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关键词： Proton transfer  

摘要： The photoreaction of 1,4-dihydropyridines (1,4-DHPs) is a powerful strategy for constructing structurally complex molecules, yet controlling product distribution remains challenging. Here, we report a visible-light-induced transformation that enables access to 3,9-diazatetraasteranes (2) and 3,12-diazatetracyclododecane-dienes (3). The product distribution is governed by the photocatalyst, solvent environment, and irradiation wavelength. Formation of 2 depends primarily on the excitation wavelength, whereas the generation of 3 requires photocatalyst engagement and occurs selectively in protic solvents. Mechanistic studies indicate that 2 arises through sequential inter- and intramolecular [2 + 2] photocycloadditions of 1,4-DHPs. In contrast, 3 is formed through an initial photocatalyst-mediated oxidation followed by proton transfer, ultimately triggering an intermolecular [3 + 2] photocycloaddition. DFT calculations further elucidate the origin of the observed selective formation of products and support mechanistic pathways.

关键词： impact toughness   ethylene/1-octene copolymers   octene content   maleic anhydride grafting   molecular weight degradation  

摘要： The impact modification of polyamide 6 (PA6) using maleic anhydride-grafted ethylene/1-octene copolymers (EOR-g-MAH) involves a trade-off between improved compatibilization, grafting-induced changes in modifier molecular weight MW, and melt processability. In this study, EOR modifiers with comparable initial MW but different octene contents (coct = 13, 15, and 16 mol%) were grafted to two MAH levels (cMAH = 0.5 and 1.0 wt%) and incorporated into PA6 at a fixed composition. The system was designed to maintain a comparable microstructure, enabling the isolation of grafting-induced changes in modifier properties from microstructural effects. MW distributions were analyzed by gel permeation chromatography, and the impact behavior was evaluated over a wide temperature range, using an instrumented Charpy impact test. The results reveal a strong, interrelated, coct- and cMAH-dependent competition between beta-scission and cross-linking during grafting, which governs the modifier's MW distribution and particle strength. Higher coct (15 and 16 mol%) enhances the impact performance up to approximate to 0 degrees C, well above the brittle-ductile transition temperature (BDTT), through increased elastic and plastic deformation capability of the modifiers. At elevated temperatures, however, successive melting of the modifiers leads to a loss of particle strength. At high coct and cMAH = 1.0 wt%, susceptibility to beta-scission increases, leading to MW reduction that, for coct = 16 mol%, is detrimental to impact performance, particularly above the BDTT. This effect is further amplified by reduced ductility due to stronger polar intermolecular interactions at high grafting levels. A moderate cMAH = 0.5 wt% and coct = 15 mol% provides an optimal compromise between strength and ductility, delivering high impact strength across a broad temperature range. At this cMAH level, the number of PA6 chains covalently anchored to the modifier particles is moderate, resulting in lower compound

摘要： Aromatic rings in drug candidates often exhibit poor developability. Three-dimensional bioisosteres like aza-bicyclo[2.1.1]­hexanes (aza-BCHs) improve properties but face limited synthetic access to diverse substitutions. Herein, we report a Yb­(OTf)₃-catalyzed [2π + 2σ] cycloaddition of methylenimines with bicyclobutanes (BCBs), featuring mild conditions, a broad substrate scope, and functional group tolerance. Compatibility with different substitution types of BCBs, amino acid-derived methylenimines, and complex bioactive molecule-derived imines was demonstrated, with gram-scale synthesis and downstream derivatization validating practical utility, expanding the toolbox for 3D heterocyclic scaffolds in drug discovery.

关键词： Antibiotics  

摘要： Non-ribosomal lipopeptide antibiotics derive much of their antibacterial performance from the structure of their lipid tail, yet genome mining remains largely peptide-centric and rarely prioritizes lipid donor formation as an entry point. Herein, we establish a lipid-donor-anchored discovery strategy using pfa-type polyunsaturated fatty acid synthase (PUFAS) core genes as the genomic anchor for long polyunsaturated acyl donors, followed by filtering for co-localization of non-ribosomal peptide synthetase (NRPS) assembly lines. This approach delineated 60 curated PUFAS-NRPS biosynthetic gene clusters, including a previously unassigned dxp family, which is distributed across Proteobacteria. Cultivation of Chitinimonas koreensis DSM 17726 enabled the isolation of dioxanopeptins, a new set of non-ribosomal lipopeptides featuring a long polyunsaturated lipid tail further functionalized by a pyruvyl-derived 1,3-dioxane ketal motif. Recombinant DxpH catalyzed the in vitro conversion of dedioxanopeptin to dioxanopeptin using phosphoenolpyruvate as the pyruvyl donor, establishing pyruvylation as a post-assembly tailoring step. Dioxanopeptins displayed selective activity against methicillin-resistant Staphylococcus aureus, and their antibacterial phenotype correlated with disruption of proton motive force homeostasis and ATP production. Removal of the pyruvyl-derived ketal markedly diminished potency, highlighting its contribution to antibacterial activity. Together, these results expand the chemical space of lipopeptides and illustrate how lipid-donor-anchored genome mining can complement NRPS-focused strategies to access functionally differentiated antibiotic scaffolds.

关键词： gout   immune response   inflammatory response   precision therapy   spatiotemporal immune gradient   trained immunity  

摘要： Gout is a crystal-associated autoinflammatory disease triggered by monosodium urate (MSU) crystals, clinically characterized by recurrent transitions between acute inflammatory flares dominated by innate immunity and a state of "trained immunity" during the remission phase. However, previous studies have mostly focused on single time points or local lesions. Such approaches fail to systematically explain the recurrent nature of acute gout flares and the mechanisms underlying multi-system involvement. By integrating evidence from single-cell and spatial transcriptomics as well as mechanistic investigations, this review systematically summarizes the immunopathological features of gout within a spatiotemporal immune framework. At the temporal level, acute gout flares are driven by innate immune activation of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3)-interleukin-1 beta (IL-1 beta) inflammatory cascade. The inflammation then undergoes self-limited resolution mediated by regulatory T cells (Tregs), M2-polarized macrophages, aggregated neutrophil extracellular traps (aggNETs), and pro-resolving lipid mediators. persistent low-grade activation of monocytes/macrophages can still be observed, sustaining a state of "trained immunity." At the spatial level, integrated evidence indicates an immune gradient across the joint, bone, and circulation, ranging from focal hyper-inflammation to systemic low-grade activation. Based on these findings, we propose a time-window stratified intervention strategy centered on the NLRP3-IL-1 beta axis, and identify inflammatory markers in the joints, subchondral bone, and peripheral blood as the basis for spatially targeted stratification. These insights provide novel perspectives for shifting gout management from the control of individual flares to recurrence risk management and personalized therapy.

摘要： Radio occultation (RO) observations provide a crucial means for estimating the global Vertical Bottomside Electron Content (VBEC) in the ionosphere. However, the limited number of low Earth orbit (LEO) satellites in existing RO missions restricts the capability for high-precision reconstruction of global VBEC spatiotemporal variations. The Tianmu-1 (TM-1) constellation significantly improving the global coverage and resolution of RO measurements. In this study, TM-1 GNSS RO data were used for the first time to retrieve global VBEC during a geomagnetic storm period (10-12 May 2024) and a geomagnetically quiet period (21-23 July 2024). Based on spatial interpolation, global bottomside ionospheric maps (GBIMs) were constructed. The GBIM derived from TM-1 (TM-1 GBIM) and that derived from COSMIC-2 (COSMIC-2 GBIM) were then compared with the IGS global ionospheric maps (GIMs) to assess their accuracy and consistency. The results indicate that the TM-1 GBIM exhibits strong spatiotemporal consistency with the IGS GBIM. During the geomagnetically quiet period, the TM-1 GBIM performs better, with a root mean square (RMS) of 6.78 TECU, compared to an RMS of 9.68 TECU during the geomagnetic storm period. Further error analysis shows that the modeling errors of TM-1 GBIM and COSMIC-2 GBIM exhibit consistent spatiotemporal patterns. In particular, a systematic underestimation of VBEC occurs in the low- and mid-latitude regions from 08:00 to 19:00 LT, resulting in a pronounced double-peak structure resembling the equatorial ionization anomaly. Moreover, geomagnetic storms expand this double-peak error structure from 08:00-19:00 LT to 08:00-24:00 LT. Plain Language Summary The ionosphere, a layer of Earth's upper atmosphere filled with charged particles, affects satellite navigation and communication. Vertical Bottomside Electron Content (VBEC) represents the number of electrons in the bottomside ionosphere and is crucial for accurately calculating the propagation delay of low-Ear

关键词： paederoside (PSG)   antioxidant   anti-aging   IGF1R   italic>C. elegans  

关键词： Acute myeloid leukemia   CASP1   EGR4   Macrophage polarization   Tumor microenvironment  

摘要： The polarization of tumor-associated macrophages (TAMs) toward an M2-like phenotype critically promotes acute myeloid leukemia (AML) progression. Building on the clinical observation that Caspase-1 (CASP1) expression is elevated in AML and correlates with M2 macrophage abundance, we identify a novel signaling axis in AML cells, involving CASP1 and the transcription factor early growth response protein 4 (EGR4), that orchestrates macrophage polarization. Knockdown (KD) of CASP1 in human AML cells (THP-1, MOLM-13) shifted their secretome, which consequently skewed macrophage polarization away from the M2 phenotype at multiple levels. Mechanistically, transcriptomic sequencing revealed that CASP1 KD significantly upregulated EGR4 expression. Crucially, EGR4 interference partially reversed the macrophage-polarizing effects of CASP1 KD, establishing EGR4 as an essential downstream effector. In a xenograft model using NOD/SCID mice—a defined system for studying human AML-macrophage crosstalk—CASP1 KD potently suppressed tumor growth. Immunohistochemical analysis revealed a remodeled microenvironment characterized by reduced proliferation (Ki67), upregulated EGR4, suppression of the M2-associated IL-10/p-STAT3 pathway and CD206, alongside a concomitant increase in M1-associated marker CD86. In conclusion, our integrated analysis delineates a novel AML cell-intrinsic pathway wherein CASP1 represses EGR4, thereby enabling an M2-like macrophage phenotype via the IL-10/p-STAT3 pathway. The identification of this CASP1-EGR4 axis identifies it as a promising therapeutic target for reshaping the immunosuppressive microenvironment in AML.

关键词： benign paroxysmal positional vertigo   Inner-ear biomarkers   otoconin-90   Otolin-1   sleep quality   vertigo severity  

摘要： Background Benign paroxysmal positional vertigo (BPPV) is the most common peripheral vestibular disorder and exhibits marked heterogeneity in symptom burden and clinical course. Objective biomarkers reflecting inner-ear structural status and their relationship with clinical manifestations remain limited. Emerging evidence suggests an association between sleep quality and vertigo symptoms;however, the biological basis underlying this relationship is poorly *** In this case-control study, 268 patients with BPPV and 268 age- and sex-matched healthy controls were enrolled. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI), and vertigo severity was evaluated using the Dizziness Handicap Inventory (DHI). Serum levels of the inner-ear-specific structural biomarkers Otolin-1 and otoconin-90 (OC90) were measured using enzyme-linked immunosorbent assays. Logistic regression was used to examine associations with BPPV presence. Among patients with BPPV, multivariable linear regression, joint models, and exploratory mediation analyses were conducted to evaluate relationships among sleep quality, biomarkers, and symptom *** Compared with healthy controls, patients with BPPV exhibited significantly higher serum levels of the inner-ear structural biomarkers Otolin-1 (median 6.38 vs. 3.94 ng/mL) and otoconin-90 (median 12.64 vs. 7.58 ng/mL), both of which were independently associated with the odds of BPPV (adjusted OR for Otolin-1: 2.08, 95% CI: 1.49-2.91;adjusted OR for otoconin-90: 1.71, 95% CI: 1.21-2.42). Among patients with BPPV, poorer sleep quality was associated with greater vertigo severity (beta = 2.14 per PSQI point, 95% CI: 1.56-2.72). Higher PSQI scores were also associated with increased levels of Otolin-1 and otoconin-90, both of which were independently related to vertigo severity. Inclusion of these biomarkers in joint models attenuated the PSQI-DHI association (beta from 2.14 to 1.28) and improved model explanat

关键词： hyperpolarized pyruvate   kinetic modeling   tumor metabolism  

摘要： Purpose To explore the relationship between potentially rate-limiting steps in lactate production and the lactate area-under-the-curve (AUC) to pyruvate AUC ratio for analysis of hyperpolarized (HP) [1-C-13]-pyruvate data. Theory and Methods Simplifying assumptions are introduced to a pharmacokinetic (PK) model with three physical compartments and two chemical pools to write the AUC ratio in terms of model parameters. Synthetic time curves are used to test sensitivity of the AUC ratio and model parameters to different physiological conditions and acquisition parameters. The simplified model is used to analyze data from patients with head and neck squamous cell carcinoma and determine the rate-limiting step in lactate production. Results The simplified model leads to an expression that explicitly demonstrates the relationship between PK model parameters and the AUC ratio. The AUC ratio depends most strongly on intracellular metabolism when pyruvate signal predominantly arises from intracellular space. Simulations confirm that the parameterized AUC ratio can be used to correct for AUC ratio sensitivity to acquisition parameters such as TE. In patient data, the proposed analysis most commonly identified k(ecP) as the predominant rate limiting step in lactate production. Conclusion Changes observed in the AUC ratio may be driven by changes in pyruvate extravasation, transport into the cell, and/or intracellular metabolism. The proposed model permits parametric representation of the AUC ratio, identification of rate-limiting steps in lactate production, and correction for differences induced by acquisition parameters.