Asymmetric catalysts exert control over the reactivity and enantioselectivity of chemical reactions, often through their large size and highly flexible geometries. Most computational approaches rely on a predefined selectivity-determining step and assume that selectivity follows the Boltzmann distribution of transition-state conformers. Going beyond this conventional framework, we constructed a reaction path network that captures the kinetically accessible regions of the potential energy surface. A delta-learning neural network potential (ΔNNP) was constructed and applied to an asymmetric organocatalyst of the imidodiphosphorimidates family, comprising over 200 atoms. The ΔNNP achieved DFT-level accuracy with GFN2-xTB as the baseline. Using the ΔNNP-based single component-artificial force induced reaction (denoted by NNP/AFIR) method, we constructed a reaction path network containing 48,463 paths. Kinetic simulations based on this network predicted the reaction mechanism and enantioselectivity. Within the network, numerous paths, including asynchronous concerted and stepwise mechanisms, were found to be energetically competitive and thus to contribute to the overall kinetics. Traffic volume analysis further revealed that intermediates with negligible yields can still play important kinetic roles. Overall, the NNP/AFIR approach provides a powerful framework not only for deepening mechanistic understanding but also for accelerating the rational design of asymmetric catalytic systems with high reactivity and enantioselectivity.

The continuous failure to account for biological sex is a key impediment to developing effective neuroprotective treatments for ischemic stroke. While epigenetic modulators such as HDAC inhibitors show promise, the mechanisms behind their sexually dimorphic effects are unknown. We present a unique, sex-specific mechanism in which HDAC2 suppression offers substantial resilience to ischemic brain injury by significantly increasing the endogenous oxytocin (OXT) signaling axis. Through integrated in vitro and in vivo models, we show that HDAC2 knockdown not only reduces infarct size and enhances functional recovery, but also does so more effectively in females. We attribute this improved protection to a strong, female-specific increase of OXT and its receptor (OTR). This increased OXT signaling, possibly mediated by estrogen, resulted in significant decreases in apoptosis, neuroinflammation, and oxidative stress. Our findings show that HDAC2 serves as a critical epigenetic brake on a built-in neuroprotective mechanism that, when activated, triggers a therapeutically potent, sex-divergent response. This study sheds light on chemical biology by identifying a druggable epigenetic target that modulates an important neurohormonal circuit. More broadly, it establishes a new paradigm for individualized stroke therapy, shifting away from a one-size-fits-all strategy and toward leveraging innate, sex-specific protective mechanisms to improve treatment efficacy.

Thrombosis underlies many life-threatening cardio-cerebrovascular diseases. Although existing anticoagulants are effective in treating thrombotic diseases, their application is limited due to the concern of bleeding. New anticoagulants that preserve hemostasis have significant clinical importance. Herein, a novel galactosylated glycosaminoglycan, with unique sequence and sulfate substitutions, was isolated from the snail Camaena cicatricose (CCG). Administration of CCG effectively inhibited thrombus formation in a rat venous thrombosis model, which is positively correlated with its ex vivo anticoagulant activity (APTT prolongation), with much lower bleeding risk compared with heparins. It is also effective in preventing thrombosis in the rat arterial-venous shunt model and endotoxin-treated mice. CCG inhibited coagulation by selectively targeting iFXase enzyme complex (FIXa-FVIIIa), in an antithrombin (AT)-independent manner. CCG can bind to FIXa with high affinity and decrease the affinity of FIXa-FVIIIa, with no effect on the FIXa activity. Compared with heparins, it cannot bind to AT and exhibits high selectivity for iFXase inhibition, consistent with its absence of the specific heparin pentasaccharide sequence. Overall, the snail galactosed glycosaminoglycan inhibits thrombosis without affecting hemostasis via disrupting iFXase (FIXa-FVIIIa). CCG may represent a promising candidate for thrombosis treatment without increased bleeding risk.

Glycolamide, a precursor to amino acids, is synthesized efficiently at cryogenic temperatures on interstellar nanoparticles through radical coupling mechanisms.

Dynamic hydrogels are powerful biomaterials whose performance in drug delivery, tissue engineering, and related applications depends on mechanical properties that remain difficult to predict. We introduce a simple, quantitative framework for tuning hydrogel mechanics through competitive inhibition, where small-molecule competitors reversibly disrupt cross-linking. Inspired by Michaelis-Menten kinetics, the model defines an apparent cross-link association constant, K a,app, that decreases as a function of competitor concentration and binding affinity. Incorporating K a,app into traditional network theory enabled quantitative prediction of modulus. When using boronate ester networks and small-molecule competitors bearing diol motifs spanning 4 orders of magnitude in affinity, the predicted and measured moduli agreed within 10% relative error. A Langmuir-type decay function further captured stress-relaxation behavior by accounting for changes in effective cross-link density. Extending the approach to hydrazone-cross-linked gels confirmed its generality across distinct dynamic chemistries and exchange mechanisms. Finally, we demonstrate practical relevance by transforming a nonextrudable gel into a hand-injectable material through competitor addition. This framework establishes competitive inhibition as a universal and predictive strategy for designing adaptive soft materials.

Spin correlations between radicals underpin key biological processes, and spin relaxation describes their decay due to environmental interactions. Radical pairs involving lipid peroxide radicals in bilayers have been proposed as a source of magnetic field effects (MFEs) in lipid autoxidation, but their viability has been questioned due to rapid relaxation in dynamic membranes. This study investigates whether MFEs can persist in lipid bilayers despite spin relaxation. Using an integrative approach combining all-atom molecular dynamics simulations, density functional theory (DFT) calculations, and spin dynamics modeling using Bloch-Redfield-Wangsness relaxation theory, we investigate a palmitoyl-linoleoyl-phosphatidylcholine (PLPC) model membrane containing 13ze-lipid peroxide radicals. We identify the peroxide group rotation and the lipid backbone dynamics as key drivers of spin relaxation. By computing g-tensors and hyperfine coupling constants via DFT and incorporating their molecular-dynamics-derived fluctuations into spin-dynamics simulations, we assess relaxation from hyperfine interactions, g-tensor fluctuations, and spin-rotational coupling. Our results demonstrate that MFEs persist in lipid bilayers despite thermal motion. Relaxation is dominated by g-fluctuations, which enhance MFEs at high magnetic fields. Surprisingly, our calculations also suggest possible MFEs in weak magnetic fields. These findings broaden the understanding of biological MFEs and highlight potential biomedical implications for ferroptosis, cancer, and oxidative stress-related diseases.

Here we report the cloning and complete in vitro reconstitution of the enzymes of the riboflavin catabolic pathway.The pathway begins with the oxidative removal of ribose to form lumichrome,which is then solubilized by a P450-catalyzed oxidation of the C7methyl group, followed by hydrolytic degradation of the C-ring pyrimidine.Loss of C4, in a thiamin-dependent heterocycle decarboxylation, isfollowed by a xanthine oxidase and Rieske dioxygenase-mediated degradationof the quinoxaline ring. Catechol dioxygenase then catalyzes the conversionof the resulting A-ring-derived catechol to form 4-methyl-6-carboxypyrone.This is cleaved through a hydrolysis/hydration/retroaldol sequenceto form pyruvate and acetoacetate, both of which are substrates forthe citric acid cycle. The elucidation of the riboflavin catabolicpathway fills an important gap in our understanding of riboflavinmetabolism and sets the stage for evaluating the impact of riboflavincatabolism on human and animal nutrition as well as the function oflumichrome as a quorum sensor mimic in the rhizosphere.

Precise, sustainable, and scalable bandgap tuning ofmetal halideperovskite (MHP) nanocrystals (NCs) is critical for their integrationinto advanced optoelectronic and photocatalytic systems. Photoinducedanion exchange reactions (PIAERs) enable uniform halide delivery withspatiotemporal control, yet their complex parameter space has limitedmechanistic understanding and rational optimization. Here, we introducea material-efficient fluidic self-driving laboratory (FSDL) that integratesa single-droplet microfluidic photoreactor, multimodal insitu spectroscopy, and a multiobjective Bayesian optimizationframework to navigate the ∼106-dimensional designspace of PIAERs autonomously. Through machine learning-guided explorationof this coupled parameter landscape, the FSDL rapidly identifies synthesisconditions that simultaneously maximize photoluminescence quantumyield and minimize emission line width for any target emission wavelengthacross the UV–visible spectrum. Mechanistic trends derivedfrom surrogate modeling revealed distinct kinetic regimes for Br–→Cl– and Br–→I– exchanges, governed respectively byreaction time and photon flux, enabling reaction-specific tuning strategies.Critically, synthesis protocols discovered at the droplet scale (∼10μL) were directly translated to continuous-flow operation (∼50–250mL·day–1) without reoptimization, maintainingoptical performance and establishing knowledge scalability across4 orders of magnitude in throughput, with low energy demand. Thisstudy demonstrates a reproducible, mechanistically informed, and industriallyrelevant route for programmable light-directed bandgap tuning in MHPNCs.