Browse Articles

Prior acute ozone injury modulates inflammatory responses to subsequent repetitive ozone exposures in mice

Single-atom substitution redirects KatG reactivity from cofactor biogenesis to stereoselective sulfoxidation

Abstract Protein-derived cofactors rely on precisely positioned heteroatoms to direct redox chemistry, yet isolating their individual contributions remains challenging. The indole N–H of tryptophan plays a central yet elusive role in biogenesis and function of the Met–Tyr–Trp (MYW) cofactor in catalase-peroxidase (KatG). Here, we use genetic code expansion to replace cofactor-forming Trp105 with thiotryptophan (S-Trp), enabling a single-heteroatom (N → S) substitution. Instead of forming the MYW crosslink, KatG bearing S-Trp105 undergoes site-specific monooxygenation to yield a chiral sulfoxide. HPLC-MS, circular dichroism, and FT-IR spectroscopy identify selective oxygen insertion at the sulfur, establishing enantioselective formation of an ( S )-configured sulfoxide. A 2.22 Å cryo-EM structure visualizes the oxidized S-Trp105, revealing the S = O moiety orienting toward the iron and confirming the absence of crosslinking. The S-atom oxygenation is heme-dependent and proceeds via a two-electron oxygen-atom transfer, contrasting with the radical-mediated one-electron chemistry of native tryptophan. This redirection suppresses catalase activity by perturbing cofactor formation. These results show that a single-atom substitution reroutes the distal heme site from radical crosslinking to stereoselective sulfoxidation, uncovering a monooxygenase-like capability within KatG. This work highlights using noncanonical amino acids to achieve atomic-level control over reaction pathways and to interrogate cofactor biogenesis with unprecedented precision.

Integrated metabolomics and antioxidant activity assessment of Sphagneticola trilobata (L.) Pruski

Abstract Sphagneticola trilobata (L.) Pruski (Asteraceae), formerly known as Wedelia trilobata , is a widely distributed ornamental plant utilized in traditional medicine for various ailments. This study aims to provide the first comprehensive comparative analysis of the metabolomic profiles of Sphagneticola trilobata flowerheads and leaves to elucidate the chemical basis for their differential antioxidant capacities. Ultra-high-performance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry was employed in both positive and negative ionization modes. The resulting datasets were subjected to multivariate chemometric analyses, including Principal Component Analysis and Orthogonal Partial Least Squares Analysis. Antioxidant potential was assessed using in vitro DPPH, FRAP, and ABTS assays. A total of 86 metabolites were tentatively annotated, spanning classes of terpenoids, flavonoids, phenolic acids, lipids, and amino acids. Notably, 18 of these compounds were observed in this plant for the first time. Chemometric analysis revealed distinct metabolic variances: flowerheads were enriched with flavonoids and phenolic acids, whereas leaves were characterized by a predominance of sesquiterpenoids and diterpenoids. Biological assays demonstrated that flowerheads possess significantly higher antioxidant activity compared to leaves. Moreover, correlation analysis identified key biomarkers responsible for this activity, including 3’,4’,7-trihydroxy-flavanone hexoside, luteolin, myricetin hexoside, and 4,5-dicaffeoyl-quinic acid. The study establishes that the superior antioxidant potential of Sphagneticola trilobata flowerheads is driven by their high flavonoid and phenolic acid content, distinguishing them from the terpenoid-rich leaves. These findings validate the utility of metabolomics in identifying bioactive markers and suggest the flowerheads as a promising source of natural antioxidants for pharmaceutical or cosmeceutical applications.

Spatial cellular order underlies locally-confined mechanisms of immune resistance in oropharyngeal cancer

Abstract Oropharyngeal squamous cell carcinomas (OPSCCs) frequently result from oncogenic human papilloma virus (HPV) infections (HPV-OPSCC). The mechanisms underlying effective immune escape, despite abundant viral antigens, are incompletely understood. Here, we performed single-cell spatial gene expression profiling of HPV-OPSCC to characterize cellular organization and mechanisms of immune resistance. We describe distinct tumor-parenchymal immune foci that differ in cytokine expression, spatial location, immune cell infiltration and cancer cell states. Furthermore, immune foci display profound differences related to co-inhibitory receptor signaling and immunosuppressive myeloid cells, suggesting that different tumor-parenchymal regions may be dominated by distinct, locally-confined mechanisms of immunosuppression. Additionally, senescent-like HPV-OPSCC cells lacking HPV transcripts (HPVoff) are evident across the tumor parenchyma and able to evade HPV-specific T cell-mediated immunity in vitro. HPVoff cells are enriched within hypoxic regions and near IFN-γ producing T cells suggesting that both hypoxia and IFN-γ signaling can promote the HPVoff phenotype. In conclusion, our findings highlight a complex cellular interplay underlying heterogeneous cancer cell states, spatial immune cell organization, and diverse mechanisms of immune escape.

Disease-related complications and risk factors in hemoglobin H disease in a Thai multicenter registry

Molecular pharmacodynamics of amoxicillin-clavulanic acid for urinary tract infections caused by Escherichia coli

Abstract Amoxicillin-clavulanic acid (AMX-CLV) is a widely used oral β-lactam/β-lactamase inhibitor combination against Escherichia coli . Clinical success is largely confined to urinary tract infections. The mechanistic basis for this site-specific efficacy remains unclear. Using a hollow-fibre infection model to replicate human plasma and urinary pharmacokinetics, we show that plasma-like exposures rapidly select for pre-existing resistant subpopulations; whereas, urinary exposures produce sustained bactericidal activity without resistance emergence. Genomic and transcriptomic analyses following plasma drug exposure reveal that treatment selectively enriches pre-existing resistant lineages already harbouring oxidative-stress-associated mutations that activate the SOS response and drive IS-mediated amplification of blaTEM-1 , leading to β-lactamase hyperproduction and treatment failure. In contrast, the high urinary concentrations of clavulanic acid exert direct antibacterial activity, eradicating these subpopulations. Our findings demonstrate that local pharmacokinetic environments fundamentally shape evolutionary trajectories under β-lactam/β-lactamase inhibitor therapy, explaining the restricted efficacy of AMX-CLV and revealing a dynamic interplay between stress responses, genome plasticity, and drug partitioning that governs treatment outcome.

The OEGMA-based hydrogel is active against all species of the ESKAPE pathogens, Streptococcus mutans and the pathogenic yeast Candida albicans

Abstract Wound dressings serve as a crucial first barrier against microbial contamination, particularly in severe wounds requiring rapid antimicrobial protection. Building on our previously established hydrogel system based on copolymers of oligo(ethylene glycol) methyl ether methacrylate (OEGMA) and 2-(dimethylamino)ethyl methacrylate (DMAEMA) crosslinked during quaternization with 1,6-dibromohexane, we extend the biological evaluation of this material to a broader spectrum of clinically relevant pathogens. The hydrogel was assessed against the complete multidrug resistant ESKAPE group, the Gram-positive bacterium Streptococcus mutans , and the opportunistic yeast Candida albicans . Pronounced contact-mediated antimicrobial activity was observed against all tested organisms, resulting in a significant reduction of microbial viability. In detail, C. albicans and P. aeruginosa viability was reduced to 30.25% and 25.34%, respectively, whereas all other strains exhibited < 5% residual viability compared to untreated controls. A. baumannii and K. quasipneumoniae retained 4.32% and 2.73% viable cells, while absolute eradication was achieved for E. faecalis VRE , S. aureus and S. mutans . Importantly, the material retained excellent biocompatibility, showing no adverse effects on mammalian skin fibroblasts or human blood cells. The combination of broad-spectrum antimicrobial efficacy, biological compatibility, and a robust yet simple fabrication approach highlights the potential of this hydrogel as a promising candidate for wound dressing applications, including emergency wound care in critical injury settings.

Electrochemical artificial humification for sustainable waste biomass valorization and soil remediation

Enhanced fragmentation of water dications upon high Rydberg states

Synthesis of functionalized hydrosilanes via titanium-catalyzed hydroboration and hydrogenation of C(sp3)–Si bonds in silacyclobutanes

The embryo game uncovers hidden cell behaviours

YBX1 Confers immunosuppressive bone metastatic traits in non-small cell lung cancer

Abstract The spread of lung cancer to bone is a devastating complication often linked to resistance against immunotherapy, but the reasons for this connection are poorly understood. Here we show that the transcription factor YBX1 acts as a central regulator driving both bone metastasis and the formation of an immunosuppressive environment in non-small cell lung cancer (NSCLC). YBX1 achieves this by activating distinct signaling pathways (IL6 and CCL5, respectively). Mechanistically, YBX1 protein levels are controlled by glycosylation that marks it for autophagic degradation inside cells. Notably, reduced YBX1 glycosylation was observed in highly bone-metastatic NSCLC cells. Importantly, we identified a drug candidate, Icaritin, which boosts this sugar-modification, leading to YBX1 degradation. This dual action inhibits bone metastasis and re-sensitizes tumors to immune attack. Our work reveals YBX1 as a promising single target for combating bone spread and overcoming immunotherapy resistance.

Crop fields complement biodiversity in permanent grasslands across European landscapes

Abstract Temperate agricultural landscapes are experiencing unprecedented biodiversity declines. Landscape simplification is commonly identified as a driver of species loss across taxonomic groups, but the contribution of crop and non-crop habitats to farmland biodiversity conservation is surprisingly poorly known. Using 86 paired permanent grasslands and oilseed rape fields in five European countries, we assess how habitat type shaped plant, butterfly, wild bee, and carabid assemblages and whether increasing grassland amount in surrounding landscapes fosters the spillover of grassland-associated biodiversity to oilseed rape fields. We find habitat type rather than landscape-level grassland amount determines diversity and shapes species assemblages: plants and butterflies are more diverse in grasslands, while wild bees and carabids are equally or more diverse in oilseed rape fields. Increasing landscape-level grassland amount affects species assemblage composition but only reduces turnover between habitats in wild bees. Overall, both grasslands and oilseed rape fields harbour distinct sets of species, together contributing complementarily to regional diversity. Safeguarding biodiversity in agricultural landscapes therefore requires not only the conservation of permanent semi-natural habitats but also biodiversity-friendly management of disturbed habitats such as crop fields that can contribute valuable species.

Robust bulk silicon carbide polymorphs sintered from collapsed hollow mesoporous structure

Deciphering small sequence differences in T cell receptor-antigen pairing

Clonal evolution and mutational trajectories of metastatic colorectal cancer shaped by anticancer therapies

Covalently bonded polymer-metal-organic framework semiconductive membranes for flexible X-ray detection

Mid-infrared snapshot spectral imaging via nonlinear radial dispersion

The PLK4 inhibitor RP-1664 demonstrates potent efficacy in neuroblastoma preclinical models through a dual mechanism of sensitivity

Abstract It was recently shown that inhibition of polo-like kinase 4 (PLK4) induces synthetic lethality in cancers with chromosome 17q-encoded TRIM37 copy number gain due to cooperative regulation of centriole duplication and mitotic spindle nucleation. We show here that chromosome 17q/TRIM37 gain is a defining feature of high-risk neuroblastoma and renders patient-derived cell lines hypersensitive to the novel PLK4 inhibitor RP-1664. We demonstrate that centriole amplification at low doses of RP-1664 contributes to this sensitivity in a TRIM37 -independent fashion. CRISPR screens and live cell imaging reveal that upon centriole amplification, neuroblastoma cells succumb to multipolar mitoses due to an inability to cluster or inactivate supernumerary centrosomes. RP-1664 monotherapy showed robust anti-tumor activity in 14/15 human neuroblastoma-derived xenograft models, and significantly extended survival in a transgenic MYCN -driven murine model of neuroblastoma. RP-1664 combined with GD2-directed chemoimmunotherapy resulted in maintained complete responses in 6/9 mice with established MYCN -driven murine neuroblastomas. These data support clinical development of PLK4 inhibitors for high-risk neuroblastoma and other cancers with somatically acquired TRIM37 overexpression.

Generative flow model on distance geometry for predicting transition states of chemical reactions