Association of life's essential 8 score with risk of all-cause and cardiovascular disease-related mortality in individuals with hypertension.

BACKGROUND: The American Heart Association (AHA) recently defined a new concept of cardiovascular health-Life's Essential 8 (LE8). We sought to examine whether LE8 score is associated with a risk of all-cause and cardiovascular disease (CVD)-related mortality in individuals with hypertension. METHODS: This longitudinal study analyzed data from the National Health and Nutrition Examination Survey from 2007 to 2018 in people 20 years or older with hypertension. LE8 score (range 0-100) was measured according to the AHA definition and divided into unweighted tertiles into groups T1 (< 50.00), T2 (50.00-61.25), and T3 (≥ 61.25). Primary outcomes included all-cause mortality and CVD-specific mortality. RESULTS: A total of 15,318 individuals with hypertension were included in this study, with a mean ± standard error age of 55.06 ± 0.25 years. During the median follow-up period of 76 months, 2525 all-cause mortality occurred, of which 806 were due to CVD. Compared with participants with hypertension in the T1 group, those in T2 and T3 respectively had 28% (adjusted HR = 0.72, 95% CI 0.63-0.83, P < 0.001) and 39% (adjusted HR = 0.61, 95% CI 0.52-0.72, P < 0.001) lower risk of all-cause mortality, the T2 and T3 groups were associated with 32% (adjusted HR = 0.68, 95% CI 0.53-0.88, P = 0.003) and 36% (adjusted HR = 0.64, 95% CI 0.49-0.84, P = 0.001) reduced risk of CVD mortality separately. CONCLUSIONS: A higher LE8 score is associated with a lower risk of all-cause mortality and CVD mortality, and the higher LE8 score can be maintained in the clinic to improve prognosis by modifying the diet and lifestyle habits of individuals with hypertension.

Synaptotagmin-1 undergoes phase separation to regulate its calcium-sensitive oligomerization.

Synaptotagmin-1 (Syt1) is a calcium sensor that regulates synaptic vesicle fusion in synchronous neurotransmitter release. Syt1 interacts with negatively charged lipids and the SNARE complex to control the fusion event. However, it remains incompletely understood how Syt1 mediates Ca2+-trigged synaptic vesicle fusion. Here, we discovered that Syt1 undergoes liquid-liquid phase separation (LLPS) to form condensates both in vitro and in living cells. Syt1 condensates play a role in vesicle attachment to the PM and efficiently recruit SNAREs and complexin, which may facilitate the downstream synaptic vesicle fusion. We observed that Syt1 condensates undergo a liquid-to-gel-like phase transition, reflecting the formation of Syt1 oligomers. The phase transition can be blocked or reversed by Ca2+, confirming the essential role of Ca2+ in Syt1 oligomer disassembly. Finally, we showed that the Syt1 mutations causing Syt1-associated neurodevelopmental disorder impair the Ca2+-driven phase transition. These findings reveal that Syt1 undergoes LLPS and a Ca2+-sensitive phase transition, providing new insights into Syt1-mediated vesicle fusion.

Optical coherence tomography analysis of lesion characteristics and thrombus types in non ST-segment elevation myocardial infarction patients.

The precise features of lesions in non-ST-segment elevation myocardial infarction (NSTEMI) patients with total occlusion (TO) of the infarct-related artery (IRA) are still unclear. This study employs optical coherence tomography (OCT) to investigate pathological features in NSTEMI patients with or without IRA TO and explores the relationship between thrombus types and IRA occlusive status. This was a single-center retrospective study. A total of 202 patients diagnosed with NSTEMI were divided into two groups: those with Thrombolysis In Myocardial Infarction (TIMI) flow grade 0 before percutaneous coronary intervention (PCI) (referred to as the TO group, n = 100) and those TIMI flow grade 1-3 (referred to as the Non-TO group, n = 102). Baseline characteristics, coronary angiography findings, and OCT results were collected. Multivariate logistic analysis identified factors influencing TO in NSTEMI. The category of NSTEMI was further subdivided based on the type of electrocardiogram (ECG) into two subgroups: ST segment unoffset myocardial infarction (STUMI) and ST segment depression myocardial infarction (STDMI). This division allows for a more specific classification of NSTEMI cases. The TO group had a younger age, higher male representation, more smokers, lower hypertension and cerebrovascular disease incidence, lower left ventricular ejection fraction (LVEF), and higher creatine kinase myocardial band (CKMB) and creatine kinase (CK) peak levels. In the TO group, LCX served as the main IRA (52.0%), whereas in the Non-TO group, LAD was the predominant IRA (45.1%). Compared to the Non-TO group, OCT findings demonstrated that red thrombus/mixed thrombus was more common in the TO group, along with a lower occurrence of white thrombus (p < 0.001). The TO group exhibited a higher prevalence of STUMI (p = 0.001), whereas STDMI was more commonly observed in the Non-TO group (p = 0.001). NSTEMI presents as STUMI and STDMI distinct entities. Red thrombus/mixed thrombus in IRA often indicates occlusive lesions with STUMI on ECG. White thrombus suggests non-occlusive lesions with STDMI on ECG.

Evaluation of an Optimized Workflow for the Radiofrequency Catheter Ablation of Paroxysmal Atrial Fibrillation.

BACKGROUND A significant number of atrial fibrillation (AF) recurrences occur after initial ablation, often due to pulmonary vein reconnections or triggers from non-pulmonary veins. MATERIAL AND METHODS Patients with paroxysmal AF who underwent radiofrequency catheter ablation for the first time were enrolled. Base on propensity score matching (1: 1 matching), 118 patients were selected for an optimized workflow for the radiofrequency catheter ablation of paroxysmal AF (OWCA) group and a conventional group. Comparative analysis of the acute and 12-month clinical outcomes was conducted. Moreover, an artificial intelligence analytics platform was used to evaluate the quality of pulmonary vein isolation (PVI) circles. RESULTS PVI was successfully achieved in all patients. Incidence of first-pass isolation of bilateral PVI circles was higher (P=0.009) and acute pulmonary vein reconnections was lower (P=0.027) in the OWCA group than conventional group. The OWCA group displayed a significant reduction in the number of fractured points (P<0.001), stacked points (P=0.003), and a greater proportion of cases in which the radiofrequency index achieved the target value (P=0.003). Additionally, the contact force consistently met the force over time criteria (P<0.001) for bilateral PVI circles in the OWCA group, accompanied by a shorter operation time (P=0.017). During the 12-month follow-up period, the OWCA group exhibited a higher atrial arrhythmia-free survival rate following the initial ablation procedure than did the conventional group. CONCLUSIONS The optimized workflow for radiofrequency catheter ablation of paroxysmal AF could play a crucial role in creating higher quality PVI circles. This improvement is reflected in a significantly elevated 12-month atrial arrhythmia-free survival rate.

Munc18c accelerates SNARE-dependent membrane fusion in the presence of regulatory proteins α-SNAP and NSF.

Intracellular vesicle fusion is driven by the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) and their cofactors, including Sec1/Munc18 (SM), α-SNAP, and NSF. α-SNAP and NSF play multiple layers of regulatory roles in the SNARE assembly, disassembling the cis-SNARE complex and the prefusion SNARE complex. How SM proteins coupled with NSF and α-SNAP regulate SNARE-dependent membrane fusion remains incompletely understood. Munc18c, an SM protein involved in the exocytosis of the glucose transporter GLUT4, binds and activates target (t-) SNAREs to accelerate the fusion reaction through a SNARE-like peptide (SLP). Here, using an in vitro reconstituted system, we discovered that α-SNAP blocks the GLUT4 SNAREs-mediated membrane fusion. Munc18c interacts with t-SNAREs to displace α-SNAP, which overcomes the fusion inhibition. Furthermore, Munc18c shields the trans-SNARE complex from NSF/α-SNAP-mediated disassembly and accelerates SNARE-dependent fusion kinetics in the presence of NSF and α-SNAP. The SLP in domain 3a is indispensable in Munc18c-assisted resistance to NSF and α-SNAP. Together, our findings demonstrate that Munc18c protects the prefusion SNARE complex from α-SNAP and NSF, promoting SNARE-dependent membrane fusion through its SLP.

IL-36 antagonism blunts the proliferation and migration of oral squamous cell carcinoma cells.

IL-36 is known to mediate inflammation and fibrosis. Nevertheless, IL-36 signalling axis has also been implicated in cancer, although understanding of exact contribution of IL-36 to cancer progression is very limited, partly due to existence of multiple IL-36 ligands with agonistic and antagonistic function. Here we explored the role of IL-36 in oral squamous cell carcinoma (OSCC). Firstly, we analyzed expression of IL-36 ligands and receptor and found that the expression of IL-36γ was significantly higher in head and neck cancer (HNSCC) than that of normal tissues, and that the high expression of IL-36γ predicted poor clinical outcomes. Secondly, we investigated the direct effect of IL-36γ on OSCC cells and found that IL-36γ stimulated proliferation of OSCC cells with high expression of IL-36R expression. Interestingly, IL-36γ also promoted migration of OSCC cells with low to high IL-36R expression. Critically, both proliferation and migration of OSCC cells induced by IL-36γ were abrogated by anti-IL-36R mAb. Fittingly, RNA sequence analysis revealed that IL-36γ regulated genes involved in cell cycle and cell division. In summary, our results showed that IL-36γ can be a tumor-promoting factor, and targeting of IL-36R signalling may be a beneficial targeted therapy for patients with abnormal IL-36 signalling.

Microvesicles facilitate the differentiation of mesenchymal stem cells into pancreatic beta-like cells via miR-181a-5p/150-5p.

Transplantation of pancreatic islet cells is a promising strategy for the long-term treatment of type 1 diabetes (T1D). The stem cell-derived beta cells showed great potential as substitute sources of transplanted pancreatic islet cells. However, the current efficiency of stem cell differentiation still cannot match the requirements for clinical transplantation. Here, we report that microvesicles (MVs) from insulin-producing INS-1 cells could induce mesenchymal stem cell (MSC) differentiation into pancreatic beta-like cells. The combination of MVs with small molecules, nicotinamide and insulin-transferrin-selenium (ITS), dramatically improved the efficiency of MSC differentiation. Notably, the function of MVs in MSC differentiation requires their entry into MSCs through giant pinocytosis. The MVs-treated or MVs combined with small molecules-treated MSCs show pancreatic beta-like cell morphology and response to glucose stimulation in insulin secretion. Using high throughput small RNA-sequencing, we found that MVs induced MSC differentiation into the beta-like cells through miR-181a-5p/150-5p. Together, our findings reveal the role of MVs or the MV-enriched miR-181a-5p/150-5p as a class of biocompatible reagents to differentiate MSCs into functional beta-like cells and demonstrate that the combined usage of MVs or miR-181a-5p/150-5p with small molecules can potentially be used in making pancreatic islet cells for future clinical purposes.

Relationship between thrombolysis in myocardial infarction blood flow before percutaneous coronary intervention and the morphological characteristics of culprit vessel plaques in patients with STEMI.

The present study aimed to investigate the relationship between morphological characteristics of culprit coronary plaques and thrombolysis in myocardial infarction (TIMI) blood flow grade in patients with ST-segment elevation myocardial infarction (STEMI). According to the TIMI blood flow of the culprit vessel before percutaneous coronary intervention (PCI), 222 patients with STEMI were divided into two groups: TIMI 0/1 group (n=164) and TIMI 2/3 group (n=58). The baseline characteristics, coronary angiographic findings and optical coherence tomography images were collected. Multivariate logistic regression analysis was used to identify factors independently associated with poor initial TIMI blood flow. Compared with TIMI 2/3 group, TIMI 0/1 group had a significantly smaller minimum lumen diameter, greater diameter stenosis and longer lesion length, a higher incidence of lipid plaque, larger lipid length, maximum lipid arc, lipid index and maximum cross-sectional area (CSA) of plaque rupture, as well as a higher prevalence of thin-cap fibroatheroma (TCFA) and healed plaque (P<0.05). Multivariate logistic analysis demonstrated that lipid plaque, lipid length, maximum lipid arc, lipid index, TCFA, maximum CSA of plaque rupture and healed plaque were significantly associated with poor initial TIMI blood flow (P<0.05). In conclusion, the present study revealed that the morphological characteristics of culprit coronary plaques (lipid plaque, lipid length, maximum lipid arc, lipid index, TCFA, maximum CSA of plaque rupture and healed plaque) are significantly associated with poor initial TIMI blood flow before PCI in patients with STEMI.

A novel stepwise catheter ablation method of the mitral isthmus for persistent atrial fibrillation: efficacy and reproducibility.

BACKGROUND: Ethanol infusion of the vein of Marshall (EI-VOM) has been widely used to facilitate mitral isthmus (MI) ablation. According to the literature, the success rate of achieving a bidirectional conduction block across the MI ranges from 51 to 96%, with no standardized strategy or method available for cardiac electrophysiologists. OBJECTIVES: This study aimed to introduce and evaluate a novel ablation method of MI. METHODS: Consecutive patients with persistent atrial fibrillation (PeAF) that underwent catheter ablation were included. The MI ablation procedure followed a stepwise approach. In step 1, ethanol infusion of the vein of Marshall (EI-VOM) was performed. In step 2, a "V-shape" endocardial linear ablation connecting the left inferior pulmonary vein (LIPV) to mitral annulus (MA) was performed. In step 3, earliest activation sites(EASs) near the ablation line were identified using activation mapping followed by reinforced ablation. In step 4, precise epicardial ablation was performed, with the catheter introduced into the coronary sinus(CS) to target key ablation targets (KATs). RESULTS: 135 patients with PeAF underwent catheter ablation with the stepwise ablation method adopted in 119 cases. Bidirectional conduction blocks were achieved in 117 patients (98.3%). The block rates of every step were 0%, 58.0%, 44.0%, and 92.9%, and the cumulative block rates for the four steps were 0%, 58.0%, 76.5%, and 98.3%, respectively. No patient experienced fatal complications. CONCLUSIONS: Our novel stepwise catheter ablation method for MI yielded a high bidirectional block rate with high reproducibility.

Deep Tumor Penetration of CRISPR-Cas System for Photothermal-Sensitized Immunotherapy via Probiotics.

Since central cells are more malignant and aggressive in solid tumors, improving penetration of therapeutic agents and activating immunity in tumor centers exhibit great potential in cancer therapies. Here, polydopamine-coated Escherichia coli Nissle 1917 (EcN) bearing CRISPR-Cas9 plasmid-loaded liposomes (Lipo-P) are applied for enhanced immunotherapy in deep tumors through activation of innate and adaptive immunity simultaneously. After accumulation in the tumor center through hypoxia targeting, Lipo-P could be detached under the reduction of reactive oxygen species (ROS)-responsive linkers, lowering the thermal resistance of cancer cells via Hsp90α depletion. Owing to that, heating induced by polydopamine upon near-infrared irradiation could achieve effective tumor ablation. Furthermore, mild photothermal therapy induces immunogenic cell death, as bacterial infections in tumor tissues trigger innate immunity. This bacteria-assisted approach provides a promising photothermal-sensitized immunotherapy in deep tumors.