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Tirzepatide Regulates Pacemaker Function by Modulating cAMP and Calcium Dynamics in Human Sinoatrial Node Cells

Under Pressure: A Rare Cause of Circulatory Collapse

Transient Boryl Assistance Enables Stereoselective Alkylation of Acyclic Tetrasubstituted Enolates

ABSTRACT The enantioselective construction of acyclic quaternary carbon stereocenters and vicinal quaternary/tertiary stereocenters represents two persistent challenges in organic synthesis. Herein, we report a unified transient boryl‐assisted, catalytic enantioselective strategy that enables the synthesis of both isolated quaternary carbon stereocenters and vicinal quaternary/tertiary stereocenters. Central to this strategy are the boryl‐organized stereodefined acyclic tetrasubstituted enolates and their subsequent stereoselective alkylation, achieved through highly enantioselective copper‐catalyzed conjugate borylation of α ‐substituted α,β ‐unsaturated esters. The resulting borylative alkylation products are obtained with high enantio‐ and diastereoselectivity (up to 98% ee and > 20:1 d.r.) and undergo diverse downstream transformations of the boryl unit, providing versatile access to acyclic quaternary/tertiary stereocenters. Following its stereodirecting role, the boron unit can be removed in a one‐pot protodeboronation to furnish esters bearing isolated α ‐quaternary stereocenters with high ee values (up to 94% ee). This catalytic strategy provides a general solution to the stereocontrolled alkylation of acyclic tetrasubstituted enolates and enables modular access to complex quaternary carbon architectures.

Correction to: 2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Dyslipidemia: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines

Regulating the Adsorption Configuration of Intermediates to Construct C─N Bonds From CO ₂ for High‐Efficiency <i>N</i> , <i>N</i> ‐Dimethylformamide Electrosynthesis

ABSTRACT N, N‐Dimethylformamide (DMF) is a widely used chemical reagent often described as a “universal solvent” due to its exceptional solvating capabilities. A sustainable synthesis route involves the green electrochemical coupling of CO 2 with dimethylamine (DMA). However, the rational design of highly efficient catalysts for this transformation remains constrained by a limited mechanistic understanding of the key reactive intermediates governing the process. In this study, *COO is identified as the pivotal intermediate facilitating C─N coupling, a finding substantiated by in situ Fourier transform infrared spectroscopy (FT‐IR) and online differential mass spectrometry (DEMS). Complementary Raman spectroscopy analyses further revealed that the intermediate adopts a stable chair‐like configuration, characterized by dual‐coordinated adsorption through both C and O atoms. Based on these mechanistic insights, a ZnCu catalyst was engineered that facilitates efficient CO 2 activation while simultaneously stabilizing this adsorption configuration, thereby enhancing the C─N coupling pathway. As a result, a DMF Faradaic efficiency (FE DMF ) of 51% and a production rate of 575 mmol·g −1 ·h −1 are achieved, outperforming all previously reported catalytic systems under comparable conditions. This study establishes a robust framework for understanding and optimizing C─N coupling via precise intermediate stabilization.

Farewell With Gratitude and Looking Ahead

Highly Emissive Double π‐Helical Molecular Carbons via Nitrogen Integration

ABSTRACT Improving the emission efficiency of chiral π‐systems is of significance for their practical applications in materials science. Herein, we report a family of highly emissive double π‐helical molecular carbons featuring a cyclooctatetraphenylene (COTt) or cyclooctahexaphenylene (COTh) core. In contrast to previously reported non‐emissive tetrabenzo‐COTt derivatives, the introduction of nitrogen via diarylamine/carbazole fusion leads to fluorescence quantum yields as high as 98%. The high configurational stability of these double π‐helices enabled successful chiral resolution of their enantiomers using high‐performance liquid chromatography. Notably, structural evolution from the COTt to the COTh core results in an approximately three‐fold increase in the luminescence dissymmetry factor ( g lum ), while the circularly polarized luminescence (CPL) brightness reached 110 M −1  cm −1 , among the highest values reported for cyclooctatetraene (COT)‐based chiral molecular carbons. Theoretical calculations further support these results, revealing large electric transition dipole moments ( | μ | ) and perfect parallel/antiparallel alignment between the μ and magnetic transition dipole moments ( m ). Our work provides valuable insight into the molecular design of high luminescent chiral emitters.

Sam68 Exacerbates Pathologic Cardiac Hypertrophy by Suppressing Cardiomyocyte Glucose Oxidation

BACKGROUND: Metabolic remodeling, marked by maladaptive shifts in substrate use and energy production, is a hallmark of pathologic cardiac hypertrophy. Yet the mechanisms linking stress signaling to impaired myocardial glucose oxidation remain incompletely defined. Sam68 (Src-associated in mitosis, 68 kDa; also known as KHDRBS1 [KH domain-containing, RNA-binding, signal transduction-associated protein 1]), a STAR (signal transduction and activation of RNA) family RNA-binding protein, has not previously been implicated in cardiac metabolic control. METHODS: SAM68 expression was examined in failing human hearts and transcriptomic data sets. Cardiomyocyte-specific Sam68 knockout mice (Sam68cKO) and AAV9 (adeno-associated virus serotype 9)–cTnT (cardiac troponin T)–mediated cardiomyocyte Sam68 overexpression (Sam68OE) were studied in transverse aortic constriction and angiotensin II models. Mechanistic studies included RNA sequencing, targeted metabolomics, in vivo [U- 13 C]-glucose tracing, coimmunoprecipitation, and protein–protein docking. Therapeutic relevance was tested with a PDK4 (pyruvate dehydrogenase kinase 4) inhibitor and the Sam68–Src interface blocker YB-0158, including pharmacokinetics, target engagement, and validation in Sam68cKO mice. RESULTS: Sam68 was increased in failing human cardiomyocytes and in murine hypertrophic hearts. Sam68cKO markedly attenuated angiotensin II– and transverse aortic constriction–induced hypertrophy, whereas Sam68OE aggravated remodeling and dysfunction. In vivo [U- 13 C]-glucose flux analysis showed that transverse aortic constriction caused sustained uncoupling of glycolysis from glucose oxidation, with increased glycolytic labeling but reduced 13 C incorporation into tricarboxylic acid cycle intermediates at 3 days and 4 weeks. Sam68 deletion restored glucose-derived carbon entry into the tricarboxylic acid cycle, enhanced PDH (pyruvate dehydrogenase)–dependent M+2 labeling, and improved oxidative–anaplerotic balance during pressure overload. Mechanistically, Sam68 served as a stress-activated scaffold that promoted Src-dependent STAT3 (signal transducer and activator of transcription 3) Tyr705 phosphorylation, nuclear accumulation, and transcriptional induction of PDK4, leading to PDH Ser293 phosphorylation and suppression of PDH activity. The PDK4 inhibitor blunted Sam68OE-driven remodeling while preserving PDH activity and mitochondrial respiratory programs. YB-0158 achieved cardiac exposure, disrupted Sam68–Src engagement in vivo, suppressed STAT3–PDK4–PDH signaling, and improved transverse aortic constriction remodeling; these effects were lost in Sam68cKO mice, supporting on-target dependence. In failing human hearts, the Src–SAM68–STAT3–PDK4 axis was activated, and SAM68 abundance increased in parallel with PDK4 and reduced left ventricular ejection fraction. CONCLUSIONS: Sam68 is a stress-activated cardiomyocyte scaffold that drives pathologic hypertrophy through a Src–STAT3–PDK4 program that inhibits PDH and suppresses glucose oxidation. Genetic or pharmacologic disruption of this axis restores PDH-dependent pyruvate oxidation and limits pressure-overload remodeling, identifying Sam68 as a druggable metabolic control node in heart failure.

Lipoprotein(a) Levels, Risk of Cardiovascular Events, and Benefit of Evolocumab: Findings From the VESALIUS-CV Trial

BACKGROUND: Lp(a) (lipoprotein[a]) is a risk factor for coronary heart disease. Whether baseline Lp(a) identifies higher-risk patients who derive more benefit from evolocumab is not established in a population without previous myocardial infarction (MI) or stroke. METHODS: From June 2019 to November 2021, the VESALIUS-CV trial (Effect of Evolocumab in Patients at High Cardiovascular Risk Without Prior Myocardial Infarctions or Stroke) enrolled patients with qualifying atherosclerosis or high-risk diabetes without previous MI or stroke and randomized them to evolocumab or placebo (median follow-up 4.6 years). In a prespecified analysis, Lp(a) was assessed at baseline in 7557 patients. Cox models were used to assess the adjusted risk of cardiovascular events by baseline Lp(a) in the placebo arm, and the efficacy of evolocumab by baseline Lp(a). The primary outcome of interest was the composite of major coronary events (coronary heart disease death, MI, or urgent coronary revascularization). RESULTS: Median age was 66 [interquartile range, 60–71] years, and 42.8% were women; median Lp(a) was 28 [interquartile range, 9–132] nmol/L. Higher baseline Lp(a) was associated with an increased risk of major coronary events (adjusted hazard ratio [HR adjusted ] per 100 nmol/L increase in Lp(a), 1.15 [95% CI, 1.05–1.26]; P =0.004), particularly for MI (HR adjusted , 1.23 [95% CI, 1.10–1.38]; P &lt;0.001). There was no association between Lp(a) and ischemic stroke (HR adjusted , 1.00 [95% CI, 0.84–1.19]; P =0.99). After 48 weeks, evolocumab reduced LDL-C (low-density lipoprotein cholesterol) by 66.8 mg/dL and Lp(a) by 38.0 nmol/L in patients with baseline Lp(a) &gt;105 nmol/L versus 61.1 mg/dL and 6.0 nmol/L in those with baseline Lp(a) ≤105 nmol/L. The relative reductions in the rate of major coronary events were 41% (HR, 0.59 [95% CI, 0.41–0.83]) in those with Lp(a) &gt;105 nmol/L compared with 35% (HR, 0.65 [95% CI, 0.51–0.82]) in those below ( P -interaction=0.45 for Lp[a] modeled as continuous variable). The corresponding absolute reductions were 3.7% versus 2.5% ( P -interaction=0.09), corresponding to a number needed to treat of 28 versus 40 to prevent 1 major coronary event at 5 years. CONCLUSIONS: In patients with atherosclerosis or high-risk diabetes but without previous MI or stroke, Lp(a) was independently associated with an increased risk of major coronary events but not ischemic stroke. Evolocumab reduced the relative risk of major coronary events to a similar degree irrespective of baseline Lp(a), with a numerically greater absolute risk reduction in patients with elevated Lp(a). REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03872401.

Air‐Stable Luminescent Schlenk Diradical With Triplet Ground State

ABSTRACT Luminescent diradicals hold great promise for optomagnetic applications, yet those with a triplet ground state remain largely underexplored for the inherent high reactivity from two spin‐parallel unpaired electrons, which hinders synthesis and enhances non‐radiative quenching. Herein, we report the first luminescent Schlenk diradical 2 with a distinct triplet ground state, concisely assembled from a methoxybenzene core and four polychlorobenzene pendants and readily isolated under air by routine silica‐gel chromatography. Good stability results from the steric hindrance of its propeller conformation, which effectively safeguards the two carbon radical centers. Comprehensive characterization elucidated the molecular structure and confirmed a triplet ground state with strong magnetic exchange interaction ( J/k B &gt; 320 K). Notably, diradical 2 shows a red emission at 619 nm with a quantum yield of 9.6% in cyclohexane, facilitated by its rigid propeller conformation and the D–A electron distribution for the coexistence of electron‐rich methoxybenzene and electron‐deficient polychlorobenzenes. The luminescence predominantly originates from the T 1 → T 0 transition, as the large energy gaps (T 0 → S 0 and T 1 → S 1 ) prohibit singlet‐state luminescence. This work not only enlarges the Schlenk hydrocarbon family but also opens new avenues for the understanding and design of luminescent high‐spin species.

JNK2 Is a Stress Integrator Driving Atrial Fibrillation Pathogenesis in Aging via Gut-Heart Crosstalk

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia and is associated with high morbidity and mortality, particularly in the aging population. Current treatment and prevention strategies remain suboptimal, highlighting the urgent need to better understand the mechanisms underlying aging-associated AF. We recently reported a causal role of the stress-activated kinase JNK2 (c-Jun N-terminal kinase 2) in aging-associated AF pathogenesis, mediated by JNK2-driven sarcoplasmic reticulum Ca 2 + dysfunction. However, the mechanisms by which cardiac JNK2 is activated during aging to promote AF remain unclear. Emerging evidence suggests that interorgan crosstalk contributes critically to the development of cardiovascular diseases. A hyperpermeable gastrointestinal epithelial barrier (“leaky gut”), commonly observed in aged individuals, is associated with elevated levels of proinflammatory cytokines and an increased risk of AF. Although proinflammatory cytokines have been proposed as predisposing factors for AF, clinical and experimental studies have yielded inconsistent results, underscoring the complexity of inflammation-associated AF pathogenesis. Here, we investigated whether cardiac JNK2 integrates diverse stress stimuli, including proinflammatory cytokines and lipopolysaccharide, to drive AF pathogenesis. METHODS: We used aged mice, intestinal epithelium–specific tight junction OD (occludin) knockdown (OD +/− ) mice, and a well-established dextran sulfate sodium–induced leaky gut mouse model characterized by reduced gastrointestinal epithelial occludin expression. A series of physiological and molecular approaches was applied to assess cardiac and gastrointestinal responses. RESULTS: We found that leaky gut significantly activates atrial JNK2, which, in turn, drives Ca 2 + -triggered arrhythmic activity and increases AF inducibility in aged, dextran sulfate sodium–treated, and OD +/− mouse models. Restoration of gut barrier function in dextran sulfate sodium mice, a clinically relevant model, reduced AF susceptibility. Similarly, either JNK2 inhibition or TNF-α (tumor necrosis factor α) blockade abolished the increased AF risk associated with leaky gut. Furthermore, we demonstrate, for the first time, that leaky gut–associated proinflammatory cytokines, including TNF-α and IL-17A (interleukin-17A), together with lipopolysaccharide, activate cardiac JNK2. This activation promotes AF pathogenesis through JNK2-mediated arrhythmogenic mechanisms, including diastolic sarcoplasmic reticulum Ca 2 + leak, Ca 2 + waves, and delayed afterdepolarizations. CONCLUSIONS: Activated JNK2 functions as a pathological nodal integrator of leaky gut–associated stress signals, mediating gut-to-heart crosstalk and driving inflammation-induced AF pathogenesis. Targeting JNK2 may represent a novel therapeutic strategy for AF.

Fundamental Understanding of Oxidative Stability in Fluorinated Asymmetric Ethers for Li Batteries

ABSTRACT Fluorination strategies for electrolyte solvents are widely used to improve the electrochemical performance and cycling stability of Li‐metal batteries. Recently, β‐fluorinated 1‐ethoxy‐2‐methoxyethane (F x EME) has been designed and shown to exhibit excellent oxidative stability. However, solvent design remains largely empirical, and its atomistic‐level effects are not fully understood. Here, we investigated how fluorination affects the oxidative stability of asymmetric ethers, (F x )EME, using multiscale modeling with density functional theory (DFT), ab initio molecular dynamics (AIMD), and machine‐learning force field (MLFF)‐MD. DFT and AIMD capture fluorination‐induced electronic‐structure changes with high accuracy, while MLFF‐MD enables exploration of interfacial reactions at larger time and length scales. Our results indicate that β‐fluorination stabilizes ethoxy C–H bonds via inductive effects and weakens solvent–cathode (Li 0.5 NiO 2 ) interactions through electron redistribution, mitigating oxidation and C–C activation. Furthermore, the increased dipole moment of F3EME drives a preferential orientation that shields the methoxy group. Overall, these three fluorination‐induced effects confer F x EME significantly higher oxidative stability than EME. This work provides atomistic insights into fluorination‐driven electronic and interfacial effects, supporting rational electrolyte design.

Challenges and Future Trends in Large Vessel Vasculitis

Based on the Chapel Hill consensus criteria, the primary forms of vasculitis are classified by the predominant size of the affected blood vessels into large, medium, or small vessels. The two main forms of large vessel vasculitis (LVV) are giant cell arteritis and Takayasu arteritis, both of which are more prevalent in women while showing distinct geographic patterns of prevalence. The pathogenesis of LVV is complex and multifactorial, involving a combination of genetic predisposition, environmental and geographic triggers, immune dysregulation, and aging or (premature) senescence of the immune system and blood vessels. Diagnosis based on clinical presentation alone can be challenging because of the wide variety and often nonspecific symptoms that are associated with LVV. This has prompted the development of novel diagnostic tools to aid patient management, in particular advanced vascular imaging approaches. New therapies targeting specific immune pathways are now becoming available to improve outcomes while limiting the side effects associated with traditional glucocorticoid treatment. Advances in molecular imaging techniques may also enhance our ability to objectively monitor disease and treatment response in patients with LVV. Ongoing research aims to better understand the underlying mechanisms and to develop better targeted therapies for LVV, and to improve patient assessment and life time management. This narrative review will provide an in-depth update on current challenges and future trends in LVV, enhancing our understanding of its pathogenesis, diagnostic features, and management strategies, including disease- and treatment-related cardiovascular complications.

Tailoring Interfaces With Poly(Ionic Liquid)‐Grafted Porous Hybrid Molecular Brushes in Quasi‐Solid‐State Composite Electrolytes Enables Ultrahigh‐Rate and High‐Voltage Lithium Metal Batteries

ABSTRACT Developing quasi‐solid‐state composite electrolytes (QSCEs) that combine high interfacial stability with rapid ion transport remains a key challenge for constructing long‐life, ultrahigh‐rate lithium metal batteries (LMBs). Herein, a highly interface‐stable and ion‐conductive QSCE (denoted as PSI) is developed by utilizing poly(ionic liquid)‐grafted porous silica hybrid molecular brush (SiO 2 ‐ g ‐PILDFOB) as a multifunctional filler. The synergistic effect of boron and fluorine in poly(ionic liquid) side chains promotes the formation of a highly stable solid electrolyte interphase (SEI) and cathode electrolyte interphase (CEI), significantly enhancing interfacial compatibility with highly active electrodes. Meanwhile, porous silica provides continuous transport channels for lithium ions, substantially improving lithium‐ion transport efficiency. As a result, the Li|PSI|NCM9055 full cell achieves a long cycle life of 1000 cycles at an ultrahigh rate of 8 C. Moreover, under a high cut‐off voltage of 4.4 V, the Li|PSI|NCM9055 pouch cell with a high cathode loading (6.9 mg cm −2 ) exhibits a specific discharge capacity of 200.9 mAh g −1 at 0.7 C and demonstrates a long lifespan of 500 cycles. A 1.54 Ah pouch cell with an energy density of 413 Wh kg −1 can also be achieved by using high‐loading cathodes (21 mg cm −2 ). This work provides a feasible design strategy for developing ultrahigh‐rate and high‐voltage LMBs.

Secondary Prevention After Coronary Artery Bypass Graft Surgery: 2026 Update: A Scientific Statement From the American Heart Association

Coronary artery bypass grafting is a well-established, durable, and safe surgical intervention. However, coronary artery disease continues to progress after the procedure. Patients who have undergone bypass surgery present unique challenges in terms of secondary prevention resulting from the often severe and diffuse nature of their coronary disease, the complexities of their postoperative recovery, the burden of their comorbid conditions, and the importance of ensuring long-term graft patency and preventing further disease progression. New evidence and advances in secondary prevention strategies in the post–coronary bypass grafting population have emerged since the American Heart Association’s 2015 scientific statement on this topic. Secondary prevention strongly correlates with improved outcomes after bypass surgery, providing the rationale and urgency for this updated scientific statement to promote evidence-based practical considerations and to improve their use.

Iterative Synthesis of Pyrene–Coronene Molecular Graphene Nanoribbons

ABSTRACT The synthesis of molecular, or monodisperse, graphene nanoribbons with full atomic precision is essential for establishing fundamental structure–property relationships, validating theoretical predictions, and meeting the property requirements for the diverse potential applications of graphene nanoribbons. The synthesis of undoped molecular graphene nanoribbons remains challenging, as many edge topologies have yet to be realized and the reported structures still exhibit limited lengths. This is mostly because iterative synthetic methods for undoped molecular GNRs remain practically undeveloped, with current approaches relying predominantly on noniterative strategies. The iterative synthesis of a new family of undoped molecular GNRs, featuring both a novel edge topology and an unprecedented length, is reported. These nanoribbons are accessed through a borylation/Suzuki/cyclodehydrogenation reaction sequence, in which the Suzuki and cyclodehydrogenation are merged into one transformation, giving rise to an effective two‐step iteration sequence. The resulting pyrene–coronene graphene nanoribbons exhibit strong absorption and high fluorescence efficiency, with molar absorptivity and fluorescence brightness values on the order of 10 5 M −1 cm −1 , and an intrinsic charger carrier mobility of 475 ± 32 cm 2 V −1 s −1 .

Correction to: The Natural History of Massive Left Ventricular Hypertrophy in Pediatric Hypertrophic Cardiomyopathy: A Multiregistry Analysis

Why We Must Rethink Universal Lp(a) Screening as a Routine Cardiovascular Prevention Strategy

π‐Extended COUPY Fluorophores for Targeted Near‐Infrared Fluorescence and Lifetime Imaging in Live Cells

ABSTRACT Fluorescent probes operating in the near‐infrared (NIR) region offer deep‐tissue visualization with minimal background interference, reduced phototoxicity, and enhanced signal‐to‐noise ratios. However, most conventional NIR fluorophores exhibit poor photostability, low fluorescence quantum yields, and limited chemical versatility, which constrain their use in demanding biological environments. Here, we report a new family of π‐extended COUPY dyes ( 3 – 7 ), rationally engineered to deliver efficient far‐red/NIR performance through vinylogation of the exocyclic double bond of the coumarin scaffold. This single structural modification induces a bathochromic shift exceeding 100 nm in both absorption and emission spectra while preserving the compact architecture and synthetic accessibility of the parent coumarin. The resulting dyes combine high molar absorptivity, moderate‐to‐high quantum yields, and exceptional photostability under biologically‐relevant conditions. Their performance was validated in live‐cell imaging using both intensity‐based and fluorescence lifetime imaging microscopy (FLIM), demonstrating compatibility with advanced imaging techniques. Furthermore, site‐specific bioconjugation to a clinically relevant peptide confirmed their suitability for targeted imaging. Collectively, π‐extended COUPY dyes represent a promising class of synthetically modular, chemically robust, and biologically compatible far‐red/NIR fluorophores for high‐resolution imaging, targeted strategies, and advanced bioimaging modalities, and provide a foundation for future studies aimed at evaluating their performance in more complex biological models.

Rational Molecular Design of a Multi‐Electron Organic Anode via Rapid Microwave Synthesis for Ultrastable NH ₄ ⁺ Storage

ABSTRACT Aqueous ammonium‐ion batteries (AAIBs) are promising energy storage devices, yet their development is hindered by the lack of high‐performance electrode materials. While small‐organic molecules possess structural tunability and diverse redox activity, their application is often limited by tedious synthesis, insufficient active‐sites, and dissolution in electrolytes. Herein, we synthesize a small‐organic molecule, DNQP, featuring multiple C═O/C═N redox‐active centers, via a rapid microwave route. This method completes the condensation between –NH 2 and C═O in 40 min (vs. 72 h for solvothermal), simultaneously introducing additional redox‐active C═N bonds and extending the π‐conjugated framework. Electronic structure analyses reveal that DNQP possesses an ultranarrow bandgap (1.053 eV), a highly delocalized π‐conjugated framework, and favorable π–π stacking channels for charge transport. These features, combined with a chelation‐coordination storage mechanism, enhance electron transfer, structural stability, and multi‐electron reactivity. As a result, DNQP achieves 79% redox‐site utilization, delivering a four‐electron capacity of 155.9 mAh g −1 at 0.1 A g −1 , and exhibits remarkable cycling performance over 12 000 cycles at 5 A g −1 . A DNQP//α‐MnO 2 full‐cell retains 99% capacity after 2000 cycles. Mechanism studies elucidate a reversible two‐step, four‐electron NH 4 + storage process governed by N─H⋯O/N─H⋯N H─bonding. This work offers a rational molecular design and rapid synthesis for high‐performance AAIBs organic materials.