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Front Cover: Decoding Double Layer Dynamics for CO ₂ Electroreduction over Cu (Angew. Chem. Int. Ed. 26/2025)

Functional SELEX and Biomedical Applications of Aptamers: Beyond Molecular Recognition

Abstract Aptamers, developed through SELEX (systematic evolution of ligands by exponential enrichment), are generally short oligonucleotide molecules with remarkable specificity and binding affinity to diverse biological targets. These molecules have shown promise across such fields as biosensing, molecular diagnostics, and bioimaging. However, while conventional aptamer selection strategies predominantly emphasize binding affinity, they overlook the broader spectrum of potential biological functionalities. This oversight results in aptamers that frequently exhibit limited capacity for direct biological regulation. This inherent limitation in the selection process significantly constrains both the widespread application of aptamers across diverse fields and their therapeutic potential as direct drug candidates. Functional SELEX represents an advancement by refining selection library construction and selection processes to create F‐aptamers that integrate precise molecular recognition with specific biological activities. F‐aptamers hold transformative potential as therapeutic agents, diagnostic tools, and molecular regulators, marking a significant step forward in biomedical applications. This minireview critically assesses recent developments in F‐aptamer SELEX strategies, addressing challenges, and exploring opportunities for future research in this dynamic field.

Unveiling an In Situ H ₂ O ₂ Production: Rechargeable Zinc‐H ₂ O ₂ Battery Powering 26 LEDs

Abstract Looking toward ever‐growing energy demand, the advancement in energy storage devices and carrying out electrocatalytic reactions in an efficient way is the need of the hour. Herein, we have employed the two birds‐one stone approach, viz. fusing energy conversion and storing system enabling 2e − oxygen reduction reaction (ORR) to value‐added hydrogen peroxide (H 2 O 2 ) product and its utilization in the energy storage devices using MnWO 4 catalyst, without any external H 2 O 2 source. The designed catalyst exhibited a remarkable H 2 O 2 production of 98% @ 0.37 V versus RHE. The real‐time H 2 O 2 production was monitored by in‐situ electrochemical Raman and in‐situ infrared spectroscopic measurements. The pivotal influence of electrolyte composition, viz. local pH and the formation of carbonate species on H₂O₂ production was meticulously examined through micro‐electrochemical studies using gold (Au) microelectrodes. Further, we have explored an aqueous rechargeable Zn‐H 2 O 2 battery utilizing MnWO 4 as bifunctional electrocatalyst for sustainable H 2 O 2 production simultaneously producing the electricity. The Zn‐H 2 O 2 battery exhibited a remarkable cycle life of 136 h and an practical energy efficiency of 43%. The galvanostatic charge–discharge measurement of Zn‐H 2 O 2 battery attained a capacity of 25 mAh cm −2 at 3 mA cm −2 . The battery also demonstrated ≥90% cycle efficiency. Interestingly, the designed Zn‐H 2 O 2 battery (two connected in series) exhibited a stable open circuit voltage (OCV) with a promising power density of 10.5 mW cm −2 . As a proof of concept, we have demonstrated Zn‐H 2 O 2 batteries by powering 26 blue LEDs for more than 180 h (7 days) without fading in the illumination of LEDs.

Ruthenium Catalyzed <i>Ortho</i> ‐Arylation Reaction of Benzoic Acids with Arylthianthrenium Salts

Abstract Arylthianthrenium salts have become key intermediates for late‐stage functionalizations of drug‐like molecules. Ruthenium‐phosphine catalysts are now shown to enable their use as aryl sources in high‐yielding ortho ‐C─H arylations of benzoic acids. The arylthianthrenium salts are converted chemo‐selectively, leaving aryl halides and boronates untouched. The carboxylate groups are uniquely effective as directing groups, ensuring exclusive ortho ‐selectivity even in the presence of competing pyridine or amide groups. This makes the reaction orthogonal to cross‐couplings and conventional C─H arylations. The carboxylate group can be removed via decarboxylation or serve as an anchor for downstream transformations. Mechanistic studies identify C─H ruthenation as the rate‐limiting step and highlight the unique efficiency of P(Cy)₃ ligands.

Structures of Polyhydroxyalkanoate Synthase PhaC from <i>Aeromonas caviae</i> , Producing Biodegradable Plastics

Abstract Polyhydroxyalkanoate (PHA) is a biodegradable polyester that can serve as a promising alternative to petrochemical plastics, which present a serious source of pollution. PHA synthase (PhaC) is a key enzyme responsible for producing a wide variety of PHAs in microorganisms. Here, we present crystal structures of full‐length PhaC from Aeromonas caviae , a high‐performance PhaC employed for industrial use. The structure reveals an N‐terminal helical domain that mediates head‐to‐head dimerization and stabilizes the C‐terminal α/β catalytic domain to form a tunnel that connects the catalytic center embedded inside the protein to the protein surface. We showed that this tunnel is a putative egress tunnel for the product PHA chain. Our results establish a fundamental understanding of the PhaC machinery that should lead to improvement of this enzyme in industrial applications.

Influence of Ligand Design and Non‐Covalent Interactions on the Isoselective Ring‐Opening Polymerization of <i>rac</i> ‐β‐Butyrolactone Using Salan and Salalen Rare‐Earth Metal Catalysts

Abstract We herein report the influence of the ligand framework on the isoselective ring‐opening polymerization (ROP) of rac ‐β‐butyrolactone using highly active in situ generated salan [ONNO] H2 and salalen [ONNO] H rare‐earth metal complexes. The stereochemistry was found to be highly dependent on the ortho ‐substituents, enabling the synthesis of either isotactic poly(3‐hydroxybutyrate) (PHB) (up to P m  = 0.92) or syndiotactic PHB (up to P r  = 0.91). To obtain further information on the mechanism of the isoselective ROP, which exhibits an enantiomorphic site control (ESC), a new hybrid Y[ONNO] H (N(SiHMe 2 ) 2 )(THF) complex was isolated and characterized via NMR, DFT, and mass‐spectrometry experiments. The impact of non‐covalent interactions (NCIs) was demonstrated by the addition of NCI inhibitors. Kinetic studies revealed a secondary kinetic isotope effect (SKIE) of 1.14, indicating that the pre‐coordination of the monomer plays a significant role in the mechanism. These findings provide a foundation for the future design of catalysts for isoselective ROP.

The Mechanism of Ruthenium‐Catalyzed Directed C─H Arylation of Arenes: The Key Role of Bis‐Cyclometalated Intermediates

Abstract The mechanism of Ru‐catalyzed N ‐directed C‐H ortho ‐arylation with haloarenes has been under intense scrutiny over the last decade, with conflicting proposals concerning the relevance of various catalytic intermediates and the nature of the key steps. This work presents experimental and computational studies that address these long‐standing questions. Stoichiometric, catalytic, and mechanistic kinetic studies, supported by DFT calculations, reveal that bis‐cyclometallated ruthenium species are key intermediates in these reactions. These studies also show that oxidative addition with bromoarenes proceeds via a concerted oxidative addition pathway, as demonstrated by DFT and experimental kinetic orders. Bromoarene activation does not proceed at mono‐cyclometalated species. In the catalytic process, zero order kinetics are observed on both reaction substrates, an observation that is rationalized by DFT calculations which predict a rate‐limiting step within the product‐release stage. These results showcase how detailed experimental and DFT studies can combine to probe mechanistic questions, as well as resolving opposing views around the mechanism of these Ru‐catalyzed arylations that form the basis of promising mild C─H functionalizations.

Concise Enantioselective Total Syntheses of Rearranged <i>ent</i> ‐Trachylobane Diterpenoids (–)‐Wallichanols A and B

Abstract Herein, we report the first enantioselective total syntheses of three rearranged ent ‐trachylobane diterpenoids, (–)‐Wallichanol A ( 1 ), (–)‐Wallichanol B ( 2 ), and (–)‐Sanguinolane ( 3 ), using a 13, 17, and 14 step longest‐linear sequences respectively, featuring a novel intramolecular [2 + 2] cycloaddition to construct the unique pentacyclic framework containing an unprecedented tricyclo[3.3.1.0 2,7 ]nonane motif. Other key steps in the synthetic route include a highly challenging, selective alkene reduction via hydrogen atom transfer (HAT), leveraging the thermodynamic preference for a tertiary carbon‐centered radical; a Robinson‐type annulation to construct the tricyclic terpenoid building block; and applying aerobic oxidation at two distinct points to form α ‐hydroxy ketones, facilitating the enantioselective syntheses of these diterpenoids.

Efficient Ammonia Electrosynthesis from Pure Nitrate Reduction via Tuning Bimetallic Sites in Redox‐Active Covalent Organic Frameworks

Abstract Electrocatalytic nitrate reduction reaction (NITRR) represents a promising approach for ammonia synthesis, but existing application has been constrained by the complex proton‐coupled electron transfer and the sluggish kinetics induced by various intermediates. Herein, we synthesized a series of metalized covalent organic frameworks: NiTP‐MTAPP MCOFs (M = 2H, Co, Cu, and Fe), based on dual redox‐active centers: thiophene‐substituted Ni‐bis(dithiolene) ligand‐Ni[C 2 S 2 (C 4 H 2 SCHO) 2 ] 2 and metallic porphyrin. Through regulating the adsorption and desorption of species at the catalytic sites, we have identified the optimal NITRR electrocatalyst: NiTP‐CoTAPP MCOF, which achieved the highest faradaic efficiency (FE) of approximately 85.6% at −0.8 V (vs. RHE) in pure nitrate solution, with an impressive yield rate of 160.2 mmol h −1 g −1 cat. The generation of active hydrogen at [NiS 4 ] sites achieved dynamic equilibrium with the timely hydrogenation reaction at CoN 4 sites, effectively suppressing the hydrogen evolution reaction. Moreover, the incorporation of thiophene (TP) groups and metal ions facilitates charge transfer. Density functional theory (DFT) calculations demonstrated the reduction in energy barriers at different catalytic sites. The CoN 4 −NiS 4 system exhibited the optimal adsorption‐to‐desorption capability and the lowest energy barrier (0.58 eV) for the rate‐determining step (*NO → *HNO), which is supported by the moderate d‐band center and Bader charge value.

Frontispiece: A Sustainable and Scalable Approach for In Situ Induction of Gradient Nucleation Sites in Biomass‐Derived Interface Layers for Ultra‐Stable Aqueous Zinc Metal Batteries

Cyclization Polymerization of Elemental Sulfur and Diisocyanate: New Polymerization Toward High‐Performance Polymer

Abstract The development of polymer materials heavily relies on new polymerization reactions. Herein, we report the discovery of cyclization polymerization of element sulfur (S 8 ) and aliphatic diisocyanate at room temperature with 1,5,7‐triazabicyclo[4.4.0]dec‐5‐ene (TBD) organic base as the catalyst, where the two monomers are covalently linked via the formation of thiadiazolidinone (TDZD) or a cyclic isocyanurate ring. The polymer of S 8 and 1,6‐diisocyanatohexane (HDI) exhibits remarkable thermal stability and mechanical properties. Particularly, it has exceptionally high adhesion to various substrates in air or under water, e.g., the underwater adhesion strength is as high as ∼26.5 MPa for poly(ethylene glycol‐co‐1,4‐cyclohexanedimethanol terephthalate) (PETG) and ∼2.3 MPa for poly(tetrafluoroethylene) (Teflon). The cyclization polymerization provides the basis for the synthesis of high‐performance polymers with elemental sulfur.

Frontispiece: Surface Chemistry of WC Powder Electrocatalysts Probed In Situ with NAP‐XPS

To Make a Painstaking Investigation: Revealing the Electrochemical Reactions in Aqueous Zn─Mn Batteries

Abstract The rechargeable aqueous Zn||MnO 2 batteries have been extensively explored, but the electrochemical reaction mechanisms, especially in terms of Mn 2+ /MnO 2 dissolution/deposition and Zn 2+ /H + intercalation chemistry, are still not fully understood. Herein, a Zn||MnO 2 ‐based battery system is constructed and the variation of the battery composition is skillfully regulated by the separation of variables. The possibility of Zn 2+ /H + intercalation chemistry is ruled out and the dominance of the dissolution/deposition mechanism is strongly demonstrated. This study confirms that the chemistry of the controversial double‐discharge platform is a dissolution reaction, determined by different proton concentrations and zinc ions hydrolysis. Discharge Plateau I is the MnO 2 dissolution dominated by the surplus H + in the electrolyte, while Discharge Plateau II is the smooth discharge plateau resulting from the hydrolysis of Zn 2+ releasing protons when the proton concentration decreases to the point of Zn(OH) 2 generation. This work provides a better understanding of the dissolution/deposition mechanism of Zn||MnO 2 and paves the way for the practical application of manganese‐based aqueous batteries. It also provides a comprehensive method to study the mechanism of electrochemical reactions.

Correction to: Toward Heart-Healthy and Sustainable Cities: A Policy Statement From the American Heart Association

Efficacy and Safety of Inclisiran in Adolescents With Genetically Confirmed Homozygous Familial Hypercholesterolemia: Results From the Double-Blind, Placebo-Controlled Part of the ORION-13 Randomized Trial

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a genetic disease characterized by high levels of low-density lipoprotein cholesterol (LDL-C) present from birth, leading to early-onset and progressive atherosclerotic cardiovascular disease. Early treatment initiation is crucial for cardiovascular risk reduction; however, many patients do not reach LDL-C treatment goals. Inclisiran, a small interfering RNA targeting hepatic PCSK9 (proprotein convertase subtilisin/kexin type 9), is effective and well tolerated in adult patients with hyperlipidemia; however, it has not yet been studied in pediatric patients. METHODS: Herein we report results of the 1-year, double-blind, placebo-controlled part of the phase 3 study ORION-13 (Study to Evaluate Efficacy and Safety of Inclisiran in Adolescents With Homozygous Familial Hypercholesterolemia) in adolescents with HoFH. This 2-part multicenter study included 13 patients ≥12 to &lt;18 years of age with a genetic diagnosis of HoFH (excluding LDL [low-density lipoprotein] receptor [ LDLR ] null/null genotypes) and elevated LDL-C levels (&gt;130 mg/dL) on maximally tolerated statin treatment, with or without other lipid-lowering therapies. Eligible patients were randomized 2:1 to receive either 300 mg of inclisiran sodium or placebo, administered on days 1, 90, and 270. The primary end point was the mean percentage change in LDL-C from baseline to day 330. RESULTS: The mean age of patients was 14.8 years, and mean baseline LDL-C was 272 mg/dL. The placebo-adjusted mean (95% CI) percentage change in LDL-C from baseline to day 330 was −33.3% (−59.2% to −7.3%). Six of 9 (66.7%) inclisiran-treated patients (versus 1 of 4 [25%] on placebo) achieved a &gt;15% reduction in LDL-C, and 5 of 9 (55.6%) inclisiran-treated patients (versus none on placebo) achieved a &gt;20% reduction. The placebo-adjusted mean (95% CI) percentage change in PCSK9 from baseline to day 330 was −60.2% (−79.8% to −40.7%); corresponding changes in apolipoprotein B, non–high-density lipoprotein cholesterol, and total cholesterol were −23.0%, −32.7%, and −27.8%, respectively. No serious adverse events, treatment discontinuations because of adverse events, or deaths occurred. No new safety findings were reported. CONCLUSIONS: In a 1-year randomized controlled study (part 1 of ORION-13), inclisiran was effective in lowering LDL-C in adolescents with HoFH and was well tolerated. These results support inclisiran as a potentially useful addition for the treatment of adolescents with HoFH and a minimum of LDLR residual activity. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04659863.

Fused Dual‐Donor Design for Accelerating Reverse Intersystem Crossing Rates of Spatially Folded Through‐Space Charge Transfer Emitters

Abstract The development of through‐space charge transfer (TSCT)‐thermally activated delayed fluorescence (TADF) material is defective in relatively low reverse intersystem crossing (RISC) rates (commonly &lt;5 × 10 5 s −1 ). Herein, we fuse two 3,6‐dimethyl‐8H‐indolo[3,2,1‐ de ]acridine (IAc) donor units to obtain large planar donors ( m ‐bIAc and p ‐bIAc) for forming spatially folded A–D|D–A configured TSCT emitters (DCT‐1 and DCT‐2). The configuration of highly parallel and large‐plane intramolecular multiple π‐stacking has been achieved. The symmetrical multi‐channel charge transfer networks of emitters induce multiple energetically proximal excited states within a small energy range (&lt;0.12 eV) at the lowest excited state, creating additional configuration interaction and spin‐orbit coupling channels to accelerate the RISC process. This molecular configuration yields enhanced RISC rates of 6.19 × 10 5  s −1 for DCT‐1 and 1.05 × 10 6 s −1 for DCT‐2. Solution‐processed organic light‐emitting diodes employing these emitters achieve maximum external quantum efficiencies of 18.9% (DCT‐1, 474 nm sky‐blue emission) and 23.9% (DCT‐2, 498 nm green emission), with attenuated efficiency roll‐offs of DCT‐2 (12% at 1000 cd m −2 ). This work provides a critical pathway for manipulating dense excited states to address the bottleneck of the RISC rates while maintaining structural rigidity, promoting further advancement of TSCT‐TADF materials.

Letter by Wang et al Regarding Article, “Bone Morphogenetic Protein 9 Protects Against Myocardial Infarction by Improving Lymphatic Drainage Function and Triggering DECR1-Mediated Mitochondrial Bioenergetics”

Supramolecular Recognition of a DNA Four‐Way Junction by an M ₂ L ₄ Metallo‐Cage, Inspired by a Simulation‐Guided Design Approach

Abstract DNA four‐way junctions (4WJs) play an important biological role in DNA repair and recombination, and viral regulation, and are attractive therapeutic targets. Compounds that recognise the junction structure are rare; in this work, we describe cationic metallo‐supramolecular M 2 L 4 cages as a new type of 4WJ binder with nanomolar affinities. A combination of molecular dynamics (MD) simulations and biophysical experiments show that the size and shape of a compound comprising square planar Pd or Pt and anthracene‐based ligands is an excellent fit for the 4WJ cavity. Whilst the cage is also capable of binding to three‐way junctions (3WJs) and Y‐fork structures, we show that the 4WJ is the preferred DNA target, and that duplex B‐DNA is not a competitor. Among 3WJs, T‐shape bulged 3WJs are bound more preferably than perfect Y‐shaped 3WJs. Whilst previous work studying M 2 L 4 metallo‐supramolecular cages has focused on binding inside their structures, this work exploits the external aromatic surfaces of the supramolecule, creating a supramolecular guest that ideally matches the DNA host cavity. This approach allows available structures to be identified as potential junction binders and then screened for their fit to a nucleic acid junction target using simulations. This has potential to significantly accelerate discovery.

Modified mRNA Treatment Restores Cardiac Function in Desmocollin-2–Deficient Mouse Models of Arrhythmogenic Right Ventricular Cardiomyopathy

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease characterized by irregular rhythms and right ventricular dysplasia. Sequence variations in desmosomal protein-encoding genes are linked to ARVC development. Effective treatments for ARVC are lacking. Whereas mRNA-based therapies have shown efficacy in humans, their therapeutic potential for inherited cardiomyopathies remains unclear. METHODS: Whole-exome sequencing identified a novel DSC2 sequence variation causing autosomal recessive ARVC in a Chinese family with consanguineous marriage. Mouse models with Dsc2 sequence variation knock-in and constitutive knock-out were generated and analyzed using echocardiography and histology. Transcriptomic and biochemical analyses were conducted to explore ARVC mechanisms. Dsc2 mRNA delivered by intracardiac or transcoronary injection was assessed as a treatment for ARVC in Dsc2 knock-out mice. In addition, effects of Dsc2 mRNA were examined in a transverse aortic constriction mouse model with noninherited right ventricular systolic dysfunction. RESULTS: Dsc2 -deficient mice exhibited right ventricular dilation and dysfunction, mimicking human disease. Transcriptomic analysis identified Myl7 as the most downregulated gene in the right ventricles of Dsc2 -deficient mice, and its restoration by adeno-associated virus 9 rescued heart function. Dsc2 mRNA delivery, with or without lipid nanoparticle encapsulation, normalized heart size and function in Dsc2 -deficient mice. Reduced DSC2 and MLC2a expression was also noted in patients with noninherited dilated cardiomyopathy and in mice with transverse aortic constriction. A single dose of mRNA provided therapeutic effects lasting 2 to 3 months before declining. CONCLUSIONS: Our study reveals novel mechanisms of ARVC caused by DSC2 loss of function, supported by human and mouse data. Loss of Myl7 contributes to reduced cardiac contractility in ARVC and dilated cardiomyopathy with right ventricular systolic dysfunction. Dsc2 mRNA treatment demonstrated significant therapeutic potential in ARVC and transverse aortic constriction models, providing a basis for future clinical applications.

Dusp14-Mediated Dephosphorylation of MLKL Protects Against Cardiomyocyte Necroptosis in Hypothyroidism-Induced Heart Failure

BACKGROUND: Hypothyroidism leads to multiple organ dysfunction, with the heart the most affected. However, the pathologic mechanism of hypothyroidism-induced heart failure remains to be completely elucidated. Thyroid hormone replacement therapy enhances myocardium systolic function but increases the occurrence of arrythmias. There is an urgent need to explore these mechanisms in detail and to discover and develop drugs that can target and manage heart failure in patients with hypothyroidism. METHODS: In this study, a mouse model of hypothyroidism-induced heart failure was established through the administration of propylthiouracil. Dusp14 knockout mice were generated, and adeno-associated virus–mediated cardiomyocyte-specific overexpression of Dusp14 (dual specificity phosphatase 14) was used in combination with related cellular experiments to investigate the protective effects of Dusp14 on hypothyroidism-induced heart failure. Further analyses confirmed the crucial involvement of necroptosis in the pathogenesis of hypothyroidism-induced heart failure, and demonstrated the protective role of Dusp14 in modulating necroptosis. In addition, a novel small molecule compound that effectively regulates Dusp14 activity in vitro was identified through molecular docking, providing a potential therapeutic avenue. RESULTS: Dusp14 regulates necroptosis and mitigates hypothyroidism-induced heart failure. Myocardial tissue sections from mice in the hypothyroidism group showed positive Evans blue dye staining, and the serum levels of the myocardial injury marker lactate dehydrogenase were significantly higher compared with the euthyroid group (n=8). In addition, phosphorylation levels of the necroptosis marker MLKL (mixed lineage kinase domain-like protein) were significantly elevated, indicating the activation of necroptosis (n=8). These findings suggest that myocardial necroptosis is activated during hypothyroidism. Myocardial-specific overexpression of Dusp14 reduced myocardial necroptosis and improved myocardial contractile function in hypothyroid mice (n=8). In contrast, Dusp14 knockout exacerbated myocardial contractile dysfunction and necroptosis in these mice (n=5–7). These results indicate that Dusp14 alleviates hypothyroidism-induced heart failure by inhibiting necroptosis. P077-0472, a small molecule compound, was identified as an activator of Dusp14, which could inhibit cardiomyocyte necroptosis from hypothyroidism (n=6). CONCLUSIONS: Dusp14 inhibits cardiomyocyte necroptosis from hypothyroidism and consequently rescues damaged cardiomyocytes. P077-0472, a novel small molecule compound that activates the dephosphorylation function of Dusp14, could inhibit cardiomyocyte necroptosis from hypothyroidism.