Activation Site Research Articles

Anatomical versus Electrophysiological Approach for Ablation of Premature Ventricular Contractions Originating from the Left Ventricular Summit (ISESHIMA-SUMMIT Study).

Catheter ablation (CA) of idiopathic ventricular arrhythmias (VAs) from the epicardial left ventricular summit is challenging. The endocardial approach targets two sites: the endocardial closest site (ECS) to the epicardial earliest activation site (epi-EAS) and the endocardial EAS (endo-EAS). We aimed to differentiate between cases where CA at the ECS was effective and where CA at the endocardial EAS yielded success. Fifty-eight patients (47 men, 60±13 years) were analyzed with VAs in which the EAS was observed in the coronary venous system (CVS). Overall, VAs were successfully eliminated in 42 (72%) patients; 8 in the CVS, 8 where the ECS matched with the endo-EAS, 11 at the ECS, and 15 at the endo-EAS. Successful ECS ablation was associated with a shorter epi-EAS-ECS distance (10.2±4.7 vs. 18.8±5.3 mm; P<0.001) and shorter epi-EAS-left main coronary trunk (LMT) ostial distance (20.3±7.6 vs. 30.3±8.4 mm; P=0.005), with optimal cut-off values of ≤12.6 mm and ≤24.0 mm, respectively. Successful endo-EAS ablation was associated with an earlier electrogram at the endo-EAS (23 [18, 36] vs. 15 [0, 19] ms preceding the QRS; P<0.001) and shorter epi-EAS-endo-EAS interval (6 [1, 8] vs. 22 [12, 25] ms; P<0.001), with optimal cut-off values of ≥18 ms and ≤9 ms, respectively. Shorter anatomical distances between the epi-EAS and ECS, and between the epi-EAS and LMT ostium, predict a successful ECS ablation. The prematurity of the endo-EAS electrogram and a shorter interval between the epi-EAS and endo-EAS predicted a successful endo-EAS ablation.

Loading Lewis Acid/Base Pair on Metal Nanocluster for Catalytic Ugi Reaction

AbstractConstructing structurally robust and catalytically active metal nanoclusters for catalyzing multi‐component reactions is an interesting while challenging task. Inspired by Lewis acid and Lewis base catalysis, we realized the combination of both Lewis acid and Lewis base sites on the surface of a stable gold nanocluster Au35Cd2. The catalytic potential of Au35Cd2 in four‐component Ugi reaction was explored, demonstrating high activity and exceptional recyclability. In‐depth mechanism studies indicate that the catalytic synergy of the Lewis acid/base pair is crucial for the high efficiency of Au35Cd2‐catalyzed Ugi reaction. Bearing the stable structure, multiple activation sites and hierarchical chirality, Au35Cd2 is expected to display further interesting catalytic performance such as asymmetric catalysis.

Impact of conduction velocity in left atrium assessing with omnipolar technology in patients with atrial fibrillation

Abstract Background There is increased interest in exploring substrate of atrial fibrillation (AF) and recent studies have shown that atrial conduction velocity (CV) reflects the electrophysiological phenomena and plays key role in perpetuating AF. The novel omnipolar technology (OT) use three unipolar and two orthogonal bipolar signals allow us to analyze the voltage, activation direction, and CV independent of catheter position. Objective The purpose of the present study was to evaluate if the left atrium (LA) CV which assessed by OT predict the any atrial tachy-arrhythmia (AT) recurrence after initial AF ablation. Methods We enrolled 58 consecutive patients who underwent initial pulmonary vein isolation (PVI) for drug refractory AF. (mean age: 68.2±10.2 years old, 32 male(55.1%), 32 persistent AF(55.1%), CHADS2 score:1.6±0.6). After electrical PVI was achieved and remained in sinus rhythm, the LA was mapped with high density mapping catheter (Advisor HD Grid, Abott USA) utilizing with the novel OT combined with Ensite X system (Abott, USA). The conduction distance and conduction times were measured from the earliest activation site to the latest activation site in LA (Figure 1). Each conduction velocity in anterior, posterior, and septal area were also calculated as conduction distance divided by conduction time. The LA voltage was also measured. Results During a mean follow up period of 316±143 days, the recurrence of AT after initial PVI was observed in 9 (15.5%) patients. There were no significant differences in baseline demographics between AT recurrence and non-recurrence group (mean age:66±13.3 vs 68.5±10.5 years old P=0.66, CHADS2 score: 1.5±0.57 vs 1.68±0.62 P=0.59, proportion of persistent AF: 15.4% vs 15.5% P=0.82, LA volume: 102±35.9 vs 93.6±37.3ml P=0.63). The earliest activation site in LA were identified in 3 areas including anterior site of right pulmonary vein (51.7%), Bachmann bundle area (41.4%), and antero-septal area (6.89%) (Figure 2). In patients with AT recurrence, the CV in LA was significantly slower than those without AF recurrence(0.61±0.21 vs 0.81±0.16 m/s, P=0.036) whereas the whole LA voltage was not (1.52±0.75 vs 2.22±1.06 mv, P=0.28). The CV in each LA portion are similar between recurrence and non-recurrence AT group. (anterior:0.57±0.24 vs 0.81±0.23 m/s, P=0.18, posterior: 0.87±0.18 vs 1.2±0.49 m/s P=0.36, septal: 0.89±0.76 vs 1.15±0.39 m/s, P=0.41). Conclusion The earliest activation site in LA was varied in each case. The whole CV in LA is a predictor of AF recurrence after PVI whereas the CV of each LA portion and LA voltage was not.

Right ventricular outflow tract arrhythmias in patients with obstructive sleep apnea- electrophysiological insights

Abstract Background Obstructive sleep apnea (OSA) was associated with atrial fibrillation and heart failure. Furthermore, the arrhythmic sudden death during sleep in patients with OSA raises serious concerns. Non-ischemic ventricular arrhythmias arise frequently from the right ventricular outflow tract (RVOT). The involvement of obstructive sleep apnea in the genesis of arrhythmia (premature ventricular contraction or tachycardia) originating specifically in the RVOT is not yet coherently established. Purpose This study aims to demonstrate the possible relationship between untreated obstructive sleep apnea and the occurrence of RVOT arrhythmia and to follow the electrophysiological features and outcomes after radiofrequency catheter ablation (RFA) in patients carrying this double burden. Methods One-hundred-twelve (112) consecutive asymptomatic and symptomatic patients admitted with RVOT arrhythmia ((PVCs and VTs) underwent a sleep study (polysomnography). Apnea was set out as the cessation of breathing and hypopnea was defined as shallow, slow, and restricted breathing occurring in episodes of ten seconds or more. The patients had normal left and right ventricle ejection fractions and no structural cardiovascular disease or other known extracardiac arrhythmia predisposing conditions. No significantly elevated systolic pressure in the pulmonary artery was assessed at echocardiography. Every patient was investigated by electrophysiologic study (EPS) and RFA of the clinical ventricular arrhythmia was immediately performed. Practicing and former professional athletes were excluded. Results Seventy-eight (69 %) of the included patients had an apnea-hypopnea index &amp;gt; 10/h. The included patients had the following characteristics: mean age 52 ± 8 years, 62% males, 81% had a BMI &amp;gt;30kg/m². The cardiac electrophysiologic study did not induce sustained VTs. The distribution of the PVCs and non-sustained VTs evidenced a predilection for the superior, septal and anterior (68%) and also superior and anterolateral aspects of the RVOT (23%). Radiofrequency catheter ablation (RFA) guided by activation mapping, precocity (the site of earliest activation &amp;gt; 30 ms before the setting of the QRS complex) and pace-mapping were performed in all patients. Immediate success was obtained in 98 patients (88%). After a mean follow-up of 24± 6 months, 28 patients (28%) from the success arm had a recurrence of the PVCs or the non-sustained VTs, 22 patients (22%) with and 6 patients (6%) without sleep apnea. Conclusions RVOT arrhythmia genesis and relapse after successful RFA seem highly associated with sleep apnea. Furthermore, patients with sleep apnea are more prone to have recurrent arrhythmias after radiofrequency catheter ablation in the absence of appropriate control of OSA.

Accuracy of a non-invasive mapping system for the localisation of re-entrant VT site of origin and its relationship to myocardial scar on cross-sectional imaging

Abstract Introduction View in ventricular onset (VIVO) is a non-invasive mapping system used for localising the site of earliest activation in ventricular arrhythmia, utilising a mathematical algorithm, patient specific cardiac model (constructed using cross-sectional imaging data), 3D images of the patient’s torso (for localising surface electrodes), and a 12-lead electrocardiogram (ECG).(1, 2) Several publications have examined its role in the localisation of premature ventricular contractions (PVCs), and a 5 patient case series assessed its role in scar related re-entrant VT.(1-4) However, its validity in a larger cohort and of the relationship to the relevant myocardial scar has not been investigated. Objective Assess the accuracy of the VIVO mapping system in localising the VT-SoO for patients with scar related re-entrant VT and its relationship to the relevant myocardial scar on cross-sectional imaging. Methods 20 patients with structural heart disease (18 ischaemic cardiomyopathy (ICM), 1 dilated cardiomyopathy (DCM), 1 hypertrophic cardiomyopathy (HCM)) (Male n=18, 63±14 years) and recent cross-sectional cardiac imaging, were recruited over a 16-month period (table 1). All patients had a clinical indication for VT ablation and were on optimal medical therapy, 19 had an implantable cardiac defibrillator. Invasive electro-anatomical mapping (EAM) was performed with the Advisor HD Grid multipolar catheter and maps were generated using Omnipolar electrograms (EGMs). The VT-SoO was identified using an activation- or pace-map by an experienced operator and the location defined using the American heart association’s 17 segment model of the left ventricle during the procedure.(5) VIVO maps were reviewed by a second independent operator and a segment allocated, scar segments were obtained from cross-sectional imaging. A "complete match" was defined as exact segment concordance between allocated segments, "partial match" as adjacent segments, and "no match" if it does not satisfy either of those requirements. Results Mean left ventricular ejection fraction was 35.5 ± 10.6%. Mean procedure time was 242 ± 70 minutes, with a mean ablation time of 20 ± 11.1 minutes. A total of 32 re-entrant VTs were mapped. The VT exit site was identified in all cases (11 activation-map; 21 pace-map). A complete match between the EAM and VIVO map was seen in 75% of VTs and partial match in a further 15% (table 2). The VT-SoO was located withing the myocardial scar (or directly adjacent to is) in 83% of accurately mapped VTs. Procedural success (defined as freedom from device treated episodes) was seen in 90% of patients at mean follow up of 7.3 ± 4.7 months. Conclusion VIVO non-invasive mapping system was able to accurately map the VT-SoO in scar dependent VT, and identify the relevant myocardial scar as seen on cross sectional imaging. Further research assessing its ability to accurately identify relevant ablation targets is ongoing.

Participation of epicardial connection in transverse conduction across the crista terminalis in patients with upper and lower loop reentry atrial tachycardias

Abstract Background The crista terminalis (CT) sometimes serves as a partial or complete conduction barrier, which is rate- and site-dependent. The basis, location and extent of the transverse conduction across the CT have been controversial. The pseudo-focal activation pattern indicates passive activation from the anatomically opposite chamber or structure. We previously reported cases of transverse CT conduction exhibiting a pseudo-focal activation pattern, indicating the CT conduction utilizing an epicardial connection (EC) in patients with upper loop reentry (ULR) atrial tachycardia (AT). Purpose This study aimed to investigate the prevalence and characteristics of transverse CT conduction using a high-resolution electroanatomical mapping system during CT-dependent AT and to compare between the ULR and lower loop reentry (LLR) ATs. Methods A total of 119 consecutive patients with macroreentrant AT were studied. The diagnosis of ULR/LLR AT was made based on endocardial activation mapping and entrainment pacing obtained from various sites around the superior/inferior vena cava. Transverse CT conduction utilizing an EC was defined as follows; (1) a centrifugal activation pattern with the earliest activation (EA) site &amp;gt;5 mm away from the CT, (2) later activation observed between the EA and the CT, and (3) the EA site exhibiting a pseudo-focal activation pattern (multiple breakthroughs or a small r wave on unipolar electrogram). Results Eighteen (15.1%) of the 119 patients were diagnosed with CT-dependent AT (15 men; median age, 71.5 years; AT cycle length, 265 ms; left atrial diameter, 42.5 mm; left ventricular ejection fraction, 49%). The 18 patients were divided into 2 groups: 9 patients with ULR and 9 with LLR AT. There were no significant differences in clinical characteristics (sex, history of cardiac surgery and organic heat disease) between ULR and LLR groups. Transverse CT conduction utilizing EC was more frequently observed in the ULR group than in the LLR group [77.8% (7/9) vs 22.2% (2/9), P=0.05]. In all patients with transverse CT conduction utilizing EC, scars extended along the CT. AT cycle length was significantly longer in the ULR group than in the LLR group (295 vs 235 ms, p=0.001). All ATs were successfully eliminated by radiofrequency ablation at the breakthrough sites and/or along the CT in ULR patients or by cavotricuspid isthmus ablation in LLR patients. Conclusions Half (9/18) of the patients with CT-dependent AT exhibited transverse CT conduction with a pseudo-focal activation pattern, suggesting the existence of an EC between the sinus venosus and the right auricle. The high prevalence of the pseudo-focal pattern in patients with the ULR compared to those with the LLR may provide insights into mechanisms.Figure1Figure2

Prevalance of incessant form of atrial fibrillation by superior vena cava (svc) firing:simplified svc and sinus node mapping(sss map) to avoid sinus node injury

Abstract Background The superior vena cava (SVC) is known as a major source of atrial fibrillation(AF), non-pulmonary vein AF foci (NPVAF). In some cases, an incessant form of AF (iAF) by SVC firing prevents obtaining the sinus node location, and anatomical SVC isolation has a risk of sinus node injury (SNI). Objective This study was aimed to explore the frequency of iAF by SVC firing and the efficacy of the simplified mapping strategy to avoid SNI. Methods Consecutive AF ablation procedures in the 3 centers were retrospectively investigated including the NPVAF prevalence. Simplified SVC/SN mapping (SSS-map: Obtaining the top-end of the SVC potential and &amp;gt;4points with 5-10mm spacing in the upper lateral side of the right atria (RA) for roughly locating the earliest activation site in sinus rhythm) was performed before PV isolation in the last 138 patients. In case of the initial rhythm at the procedure was atrial fibrillation, cardioversion was performed for obtaining the SSS-map. In the cases in which the high-density mapping catheters were available, the high-density activation maps of the RA in sinus rhythm were obtained to investigate the dislocation of the earliest activation site of the SSS map from the SN location. When SVC isolation was required due to iAF, SVC isolation line was designed based on the location of the top-end of the SVC potential during AF and ablative linear lesions were created to keep the distance of 5-10 mm above the second earliest activation site. Results A total of 1160 procedures in 1089 patients (male: 736[63.4%], age: 69.9, paroxysmal AF: 544[49.9%], first session: 997[85.9%]) was investigated. Prevalence of NPVAF was revealed in 160 of the all procedures (13.7%) (the SVC: 64, the posterior wall of the left atria: 24, the coronary sinus: 19, and others: 53). 16 of 160 NPVAFs (10.0%) developed to iAF by SVC firing. The SSS-map was successfully obtained in all of the last 138 patients (Initial rhythm at the procedure: AF 43.7%, Mapping time: 1.3±0.6 min, number of obtained points: 8.4±1.3). In 21 patients in which the high-density RA map was obtained, the SN dislocation distance was 5.1±2.2mm between the SSS map and the high-density RA map. Five of 138 developed to iAF by SVC firing, and SVC isolation based on the SSS-map was successfully achieved without SNI in the cases. Conclusion This study indicated iAF driven by SVC firing after PV isolation occurred in certain number of patients. The SSS-map before PV isolation was practical and showed the potential to be the mapping strategy avoid the SN injury in such cases.

Novel strategies for enhancing energy metabolism and wastewater treatment in algae-bacteria symbiotic system through carbon dots-induced photogenerated electrons: The definitive role of accelerated electron transport

The nitrogen removal efficiency of the algae-bacteria symbiotic system (ABSS) remains challenging due to competition for light capture and insufficient electron donors in aquaculture wastewater. To overcome this bottleneck issue, we first identified and reported the introduction of photogenerated electrons into ABSS by coupling them with carbon dots (CDs). The energy metabolism (21.52 %-56.25 %) and pollutant degradation efficiency (89.36 %-96.42 %) of ABSS/CDs surpassed the biochemical limit observed in traditional ABSS. Notably, the addtion of CDs facilitated an opening of the plastoquinone-pool (PQ-pool) valve and accelerated electron transfer rates, enabling photogenerated electrons to selectively target light-harvesting complexs as activation sites, thereby mobilizing photosynthesis and respiratory system activity to enhance nicotinamide adenine dinucleotide reduced (NADH) and adenosine triphosphate (ATP) production while promoting tricarboxylic acid (TCA) and Calvin cycle processes. In simulated swine wastewater treatment, ABSS/CDs achieved higher removal rates for the chemical oxygen demand (COD), total nitrogen (TN) and ammonium-nitrogen (NH4+-N) (100 %, 99.23 % and 98.62 % respectively) compared to pure culture systems alone. Network-based analysis revealed that ABSS/CDs improved microbial community structure stability within the photobioreactor while demonstrating efficient coupling between fungi, nitrifying bacteria, and denitrifying bacteria for enhanced performance in nitrogen removal processes. The upregulation of nitrogen metabolism and PQ-pool genes maintains efficient electron transport rates and contributes to nitrogen removal. This study expands our understanding of the physiological aptitudes of ABSS and provides valuable insights into applying CDs photoelectrons for enhanced wastewater treatment.

Mapping RANKL- and OPG-expressing cells in bone tissue: the bone surface cells as activators of osteoclastogenesis and promoters of the denosumab rebound effect.

Denosumab is a monoclonal anti-RANKL antibody that inhibits bone resorption, increases bone mass, and reduces fracture risk. Denosumab discontinuation causes an extensive wave of rebound resorption, but the cellular mechanisms remain poorly characterized. We utilized in situ hybridization (ISH) as a direct approach to identify the cells that activate osteoclastogenesis through the RANKL/OPG pathway. ISH was performed across species, skeletal sites, and following recombinant OPG (OPG:Fc) and parathyroid hormone 1-34 (PTH) treatment of mice. OPG:Fc treatment in mice induced an increased expression of RANKL mRNA mainly in trabecular, but not endocortical bone surface cells. Additionally, a decreased expression of OPG mRNA was detected in bone surface cells and osteocytes of both compartments. A similar but more pronounced effect on RANKL and OPG expression was seen one hour after PTH treatment. These findings suggest that bone surface cells and osteocytes conjointly regulate the activation of osteoclastogenesis, and that OPG:Fc treatment induces a local accumulation of osteoclastogenic activation sites, ready to recruit and activate osteoclasts upon treatment discontinuation. Analysis of publicly available single-cell RNA sequencing (scRNAseq) data from murine bone marrow stromal cells revealed that Tnfsf11+ cells expressed high levels of Mmp13, Limch1, and Wif1, confirming their osteoprogenitor status. ISH confirmed co-expression of Mmp13 and Tnfsf11 in bone surface cells of both vehicle- and OPG:Fc-treated mice. Under physiological conditions of human/mouse bone, RANKL is expressed mainly by osteoprogenitors proximate to the osteoclasts, while OPG is expressed mainly by osteocytes and bone-forming osteoblasts.

The Evolution of NLR Inflammasome and Its Mediated Pyroptosis in Metazoa.

Nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) inflammasomes are multiprotein signaling platforms that control the inflammatory response and coordinate antimicrobial defense. In the present study, the distribution of NLR, Caspase-1, and gasdermin (GSDM) homologues and their structural characteristics and evolutionary relationships were systematically analyzed in metazoa according to the genomes of species. In invertebrates, there were only NLRC and/or NLRD presented from sponge to amphioxus, and according to the evolutionary tree, NLR from sponge located in the most primitive position. Caspase-1 existed in some metazoan phyla (Brachiopoda, Ectoprocta, Arthropoda, Mollusca, Annelia, Nematoda, Platyelminthes, Coelenterate, and Porifera) and its activation sites were relatively conserved. The amino acid sequences and three-dimensional structures of N-terminal CARD/Death domain of NLR and Caspase-1 were similar in species from sponge to human. NLR and Caspase-1 co-existed in species of Brachiopoda, Mollusca, Annelia, Coelenterate, and Porifera. There was only GSDME or PJVK found in some phyla of invertebrates and their cleavage sites were conserved (DxxD). And it was predicted that the NLR inflammasome in inducing pyroptosis could occur in species of Brachiopoda, Mollusca, Annelia, and Coelenterate. These studies indicated that NLR inflammasome emerged early in sponges of metazoa, and NLR inflammasome in inducing pyroptosis first appeared in Coelenterate, suggesting that inflammasome and its mediated pyroptosis had existed in the early stage of metazoa, but they had been lost in many species during evolution.

Platelet integrin αIIbβ3 plays a key role in a venous thrombogenesis mouse model

Venous thrombosis (VT) is a common vascular disease associated with reduced survival and a high recurrence rate. VT is initiated by the accumulation of platelets and neutrophils at sites of endothelial cell activation. A role for platelet αIIbβ3 in VT is not established, a task complicated by the increased bleeding risk caused by partial agonists such as tirofiban. Here, we show that m-tirofiban, a modified version of tirofiban, does not agonize αIIbβ3 based on lack of neoepitope expression and the cryo-EM structure of m-tirofiban/full-length αIIbβ3 complex. m-tirofiban abolishes agonist-induced platelet aggregation while preserving clot retraction ex vivo and, unlike tirofiban, it suppresses venous thrombogenesis in a mouse model without increasing bleeding. These findings establish a key role for αIIbβ3 in VT initiation and suggest that m-tirofiban and compounds with a similar structurally-defined mechanism of action merit consideration as potential thromboprophylaxis agents in patients at high risk for VT and hemorrhage.

ZBTB16 drives vascular calcification through accelerating VSMCs osteoblastic transition in chronic kidney disease via Wnt/β-catenin pathway.

Chronic kidney disease (CKD)-related vascular calcification (VC) is a common degenerative phenomenon of the vessel wall and its pathological basis is the phenotypic transformation of vascular smooth muscle cell (VSMCs). Zinc finger and BR-C (Broad-Complex), ttk (tramtrack) and bab (bric à brac) (BTB) domain containing 16 (ZBTB16) has been reported to be expressed in the aortic tissues in a rat model of VC. This work is conducted to reveal the functions of ZBTB16 on VC in CKD and to probe its involved reaction mechanisms. In vivo CKD rat models were established by adenine and VSMC calcification were stimulated with high phosphate (Pi) in vitro. Renal function indexes were estimated with relevant assay kits. Renal tissues were histologically examined with Hematoxylin and Eosin (H&E) staining. Alizarin red and von kossa staining were used to measure arterial calcification. Reverse transcription-quantitative PCR (RT-qPCR) and western blot were used to detect ZBTB16 expression. Western blot, immunohistochemistry and immunofluorescence staining were used to detect osteogenic markers and smooth muscle cell markers. Western blot was used to measure the expressions of proteins implicated in Wnt/β-catenin pathway. In the blood samples of CKD patients with VC, aortic tissues of CKD rats and Pi-treated VSMCs, ZBTB16 expression was significantly increased. ZBTB16 knockdown reduced renal dysfunction, calcium deposition and inhibited VSMCs osteoblast differentiation in both in vitro and in vivo. Moreover, silencing with ZBTB16 inactivated Wingless-related integration site (Wnt)/β-catenin pathway. LiCl (Wnt/β-catenin agonist) reversed the protective effects of ZBTB16 knockdown on the calcification and osteoblastic transformation in vitro. Together, ZBTB16 silencing may down-regulate Wnt/β-catenin pathway to protect against CKD-associated VC via repressing the osteoblastic transformation of VSMCs.

Identification of two repurposed drugs targeting GSDMD oligomerization interface I to block pyroptosis.

As an executor of pyroptosis, gasdermin D (GSDMD) plays a critical role in inflammatory diseases and cancer. Thus, GSDMD is currently being widely explored as a drug target. Existing inhibitors targeting GSDMD, such as necrosulfonamide, disulfiram, and fumarate, primarily prevent pyroptosis by modifying human/mouse C191/C192 in the N-terminal fragment of GSDMD. However, cysteine modification can prevent the function of important proteins or enzymes, thereby leading to adverse reactions. Here, we chose an alternative key intervention site for GSDMD activation, which is located at the oligomerization interface I of its pore-forming structure. Through high-throughput virtual and experimental screening and in combination with efficacy and pharmacological validation, we have identified two safe, specific "repurposed drugs" that potently suppress GSDMD-mediated pyroptosis. Moreover, the candidates exhibited synergistic therapeutic effects of "1+ 1>2" in murine sepsis and tumorigenesis models. These recently identified GSDMD inhibitors hold great promise for clinical translation in the development of anti-inflammatory and anti-cancer immunotherapies.

Heterobimetallic Synergism in Triple-Redox 2D Framework for Largely Boosted Water Oxidation and Flanked Carboxylic-Acid-Triggered Unconventional Tandem Catalysis.

A fish-bone-shaped and thermochemically stable 2D metal-organic framework (MOF) with multimodal active center-decked pore-wall is devised. Redox-active [Co2(COO)4] node and thiazolo[5,4-d]thiazole functionalization benefit this mixed-ligand MOF exhibiting electrochemical water oxidation with 375mV overpotential at 10mA cm-2 current density and 78mV per dec Tafel slope in alkaline medium. Pair of oppositely oriented carboxylic acids aids postmetalation with transition metal ions to engineer heterobimetallic materials. Notably, overpotential of Ni2+ grafted triple-redox composite reduces to 270mV with twofold declined Tafel slope than the parent MOF, ranking among the best-reported values, and outperforming majority of related catalysts. Significantly, turnover frequency and charge transfer resistance display 35.5 and 1.4-fold upsurge, respectively, with much uplifted chronopotentiometric stability and increase active surface area owing to synergistic Co(II)-Ni(II) coupling. The simultaneous presence of ─COOH and nitrogen-rich moieties renders this hydrogen-bonded MOF as acid-base synergistic catalyst for recyclable deacetalization-Knoevenagel reaction with >99% product yield under solvent-free mild condition. Besides control experiments, unique role of ─COOH as hydrogen-bond donor site in substrate activation is validated from comparing the performances of molecular-shearing approach-derived structurally similar unfunctionalized MOF, and the heterobimetallic composite. To the best of tandem Knoevenagel condensation, larger-sized acetal exhibits poor yield of α,β-unsaturated dicyanides, and demonstrates pore-fitting-mediated size-selectivity.

Synergistic catalysis of dual-sites promoted cycloaddition of CO2 with epoxides

This study explores the catalytic efficacy of fluorine-modified 1 wt% copper oxide on MCM-41 (F-1Cu/MCM-41) in carbon dioxide cycloaddition reactions. It delves into reaction mechanisms, active sites, and the practical applicability of the catalyst. Comprehensive examination through in situ diffuse reflectance infrared Fourier transform spectroscopy and other analytical methods substantiated the role of halogen-modified mono-dispersed copper species in carbon dioxide activation and silicon hydroxide sites in epoxide activation, while underscoring the role of Lewis bases and Brønsted acids. Kinetic studies and density functional theory calculations pinpointed carbon dioxide activation as the pivotal step. Furthermore, the catalyst exhibited robust stability and efficiency in continuous flow experiments, sustaining a 99% selectivity towards cyclic carbonate over 150 h. An eco-friendly evaluation confirmed the sustainability of the process, emphasizing its minimal environmental footprint and high efficiency. These results establish fluorine-modified 1 wt% copper oxide on MCM-41 as a formidable candidate for industrial-scale cyclic carbonate production, due to its promising performance and sustainability.

Atomically dispersed Fe-N4 sites in activation of peroxymonosulfate for wastewater purification: Mechanism of non-radical pathways and their quantification

Single-atom catalysts are promising alternatives to homogeneous and heterogeneous catalysts in the advanced oxidation processes for contaminant degradation; however, quantifying the exact contribution of nonradical reactive oxygen species has remained challenging. Herein, Fe single atoms anchored on nitrogen-doped carbonaceous substrates (Fe SAs-N-C) were synthesized for peroxymonosulfate (PMS) activation toward pollutant degradation. Fe SAs-N-C achieved high activity within 30 min, which is 17.20 and 5.08 times higher than those of N-C catalysts without or with Fe nanoparticles, respectively. A synergistic mechanism of singlet oxygen (1O2) and electron transfer for dominating pollutant degradation was revealed. The former contributed 78.50 % while the latter contributed 21.50 % in pollutant elimination. Density functional theory calculations uncovered that the O atom in −SO4 moiety of PMS was adsorbed on the Fe atoms, leading to the OH bond elongation and generating 1O2. While the absorbed O atom in OO bond near to −SO4 moiety of PMS tended to enlarge the OO bond and accelerate the electron transfer. The adsorbed PMS was prone to being decomposed into 1O2 due to a lower energy barrier (0.43 eV) of 1O2 rate-determining step than that of electron transfer (0.95 eV). Fe-N4 sites are both electron transfer channels and 1O2 formation sites. This work provides insights into the quantitative contributions of non-radical active species to pollutant degradation.

Differential functional role of Orai1 variants in constitutive Ca2+ entry and calcification in luminal breast cancer cells

Resting cytosolic Ca2+ concentration is tightly regulated to fine-tune Ca2+-dependent cellular functions. Luminal breast cancer cells exhibit constitutive Ca2+ entry mediated by Orai1 and the secretory pathway Ca2+-ATPase, SPCA2, which result in mammary microcalcifications that constitute a prognostic marker of mammary lesions. Two Orai1 isoforms have been identified, the full-length Orai1α, consisting of 301 amino acids, and the short variant, Orai1β, lacking the 63 or 70 N-terminal amino acids comprising residues involved in channel inactivation and binding sites with Orai1 partners. We show that only the mammalian-specific Orai1α rescues SPCA2-dependent constitutive Ca2+ entry in Orai1-knockout MCF7 cells, a widely used luminal breast cancer cell line. FRET analysis and immunoprecipitation revealed that Orai1α shows a greater ability to interact with SPCA2 than Orai1β. Deletion of the first 38 amino acids in Orai1α reduced the interaction with SPCA2 to a similar extent as Orai1β, thus suggesting that the N-terminal 38 amino acids play a relevant role in Orai1α-SPCA2 interaction. Finally, Orai1α, but not Orai1β, rescue the ability of Orai1-deficient cells to form in vitro microcalcifications. These findings provide compelling evidence for a functional role of Orai1α in constitutive Ca2+ entry in MCF7 cells, which might be a target to prevent the development of mammary microcalcifications in luminal breast cancer.

Deciphering Asymmetric Brønsted Base-Aminocatalytic Mode in Pudovik/[1,2]-Phospha-Brook Rearrangement/Michael Cascade Reaction.

An approach involving the use of a bifunctional aminocatalyst containing Brønsted base and iminium activation sites for asymmetric multicomponent reactions involving [1,2]-phospha-Brook rearrangement has yet to be realized. Herein, we present an aminocatalytic enantioselective conjugate addition of α-phosphonyloxy enolates formed via [1,2]-phospha-Brook rearrangement to α,β-unsaturated ketones. The methodology unfolds a simple one-pot operation consisting of a robust additive-free catalytic system providing a series of oxindole derivatives having two contiguous stereocenters in high yields with excellent stereoselectivities.

One Iron for Two Iron Sites in a Metal–Organic Framework Toward Simultaneous N2−H2 Activation under Mild Conditions

AbstractIron‐based catalysts play an important role in the ammonia industry. As one of the most abundant iron minerals, Fe3O4 containing FeII and FeIII sites is widely distributed in the earth's crust and even on exoplanets, theoretically giving it both economic and catalytic potentials in ammonia synthesis. However, in the absence of specific active co‐catalyst and harsh conditions, Fe3O4 is impossible to achieve ammonia synthesis alone. Here, we designed to activate the relatively inert FeII and FeIII sites in Fe3O4 with a third FeIII site inlayed in a coordination framework (MIL‐101(Fe)) to achieve the unpresented multi‐site collaborative catalysis. In‐depth mechanism study confirmed the roles of three different Fe sites in N2 activation, H2 activation, and product transfer, respectively. Efficient N2−H2 activation to NH3 on the Fe3O4‐based catalytic system has been achieved at extremely mild conditions. Our research provides a theoretical basis and a new strategy for designing efficient non‐noble metal‐based ammonia synthesis catalyst with minimized energy consumption.

Spatial organization of translation and translational repression in two phases of germ granules

Most RNA-protein condensates are composed of heterogeneous immiscible phases. However, how this multiphase organization contributes to their biological functions remains largely unexplored. Drosophila germ granules, a class of RNA-protein condensates, are the site of mRNA storage and translational activation. Here, using super-resolution microscopy and single-molecule imaging approaches, we show that germ granules have a biphasic organization and that translation occurs in the outer phase and at the surface of the granules. The localization, directionality, and compaction of mRNAs within the granule depend on their translation status, translated mRNAs being enriched in the outer phase with their 5′end oriented towards the surface. Translation is strongly reduced when germ granule biphasic organization is lost. These findings reveal the intimate links between the architecture of RNA-protein condensates and the organization of their different functions, highlighting the functional compartmentalization of these condensates.