The formation of Tau amyloids is a hallmark of several neurodegenerative diseases, called Tauopathies, including Alzheimer's disease. In different Tauopathies, Tau amyloid filaments adopt a distinct structure, highlighting the existence of disease specific pathways. In this pathological context, lipid metabolism is heavily disrupted, leading to a perturbation of membrane composition. Lipid membranes have been shown to nucleate tau aggregation under some conditions. However, no general model has been established to explain how the organization of the lipid membrane modulates Tau aggregation. Here, we combined biochemistry and biophysical tools, including EPR spectroscopy, to investigate the mechanisms of membrane-induced Tau aggregation. After showing the importance of the electrostatic interaction between Tau and anionic lipids, we investigate how the amount and density of charges influence Tau aggregation. This work allows us to draw a general model where membrane-induced Tau aggregation is a two-step process. First, the binding to the membrane through electrostatic interactions is a necessary but not a sufficient step. Second, the nucleation of Tau amyloids at the membrane surface occurs only when specific conditions are fulfilled, i.e., high surface density altering Tau conformation and spatial proximity between aggregation-prone conformers. A direct implication of this model is that local membrane heterogeneities, such as phase separation or lipid rafting, are strong modulators of Tau aggregation. This work provides the molecular basis to predict how different membrane states regulate Tau aggregation.
Large language model (LLM)-based agents are reshaping how self-driving laboratories (SDLs) may support autonomous chemical and materials research. Although SDLs have enabled major advances in mechanized experimentation and closed-loop optimization, their scientific utility remains limited when tasks require literature-grounded reasoning, adaptive coordination, and interpretation beyond predefined search spaces. In this perspective, we examine how LLM-based agents may help bridge this gap by translating scientific intent into machine-executable workflows. We propose a five-module frameworkComprehension, Design, Execution, Analysis, and Optimizationto organize the capabilities required for agent-enabled SDLs, and we discuss representative systems, including Coscientist, ChemCrow, LLM-RDF, and AI-Chemist, as milestones in this transition. We also emphasize that agent-enabled SDLs should not be conflated with autonomous scientific discovery. Safety in physical execution, hardware interoperability, reproducibility, and auditability remain central challenges. To support a more critical assessment, we introduce the HYDRA framework for benchmarking trustworthy agent-enabled workflows. Finally, we outline a human-AI-SDL collaborative model in which scientists remain responsible for scientific framing, interpretation, and oversight.
Supramolecular polymer blends (SPBs) offer tunable morphologies that dictate their macroscopic properties, yet their rational design is limited by the absence of predictive structure-morphology models. Here, we introduce a data-driven high-throughput workflow that integrates modular polymer synthesis, robotic formulation, automated morphology characterization, and machine learning (ML) for accelerated SPB discovery. Using a plug-and-play synthetic strategy, 33 hydrogen-bonding end-functional homopolymers were prepared and orthogonally combined to generate 260 SPBs in 1 day. A fully automated atomic force microscopy (AFM) pipeline enabled systematic imaging, producing 2340 morphology data sets with minimal human intervention. Domain spacings were extracted through complementary image-processing methods and used to train ML models. A support vector regression (SVR) model accurately predicted target phase-separation sizes (50, 100, and 150 nm), which were experimentally validated. This work demonstrates the power of coupling high-throughput experimentation with ML to accelerate morphology discovery and provides one of the first large-scale experimental data sets for supramolecular polymer systems.
Photolabile protecting groups (PPGs) are central tools for achieving precise spatial and temporal control of bioactive molecules in living systems. Their practical utility is critically dependent on efficient uncaging under biologically compatible conditions. Here, we report a coumarin-based PPG specifically optimized for 488 nm excitation, a ubiquitous laser line in fluorescence microscopy, enabling uncaging under irradiation conditions comparable to those used for GFP imaging. We applied the optimized PPG to cage the C-terminal carboxylate of monomethyl auristatin F (cMMAF), converting a membrane-impermeant antimitotic agent into a cell-permeant prodrug that regenerates an impermeant MMAF upon photoactivation. We showcase its utility through the light-triggered release of MMAF using irradiance typically used for imaging. We demonstrate the ability to confine the pharmacological activity of MMAF to a single cell, sparing adjacent cells (neighboring effect).
Artificial ion transporters with integrated selectivity and stimuli responsiveness remain challenging to design. Herein, we report a highly efficient 18-crown-6-ether-derived K+ carrier (EC50(K+) = 0.28 μM, 0.14 mol % relative to lipid), governed by a pH- and concentration-dependent self-regulatory mechanism centered on host-guest interaction through amino group functionalization. This minimalist design enables pH-gated ion transport with enhanced K+/Na+ selectivity (R K+/R Na+ = 7.2). Furthermore, the carrier acts as a potent ionic perturbagen, disrupting cytosolic K+ homeostasis and efficiently triggering mitochondria-associated apoptosis, which underscores its potential as an anticancer agent. This work demonstrates that built-in dynamic control is key to intelligent function in minimalist transmembrane systems.
Interactions between individual atoms underpin the structure and behavior of matter. These interactions govern atomic positions and dynamics, as well as the organization of electronsparticularly in the frontier region. Because electrons lie at the core of chemical phenomena, numerous theoretical frameworks have been developed to rationalize the molecular structure and properties. Electronic motion within molecules and the resulting induced currents provide powerful probes of the molecular or supramolecular structure, building on and going beyond molecular orbital and valence bond theories. In particular, current density offers a spatially-resolved description of the electronic response to external perturbations, enabling direct analysis of electron delocalization and magnetic response in molecular systems. In this work, the effect of relativistic spin-orbit (SO) coupling on the strength and topology of the magnetically induced current density (MICD) is analyzed in depth for a series of model heavy-atom hydrides at the four-component Dirac-Kohn-Sham level. For the most simple molecules, TlH, HAt, and AuH, we demonstrate a connection between the SO effects on the molecular geometry, strength and topology of MICDs, and ligand 1H NMR shielding. For model HMX molecules, where M = AuI, HgII; X = F, Cl, Ph, CH3, H, SiH3, BH2, the hydride deshielding due to the slight elongation of the M-H bond upon increasing the trans-ligand influence (TLI) of X is shown to be marginal when compared to that originating from the electronic SO effect. In particular, the inclusion of SO effects gives rise to highly localized paratropic MICD vortices on the hydride position of those complexes bearing strong TLI ligands. Our results disprove the previously proposed governing role of the current around the metal atom (similar to the classical Buckingham-Stephens model for transition metal hydrides) associated with TLI-induced variations in the metal-hydrogen bond length in determining the characteristic ligand 1H NMR shifts.
[This corrects the article DOI: 10.1021/jacsau.5c01642.].
Amphiphilic nucleic acids enable programmable supramolecular assembly toward functional nanosystems, yet their typical construction via the covalent conjugation of hydrophobic groups limits architectural versatility. Achieving noncovalent amphiphilic nucleic acid architectures remains a significant challenge. Here, we report a strategy to assemble supra-amphiphilic nucleic acids through noncovalent interactions. The building blocks are partially phosphorothioate-modified single-stranded DNA and hydrophobic, atomically precise gold nanoclusters (Au NCs). The assembly is driven by hydrophobic contacts between nucleobases and the ligand shell of the Au NCs and coordination between the phosphorothioate backbone and the metal core. By precisely modulating the length of the hydrophilic DNA segment, these supra-amphiphiles self-assemble in the presence of Mg2+ into well-defined micelles with tunable sizes. The surface-exposed DNA sequences retain their hybridization capability, enabling programmable higher-order assembly through base complementarity. Furthermore, these nanocluster-based micelles can be organized into spatially addressable arrays via DNA origami scaffolds. This strategy establishes a versatile platform for constructing functional nanomaterials with applications in catalysis, bioimaging, and nanodevices.
16α-Methyl glucocorticoids are a renowned family of steroid molecules with diverse important pharmaceutical applications, and development of innovative, practical, and divergent synthetic routes toward these steroids is highly desirable. Herein, we report a unified stereocontrolled synthesis of five 16α-methyl glucocorticoid pharmaceuticals, namely, (+)-dexamethasone, (+)-mometasone, (+)-flumethasone, (+)-halometasone, and (+)-vamorolone, in 9.9-26.8% overall yields starting from commercially available 9α-hydroxyandrost-4-ene-3,17-dione (9α-OH-AD), featuring a telescoped in-flow synthesis consisting of an acidic resin-mediated dehydration and an enzyme-catalyzed C1,2-dehydrogenation, an Au-(I)-catalyzed hydration of enyne to enone, and a conjugate addition-dihydroxylation sequence-enabled construction of the chiral C16α-methyl and C17α,21-dihydroxyacetone moieties. This established chemoenzymatic platform provides a versatile and generic access to other valuable 16α-methyl glucocorticoids.
Rapid discrimination of colorectal cancer (CRC) at the time of tissue sampling remains clinically challenging. Although DNAzyme-based assays enable selective analysis of complex biological samples, their diagnostic translation is constrained by undefined endogenous activators. Here, using an iterative DNAzyme activity-guided isolation strategy that integrates chromatographic fractionation with affinity enrichment, we identified malic enzyme 1 (ME1) as the molecular activator of a DNAzyme newly selected against colorectal cancer tissue lysates. The ME1-triggered catalytic reaction was then translated into a lateral flow format, enabling instrument-free visual detection within 35 min. In clinical specimens, the platform discriminated CRC from low- and high-grade intraepithelial neoplasia with an AUC of 0.98. By defining the molecular basis of DNAzyme activation and coupling it to a portable readout, this work provides a direct route from evolving DNAzyme probes for sensing complex tissues to rapid, near-point-of-care detection of CRC.
Recent developments in photoactive transition metal complexes have largely centered on mononuclear systems. Polynuclear architectures that are capable of metal-metal interactions and cooperative effects, such as enhanced luminescence or multielectron photoreactivity, have received less attention, however. A key challenge in advancing such systems lies in achieving structural precision to prevent the formation of complex mixtures, including ill-defined oligomers of variable lengths. Here, we report the controlled assembly of discrete dimers composed of stacked square-planar complexes, notably without the use of bridging ligands, but also with them. Using new tridentate pincer-type isocyanide ligands with varying backbones and coordination bite angles, we obtain rhodium-(I) complexes that can be further modulated at the fourth coordination site. Pincer bite angle, the auxiliary ligand at the fourth coordination site, and solvent polarity control the distinct aggregation behavior of the complexes. The resulting dimers exhibit metal-metal interactions that produce near-infrared fluorescence and substantially longer triplet excited-state lifetimes than the nonemissive monomers. This work demonstrates how molecular design and synthetic control over cooperative interactions between individual metal complexes can give rise to emergent photophysical properties. It establishes design principles for precise supramolecular assembly of photoactive coordination units, highlighting new opportunities for photonic applications beyond mononuclear systems.
Although the electrochemical CO2 reduction reaction (CO2RR) plays a crucial role in achieving carbon neutrality, its practical deployment is still limited by insufficient catalytic activity and product selectivity. Elevating pressure has been recognized as an effective strategy to improve CO2RR performance, yet the underlying mechanisms remain insufficiently understood. Here, we establish a quantitative framework combining distribution of relaxation times analysis and kinetic modeling to elucidate pressure effects on mass-transport and charge-transfer resistances and competitive coverages of *COOH, *CO, and *H. The results demonstrate that the pressure effect is finite. While increasing pressure initially boosts performance (1-10 bar) by enhancing mass transport and increasing *COOH/*CO coverages, this pressure effect decreases between 20-30 bar. This is because the reaction becomes kinetically controlled and intermediate coverage (the sum of *COOH and *CO) reaches saturation, leading to further pressurization being ineffective. Finally, in situ spectroscopic characterization confirms the increased *CO signal intensity under high pressure, supporting the mechanistic conclusions. The quantitative methods carried out in this work offer fundamental insights into pressure-governed mass transport and reaction kinetics.
This study employs density functional theory (DFT) calculations and ab initio molecular dynamics (AIMD) simulations to elucidate the mechanism of Ni0-catalyzed C-(sp2)-F bond activation and unveils the pivotal role of alkali metal cations in modulating enantioselectivity. Results reveal that the reaction between indanone and NaO t Bu in situ generates an enolate intermediate with the keto-enol tautomerism character, which enables inert C-(sp2)-F bond activation, affording both enol- and keto-type products. Significantly, in the presence of Ni0(cod)2, the enolate coordinates to the Ni0 center to form a highly nucleophilic Ni0(enolate)-ate complex. Computational results show that the Ni0(enolate)-ate complex is an active species for the C-(sp2)-F bond activation, which chemoselectively achieves a keto-type product. This unexpected Ni0-mediated SNAr pathway, which involves a Na+-nucleophile interaction, exhibits a lower activation energy than the other four pathways. The characteristic reactivity of the Ni0(enolate)-ate complex is attributed to the synergistic effect arising from the nucleophilic Ni0 center and Lewis acidic countercation of the Ni0(enolate)-ate complex. AIMD simulations further corroborate that an ensemble of multiple noncovalent interactions provides an indispensable driving force for the activation of the inert C-(sp2)-F bond. Moreover, the alkali metal cation plays a decisive role in modulating both the reactivity and enantioselectivity. The experimentally observed R selectivity originates from a critical cation-π interaction that preferentially stabilizes the (R)-transition state, while the high reactivity is attributed to hydrogen bonding, which effectively stabilizes the transition state.
Pesticides are essential for maintaining the global crop productivity and food security. Improving their efficiency and minimizing their environmental impact require a detailed understanding of their uptake and translocation in plants. However, existing techniques for tracking pesticides in living plants are largely destructive, ex situ, and incapable of real-time monitoring, which limits progress toward sustainable agriculture. To address this gap, we developed noninvasive, ratiometric surface-enhanced Raman scattering (SERS) nanosensors that enable in situ, real-time mapping of pesticide dynamics in plants. The nanosensors feature gap-enhanced gold nanorods (AuNNRs) with 4-mercaptobenzonitrile (4-MBN) embedded in the nanogap as a stable internal standard for ratiometric SERS quantification. Once delivered into the leaf intercellular spaces, the nanosensors create functional "sensor-equipped" plants for real-time mapping of pesticide distribution. Using this platform, we compared pesticide translocation under different application methods. The results show that root-irrigated tricyclazole moves upward in a concentration- and time-dependent manner, whereas foliar-sprayed pesticides are poorly absorbed due to the barrier posed by the leaf cuticle. Furthermore, commercial tricyclazole formulations are taken up and transported more efficiently than pure reagent-grade compounds. This SERS-based sensing strategy offers a powerful tool for optimizing pesticide delivery and supports the development of precision agriculture practices that are aimed at sustainability.
van der Waals (vdW) interactions are known to be important in chemical and biological processes, yet the understanding of their roles in polyatomic complex-forming reactions remains quite limited. In this work, we combine experimental and theoretical approaches to investigate the kinetics and mechanisms of the O-(1D)+C2H4 reaction. We find that vdW interactions between O-(1D) and ethylene cause a long-range submerged peak to form associated with a vdW well, decreasing the rate coefficients, altering their temperature dependence, and transforming the channel of O-(1D) attack on the H-C bond to a minor one. The underlying microscopic mechanism is revealed and is shown to differ significantly from the conventional insertion-type mechanism. The reaction channel involving O-(1D) addition to the CC bond is identified as dominant. The calculated rate coefficients are in very good agreement with experimental measurements. The product H atom yields are reported and elucidated. This work demonstrates that weak vdW interactions can be used to control chemical reactivity and reaction pathways, providing new insights into the kinetics and mechanisms of complex-forming reactions involving excited-state atoms.
Tuberculosis (TB), a respiratory infectious disease caused by Mycobacterium tuberculosis (M.tb), poses a serious threat to human health due to its complex pathogenesis and limited treatment options. Diagnosing TB is challenging due to the poor sensitivity and specificity of current methods, while drug-resistance mechanisms further diminish the effectiveness of treatment. In this study, we developed a fluorescent nanoprobe named BM2-AgNCs by functionalizing silver nanoclusters with the DNA aptamer BM2. BM2-AgNCs facilitate efficient detection of lipoarabinomannan (LAM) and exhibit effective anti-M.tb activity, reducing bacterial viability by 80% both intracellularly and extracellularly. BM2 enhances the biocompatibility and targeting capabilities of AgNCs, which retain their fluorescence properties and antibacterial activity. AgNCs can serve as efficient quenchers of the FAM-labeled BM2, with fluorescence recovering in the presence of targets. Leveraging this property, we constructed a biosensor for the highly sensitive detection of LAM and for fluorescent tracking of M.tb. Regarding treatment, we demonstrated that BM2-AgNCs significantly inhibited M.tb activity while inducing M1 polarization in macrophages, resulting in a synergistic therapeutic effect. Furthermore, BM2-AgNCs can counteract immune evasion of M.tb by promoting phagolysosomal maturation. This work presents an integrated approach for TB diagnosis and treatment based on the fluorescent nanoprobe, utilizing the diverse fluorescent properties of the nanoprobe to visualize the underlying mechanisms.
Polycyclic bacterial specialized metabolites such as anthraquinones, angucyclines, and tetracyclines are predominantly produced by type II polyketide synthase (PKS) systems and represent an important source of antibiotics and anticancer agents. While type II PKS pathways are well characterized in Gram-positive bacteria, their biosynthetic potential in Gram-negative bacteria remains largely unexplored. Here, we report the discovery and activation of a cryptic type II PKS biosynthetic gene cluster from the myxobacterium Aggregicoccus edonensis MCy10622. Using a rapid PCR-based cloning and promoter-exchange strategy, the compact gene cluster was heterologously expressed in Myxococcus xanthus DK1622, leading to the production of two previously unknown specialized metabolites, aggregicyclin and oxyaggregicyclin. Structural analysis revealed an unusual polycyclic scaffold featuring a wide-spanning biaryl ether linkage. Biosynthetic analysis supports an early diversification event during first-ring cyclization as the basis for product divergence. Aggregicyclin exhibits antibacterial activity against Staphylococcus aureus and cytotoxicity against human cancer cells. Together, these findings expand the current knowledge of type II polyketide biosynthesis in Gram-negative bacteria.
Organic optoelectronic materials (OOMs) are pivotal for advancing technologies such as organic photovoltaics and light-emitting diodes. Traditional methods for discovering new OOMs are inefficient and limited by chemical space exploration. We introduce O 2 -GEN, a novel framework leveraging a 3D pretraining backbone trained on a diverse data set of over ten million molecules, enabling comprehensive exploration of chemical space. O 2 -GEN is effective at generating novel fused-ring systems and conjugated fragment assemblies. It significantly outperforms existing models in these specific tasks in speed and chemical structural validity, particularly for larger molecules. The framework supports both global and local generation modes, allowing for the design of new molecules or modifications of existing molecules. Additionally, O 2 -GEN integrates a property selector fine-tuned with density functional theory data, enabling precise multiproperty screening. Overall, our O 2 -GEN allows the construction of data sets with multiproperty-biased distributions tailored to specific application scenarios, facilitating the discovery of novel optoelectronic materials.
We have developed a multimodal biosensing platform for the in situ monitoring of exosomal RNAs without cell lysis. This system employs a cascade of aptamer recognition, rolling circle amplification (RCA), and G-quadruplex/hemin signal transduction. Electrochemical and colorimetric outputs are seamlessly integrated using an inverse-variance-weighted data fusion algorithm, achieving ultrasensitive and precise detection. Applying this method to oxidative stress-induced cellular senescence, we successfully constructed a comprehensive RNA dynamic map. This analysis revealed time-resolved molecular logic: miRNA-21 displayed transient early upregulation as an adaptive response, while miRNA-29c and miRNA-34a accumulated progressively at later stages, driving irreversible senescence. Clinical validation further demonstrated the platform's efficacy in staging Alzheimer's disease (AD), where the integrated trimodal signals effectively distinguished between mild cognitive impairment (MCI) and progressive AD stages. Detailed statistical analysis identified exosomal miRNA-21 and miRNA-34a as significant independent risk factors, establishing a robust molecular signature for precision AD diagnostics. This work establishes an amplified, multimodal biosensing framework for profiling exosomal RNA communication during aging, offering a powerful tool for stage-resolved biomolecular mapping in precision geroscience.
Understanding crystallization modifier mechanisms remains a central challenge in crystal engineering, particularly for growth promoters whose modes of action are far less understood than inhibitors. Here, we investigate riboflavin (RF) as a crystallization promoter for ammonium urate (NH4HU) using combined microfluidic experiments and molecular dynamics simulations to elucidate its underlying mechanism. We discovered that RF reorganizes neighboring urate ions into growth-compatible coplanar conformations, contrasting with their naturally preferred growth-incompatible stacked arrangements. This identifies a solution-phase preassembly mechanism for enhancing crystal growth, distinct from classical monomer addition or traditional surface-based pathways. We found that the modifier's ability to reorganize surrounding urate correlates with its aromatic ring size, explaining why the large RF framework exhibits unique promotion effects among known modifiers. Guided by detailed contact analysis between RF and urate ions, we rationally designed RF derivatives with enhanced promotion capabilities and experimentally validated their predicted performance, with the natural metabolite lumichrome showing a 40% growth enhancement compared to the 20% enhancement observed for RF. Our findings establish solution-phase preorganization as a viable mechanism for crystallization control.