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Biocatalytic Alkylation of Ambident Nucleophiles Enables Selective <i>N</i> ‐Functionalization of Heterocycles and Late‐Stage Modifications
Abstract The alkylation with electrophilic haloalkanes is a key methodology in chemical synthesis to build desired molecules. Although alkylation of compounds bearing a single nucleophilic site is routine, the selective alkylation of polyfunctional molecules with multiple competing nucleophilic positions of comparable reactivity is often very challenging. In this work, we report a generalizable solution for selective alkylation chemistry that combines the selectivity of enzyme catalysis with the reactivity of off‐the‐shelf alkylation reagents. We employ engineered transferases in a modular cyclic cascade and use functionalized N ‐heteroarenes as challenging proof‐of‐concept substrates. This catalytic alkylation approach is mild, highly chemo‐ and regioselective, proceeds on gram‐scale, provides rapid access to important N ‐alkylated heterocyclic building blocks and enables challenging late‐stage alkylations. This study demonstrates a generalizable strategy to streamline synthetic routes to many pharmaceutically important compounds by selective biocatalytic alkylation of polyfunctional molecules and ambident nucleophiles.
Ayahuasca-assisted meaning reconstruction therapy as an early resource for bereavement: a non-randomized clinical trial
Abstract Preliminary evidence suggests that ayahuasca may alleviate severe grief symptoms. This three-arm, sequentially allocated, open-label study examines the therapeutic changes associated with ayahuasca-assisted meaning reconstruction therapy (A-MR) compared to meaning reconstruction therapy alone (MR) and a no-treatment control (NT). A total of 84 adults experiencing severe grief within 12 months of losing a first-degree relative were allocated to A-MR (n = 28), MR (n = 28), or NT (n = 28). Grief severity, prolonged grief disorder symptoms, post-traumatic growth, and quality of life were assessed at baseline, after the intervention, and 3 months post-intervention. Ayahuasca was well tolerated, with no serious adverse events reported. All groups showed significant grief severity reduction (A-MR: p < .0001, d = 2.44; MR: p < .0001, d = 1.84; NT: p < .002, d = 0.74). Greater reductions were observed in the A-MR compared to MR (p = .012, d = 0.86) and NT (p = .0008, d = 1.07). A-MR was also associated with significant improvements in prolonged grief symptomatology, post-traumatic growth, and quality of life, with medium-to-large effect sizes. This is the first controlled prospective study to provide preliminary support for A-MR as a safe and potentially effective intervention for severe grief, though replication in larger randomized trials is required.
Precision Screening and Surgical Resection of Pan‐Cancer Using a Tandem‐Locked NIR‐II Fluorescent Probe with Optimized Activation Efficiency
Abstract The development of fluorescent probes for cancer detection and imaging that balance high sensitivity, precision, and broad applicability remains a significant challenge. Although “dual‐locked” probes have been devised to enhance diagnostic accuracy via two biomarkers, most fall short in sensitivity, response time, and generalizability for pan‐cancer use. We address these gaps with ACy‐H‐NTR , a cascaded‐activation, doubly quenched NIR‐II probe. Engineered to respond to hypoxia and acidity—universal tumor hallmarks—it offers fast response, high sensitivity, and specificity for pan‐cancer screening and imaging. In contrast to existing probes, its tandem‐locked design ensures robust activation exclusively within pan‐tumor microenvironments, effectively reducing false positives and delineating precise diagnostic boundaries. Its NIR‐II emission and “activation–retention” mechanism enhance tumor imaging efficacy and effectively tackle issues of rapid clearance and background noise, achieving 4.9‐fold higher tumor‐to‐normal (T/N) ratio than ICG and retaining tumor specificity for over 2 days. In pan‐cancer models, it enabled high‐contrast imaging (T/N ∼7.8) and precise resection with sub‐2 mm margins. Crucially, it differentiates human carcinoma from adjacent tissues with sharp boundaries, confirming clinical potential. By integrating a tandem‐locked and doubly quenched design that simultaneously optimizes activation efficiency, NIR‐II imaging capabilities, and activation‐retention mechanisms, this probe overcomes current limitations to enable precise pan‐cancer identification and surgical navigation.
A ddPCR method for simultaneous detection and quantification of Salmonella enterica, Staphylococcus aureus, Listeria monocytogenes, and Bacillus cereus in foods
IL4I1 overexpression protects against nonalcoholic fatty liver disease in part by inhibiting the AKT/FOXO1 pathway-mediated Th17 cell differentiation
Tertiary Phosphine Diversification via Photochemical P─C Chemoselective Cleavage of Phosphonium Salts
Abstract Differentially substituted phosphines are indispensable in medicines, materials, and catalysis, yet their customizable synthesis, traditionally depending on unstable P─H/halogen reagents, remains formidably challenging. Here, we report a photoredox strategy enabling controllable aryl substitution through chemoselective P─C cleavage. By engineering electron donor‐acceptor complexes between phosphonium salts and tertiary amines, this metal‐free protocol realizes three consecutive hydrocarbyl exchanges for delivering tri‐diverse‐aryl phosphines with transition metal contamination elimination and broad functional group tolerance including unprotected amines and hydroxyls, facilitating late‐stage modification of drugs/commercial ligands and construction of P,O,S‐tridentate architectures and chiral P‐stereogenic centers. Mechanistic studies reveal the dynamic pentacoordinated‐phosphorane‐complex formation nature and the radical‐intermediate pathway, while the chemoselectivity originates from different P─C bond strengths. This work establishes a modular and sustainable platform for programming‐level precision phosphine engineering.
A shared frailty model for assessing time to seizure remission in adults with epilepsy
Abstract Epilepsy remains a significant global health concern with increasing prevalence and incidence. This study aimed to model the time to first remission among epilepsy patients at Jimma University Medical Center, Ethiopia, using parametric shared frailty models. A retrospective study was conducted on epilepsy patients treated between 1st January 2018 and 30th December 2023. All patients received anti-seizure medications (ASMs) upon enrollment. Additionally, 12% of the cohort had received ASM treatment prior to enrollment outside JUMC. Log-logistic, log-normal, and Weibull baseline hazard functions were combined with gamma and inverse Gaussian frailty distributions to model time to first remission. Model selection was based on the Akaike Information Criterion (AIC). The median time for patients to achieve their first seizure remission was 38 months, with 45.5% (95% CI: 40.9–50.1%) of patients experiencing remission. The variability in remission times across different districts, as modelled by the log-normal-inverse Gaussian shared frailty model, was estimated to be θ = 0.454. Patients aged 25–44 years (acceleration factor 1.13 [95% CI 1.04–1.23], p = 0.005], those with more than five pre-treatment seizures (acceleration factor 1.08 [95% CI 1.02–1.15, p = 0.018]), and individuals with focal epilepsy (acceleration factor 1.15 [95% CI 1.07–1.25, p = 0.003]) were associated with significantly longer remission times compared to other patient groups while those with good treatment adherence (acceleration factor 0.88 [95% CI 0.81–0.96, p = 0.005]) were associated with significantly shorter remission times compared to poor treatment adherence. The log-normal-inverse Gaussian shared frailty model offers valuable insights into the variability of remission patterns among patients. Specifically, individuals aged 25–44 years, those with a history of more than five pre-treatment seizures, and patients with focal epilepsy experienced significantly longer remission times. In contrast, patients who adhered well to their treatment regimens achieved remission more quickly than other groups.
Peroxynitrite detoxification by Trypanosoma cruzi heme peroxidase supports parasite survival in macrophages
Ultra‐Fast Self‐Powered Heterojunction Blue‐Light Photodetector Based on Boronate‐Ester‐Linked COF‐5
Abstract Covalent organic framework materials have recently garnered significant interest from the scientific community due to their fascinating properties that include highly ordered porosity, structural versatility, high chemical and thermal stabilities, and facile surface modification. Herein, for the first time, we present the design and fabrication of a self‐powered blue‐light photodetector based on boronate‐ester‐linked 2D covalent organic framework (COF‐5) film, synthesized using hexahydroxytriphenylene and 1,4‐phenylenediboronic acid organic linkers. Specifically, we have developed a COF‐5/n‐Si photodetector that exhibits an ultra‐short rise response time of 41 µs and a decay response time of 222 µs under 0 V bias. Our work integrated rapid response times and the distinctive benefit of self‐powering, setting it apart from existing COF‐based photodetectors.
Optimization of immobilized activated sludge performance in electro-sprayed matrices for treatment of cellulose industry wastewater
Two distinct protein-protein interfaces drive cooperative binding of the herpes simplex virus protein ICP8 to ssDNA, filament formation and annealing essential for viral replication
Regioselective Hydration of Terpenes with Cofactor‐Independent Carotenoid 1,2‐Hydratase
Abstract Terminally hydrated terpenes are highly sought‐after compounds in the flavor and fragrance industries. However, their selective synthesis remains a considerable challenge in catalysis. Regioselective hydration of non‐activated C─C double bonds is typically hindered by poor selectivity and low atom efficiency in conventional methods. In this study, we harness the underexplored potential of the acyclic carotenoid 1,2‐hydratase from Rubrivivax gelatinosus IL144, employing it as a whole‐cell biocatalyst for cofactor‐independent terminal hydration of a diverse range of terpenes. This enzyme demonstrates exceptional activity across more than 20 C 12 ─C 20 terpenes and shows notable tolerance to various functional groups, establishing it as a valuable tool for sustainable organic synthesis. We emphasize the critical influence of expression system choice in maximizing enzymatic performance, enabling high‐yield transformations on the gram scale. Through a combination of homology modeling, consensus analysis, and targeted mutagenesis, essential residues involved in catalytic activity were identified. Notably, enhanced catalytic efficiency was only achievable through the epistatic effect of three specific mutations. These findings highlight the biocatalytic potential of acyclic carotenoid hydratase, offering a green and efficient route to the production of valuable tertiary alcohols.
Visibility graph analysis for educational data: potentials and a case study of predicting at-risk online students
Sidt2 inhibits islet β-cell dedifferentiation by regulating insulin secretion
Chiral Tin‐Oxo Cluster Matrices with Fluorophore Embedment for Multichromatic Circularly Polarized Luminescence
Abstract Tin‐oxo clusters, characterized by their well‐defined chemical compositions and architectures, are multi‐metal aggregates composed of Sn‐oxide cores and surface ligands. Chirality, a fundamental characteristic governing biological recognition and signal transduction, remains underexplored in stannate clusters compared to extensively studied precious metal clusters. Herein, three enantiomeric pairs of chiral tin‐oxo clusters were constructed using axially chiral 1,1′‐bi‐2‐naphthol (BINOL) ligands. Structural analyses revealed supramolecular helical assemblies mediated by directional C─H···π interactions, while circular dichroism (CD) spectroscopy confirmed their intrinsic chirality. Through in situ doping engineering, non‐chiral fluorophores with distinct emission profiles were incorporated during chiral cluster crystallization, yielding composite materials exhibiting circularly polarized luminescence (CPL). The optimized system achieved a maximum dissymmetry factor ( g lum ) of 1.5 × 10 −2 . Mechanistic studies established that the spiral packing of the tin‐oxo clusters facilitates stereochemical information transfer to the dyes via the spatial confinement effect. This supramolecular chirality induction paradigm offers new insights into the rational design of multifunctional optical materials.