JWS). METHODS: We studied 52 patients with ERS (4 women; median age, 35 years) with recurrent VF episodes. Body surface electrocardiographic imaging and endocardial and epicardial electroanatomical mapping of both ventricles were performed during sinus rhythm and VF for localization of triggers, substrates, and drivers. Ablations were performed on VF substrates, defined as areas that had late depolarization abnormalities characterized by low-voltage fractionated late potentials, and VF triggers. RESULTS: Fifty-one of the 52 patients had detailed mapping that revealed 2 phenotypes: group 1 had late depolarization abnormalities predominantly at the right ventricular (RV) epicardium (n=40), and group 2 had no depolarization abnormalities (n=11). Group 1 can be subcategorized into 2 groups: Group 1A included 33 patients with ERS with Brugada electrocardiographic pattern, and group 1B included 7 patients with ERS without Brugada electrocardiographic pattern. Late depolarization areas colocalize with VF driver areas. The anterior RV outflow tract/RV epicardium and the RV inferior epicardium are the major substrate sites for group 1. The Purkinje network is the leading underlying VF trigger in group 2 that had no substrates. Ablations were performed in 43 patients: 31 and 5 group 1 patients had only VF substrate ablation and VF substrates plus VF trigger, respectively (mean, 1.4±0.6 sessions); 6 group 2 patients and 1 patient without group classification had only Purkinje VF trigger ablation (mean, 1.2±0.4 sessions). Ablations were successful in reducing VF recurrences (P<0.0001). After follow-up of 31±26 months, 39 (91%) had no VF recurrences. CONCLUSIONS: There are 2 phenotypes of ERS/J-wave syndrome: one with late depolarization abnormality as the underlying mechanism of high-amplitude J-wave elevation that predominantly resides in the RV outflow tract and RV inferolateral epicardium, serving as an excellent target for ablation, and the other with pure ERS devoid of VF substrates but with VF triggers that are associated with Purkinje sites. Ablation is effective in treating symptomatic patients with ERS/J-wave syndrome with frequent VF episodes.

Deep-Ultraviolet Emissive Carbon Nanodots.

Deep-ultraviolet (DUV) emissive carbon nanodots (CNDs) have been designed theoretically and demonstrated experimentally based on the results of first-principles calculations using the density functional theory method. The emission of the CNDs is located in the range from 280 to 300 nm, which coincides well with the results of theoretical calculation results. The photoluminescence (PL) quantum yield (QY) of the CNDs is up to 31.6%, and the strong emission of the CNDs originates from core-state (π-π*) carriers' radiative recombination and surface passivation. Benefiting from the core-state emission and surface group passivation, the emission of the CNDs is independent of the excitation wavelength and ambient solvent. DUV light-emitting diodes (LEDs) have been fabricated based on the DUV emissive CNDs, and the LEDs can be used as the excitation source to excite blue, green, and red CNDs, indicating their potential application in DUV light sources. This work may provide a clue for the designing and realizing of DUV emissive CNDs, thus promising the potential application of CNDs in DUV light-emitting sources.

Conditional Up-Regulation of SERCA2a Exacerbates RyR2-Dependent Ventricular and Atrial Arrhythmias.

Ryanodine receptor 2 (RyR2) and SERCA2a are two major players in myocyte calcium (Ca) cycling that are modulated physiologically, affected by disease and thus considered to be potential targets for cardiac disease therapy. However, how RyR2 and SERCA2a influence each others' activities, as well as the primary and secondary consequences of their combined manipulations remain controversial. In this study, we examined the effect of acute upregulation of SERCA2a on arrhythmogenesis by conditionally overexpressing SERCA2a in a mouse model featuring hyperactive RyR2s due to ablation of calsequestrin 2 (CASQ2). CASQ2 knock-out (KO) mice were crossbred with doxycycline (DOX)-inducible SERCA2a transgenic mice to generate KO-TG mice. In-vivo ECG studies have shown that induction of SERCA2a (DOX+) overexpression markedly exacerbated both ventricular and atrial arrhythmias in vivo, compared with uninduced KO-TG mice (DOX-). Consistent with that, confocal microscopy in both atrial and ventricular myocytes demonstrated that conditional upregulation of SERCA2a enhanced the rate of occurrence of diastolic Ca release events. Additionally, deep RNA sequencing identified 17 downregulated genes and 5 upregulated genes in DOX+ mice, among which Ppp1r13l, Clcn1, and Agt have previously been linked to arrhythmias. Our results suggest that conditional upregulation of SERCA2a exacerbates hyperactive RyR2-mediated arrhythmias by further elevating diastolic Ca release.

Ammonia reduced graphene oxides as a hole injection layer for CdSe/CdS/ZnS quantum dot light-emitting diodes.

In this study, we report quantum-dot light-emitting devices (QD-LEDs) using ammonia reduced graphene oxide (rGO) as a hole injection layer (HIL). Compared with pristine GO, QD-LEDs employing rGO as a HIL show higher maximum luminance (936 cd m(-2) versus 699 cd m(-2)) and lower turn-on voltage (V th, 5.0 V versus 7.5 V). The improved performance can be attributed to the synergistic effect of the improved conductivity (1.27 µS cm(-1) versus 0.139 µS cm(-1)) and decreased work function (5.27 eV versus 5.40 eV) of the GO after the reduction process. The above results indicate that ammonia functionalized graphene may be a promising hole injection material for QD-LEDs.

Decreased RyR2 refractoriness determines myocardial synchronization of aberrant Ca2+ release in a genetic model of arrhythmia.

Dysregulated intracellular Ca(2+) signaling is implicated in a variety of cardiac arrhythmias, including catecholaminergic polymorphic ventricular tachycardia. Spontaneous diastolic Ca(2+) release (DCR) can induce arrhythmogenic plasma membrane depolarizations, although the mechanism responsible for DCR synchronization among adjacent myocytes required for ectopic activity remains unclear. We investigated the synchronization mechanism(s) of DCR underlying untimely action potentials and diastolic contractions (DCs) in a catecholaminergic polymorphic ventricular tachycardia mouse model with a mutation in cardiac calsequestrin. We used a combination of different approaches including single ryanodine receptor channel recording, optical imaging (Ca(2+) and membrane potential), and contractile force measurements in ventricular myocytes and intact cardiac muscles. We demonstrate that DCR occurs in a temporally and spatially uniform manner in both myocytes and intact myocardial tissue isolated from cardiac calsequestrin mutation mice. Such synchronized DCR events give rise to triggered electrical activity that results in synchronous DCs in the myocardium. Importantly, we establish that synchronization of DCR is a result of a combination of abbreviated ryanodine receptor channel refractoriness and the preceding synchronous stimulated Ca(2+) release/reuptake dynamics. Our study reveals how aberrant DCR events can become synchronized in the intact myocardium, leading to triggered activity and the resultant DCs in the settings of a cardiac rhythm disorder.

Calsequestrin 2 deletion causes sinoatrial node dysfunction and atrial arrhythmias associated with altered sarcoplasmic reticulum calcium cycling and degenerative fibrosis within the mouse atrial pacemaker complex1.

AIMS: Loss-of-function mutations in Calsequestrin 2 (CASQ2) are associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT patients also exhibit bradycardia and atrial arrhythmias for which the underlying mechanism remains unknown. We aimed to study the sinoatrial node (SAN) dysfunction due to loss of CASQ2. METHODS AND RESULTS: In vivo electrocardiogram (ECG) monitoring, in vitro high-resolution optical mapping, confocal imaging of intracellular Ca(2+) cycling, and 3D atrial immunohistology were performed in wild-type (WT) and Casq2 null (Casq2(-/-)) mice. Casq2(-/-) mice exhibited bradycardia, SAN conduction abnormalities, and beat-to-beat heart rate variability due to enhanced atrial ectopic activity both at baseline and with autonomic stimulation. Loss of CASQ2 increased fibrosis within the pacemaker complex, depressed primary SAN activity, and conduction, but enhanced atrial ectopic activity and atrial fibrillation (AF) associated with macro- and micro-reentry during autonomic stimulation. In SAN myocytes, CASQ2 deficiency induced perturbations in intracellular Ca(2+) cycling, including abnormal Ca(2+) release, periods of significantly elevated diastolic Ca(2+) levels leading to pauses and unstable pacemaker rate. Importantly, Ca(2+) cycling dysfunction occurred not only at the SAN cellular level but was also globally manifested as an increased delay between action potential (AP) and Ca(2+) transient upstrokes throughout the atrial pacemaker complex. CONCLUSIONS: Loss of CASQ2 causes abnormal sarcoplasmic reticulum Ca(2+) release and selective interstitial fibrosis in the atrial pacemaker complex, which disrupt SAN pacemaking but enhance latent pacemaker activity, create conduction abnormalities and increase susceptibility to AF. These functional and extensive structural alterations could contribute to SAN dysfunction as well as AF in CPVT patients.

Alternating membrane potential/calcium interplay underlies repetitive focal activity in a genetic model of calcium-dependent atrial arrhythmias.

KEY POINTS: Atrial fibrillation is often initiated and perpetuated by abnormal electrical pulses repetitively originating from regions outside the heart's natural pacemaker. In this study we examined the causal role of abnormal calcium releases from the sarcoplasmic reticulum in producing repetitive electrical discharges in atrial cells and tissues. Calsequestrin2 is a protein that stabilizes the closed state of calcium release channels, i.e. the ryanodine receptors. In the atria from mice predisposed to abnormal calcium releases secondary to the absence of calsequestrin2, we observed abnormal repetitive electrical discharges that may lead to atrial fibrillation. Here, we report a novel pathological rhythm generator. Specifically, abnormal calcium release leads to electrical activation, which in turn results in another abnormal calcium release. This process repeats itself and thus sustains the repetitive electrical discharges. These results suggest that improving the stability of ryanodine receptors might be useful to treat atrial fibrillation. ABSTRACT: Aberrant diastolic calcium (Ca) release due to leaky ryanodine receptors (RyR2s) has been recently associated with atrial fibrillation (AF) and catecholaminergic polymorphic ventricular tachycardia (CPVT). However, it remains unclear how diastolic Ca release contributes to the rising of rapid repetitive focal activity, which is considered as a common AF triggering mechanism. To address this question, we conducted simultaneous voltage/Ca optical mapping in atrial tissue and one-/two-dimensional confocal imaging in atrial tissue and myocytes from wild-type (WT, n = 15) and CPVT mice lacking calsequestrin 2 (Casq2(-/-), n = 45), which promotes diastolic Ca release. During ß-adrenergic stimulation (100 nM isoproterenol), only Casq2(-/-) atrial myocytes showed pacing-induced self-sustained repetitive activity (31 ± 21 s vs. none in WT). Importantly, in atrial tissue, this repetitive activity could translate to Ca-dependent focal arrhythmia. Ectopic action potential (AP) firing during repetitive activity occurred only when diastolic Ca release achieved a sufficient level of synchronization. The AP, in turn, synchronized subsequent diastolic Ca release by temporally aligning multiple sources of Ca waves both within individual myocytes and throughout the atrial tissue. This alternating interplay between AP and diastolic Ca release perpetuates the self-sustaining repetitive activity. In fact, pharmacological disruption of synchronized diastolic Ca release (by ryanodine) prevented aberrant APs; and vice versa, the inhibition of AP (by TTX or 0 Na, 0 Ca solution) de-synchronized diastolic Ca release. Taken together, these results suggest that a cyclical interaction between synchronized diastolic Ca release and AP forms a pathological rhythm generator that is involved in Ca-dependent atrial arrhythmias in CPVT.

Upregulation of adenosine A1 receptors facilitates sinoatrial node dysfunction in chronic canine heart failure by exacerbating nodal conduction abnormalities revealed by novel dual-sided intramural optical mapping.

BACKGROUND: Although sinoatrial node (SAN) dysfunction is a hallmark of human heart failure (HF), the underlying mechanisms remain poorly understood. We aimed to examine the role of adenosine in SAN dysfunction and tachy-brady arrhythmias in chronic HF. METHODS AND RESULTS: We applied multiple approaches to characterize SAN structure, SAN function, and adenosine A1 receptor expression in control (n=17) and 4-month tachypacing-induced chronic HF (n=18) dogs. Novel intramural optical mapping of coronary-perfused right atrial preparations revealed that adenosine (10 µmol/L) markedly prolonged postpacing SAN conduction time in HF by 206 ± 99 milliseconds (versus 66 ± 21 milliseconds in controls; P=0.02). Adenosine induced SAN intranodal conduction block or microreentry in 6 of 8 dogs with HF versus 0 of 7 controls (P=0.007). Adenosine-induced SAN conduction abnormalities and automaticity depression caused postpacing atrial pauses in HF versus control dogs (17.1 ± 28.9 versus 1.5 ± 1.3 seconds; P<0.001). Furthermore, 10 µmol/L adenosine shortened atrial repolarization and led to pacing-induced atrial fibrillation in 6 of 7 HF versus 0 of 7 control dogs (P=0.002). Adenosine-induced SAN dysfunction and atrial fibrillation were abolished or prevented by adenosine A1 receptor antagonists (50 µmol/L theophylline/1 µmol/L 8-cyclopentyl-1,3-dipropylxanthine). Adenosine A1 receptor protein expression was significantly upregulated during HF in the SAN (by 47 ± 19%) and surrounding atrial myocardium (by 90 ± 40%). Interstitial fibrosis was significantly increased within the SAN in HF versus control dogs (38 ± 4% versus 23 ± 4%; P<0.001). CONCLUSIONS: In chronic HF, adenosine A1 receptor upregulation in SAN pacemaker and atrial cardiomyocytes may increase cardiac sensitivity to adenosine. This effect may exacerbate conduction abnormalities in the structurally impaired SAN, leading to SAN dysfunction, and potentiate atrial repolarization shortening, thereby facilitating atrial fibrillation. Atrial fibrillation may further depress SAN function and lead to tachy-brady arrhythmias in HF.

Comprehensive analysis of patient and caregiver predictors for caregiver burden, anxiety and depression in Alzheimer's disease.

AIMS AND OBJECTIVES: The primary aim of this study was to examine the correlations between patient and caregiver characteristics with caregiver burden, anxiety and depression in Alzheimer's Disease. Secondary aim was to determine which behavioural and psychological symptoms had the greatest impact on caregiver burden, anxiety and depression in Alzheimer's Disease. BACKGROUND: Caregivers of individuals with Alzheimer's Disease experience high levels of burden, both psychologically and physically. Previous studies have examined caregiver burden, anxiety and depression separately. However, no paper has examined these three psychological conditions simultaneously. DESIGN: A cross-sectional design. METHODS: A total of 310 patients with probable Alzheimer's Disease and their primary caregivers were assessed. Cognitive impairment and neuropsychiatric symptoms were assessed with the Mini Mental State Examination, Montreal Cognitive Assessment, Clock Drawing Test and Neuropsychiatric Inventory, respectively. Caregiver burden, anxiety and depression were assessed with the ZBI, Generalised Anxiety Disorder Scale-7 and Patient Health Questionnaire-9, respectively. RESULTS: All 12 neuropsychiatric symptoms in the Neuropsychiatric Inventory were significantly correlated with caregiver burden, anxiety and depression, with the top three neuropsychiatric predictors being depression, apathy and anxiety. Furthermore, higher levels of caregiver anxiety were associated with a longer duration of being a caregiver. Within caregivers, higher levels of depression were independently associated with higher numbers of additional caregivers, lower educational background and being the spouse of the patient. Higher levels of burden were associated with a longer duration of being a caregiver and being the spouse of the patient. Caregiver burden, anxiety or depression were not significantly correlated with hours/day of caring for the patient. CONCLUSIONS: Caregiver burden, anxiety and depression were significantly correlated with different neuropsychiatric symptoms in the Neuropsychiatric Inventory. RELEVANCE TO CLINICAL PRACTICE: Practitioners are able to identify caregivers at risk for burden, anxiety and depression. Understanding which Neuropsychiatric Inventory symptom is more closely associated with distress in caregivers will help practitioners to be more specific and effective in detecting caregiver distress.

Genetic ablation of ryanodine receptor 2 phosphorylation at Ser-2808 aggravates Ca(2+)-dependent cardiomyopathy by exacerbating diastolic Ca2+ release.

Phosphorylation of the cardiac ryanodine receptor (RyR2) by protein kinase A (PKA) at Ser-2808 is suggested to mediate the physiological 'fight or flight' response and contribute to heart failure by rendering the sarcoplasmic reticulum (SR) leaky for Ca(2+). In the present study, we examined the potential role of RyR2 phosphorylation at Ser-2808 in the progression of Ca(2+)-dependent cardiomyopathy (CCM) by using mice genetically modified to feature elevated SR Ca(2+) leak while expressing RyR2s that cannot be phosphorylated at this site (S2808A). Surprisingly, rather than alleviating the disease phenotype, constitutive dephosphorylation of Ser-2808 aggravated CCM as manifested by shortened survival, deteriorated in vivo cardiac function, exacerbated SR Ca(2+) leak and mitochondrial injury. Notably, the deteriorations of cardiac function, myocyte Ca(2+) handling, and mitochondria integrity were consistently worse in mice with heterozygous ablation of Ser-2808 than in mice with complete ablation. Wild-type (WT) and CCM myocytes expressing unmutated RyR2s exhibited a high level of baseline phosphorylation at Ser-2808. Exposure of these CCM cells to protein phosphatase 1 caused a transitory increase in Ca(2+) leak attributable to partial dephosphorylation of RyR2 tetramers at Ser-2808 from more fully phosphorylated state. Thus, exacerbated Ca(2+) leak through partially dephosphorylated RyR2s accounts for the prevalence of the disease phenotype in the heterozygous S2808A CCM mice. These results do not support the importance of RyR2 hyperphosphorylation in Ca(2+)-dependent heart disease, and rather suggest roles for the opposite process, the RyR2 dephosphorylation at this residue in physiological and pathophysiological Ca(2+) signalling.

Prediction of 19F NMR chemical shifts for organic compounds with ORCA.

Accurate assignment of 19F NMR has long been a challenge, and quantum chemical methods are possible solutions. Herein we reported a scaling method for the prediction of 19F NMR chemical shift with freely available ORCA program package. Performance of 31 DFT functionals coupled with 11 basis sets were evaluated and influence of geometry optimization was also studied with five functionals coupled with three basis sets. The significance of geometry was further examined through the execution of relaxed surface scans of seven flexible compounds, and averaged shieldings of obtained conformers yielded notable improvement of the correlation between calculated isotropic shielidings and experimental chemical shifts. Utilization of the best scaling factor obtained successfully assigned of fluorine atoms in multifluorinated molecules with different conformations. The method reported here was computationally inexpensive, easily available with acceptable accuracy.

Photooxidation triggered ultralong afterglow in carbon nanodots.

It remains a challenge to obtain biocompatible afterglow materials with long emission wavelengths, durable lifetimes, and good water solubility. Herein we develop a photooxidation strategy to construct near-infrared afterglow carbon nanodots with an extra-long lifetime of up to 5.9 h, comparable to that of the well-known rare-earth or organic long-persistent luminescent materials. Intriguingly, size-dependent afterglow lifetime evolution from 3.4 to 5.9 h has been observed from the carbon nanodots systems in aqueous solution. With structural/ultrafast dynamics analysis and density functional theory simulations, we reveal that the persistent luminescence in carbon nanodots is activated by a photooxidation-induced dioxetane intermediate, which can slowly release and convert energy into luminous emission via the steric hindrance effect of nanoparticles. With the persistent near-infrared luminescence, tissue penetration depth of 20 mm can be achieved. Thanks to the high signal-to-background ratio, biological safety and cancer-specific targeting ability of carbon nanodots, ultralong-afterglow guided surgery has been successfully performed on mice model to remove tumor tissues accurately, demonstrating potential clinical applications. These results may facilitate the development of long-lasting luminescent materials for precision tumor resection.

Conduction remodeling in human end-stage nonischemic left ventricular cardiomyopathy.

BACKGROUND: Several arrhythmogenic mechanisms have been inferred from animal heart failure models. However, the translation of these hypotheses is difficult because of the lack of functional human data. We aimed to investigate the electrophysiological substrate for arrhythmia in human end-stage nonischemic cardiomyopathy. METHODS AND RESULTS: We optically mapped the coronary-perfused left ventricular wedge preparations from human hearts with end-stage nonischemic cardiomyopathy (heart failure, n=10) and nonfailing hearts (NF, n=10). Molecular remodeling was studied with immunostaining, Western blotting, and histological analyses. Heart failure produced heterogeneous prolongation of action potential duration resulting in the decrease of transmural action potential duration dispersion (64 ± 12 ms versus 129 ± 15 ms in NF, P<0.005). In the failing hearts, transmural activation was significantly slowed from the endocardium (39 ± 3 cm/s versus 49 ± 2 cm/s in NF, P=0.008) to the epicardium (28 ± 3 cm/s versus 40 ± 2 cm/s in NF, P=0.008). Conduction slowing was likely due to connexin 43 (Cx43) downregulation, decreased colocalization of Cx43 with N-cadherin (40 ± 2% versus 52 ± 5% in NF, P=0.02), and an altered distribution of phosphorylated Cx43 isoforms by the upregulation of the dephosphorylated Cx43 in both the subendocardium and subepicardium layers. Failing hearts further demonstrated spatially discordant conduction velocity alternans which resulted in nonuniform propagation discontinuities and wave breaks conditioned by strands of increased interstitial fibrosis (fibrous tissue content in heart failure 16.4 ± 7.7 versus 9.9 ± 1.4% in NF, P=0.02). CONCLUSIONS: Conduction disorder resulting from the anisotropic downregulation of Cx43 expression, the reduction of Cx43 phosphorylation, and increased fibrosis is likely to be a critical component of arrhythmogenic substrate in patients with nonischemic cardiomyopathy.