Spexin Diminishes Atrial Fibrillation Vulnerability by Acting on Galanin Receptor 2.

BACKGROUND: G protein-coupled receptors play a critical role in atrial fibrillation (AF). Spexin is a novel ligand of galanin receptors (GALRs). In this study, we investigated the regulation of spexin and GALRs on AF and the underlying mechanisms. METHODS: Global spexin knockout (SPX-KO) and cardiomyocyte-specific GALRs knockout (GALR-cKO) mice underwent burst pacing electrical stimulation. Optical mapping was used to determine atrial conduction velocity and action potential duration. Atrial myocyte action potential duration and inward rectifying K+ current (IK1) were recorded using whole-cell patch clamps. Isolated cardiomyocytes were stained with Fluo-3/AM dye, and intracellular Ca2+ handling was examined by CCD camera. A mouse model of AF was established by Ang-II (angiotensin II) infusion. RESULTS: Spexin plasma levels in patients with AF were lower than those in subjects without AF, and knockout of spexin increased AF susceptibility in mice. In the atrium of SPX-KO mice, potassium inwardly rectifying channel subfamily J member 2 (KCNJ2) and sarcolipin (SLN) were upregulated; meanwhile, IK1 current was increased and Ca2+ handling was impaired in isolated atrial myocytes of SPX-KO mice. GALR2-cKO mice, but not GALR1-cKO and GALR3-cKO mice, had a higher incidence of AF, which was associated with higher IK1 current and intracellular Ca2+ overload. The phosphorylation level of CREB (cyclic AMP responsive element binding protein 1) was upregulated in atrial tissues of SPX-KO and GALR2-cKO mice. Chromatin immunoprecipitation confirmed the recruitment of p-CREB to the proximal promoter regions of KCNJ2 and SLN. Finally, spexin treatment suppressed CREB signaling, decreased IK1 current and decreased intracellular Ca2+ overload, which thus reduced the inducibility of AF in Ang-II-infused mice. CONCLUSIONS: Spexin reduces atrial fibrillation susceptibility by inhibiting CREB phosphorylation and thus downregulating KCNJ2 and SLN transcription by GALR2 receptor. The spexin/GALR2/CREB signaling pathway represents a novel therapeutic avenue in the development of agents against atrial fibrillation.

Creation of Room-Temperature Sub-100 nm Antiferromagnetic Skyrmions in an Antiferromagnet IrMn through Interfacial Exchange Coupling.

Antiferromagnetic (AFM) skyrmions are magnetic vortices composed of antiparallell-aligned neighboring spins. In stark contrast to conventional skyrmions based on ferromagnetic order, AFM skyrmions have vanished stray fields, higher response frequencies, and rectified translational motion driven by an external force. Therefore, AFM skyrmions promise highly efficient spintronics devices with high bit mobility and density. Nevertheless, the experimental realization of intrinsic AFM skyrmions remains elusive. Here, we show that AFM skyrmions can be nucleated via interfacial exchange coupling at the surface of a room-temperature AFM material, IrMn, exploiting the particular response from uncompensated moments to the thermal annealing and imprinting effects. Further systematic magnetic characterizations validate the existence of such an AFM order at the IrMn/CoFeB interfaces. Such AFM skyrmions have a typical size of 100 nm, which presents pronounced robustness against field and temperature. Our work opens new pathways for magnetic topological devices based on AFM skyrmions.

Silanol-Stabilized Atomically Dispersed Ptδ+-Ox-Sn Active Sites in Protozeolite for Propane Dehydrogenation.

Crystalline zeolites have been proven to be excellent supports for confining subnanometric metal catalysts to boost the propane dehydrogenation (PDH) reaction. However, the introduced metallic species may suffer from severe sintering and limited stability during the catalytic process, especially when utilizing an industrial impregnation method for metal incorporation. In this study, we developed a new type of support based on amorphous protozeolite (PZ), taking advantage of its adjustable silanol chemistry and zeolitic microporous characteristic for stabilizing atomically dispersed PtSn catalyst via a simple, cost-effective coimpregnation process. The combination of X-ray absorption spectroscopy, X-ray photoelectron spectroscopy, in situ diffuse reflectance infrared Fourier transform spectroscopy under CO atmosphere, and density functional theory calculations confirmed the formation of highly dispersed active Ptδ+-Ox-Sn species in PtSn/PZ. The PtSn/PZ catalyst exhibited a high propane conversion of 45.4% and a high propylene selectivity of 99% (WHSV= 3.6 h-1, 550 °C), with a high apparent rate coefficient of 565 molC3H6·gPt-1·h-1·bar-1 at a high WHSV of 108 h-1, presenting a top-level performance among the state-of-the-art Pt-based catalysts prepared by in situ synthesis and impregnation methods. The silanol density determined the chemical state of PtSn species, showing a change from atomically dispersed Ptδ+-Ox-Sn sites to PtSn alloy with decreasing silanol density of supports. This work provides a general strategy using silanol-rich amorphous protozeolite as support for stabilizing various metal catalysts by the simple impregnation method and also offers an effective way for fine tailoring the chemical state of metallic species via a silanol-engineered approach.

Quantum random number generation based on phase reconstruction.

Quantum random number generator (QRNG) utilizes the intrinsic randomness of quantum systems to generate completely unpredictable and genuine random numbers, finding wide applications across many fields. QRNGs relying on the phase noise of a laser have attracted considerable attention due to their straightforward system architecture and high random number generation rates. However, traditional phase noise QRNGs suffer from a 50% loss of quantum entropy during the randomness extraction process. In this paper, we propose a phase-reconstruction quantum random number generation scheme, in which the phase noise of a laser is reconstructed by simultaneously measuring the orthogonal quadratures of the light field using balanced detectors. This enables direct discretization of uniform phase noise, and the min-entropy can achieve a value of 1. Furthermore, our approach exhibits inherent robustness against the classical phase fluctuations of the unbalanced interferometer, eliminating the need for active compensation. Finally, we conducted experimental validation using commercial optical hybrid and balanced detectors, achieving a random number generation rate of 1.96 Gbps at a sampling rate of 200 MSa/s.

Outcomes of covered vs bare metal stents for the treatment of aortoiliac occlusive disease.

OBJECTIVE: We retrospectively compared the clinical outcomes of self-expanding covered stents (CSs) and bare metal stents (BMSs) in the treatment of aortoiliac occlusive disease (AIOD) at a single center between 2016 and 2022. METHODS: All patients with AIOD receiving endovascular therapy at a single center from January 2016 to October 2022 were continuously analyzed, including patients with lesions of all classes according to the Trans-Atlantic Inter-Society Consensus II (TASC-II). Relevant clinical and baseline data were collected, and propensity score matching was performed to compare CSs and BMSs in terms of baseline characteristics, surgical factors, 30-day outcomes, 5-year primary patency, and limb salvage. The follow-up results were analyzed by Kaplan-Meier curves. Cox proportional hazard models were used to identify predictors of primary patency. RESULTS: A total of 209 patients with AIOD were enrolled in the study, including 135 patients (64.6%) in the CS group and 74 patients (35.4%) in the BMS group. Surgical success rates (100% vs 100%; P = 1.00), early (<30-day) mortality rates (0% vs 0%; P = 1.00), cumulative surgical complication rate (12.0% vs 8.0%; P = .891), 5-year primary patency rate (83.4% vs 86.9%; P = .330), secondary patency rate (96% vs 100%; P = .570), and limb salvage rate (100% vs 100%; P = 1.00) did not exhibit significant differences between the two groups. Patients in the CS group had a lower preoperative ankle-brachial index (0.48 ± 0.26 vs 0.52 ± 0.19; P = .032), more cases of complex AIOD (especially TASC D) (47.4% vs 9.5%; P < .001), more chronic total occlusive lesions (77.0% vs 31.1%; P < .001), and more severe calcification (20.7% vs 14.9%; P < .036). After propensity score matching, 50 patients (25 with CS and 25 with BMS) were selected. The results showed that only severe calcification (32.0% vs 8.0%; P = .034) and ankle-brachial index increase (0.45 ± 0.15 vs 0.41 ± 0.22; P = .038) were significantly different between the groups. In terms of surgical factors, patients in the CS group had more use of bilateral femoral or combined brachial artery percutaneous access (60.0% vs 12.0%; P < .001), more number of stents used (2.3 ± 1.2 vs 1.3 ± 0.7; P < .001), longer mean stent length (9.3 ± 3.3 vs 5.8 ± 2.6 cm; P < .001), and more catheter-directed thrombolysis treatment (32.0% vs 4.0%; P = .009). Multivariate Cox survival analysis showed that severe calcification (hazard ratio, 1.32; 95% confidence interval, 1.04-1.85; P = .048) was the only independent predictor of the primary patency rate. CONCLUSIONS: All patients with AIOD who underwent endovascular therapy were included and achieved good outcomes with both CSs and BMSs. The influence of confounding factors in the two groups was minimized by propensity score matching, and the 5-year patency rates were generally similar in the unmatched and matched cohorts. Postoperative hemodynamic improvement was more obvious in patients in the CS group. For more complex lesions, CS is recommended to be preferred. Especially for severe calcification lesions, which is the only independent predictor of primary patency, CS showed obvious advantages. Further studies with more samples are needed to investigate the role of stent types in AIOD treatment.

Hypothesis tests in ordinal predictive models with optimal accuracy.

In real-world applications involving multi-class ordinal discrimination, a common approach is to aggregate multiple predictive variables into a linear combination, aiming to develop a classifier with high prediction accuracy. Assessment of such multi-class classifiers often utilizes the hypervolume under ROC manifolds (HUM). When dealing with a substantial pool of potential predictors and achieving optimal HUM, it becomes imperative to conduct appropriate statistical inference. However, prevalent methodologies in existing literature are computationally expensive. We propose to use the jackknife empirical likelihood method to address this issue. The Wilks' theorem under moderate conditions is established and the power analysis under the Pitman alternative is provided. We also introduce a novel network-based rapid computation algorithm specifically designed for computing a general multi-sample $U$-statistic in our test procedure. To compare our approach against existing approaches, we conduct extensive simulations. Results demonstrate the superior performance of our method in terms of test size, power, and implementation time. Furthermore, we apply our method to analyze a real medical dataset and obtain some new findings.

Renewable risk assessment of heterogeneous streaming time-to-event cohorts.

The analysis of streaming time-to-event cohorts has garnered significant research attention. Most existing methods require observed cohorts from a study sequence to be independent and identically sampled from a common model. This assumption may be easily violated in practice. Our methodology operates within the framework of online data updating, where risk estimates for each cohort of interest are continuously refreshed using the latest observations and historical summary statistics. At each streaming stage, we introduce parameters to quantify the potential discrepancy between batch-specific effects from adjacent cohorts. We then employ penalized estimation techniques to identify nonzero discrepancy parameters, allowing us to adaptively adjust risk estimates based on current data and historical trends. We illustrate our proposed method through extensive empirical simulations and a lung cancer data analysis.

Development and External Validation of Machine Learning Models for Diabetic Microvascular Complications: Cross-Sectional Study With Metabolites.

BACKGROUND: Diabetic kidney disease (DKD) and diabetic retinopathy (DR) are major diabetic microvascular complications, contributing significantly to morbidity, disability, and mortality worldwide. The kidney and the eye, having similar microvascular structures and physiological and pathogenic features, may experience similar metabolic changes in diabetes. OBJECTIVE: This study aimed to use machine learning (ML) methods integrated with metabolic data to identify biomarkers associated with DKD and DR in a multiethnic Asian population with diabetes, as well as to improve the performance of DKD and DR detection models beyond traditional risk factors. METHODS: We used ML algorithms (logistic regression [LR] with Least Absolute Shrinkage and Selection Operator and gradient-boosting decision tree) to analyze 2772 adults with diabetes from the Singapore Epidemiology of Eye Diseases study, a population-based cross-sectional study conducted in Singapore (2004-2011). From 220 circulating metabolites and 19 risk factors, we selected the most important variables associated with DKD (defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2) and DR (defined as an Early Treatment Diabetic Retinopathy Study severity level ≥20). DKD and DR detection models were developed based on the variable selection results and externally validated on a sample of 5843 participants with diabetes from the UK biobank (2007-2010). Machine-learned model performance (area under the receiver operating characteristic curve [AUC] with 95% CI, sensitivity, and specificity) was compared to that of traditional LR adjusted for age, sex, diabetes duration, hemoglobin A1c, systolic blood pressure, and BMI. RESULTS: Singapore Epidemiology of Eye Diseases participants had a median age of 61.7 (IQR 53.5-69.4) years, with 49.1% (1361/2772) being women, 20.2% (555/2753) having DKD, and 25.4% (685/2693) having DR. UK biobank participants had a median age of 61.0 (IQR 55.0-65.0) years, with 35.8% (2090/5843) being women, 6.7% (374/5570) having DKD, and 6.1% (355/5843) having DR. The ML algorithms identified diabetes duration, insulin usage, age, and tyrosine as the most important factors of both DKD and DR. DKD was additionally associated with cardiovascular disease history, antihypertensive medication use, and 3 metabolites (lactate, citrate, and cholesterol esters to total lipids ratio in intermediate-density lipoprotein), while DR was additionally associated with hemoglobin A1c, blood glucose, pulse pressure, and alanine. Machine-learned models for DKD and DR detection outperformed traditional LR models in both internal (AUC 0.838 vs 0.743 for DKD and 0.790 vs 0.764 for DR) and external validation (AUC 0.791 vs 0.691 for DKD and 0.778 vs 0.760 for DR). CONCLUSIONS: This study highlighted diabetes duration, insulin usage, age, and circulating tyrosine as important factors in detecting DKD and DR. The integration of ML with biomedical big data enables biomarker discovery and improves disease detection beyond traditional risk factors.

Deterministic Magnetization Switching via Tunable Noncollinear Spin Configurations in Canted Magnets.

Spin obit torque (SOT) driven magnetization switching has been used widely for encoding consumption-efficient memory and logic. However, symmetry breaking under a magnetic field is required to realize the deterministic switching in synthetic antiferromagnets with perpendicular magnetic anisotropy (PMA), which limits their potential applications. Herein, we report all electric-controlled magnetization switching in the antiferromagnetic Co/Ir/Co trilayers with vertical magnetic imbalance. Besides, the switching polarity could be reversed by optimizing the Ir thickness. By using the polarized neutron reflection (PNR) measurements, the canted noncollinear spin configuration was observed in Co/Ir/Co trilayers, which results from the competition of magnetic inhomogeneity. In addition, the asymmetric domain walls demonstrated by micromagnetic simulations result from introducing imbalance magnetism, leading to the deterministic magnetization switching in Co/Ir/Co trilayers. Our findings highlight a promising route to electric-controlled magnetism via tunable spin configuration, improve our understanding of physical mechanisms, and significantly promote industrial applications in spintronic devices.

Impact of residual stenosis on clinical outcomes when performing carotid artery stenting without postdilation.

OBJECTIVE: Many centers consider postdilation if the final angiography after carotid artery stenting (CAS) shows residual stenosis of >30% to 40%. Postdilation has been demonstrated to potentially increase the risk of developing neurologic events. This study aimed to investigate the safety of CAS without postdilation regardless of the degree of residual stenosis. METHODS: We retrospectively investigated 191 patients who underwent transfemoral CAS without postdilation intendedly. All cases underwent mild predilation and self-expanding stent implantation. We divided the patients into a residual stenosis of ≥40% group (n = 69 [36.1%]) and a residual stenosis of <40% group (n = 122 [63.9%]) according to their final angiography. We compared the procedural (within 30 days after CAS) and nonprocedural (afterward) adverse cardiovascular events and in-stent restenosis between the two groups. We also investigated the incidence of perioperative hemodynamic depression between the groups and the changes in residual stenosis over the follow-up time. RESULTS: Patients in the residual stenosis of ≥40% group had a higher preoperative stenosis rate and a greater proportion of severely calcified lesions than those in the <40% group. There was one procedural cardiac death (0.5%), five strokes (2.6%), and four myocardial infarctions (2.1%). A total of 2.9% had stroke or death procedurally in the residual stenosis of ≥40% group and 3.2% in the residual stenosis of <40% group (P > .950). The median nonprocedural follow-up time was 22 months, with a total of six deaths and four strokes. The cumulative 2-year death or stroke rate was 6.2%, with 5.9% in the residual stenosis of ≥40% group versus 6.7% in the residual stenosis of <40% group (P = .507). There were two cases of in-stent restenosis in the residual stenosis of ≥40% group and three in the residual stenosis of <40% group (P = .927). The difference in the peak systolic velocity of the target lesion between groups at 3 months after CAS was no longer present, and residual stenosis stabilized at 10% to 20% at 6 months in both groups. The patients showed an association between increasing hemodynamic depression incidence and residual stenosis in a significantly graded response (P = .021). CONCLUSIONS: Residual stenosis after carotid stenting without postdilation is not associated with a risk of postoperative adverse events. This study provides evidence for the feasibility of a no postdilation strategy for CAS.