Browse Articles

Degron-independent recruitment of KAT2A expands the target space of CRBN molecular glues

Lysine acetyltransferases (KATs) cooperate with oncogenes such as c-Myc, estrogen receptor, and lysine methyltransferase 2A (KMT2A) fusions to sustain malignant programs. Targeting of KAT proteins has shown clinical efficacy; however, achieving homolog selectivity for most KATs remains a major challenge. By extending cereblon (CRBN)–based molecular glues beyond the canonical degron space, we developed an exquisitely selective degrader of KAT2A. Cryo–electron microscopy revealed that CRBN recruits KAT2A independently of a degron; instead, the molecular glue engages a surface-exposed tyrosine, mimicking antibody-like molecular recognition. Selective KAT2A degradation leads to potent ablation of histone H3 lysine 9 acetylation (H3K9Ac), antiproliferative effects in acute myeloid leukemia cell lines, and in vivo efficacy in a patient-derived xenograft model, establishing KAT2A as a targetable vulnerability to treat a wide range of malignancies. More generally, degron-independent recruitment extends the CRBN-targetable proteome.

Anodal tDCS attenuates hippocampal neurodegeneration and cognitive deficits after traumatic brain injury via glutamatergic and redox modulation

MicroSight-DETR: spatial-preserving real-time transformer with multi-domain fusion for UAV micro-object detection

Uncertainty analysis of spatiotemporal wake characteristics in groove-flap wind turbines based on turbulence intensity

Dementia risk in middle-aged people linked to a blood protein

Warming of the high-mountainous climate sensitive Jammu and Kashmir during the period 1980–2024

Europe’s record heatwave: does the continent have a new climate?

Genetic parameters and genome-wide association for social network traits based on feeder replacement events in beef cattle

Direct Regioselective <i>para</i> ‐Fluorination via I(I)/I(III) Catalysis

ABSTRACT Fluorine scanning is an expansive strategy to refine the physicochemical profile of clinically important small molecule drugs. Of the possible regioisomers derived from mono‐substituted benzenes, the para ‐fluorophenyl motif has emerged as a conspicuous chemotype: Lipitor is a compelling exemplar. When considered through this molecular design lens, the development of effective routes to generate this privileged module, without substrate pre‐functionalization, remains very much in focus. Herein, we report a direct, para ‐selective fluorination that operates under the auspices of I(I)/I(III) catalysis. This enabling strategy leverages the venerable Leonard link inherent to phenylpropanoate and phenylpropanamides to promote a spirocyclization/ para ‐selective activation sequence. Aside from biasing regioselectivity, the C 3 ‐side chain of the Leonard link maps onto a range of common drug scaffolds and allows the substrate scope to be extended to amino acids and dipeptides (up to 94% yield). X‐ray crystallographic analyses of selected products reveal intermolecular Dunitz–Diederich‐type interactions between the C(sp 2 )‐F bond and the π* C═O orbital of proximal amides. It is envisaged that this organocatalytic platform to enable direct para ‐fluorination will facilitate the exploration of organo‐fluorine chemical space.

Quantifying temperature and salinity effects on real-time moisture dynamics of clay-sand liners via explainable machine learning

Coupled Fe ₃ O ₄ ‐Cluster Precipitates and Single Fe‐Atom Catalysts Can Boost Oxygen Reduction via Concomitantly Accelerated Water Dissociation

ABSTRACT Fe–N–C single‐atom catalysts (SACs) can deliver high activity for catalyzing the oxygen reduction reaction (ORR) in alkaline conditions. However, the sluggish water dissociation upon Fe–N 4 active sites limits their proton‐coupled electron transfer (PCET) capability, impeding their practical applications like anion‐exchange membrane fuel cells (AEMFCs). Here, inspired by the known nanoprecipitation behavior in solid‐solution alloys, a residual‐oxygen‐assisted precipitation strategy is undertaken to fabricate coupled Fe 3 O 4 ‐cluster precipitates along with single Fe‐atom catalysts (Fe 3 O 4 /Fe SA @NC), where Fe 3 O 4 clusters are generated by slight oxidation and local enrichment of Fe atoms in the Fe SA @NC matrix. Operando spectroscopy and theoretical calculations suggest that the Fe 3 O 4 ‐cluster precipitates not only induce asymmetric electronic structures of the Fe‐N 4 active center to optimize the OH* adsorption, but also accelerate the water dissociation on Fe‐N 4 sites to boost the PCET steps, thereby promoting the ORR. Notably, the coupled Fe 3 O 4 /Fe SA @NC exhibits superb alkaline ORR performance with a high half‐wave potential of 0.953 V versus RHE. When employed as cathode catalysts, the Fe 3 O 4 /Fe SA @NC demonstrates a high peak power density of 909.3 mW cm −2 and 219.4 mW cm −2 in AEMFCs and Zn‐air batteries, respectively, far exceeding that of the commercial Pt/C catalyst. The novel coupled metal‐oxide cluster/SAC strategy can be exploited as a generic approach for improving electrocatalytic performance.

Attitudes of specialist memory-clinic patients with early symptomatic Alzheimer’s disease towards lecanemab: results from a multicenter survey in Europe

Abstract Lecanemab approval in the European Union (EU) was granted after a delay. This delay resulted in concerns from many stakeholders, but attitudes of patients with early symptomatic Alzheimer’s disease receiving specialist memory-clinic care remained insufficiently assessed. Therefore, we evaluated attitudes of specialist memory-clinic patients with early symptomatic Alzheimer’s disease towards lecanemab in Europe. In this anonymous, international, multicentre, cross-sectional survey conducted from October 14, 2024 to February 18, 2025, a standardized, expert-developed questionnaire assessed attitudes towards lecanemab treatment and EU approval. Before answering four binary questions, participants received brief explanatory information on expected clinical benefit, amyloid-related imaging abnormalities (ARIA), and the increased ARIA risk associated with APOE ε4 homozygosity. The survey was conducted in specialist memory clinics within the European Alzheimer’s Disease Consortium (EADC), the German memory clinic network (DNG), and Austrian memory centers. Available recruitment-flow data were limited to completed questionnaires because the survey was anonymous and distributed locally. 281 patients with early symptomatic Alzheimer’s disease completed the survey. Network-level sample sizes were EADC n = 202, DNG n = 60, and Austria n = 19; country-specific sample sizes within the EADC and response rates were not available. Endorsement was high for both individual treatment with lecanemab (81.9%, 95% confidence interval [CI] 76.8–86.2) and general EU approval (91.8%, 95% CI 87.9–94.7). Endorsement remained substantial, but was lower, in the context of APOE ε4 homozygosity (treatment: 61.2%, 95% CI 55.2–66.9; approval: 76.5%, 95% CI 71.1–81.3). Approval-related questions received higher endorsement than treatment-related questions (84% vs. 72%; p  &lt; 0.001). Support for approval for APOE ε4 homozygotes declined after regulatory recommendations excluded this group (from 87% to 73%; p  = 0.025); this comparison reflects independent respondents completing the anonymous survey before versus after November 14, 2024. Network-level comparisons were descriptive and underpowered for geographic inference. High endorsement within this specialist memory-clinic sample suggests perceived value of access to lecanemab. Greater endorsement for approval than for individual treatment may reflect support for treatment access beyond personal treatment choice, but alternative explanations such as social desirability, acquiescence, misunderstanding, or effects of the survey information cannot be excluded. The findings should not be generalized beyond specialist memory-clinic patients and should be interpreted in view of potential selection and response biases, absent response-rate data, and the brief, non-validated binary questionnaire.

Molecular‐Extrusion‐Driven Halogen Homogenization for Efficient Perovskite‐Silicon Tandem Solar Cells

ABSTRACT Phase segregation is an inevitable phenomenon in wide‐bandgap perovskites, triggering nonradiative recombination and degrading device performance. Herein, we propose a molecular‐extrusion‐driven passivation strategy by introducing bromomethyl‐triphenylphosphonium bromide (TPB‐Br) into perovskite precursors to achieve halogen homogenization. This approach simultaneously passivates bulk and interfacial defects, significantly mitigates phase segregation, and suppresses nonradiative recombination in wide‐bandgap perovskites. As a result, we realize high‐quality wide‐bandgap perovskite films with high crystallinity, low defect density and released residual strain. Champion devices based on these films deliver impressive power conversion efficiencies (PCEs) of 23.63% in the 1.68 eV perovskite sub‐cell and 32.03% (1.05 cm 2 ) in the perovskite/silicon tandem solar cell. More importantly, the unencapsulated devices maintained 90.1%, 81.2%, and 93.4% of their initial PCEs under long‐term storage, thermal‐aging, and light‐soaking for 1200 h, respectively. Our work demonstrates the advantage and feasibility of the synergistic passivation strategy in preparing high‐quality wide‐bandgap perovskite films and tandem solar cells.

Molecular metabarcoding reveals an omnivorous diet in Smaragdinella haminoeid snails and sheds light on their unique evolution

Abstract Smaragdinella marine snails are the only members of the family Haminoeidae and the order Cephalaspidea that inhabit hard substrates in the upper tidal zone, making them of special evolutionary interest. To investigate whether possible novel trophic adaptations coupled with unique morphological traits may underlie this ecological shift, we analysed the gut contents and microbiota of Smaragdinella viridis using DNA metabarcoding (COI and 16S rRNA) and scanning electron microscopy (SEM). COI metabarcoding revealed a diverse assemblage of dietary components dominated by diatoms, rotifers, small arthropods, and fungi. SEM observations partially corroborated these findings, indicating an omnivorous feeding strategy rather than strict herbivory. The gut bacterial community was dominated by Firmicutes ( Mycoplasma ), Proteobacteria ( Vibrio , Photobacterium ), and Fusobacteriota ( Psychrilyobacter , Propionigenium ), taxa associated with the degradation of complex carbohydrates and proteins. Morphological traits in Smaragdinella , including an increased number of gizzard plate ridges, a flattened ovoid shell, and an enlarged foot, most likely facilitate the processing of diverse food items and survival in wave-exposed environments. In addition, the functionality of the gut microbiome may contribute to dietary flexibility enhancing survival in dynamic, resource-variable tidal habitats. The adaptation of these snails to tidal hard bottom habitats could have been prompted by the acquisition of novel morphological features and by a diet shift, but the data do not permit to establish a causal relationship and alternative hypotheses may have to be considered.

Genetically Encoded Lysine‐Selective Photocyclization Enables Phage Display Selection of Cyclic Peptide Binders

ABSTRACT Genetically encoded macrocyclization strategies have expanded the cyclic peptide chemical space accessible to phage display but remain constrained by reliance on cysteine‐based reactivity or hydrolytically unstable lysine‐targeted reagents. Here, we introduce a lysine‐selective and proximity‐induced photocyclization platform enabled by the noncanonical amino acid o ‐nitrobenzyl alcohol lysine ( o ‐NBAK), incorporated into phage‐displayed peptides and activated using the mild and fully biocompatible PANAC photoclick reaction. Photocyclization proceeded efficiently on both purified pIII fusion proteins and intact phage particles with no detectable loss of infectivity, driven by intramolecular proximity between o ‐NBAK and a neighboring lysine, yielding well‐defined stable indazolone macrocycles. Screening PANAC‐cyclized libraries against disease‐relevant proteins produced cyclic ligands with nanomolar to low‐micromolar affinities, and cyclization enhanced proteolytic stability by more than an order of magnitude. These findings establish the first lysine‐selective cyclic peptide library constructed on phage through ncAA incorporation and demonstrate a robust, chemoselective, and broadly applicable strategy for discovering bioactive cyclic peptides.

Early childhood caries at its start: oral health disparities in Thai toddlers

A Multi‐Stimuli Transformational Network of Benzil‐Based Pd(II) Assemblies

ABSTRACT Achieving precise control over supramolecular topology and nuclearity in coordination‐driven self‐assemblies through integration of multiple stimuli remains a challenge. We here introduce ligand L A , based on a flexible and reactive 1,2‐dicarbonyl benzil‐based backbone, able to adopt several conformations. A range of homo‐ and heteroleptic Pd(II) assemblies is formed with different nuclearities and topologies, connected through distinct transformation pathways. In homoleptic systems, folded and open conformations of L A afford the mononuclear complex Pd L A 2 and the lantern‐shaped cage Pd 2 L A 4 . Incorporation of secondary ligands L C or L D induces more expanded L A conformations, yielding cis ‐Pd 2 L A 2 L C 2 or a rare isosceles triangular Pd 3 L A 2 L D 4 ring. These heteroleptic architectures can be interconverted, and both can undergo guest‐induced retro‐cage‐to‐cage transformation to regenerate homoleptic species. Furthermore, L A can also be conformationally locked through condensation of its benzil backbone with 1,2‐phenylenediamine, producing the rigid quinoxaline ligand L B . This transformation can occur in a post‐assembly fashion, converting both homoleptic and heteroleptic L A ‐based structures into the Pd L B 2 complex. The conformation and accessibility of L A reactive sites within the architectures, as well as the nature of the encapsulated guest, strongly influence assembly stability and reactivity in this condensation, reminiscent of how nature controls functional group reactivity through effects of nanoscopic confinement, conformational restriction, and allosteric regulation.

The role of PE teacher exchanges rotation (TER) in teaching quality: moderated mediation of job satisfaction and cross cultural competence

In Silicon Deciphering Atomic‐Scale Structural Units in Peptide Glass

ABSTRACT Peptide glasses are an emerging class of biofunctional amorphous materials, but their atomic‐level structure has remained elusive. Here, we resolve the three‐dimensional (3D) organization of peptide glasses using a cyclic dipeptide model, combining molecular dynamics simulations with 2D solid‐state NMR fingerprinting. Our analysis quantifies three defining hallmarks of the glassy state: (i) pronounced conformational heterogeneity that distinguishes it from the crystalline state; (ii) reorganization of diverse H‐bonding types producing annealing‐rate‐dependent spectral fingerprints; and (iii) dominance of non‐hydrogen‐bonded contacts that generate annealing ‐ temperature‐dependent spectroscopic signatures. These features give rise to molecular clusters with a branched H‐bonding topology that quantitatively reproduce bulk spectroscopic properties, establishing a representative structural unit analogous to the crystalline unit cell. This framework enables the identification of structural organization in amorphous peptide glasses with different thermal histories, paving the way for rational design of functional small‐molecule glassy materials.

QRS fragmentation and long-term cardiovascular outcomes and mortality: a population-based cohort study