The oxidative addition of electrophiles to transition metals is a fundamental step in transition-metal-mediated cross-coupling reactions. Although the mechanism of transition-metal-enabled C-X bond cleavage has garnered significant attention due to its impact on reaction selectivity and reactivity, the preceding association step between the electrophile and metal has long been underappreciated, particularly with regard to its kinetic effects. Here, we report and validate an associative electrophile-alkene exchange (E(A)A) strategy using nickel(0)-alkene complexes. This approach shifts the rate-determining step from C-X bond cleavage to electrophile-alkene exchange. By doing so, it enables selective recognition of C(sp(2))-electrophiles based on their coordination kinetics rather than bond dissociation energies, thereby facilitating the selective oxidative addition of C-F bonds over more reactive C-Cl, C-Br, and C-I bonds. Mechanistic studies reveal that the selective coordination of C(sp(2))-electrophiles depends on the coordination propensity of the pre-coordinated alkene and the supporting ligand on the nickel(0) complex. This strategy not only complements the traditional reactivity trends of C-X bonds in oxidative addition but also provides a foundation for the rational design of catalysts and the development of more efficient chemical processes.

Organic long-persistent luminescence (OLPL) materials have recently garnered increasing attention due to their promising applications in anti-counterfeiting and display technologies. However, smart or responsive OLPL systems capable of multilevel information encoding and sensing remain unexplored. Here, three twisted phosphors of difluoroboron beta-diketonate (BF2bdk) are designed for constructing OLPL materials. When co-doped with the electron donor N,N,N ',N '-tetramethylbenzidine (TMB) into various matrices, these BF2bdk emitters exhibit distinct afterglow colors while maintaining OLPL, demonstrating pronounced matrix-dependent responsiveness. Experimental and computational studies reveal that conformational twisting of BF2bdk molecules in distinct matrices modulates their T1 energy levels, enabling afterglow color tunability from a single molecule. Furthermore, the torsional freedom of the molecules can be finely tuned by varying substituents, allowing additional control over T1 energies. This strategy provides a versatile and differentiated approach for designing smart or responsive OLPL materials with tunable multicolor afterglow.

Recent advances in regulatory T cell (Treg) biology and clinical application of Treg-based treatments show promise as a new generation of transforming therapeutics for immune-related disorders, positioning Tregs as a living drug to rebuild immune tolerance and repair damaged tissues simultaneously. This perspective summarizes the key knowledge on Treg biology and highlights the recent important discoveries in the development of clinical applications based on Treg biology, from low-dose interleukin-2 therapy showing promising results in trials for ALS and adoptive Treg transfer demonstrating efficacy in preventing GVHD to early pilot studies of CAR Tregs. Drawing on these advances, we provide perspectives on key research priorities and translational challenges and set forth a roadmap that integrates basic and clinical insights into developing next-generation therapies focusing on precision tolerance strategies.

Malignant serous effusion (MSE), including malignant pleural effusion (MPE) and malignant ascites (MA), is a common and severe complication in advanced malignancies, associated with poor prognosis and high recurrence rates. Currently, no standardized treatments are available for MSE management, posing significant clinical challenges. Here, we identify elevated LIN28B expression and dysregulation of DNA repair pathways as two major features associated with MSE from patient and preclinical samples. We develop a targeted siRNA nanoparticle delivery system (siLin28B/DSSP@lip-PEG-FA) in combination with the PARP inhibitor BMN673, providing a synergistic therapeutic strategy against MSE. This combination significantly alleviated MA accumulation and prolonged survival in a preclinical ovarian cancer (OC) model without causing systemic cytotoxicity. Mechanistically, single-cell RNA sequencing (scRNA-seq) revealed that this combination therapy markedly remodeled the immune microenvironment by decreasing M2 macrophages and neutrophil populations with altered subtypes. Notably, Arg1-positive neutrophils, producing pro-inflammatory cytokines to increase vascular permeability, were diminished after the combination treatment. Furthermore, in vitro and in vivo experiments demonstrated that suppression of PARP and LIN28B inhibited vascular leakage and reinforced tight junction integrity. Collectively, our findings highlight dual targeting of PARP and LIN28B as a promising MA management approach in patients with advanced cancers, with the potential to improve patient quality of life.

The selectivity control of C=C double bonds, especially in tetrasubstituted olefins, is a fundamental issue due to their importance in organic chemistry, medicinal chemistry, and material chemistry. Herein, we observed that the stereoselectivity of chlorosulfonylation of allenoic acids or allenoates was reversed by applying an organic photocatalyst in combination with a copper catalyst Cu(acac)2, affording Z-selective tetrasubstituted olefins substituted with a heteroatom of sulfur. This reaction tolerates a broad range of functional groups. In addition, the intermediate trapping experiment and the reaction of optically active allenoate confirmed the presence of sulfonyl and allylic radicals. Cyclic voltammetry studies and Stern-Volmer quenching experiments demonstrated that the reaction proceeds via an oxidative quenching mechanism. Cu(acac)2 was found to play a crucial role in the formation of stereodefined pi-allyl Cu species in stereoselective chlorosulfonylation.

A highly efficient, iron(III)-BPsalan complex-catalyzed asymmetric 1,3-dipolar cycloaddition of nitrones and alpha,beta-unsaturated acyl imidazoles has been developed to afford isoxazolidine (31 examples) and isoxazoline derivatives (13 examples) in moderate to excellent yields (up to 99%) and excellent stereoselectivity (up to 99% ee and >20:1 dr). The reaction proceeds readily in acetone under air conditions, maintaining high efficiency and selectivity.

Amyloid aggregation of tau is the key pathological event in various tauopathies including Alzheimer's and Pick's disease. Recently, dopamination was identified to modify tau on cysteine, which protects against tau pathology, yet its structural and functional consequences remain unclear. Here, we show that dopamination of the three-repeat (3R) tau fragment K19 alleviates disease-associated tau phosphorylation and alters the tau fibril structure. Solution NMR analysis reveals that dopamine modification at Cys322 of tau suppresses phosphorylation at several pathogenic sites across the microtubule-binding region. Dopaminated tau also exhibited greatly diminished fibrillization in vitro and reduced seeding activity in cells. Finally, we determined the cryo-EM structure of dopaminated tau fibrils at 3.55 & Aring; resolution, revealing a unique fibril polymorph with the smallest core region reported to date for tau. The dopaminated fibril core comprises only 11 residues (centered on the VQIVYK motif) and is stabilized by a minimal hydrophobic interface, explaining its decreased stability compared to that of unmodified tau fibrils. Our results provide atomic-level insight into how dopamine modification imparts a protective effect on tau and underscore the profound influence of post-translational modifications in modulating amyloid protein structure and pathology.

SARS-CoV-2 continues to propagate globally, posing non-negligible risks of severe COVID-19. Although several clinical antivirals and immunosuppressants offer crucial protection, there is a persistent need for additional therapeutic options to counter emerging viral variants and drug resistances. New strategies focusing on host targets, or simultaneously suppressing viral replication and inflammation, particularly require rigorous validation. Compared to established antiviral targets, PLpro presents an alternative actionable vulnerability in SARS-CoV-2 infection. Meanwhile, RIPK1 was pinpointed to enhance both viral replication and the resulting cytokine storm in host cells. However, inhibitors targeting PLpro or RIPK1 require further optimization for preclinical studies, and their combined efficacy in vivo has yet to be explored. Here, we report the discoveries of potent and selective PLpro inhibitors and RIPK1 inhibitors through high-throughput approaches. Our lead compounds, SHY1643 and QY1892, demonstrated synergistic and robust effects in reducing the viral loads and cytokine release syndromes in SARS-CoV-2-infected mice. These findings establish a proof-of-concept combination therapy strategy for treating severe COVID-19, and provide promising leads for the clinical drug development. (c) 2025 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).